85 results on '"Arnold GL"'
Search Results
2. Recurrent reciprocal 1q21.1 deletions and duplications are novel genomic disorders associated with micro- or macrocephaly and a spectrum of developmental and behavioral abnormalities
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BRUNETTI PIERRI, NICOLA, Berg JS, Scaglia F, Belmont J, Bacino CA, Sahoo T, Lalani SR, Graham H, Lee B, Shinawi M, Shen J, Kang S. HL, Pursley A, Lotze T, Kennedy G, Lansky Shafer S, Weaver C, Roeder ER, Grebe TA, Arnold GL, Hutchison T, Reimschisel T, Amato S, Geragthy MT, Innis JW, Obersztyn E, Nowakowska B, Rosengren SS, Bader PI, Grange DK, Naqvi S, Garnica AD, Bernes SM, Fong C. T, Summers A, Walters WD, Lupski JR, Stankiewicz P, Cheung S. W, Patel A., BRUNETTI PIERRI, Nicola, Berg, J, Scaglia, F, Belmont, J, Bacino, Ca, Sahoo, T, Lalani, Sr, Graham, H, Lee, B, Shinawi, M, Shen, J, Kang S., Hl, Pursley, A, Lotze, T, Kennedy, G, Lansky Shafer, S, Weaver, C, Roeder, Er, Grebe, Ta, Arnold, Gl, Hutchison, T, Reimschisel, T, Amato, S, Geragthy, Mt, Innis, Jw, Obersztyn, E, Nowakowska, B, Rosengren, S, Bader, Pi, Grange, Dk, Naqvi, S, Garnica, Ad, Bernes, Sm, Fong, C. T., Summers, A, Walters, Wd, Lupski, Jr, Stankiewicz, P, Cheung, S. W., and Patel, A.
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- 2008
3. Factors affecting cognitive, motor, behavioral and executive functioning in children with phenylketonuria
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Arnold, GL, primary, Kramer, BM, additional, Kirby, RS, additional, Plumeau, PB, additional, Blakely, EM, additional, Cregan, LS Sanger, additional, and Davidson, PW, additional
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- 1998
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4. Plasma amino acids profiles in children with autism: potential risk of nutritional deficiencies.
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Arnold GL, Hyman SL, Mooney RA, and Kirby RS
- Abstract
The plasma amino acid profiles of 36 children with autism spectrum disorders were reviewed to determine the impact of diet on amino acid patterns. Ten of the children were on gluten and casein restricted diets administered by parents, while the other 26 consumed unrestricted diets. No amino acid profile specific to autism was identified. However, children with autism had more essential amino acid deficiencies consistent with poor protein nutrition than an age/gender matched control group. There was a trend for children with autism who were on restricted diets to have an increased prevalence of essential amino acid deficiencies and lower plasma levels of essential acids including the neurotransmitter precursors tyrosine and tryptophan than both controls and children with autism on unrestricted diets. These data indicate that larger, more focused studies of protein nutrition in children with autism are needed in order to determine the extent to which restricted diets might place the developing brains of children with autism at risk from protein malnutrition. The high rate of tryptophan and tyrosine deficiency in this group is also of concern given their role as neurotransmitter precursors. [ABSTRACT FROM AUTHOR]
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- 2003
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5. Pyruvate carboxylase deficiency: report of a case and additional evidence for the 'mild' phenotype.
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Arnold GL, Griebel ML, Porterfield M, and Brewster M
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- 2001
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6. Pituitary-Thyroid Function after Cessation of Prolonged Thyroid Suppression
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Spare Sv, Arnold Gl, Fawaz K, Mark E. Molitch, Scally J, and Zack N
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medicine.medical_specialty ,Endocrinology ,medicine.anatomical_structure ,business.industry ,Internal medicine ,Thyroid ,medicine ,General Medicine ,Thyroid function ,business - Published
- 1976
7. Outcomes and genotype correlations in patients with mitochondrial trifunctional protein or isolated long chain 3-hydroxyacyl-CoA dehydrogenase deficiency enrolled in the IBEM-IS database.
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Lim CC, Vockley J, Ujah O, Kirby RS, Edick MJ, Berry SA, and Arnold GL
- Abstract
Purpose: Mitochondrial trifunctional protein deficiency (TFPD) and isolated long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) are two related defects of fatty acid β -oxidation. While NBS has decreased mortality, morbidity remains significant. Additionally, the relationship of genotype to clinical outcome remains unclear. To better understand these issues, we collected natural history data for these conditions by reviewing seven years of retrospective data from 45 cases of TFPD or LCHADD in the Inborn Errors of Metabolism - Information System., Methods: Available data included age at database entry, last datapoint, and development of various complications. Data were analyzed by clinical assigned diagnosis (LCHADD or TFPD), subdivided by method of ascertainment (newborn screening-NBS, or other than by newborn screening-NNBS), then re-analyzed based on four genotype groups: homozygous c.1528GC (p.E510Q) (common LCHAD variant); heterozygous c.1528GC (p.E510Q), other HADHA variants; and HADHB variants., Results: Forty-five patients from birth to 34 years of age were analyzed by assigned diagnosis (30 LCHADD and 15 TFPD) and method of ascertainment. Thirty had further analysis by genotype (22 biallelic HADHA variants and 8 biallelic HADHB variants). With regards to maternal complications, retinopathy, cardiomyopathy and hypoglycemia, patients with biallelic HADHA variants (with or without the common LCHAD variant) manifest a traditional LCHADD phenotype, while those with HADHB gene variants more commonly reported neuromusculoskeletal type TFPD phenotype. While retinopathy, rhabdomyolysis and peripheral neuropathy tended to present later in childhood, many features including initial report of cardiomyopathy and hypoglycemia presented across a wide age spectrum., Conclusion: This study demonstrates the utility of genotypic confirmation of patients identified with LCHADD/TFPD as variants in the HADHA and HADHB genes lead to different symptom profiles. In our data, biallelic HAHDA variants conferred a LCHADD phenotype, regardless of the presence of the common LCHAD variant., (© 2022 The Authors.)
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- 2022
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8. Improved attention linked to sustained phenylalanine reduction in adults with early-treated phenylketonuria.
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Bilder DA, Arnold GL, Dimmock D, Grant ML, Janzen D, Longo N, Nguyen-Driver M, Jurecki E, Merilainen M, Amato G, and Waisbren S
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- Adult, Clinical Studies as Topic, Humans, Phenylalanine, Attention Deficit Disorder with Hyperactivity, Phenylketonurias
- Abstract
Pegvaliase is approved to reduce phenylalanine (Phe) levels for people with phenylketonuria (PKU). PRISM-1 (NCT01819727) and PRISM-2 (NCT01889862) data were analyzed to evaluate the relationship between Phe and inattention in adult participants with PKU. In the modified-intent-to-treat population (N = 156), baseline mean (SE) plasma Phe was 1263 (29) μmol/L and the Attention Deficit Hyperactivity Disorder Rating Scale-IV Inattentive (IA) symptoms score was 9.8 (0.5). Mean (SE) IA scores fell 9.0 (1.1) in Quartile 1 (Phe reduction between 1166 and 2229 μmol/L) versus 4.3 (0.7) in Quartile 4 (Phe reduction of 139 μmol/L to increase of 934 μmol/L), p = 0.004. Least squares mean (SE) change from baseline IA score was -7.9 (0.7) for participants with final Phe ≤ 360 μmol/L and -4.5 (0.7) for final Phe > 360 μmol/L, p < 0.001. In the inattention subgroup, IA scores fell 13.3 (1.5) in Quartile 1 (Phe reduction between 1288 and 2229 μmol/L) versus 6.2 (1.3) in Quartile 4 (Phe reduction of 247 to increase of 934 μmol/L), p = 0.009. Inattention symptoms improved among those whose Phe levels decreased, particularly those with high baseline IA scores. IA improvements were larger among participants with the greatest plasma Phe reductions, supporting this value as a therapeutic goal., (© 2021 BioMarin Pharmaceutical Inc. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)
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- 2022
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9. Metabolic providers in crisis - Burning out on the road to burnout?
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Arnold GL, Kanungo S, and Bush L
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- Adult, Aged, Female, Humans, Male, Middle Aged, Burnout, Professional epidemiology, Genetics education, Health Personnel psychology, Metabolism, Inborn Errors therapy
- Abstract
Competing Interests: Declaration of Competing Interest None.
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- 2021
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10. Successful orthotopic heart transplantation in CPTII deficiency.
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Arnold GL, Yester J, McCracken E, Feingold BD, and Vockley J
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- Adolescent, Adult, Age of Onset, Cardiomyopathies genetics, Cardiomyopathies pathology, Cardiomyopathies therapy, Carnitine O-Palmitoyltransferase metabolism, Fatty Acids metabolism, Humans, Hyperammonemia genetics, Hyperammonemia pathology, Hyperammonemia therapy, Hypoglycemia genetics, Hypoglycemia pathology, Hypoglycemia therapy, Infant, Newborn, Metabolism, Inborn Errors genetics, Metabolism, Inborn Errors metabolism, Metabolism, Inborn Errors pathology, Neonatal Screening, Rhabdomyolysis genetics, Rhabdomyolysis pathology, Rhabdomyolysis therapy, Young Adult, Carnitine O-Palmitoyltransferase deficiency, Carnitine O-Palmitoyltransferase genetics, Heart physiopathology, Heart Transplantation methods, Metabolism, Inborn Errors therapy
- Abstract
Carnitine palmitoyl transferase II (CPT II) catalyzes the release of activated long-chain fatty acids from acylcarnitines into mitochondria for subsequent fatty acid oxidation. Depending on residual enzyme activity, deficiency of this enzyme leads to a spectrum of symptoms from early onset hypoglycemia, hyperammonemia, cardiomyopathy and death to onset of recurrent rhabdomyolysis in adolescents and young adults. We present a case of successful orthotopic heart transplantation in a patient with severe infantile onset cardiomyopathy due to CPT II deficiency identified through newborn screening. Excellent cardiac function is preserved 12 years post-transplantation; however, the patient has developed intermittent episodes of hyperammonemia and rhabdomyolysis later in childhood and early adolescence readily resolved with intravenous glucose. Successful heart transplant in this patient demonstrates the feasibility of this management option in patients with even severe forms of long chain fatty acid oxidation disorders., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021. Published by Elsevier Inc.)
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- 2021
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11. Similarities and differences in key diagnosis, treatment, and management approaches for PAH deficiency in the United States and Europe.
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Lowe TB, DeLuca J, and Arnold GL
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- Adolescent, Adult, Diet, Europe, Female, Genomics, Humans, Phenylalanine, Pregnancy, United States, Phenylketonuria, Maternal, Phenylketonurias diagnosis, Phenylketonurias genetics, Phenylketonurias therapy
- Abstract
Background: Individuals with phenylalanine hydroxylase (PAH) deficiency lack an enzyme needed to metabolize the amino acid, phenylalanine. This leads to an increase of phenylalanine in the blood, which is associated with changes in cognitive and psychological functioning. Skilled clinical management is essential for preventing complications and providing comprehensive care to patients. In the last decade, the American College of Genetics and Genomics (ACMG) and a group of European experts developed separate guidelines to provide recommendations for the management and care of persons with PAH deficiency. The purpose of this paper was to compare and contrast these guidelines in order to understand the different approaches to PAH deficiency care., Methods: We examined the procedures used to develop both guidelines, then evaluated key areas in PAH deficiency care which included screening, diagnostic approaches, dietary treatment (initiation and duration), ongoing phenylalanine level/ nutritional monitoring, neurocognitive screening, adherence issues in treatment, and special populations (women and maternal PKU, late or untreated PAH deficiency, and transitioning to adult services). We conducted a scoping review of four key topics in PAH deficiency care to explore recent research studies performed since the publication of the guidelines., Results: The ACMG and European expert group identified limited numbers of high quality studies to use as evidence for their recommendations. The ACMG and European guidelines had many similarities in their respective approaches PAH deficiency care and recommendations for the diagnosis, treatment, and management for persons with PAH deficiency. There were also a number of differences between the guidelines regarding the upper range for phenylalanine levels in adolescents and adults, the types of instruments used and frequency of neuropsychiatric examinations, and monitoring of bone health. Treatment adherence can be associated with a number of challenges, such as aversions to medical foods and formulas, as well as factors related to educational, social, and psychosocial issues. From the scoping review, there were many new studies addressing issues in treatment and management including new research on sapropterin adherence and increased dietary protein tolerance and pegvaliase on the reduction in phenylalanine levels and hypersensitivity reactions., Conclusions: In the last decade, ACMG and European experts developed comprehensive guidelines for the clinical management of phenylalanine hydroxylase deficiency. The guidelines offered background and recommendations for clinical care of patients with PAH deficiency throughout the lifespan. New research evidence is available and updates to guidelines can keep pace with new developments. Evidence-based guidelines for diagnosis and treatment are important for providing expert care to patients.
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- 2020
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12. Familial Cerebral Cavernous Malformation Syndrome with Concomitant Fourth Ventricular Ependymoma: True Association or Mere Coincidence?
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Algattas H, Abou-Al-Shaar H, Mendelson M, Arnold GL, Felker J, Meade J, and Greene S
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- Adolescent, Cerebral Ventricle Neoplasms complications, Ependymoma complications, Female, Hemangioma, Cavernous, Central Nervous System complications, Humans, KRIT1 Protein genetics, Male, Mutation, Pedigree, Prognosis, Syndrome, Cerebral Ventricle Neoplasms pathology, Ependymoma pathology, Hemangioma, Cavernous, Central Nervous System pathology
- Abstract
Familial cerebral cavernous malformation syndromes are most commonly caused by mutations in one of three genes. The overlap of these genetic malformations with other acquired neoplastic lesions and congenital malformations is still under investigation. To the best of our knowledge, the concurrent occurrence of familial cavernous malformations and ependymoma has not been previously reported in the literature. Herein, we describe a patient with familial cerebral cavernous malformation syndrome and posterior fossa ependymoma. A 17-year-old asymptomatic male was referred to our outpatient neurosurgery clinic after genetic testing identified a familial KRIT1 (CCM1) mutation. The patient's sister had presented with a seizure disorder previously; multiple cavernous malformations were discovered, and a symptomatic large cavernous malformation required a craniotomy for resection. Two years later, she was diagnosed with follicular thyroid cancer due to HRAS (c.182A>G) mutation. The patient and his sister were found to have a novel germline KRIT1 disease-causing variant (c.1739deletion, p.ASN580Ilefs*2) and a variant of uncertain significance, potentially pathogenic (c.1988 A>G, p.Asn663Ser) in cis in CCM1 (KRIT1), of paternal inheritance. Due to the presence of genetic abnormalities, the patient underwent screening imaging of his neuraxis. Multiple cavernous malformations were identified, as was an incidental fourth ventricular mass. Resection of the fourth ventricular lesion was performed, and histopathological examination was consistent with ependymoma. We report a unique case of posterior fossa ependymoma in an individual with a familial cerebral cavernous malformation syndrome and a novel genetic abnormality in KRIT1. The association of these two findings may be valuable in determining a potential genetic association between the two pathologies and elucidating the pathogenesis of both cavernous malformations and ependymomas., (Copyright © 2020. Published by Elsevier Inc.)
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- 2020
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13. Four children with postnatally diagnosed mosaic trisomy 12: Clinical features, literature review, and current diagnostic capabilities of genetic testing.
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Hu J, Ou Z, Surti U, Kochmar S, Hoffner L, Madan-Khetarpal S, Arnold GL, Walsh L, Acquaro R, Sebastian J, and Yatsenko SA
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- Abnormalities, Multiple genetics, Child, Child, Preschool, Chromosome Disorders genetics, Chromosomes, Human, Pair 12 genetics, Congenital Abnormalities genetics, Developmental Disabilities genetics, Female, Genetic Testing, Humans, Infant, Infant, Newborn, Male, Mosaicism, Phenotype, Prenatal Diagnosis, Abnormalities, Multiple diagnosis, Chromosome Disorders diagnosis, Congenital Abnormalities diagnosis, Developmental Disabilities diagnosis, Trisomy genetics
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Children or adults with mosaic trisomy 12 diagnosed postnatally are extremely rare. Only a small number of patients with this mosaicism have been reported in the literature. The clinical manifestation of mosaic trisomy 12 is variable, ranging from mild developmental delay to severe congenital anomaly and neonatal death. The trisomy 12 cells are not usually able to be detected by phytohemagglutinin stimulated peripheral blood chromosome analysis. The variability of phenotypes and the limited number of patients with this anomaly pose a challenge to predict the clinical outcomes. In this study, we present the phenotypes and laboratory findings in four patients and review the 11 previously reported patients with mosaic trisomy 12 diagnosed postnatally, as well as 11 patients with mosaic trisomy 12 diagnosed prenatally. The findings of this study provide useful information for laboratory diagnosis and clinical management of these patients., (© 2020 Wiley Periodicals, Inc.)
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- 2020
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14. Complex patterns of inheritance, including synergistic heterozygosity, in inborn errors of metabolism: Implications for precision medicine driven diagnosis and treatment.
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Vockley J, Dobrowolski SF, Arnold GL, Guerrero RB, Derks TGJ, and Weinstein DA
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- Databases, Genetic, Genetic Testing, Humans, Mutation, Phenotype, Heterozygote, Inheritance Patterns, Metabolism, Inborn Errors diagnosis, Metabolism, Inborn Errors drug therapy, Precision Medicine
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Inborn errors of metabolism have traditionally been viewed as the quintessential single gene disorders; defects in one gene leads to loss of activity of one enzyme causing a metabolic imbalance and clinical disease. However, reality has never been quite that simple, and the classic "one gene-one enzyme" paradigm has been upended in many ways. Multiple gene defects can lead to the same biochemical phenotype, often with different clinical symptoms. Additionally, different mutations in the same gene can cause variable phenotypes, often most dramatic when a disease can be identified by pre-symptomatic screening. Moreover, response to therapy is not homogeneous across diseases and specific mutations. Perhaps the biggest deviation from traditional monogenic inheritance is in the setting of synergistic heterozygosity, a multigenic inheritance pattern in which mutations in multiple genes in a metabolic pathway lead to sufficient disruption of flux through the pathway, mimicking a monogenic disorder caused by homozygous defects in one gene in that pathway. In addition, widespread adoption of whole exome and whole genome sequencing in medical genetics has led to the realization that individual patients with apparently hybrid phenotypes can have mutations in more than one gene, leading to a mixed genetic disorder. Each of these situations point to a need for as much precision as possible in diagnosing metabolic disease, and it is likely to become increasingly critical to drive therapy. This article examines examples in traditional monogenic disorders that illustrates these points and define inborn errors of metabolism as complex genetic traits on the leading edge of precision medicine., (Copyright © 2019. Published by Elsevier Inc.)
- Published
- 2019
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15. PLPHP deficiency: clinical, genetic, biochemical, and mechanistic insights.
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Johnstone DL, Al-Shekaili HH, Tarailo-Graovac M, Wolf NI, Ivy AS, Demarest S, Roussel Y, Ciapaite J, van Roermund CWT, Kernohan KD, Kosuta C, Ban K, Ito Y, McBride S, Al-Thihli K, Abdelrahim RA, Koul R, Al Futaisi A, Haaxma CA, Olson H, Sigurdardottir LY, Arnold GL, Gerkes EH, Boon M, Heiner-Fokkema MR, Noble S, Bosma M, Jans J, Koolen DA, Kamsteeg EJ, Drögemöller B, Ross CJ, Majewski J, Cho MT, Begtrup A, Wasserman WW, Bui T, Brimble E, Violante S, Houten SM, Wevers RA, van Faassen M, Kema IP, Lepage N, Lines MA, Dyment DA, Wanders RJA, Verhoeven-Duif N, Ekker M, Boycott KM, Friedman JM, Pena IA, and van Karnebeek CDM
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- Animals, Disease Models, Animal, Epilepsy physiopathology, Female, HEK293 Cells, Humans, Male, Phenotype, Pyridoxal Phosphate therapeutic use, Pyridoxine deficiency, Vitamin B 6 metabolism, Vitamin B 6 Deficiency genetics, Vitamin B 6 Deficiency metabolism, Zebrafish, Epilepsy etiology, Proteins genetics, Proteins metabolism
- Abstract
Biallelic pathogenic variants in PLPBP (formerly called PROSC) have recently been shown to cause a novel form of vitamin B6-dependent epilepsy, the pathophysiological basis of which is poorly understood. When left untreated, the disease can progress to status epilepticus and death in infancy. Here we present 12 previously undescribed patients and six novel pathogenic variants in PLPBP. Suspected clinical diagnoses prior to identification of PLPBP variants included mitochondrial encephalopathy (two patients), folinic acid-responsive epilepsy (one patient) and a movement disorder compatible with AADC deficiency (one patient). The encoded protein, PLPHP is believed to be crucial for B6 homeostasis. We modelled the pathogenicity of the variants and developed a clinical severity scoring system. The most severe phenotypes were associated with variants leading to loss of function of PLPBP or significantly affecting protein stability/PLP-binding. To explore the pathophysiology of this disease further, we developed the first zebrafish model of PLPHP deficiency using CRISPR/Cas9. Our model recapitulates the disease, with plpbp-/- larvae showing behavioural, biochemical, and electrophysiological signs of seizure activity by 10 days post-fertilization and early death by 16 days post-fertilization. Treatment with pyridoxine significantly improved the epileptic phenotype and extended lifespan in plpbp-/- animals. Larvae had disruptions in amino acid metabolism as well as GABA and catecholamine biosynthesis, indicating impairment of PLP-dependent enzymatic activities. Using mass spectrometry, we observed significant B6 vitamer level changes in plpbp-/- zebrafish, patient fibroblasts and PLPHP-deficient HEK293 cells. Additional studies in human cells and yeast provide the first empirical evidence that PLPHP is localized in mitochondria and may play a role in mitochondrial metabolism. These models provide new insights into disease mechanisms and can serve as a platform for drug discovery., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2019
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16. Amino acid disorders.
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Aliu E, Kanungo S, and Arnold GL
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Amino acids serve as key building blocks and as an energy source for cell repair, survival, regeneration and growth. Each amino acid has an amino group, a carboxylic acid, and a unique carbon structure. Human utilize 21 different amino acids; most of these can be synthesized endogenously, but 9 are "essential" in that they must be ingested in the diet. In addition to their role as building blocks of protein, amino acids are key energy source (ketogenic, glucogenic or both), are building blocks of Kreb's (aka TCA) cycle intermediates and other metabolites, and recycled as needed. A metabolic defect in the metabolism of tyrosine (homogentisic acid oxidase deficiency) historically defined Archibald Garrod as key architect in linking biochemistry, genetics and medicine and creation of the term 'Inborn Error of Metabolism' (IEM). The key concept of a single gene defect leading to a single enzyme dysfunction, leading to "intoxication" with a precursor in the metabolic pathway was vital to linking genetics and metabolic disorders and developing screening and treatment approaches as described in other chapters in this issue. Amino acid disorders also led to the evolution of the field of metabolic nutrition and offending amino acid restricted formula and foods. This review will discuss the more common disorders caused by inborn errors in amino acid metabolism., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.
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- 2018
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17. Inborn errors of metabolism in the 21 st century: past to present.
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Arnold GL
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The 21
st century is an exciting time to be in the field of metabolic medicine. As with many fields, one of the keys to anticipating the future is to understand the past. The term "inborn error of metabolism" was first coined in 1908 by Sir Archibald Garrod, in reference to four disorders (alkaptonuria, pentosuria, cystinuria and albinism). The first (and still most definitive) textbook on the subject, "The Metabolic Basis of Inherited Disease" was initially published in 1960 and covered 80 disorders in 1,477 pages. After the eighth edition of this text became unwieldy at 6,338 pages in 4 volumes covering more than 1,000 disorders, the book was changed to an online reference text with 259 chapters and is still growing. Current newborn screening on a few dried blood spots on filter paper identifies more than 1 in 2,000 newborns as having a metabolic disorder. The availability of metabolomic and genomic analyses is resulting in the diagnosis of many new disorders. Enzyme replacement therapy (ERT) has provided treatments for previously untreatable metabolic disorders, and the promise of gene therapy on the near horizon will certainly revolutionize the field., Competing Interests: Conflicts of Interest: The author has no conflicts of interest to declare.- Published
- 2018
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18. Deep-biosphere methane production stimulated by geofluids in the Nankai accretionary complex.
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Ijiri A, Inagaki F, Kubo Y, Adhikari RR, Hattori S, Hoshino T, Imachi H, Kawagucci S, Morono Y, Ohtomo Y, Ono S, Sakai S, Takai K, Toki T, Wang DT, Yoshinaga MY, Arnold GL, Ashi J, Case DH, Feseker T, Hinrichs KU, Ikegawa Y, Ikehara M, Kallmeyer J, Kumagai H, Lever MA, Morita S, Nakamura KI, Nakamura Y, Nishizawa M, Orphan VJ, Røy H, Schmidt F, Tani A, Tanikawa W, Terada T, Tomaru H, Tsuji T, Tsunogai U, Yamaguchi YT, and Yoshida N
- Abstract
Microbial life inhabiting subseafloor sediments plays an important role in Earth's carbon cycle. However, the impact of geodynamic processes on the distributions and carbon-cycling activities of subseafloor life remains poorly constrained. We explore a submarine mud volcano of the Nankai accretionary complex by drilling down to 200 m below the summit. Stable isotopic compositions of water and carbon compounds, including clumped methane isotopologues, suggest that ~90% of methane is microbially produced at 16° to 30°C and 300 to 900 m below seafloor, corresponding to the basin bottom, where fluids in the accretionary prism are supplied via megasplay faults. Radiotracer experiments showed that relatively small microbial populations in deep mud volcano sediments (10
2 to 103 cells cm-3 ) include highly active hydrogenotrophic methanogens and acetogens. Our findings indicate that subduction-associated fluid migration has stimulated microbial activity in the mud reservoir and that mud volcanoes may contribute more substantially to the methane budget than previously estimated.- Published
- 2018
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19. Germline mutations in ABL1 cause an autosomal dominant syndrome characterized by congenital heart defects and skeletal malformations.
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Wang X, Charng WL, Chen CA, Rosenfeld JA, Al Shamsi A, Al-Gazali L, McGuire M, Mew NA, Arnold GL, Qu C, Ding Y, Muzny DM, Gibbs RA, Eng CM, Walkiewicz M, Xia F, Plon SE, Lupski JR, Schaaf CP, and Yang Y
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- Animals, Cell Line, Female, HEK293 Cells, Humans, Male, Mice, Mice, Knockout, Philadelphia Chromosome drug effects, Phosphorylation genetics, Proto-Oncogene Mas, Signal Transduction genetics, Abnormalities, Multiple genetics, Bone Diseases, Developmental genetics, Chromosome Disorders genetics, Craniofacial Abnormalities genetics, Feeding and Eating Disorders genetics, Fusion Proteins, bcr-abl genetics, Germ-Line Mutation genetics, Heart Defects, Congenital genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Limb Deformities, Congenital genetics
- Abstract
ABL1 is a proto-oncogene well known as part of the fusion gene BCR-ABL1 in the Philadelphia chromosome of leukemia cancer cells. Inherited germline ABL1 changes have not been associated with genetic disorders. Here we report ABL1 germline variants cosegregating with an autosomal dominant disorder characterized by congenital heart disease, skeletal abnormalities, and failure to thrive. The variant c.734A>G (p.Tyr245Cys) was found to occur de novo or cosegregate with disease in five individuals (families 1-3). Additionally, a de novo c.1066G>A (p.Ala356Thr) variant was identified in a sixth individual (family 4). We overexpressed the mutant constructs in HEK 293T cells and observed increased tyrosine phosphorylation, suggesting increased ABL1 kinase activities associated with both the p.Tyr245Cys and p.Ala356Thr substitutions. Our clinical and experimental findings, together with previously reported teratogenic effects of selective BCR-ABL inhibitors in humans and developmental defects in Abl1 knockout mice, suggest that ABL1 has an important role during organismal development.
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- 2017
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20. 221 newborn-screened neonates with medium-chain acyl-coenzyme A dehydrogenase deficiency: Findings from the Inborn Errors of Metabolism Collaborative.
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Bentler K, Zhai S, Elsbecker SA, Arnold GL, Burton BK, Vockley J, Cameron CA, Hiner SJ, Edick MJ, and Berry SA
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- Acyl-CoA Dehydrogenase physiology, Female, Genotype, Homozygote, Humans, Infant, Newborn, Lipid Metabolism, Inborn Errors diagnosis, Male, Metabolism, Inborn Errors physiopathology, Mutation, Acyl-CoA Dehydrogenase deficiency, Acyl-CoA Dehydrogenase genetics, Lipid Metabolism, Inborn Errors genetics, Metabolism, Inborn Errors genetics, Neonatal Screening
- Abstract
Introduction: There is limited understanding of relationships between genotype, phenotype and other conditions contributing to health in neonates with medium-chain acyl-coenzyme A dehydrogenase deficiency (MCADD) identified through newborn screening., Methods: Retrospective analysis of comprehensive data from a cohort of 221 newborn-screened subjects identified as affected with MCADD in the Inborn Errors of Metabolism - Information System (IBEM-IS), a long term follow-up database of the Inborn Errors of Metabolism Collaborative, was performed., Results: The average age at notification of first newborn screen results to primary care or metabolic providers was 7.45days. The average octanoylcarnitine (C8) value on first newborn screen was 11.2μmol/L (median 8.6, range 0.36-43.91). A higher C8 level correlated with an earlier first subspecialty visit. Subjects with low birth weight had significantly lower C8 values. Significantly higher C8 values were found in symptomatic newborns, in newborns with abnormal lab testing in addition to newborn screening and/or diagnostic tests, and in subjects homozygous for the c.985A>G ACADM gene mutation or compound heterozygous for the c.985A>G mutation and deletions or other known highly deleterious mutations. Subjects with neonatal symptoms, or neonatal abnormal labs, or neonatal triggers were more likely to have at least one copy of the severe c.985A>G ACADM gene mutation. C8 and genotype category were significant predictors of the likelihood of having neonatal symptoms. Neonates with select triggers were more likely to have symptoms and laboratory abnormalities., Conclusions: This collaborative study is the first in the United States to describe health associations of a large cohort of newborn-screened neonates identified as affected with MCADD. The IBEM-IS has utility as a platform to better understand the characteristics of individuals with newborn-screened conditions and their follow-up interactions with the health system., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
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21. Outcomes and genotype-phenotype correlations in 52 individuals with VLCAD deficiency diagnosed by NBS and enrolled in the IBEM-IS database.
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Pena LD, van Calcar SC, Hansen J, Edick MJ, Walsh Vockley C, Leslie N, Cameron C, Mohsen AW, Berry SA, Arnold GL, and Vockley J
- Subjects
- Acyl-CoA Dehydrogenase, Long-Chain blood, Adolescent, Carnitine analogs & derivatives, Carnitine blood, Child, Child, Preschool, Congenital Bone Marrow Failure Syndromes, Creatine Kinase genetics, Female, Genetic Association Studies, Genotype, Humans, Infant, Infant, Newborn, Lipid Metabolism, Inborn Errors blood, Lipid Metabolism, Inborn Errors physiopathology, Male, Mitochondrial Diseases blood, Mitochondrial Diseases physiopathology, Muscular Diseases blood, Muscular Diseases physiopathology, Mutation, Retrospective Studies, Acyl-CoA Dehydrogenase, Long-Chain deficiency, Acyl-CoA Dehydrogenase, Long-Chain genetics, Lipid Metabolism, Inborn Errors genetics, Mitochondrial Diseases genetics, Muscular Diseases genetics, Neonatal Screening
- Abstract
Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency can present at various ages from the neonatal period to adulthood, and poses the greatest risk of complications during intercurrent illness or after prolonged fasting. Early diagnosis, treatment, and surveillance can reduce mortality; hence, the disorder is included in the newborn Recommended Uniform Screening Panel (RUSP) in the United States. The Inborn Errors of Metabolism Information System (IBEM-IS) was established in 2007 to collect longitudinal information on individuals with inborn errors of metabolism included in newborn screening (NBS) programs, including VLCAD deficiency. We retrospectively analyzed early outcomes for individuals who were diagnosed with VLCAD deficiency by NBS and describe initial presentations, diagnosis, clinical outcomes and treatment in a cohort of 52 individuals ages 1-18years. Maternal prenatal symptoms were not reported, and most newborns remained asymptomatic. Cardiomyopathy was uncommon in the cohort, diagnosed in 2/52 cases. Elevations in creatine kinase were a common finding, and usually first occurred during the toddler period (1-3years of age). Diagnostic evaluations required several testing modalities, most commonly plasma acylcarnitine profiles and molecular testing. Functional testing, including fibroblast acylcarnitine profiling and white blood cell or fibroblast enzyme assay, is a useful diagnostic adjunct if uncharacterized mutations are identified., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
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22. Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy.
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Lemke JR, Geider K, Helbig KL, Heyne HO, Schütz H, Hentschel J, Courage C, Depienne C, Nava C, Heron D, Møller RS, Hjalgrim H, Lal D, Neubauer BA, Nürnberg P, Thiele H, Kurlemann G, Arnold GL, Bhambhani V, Bartholdi D, Pedurupillay CR, Misceo D, Frengen E, Strømme P, Dlugos DJ, Doherty ES, Bijlsma EK, Ruivenkamp CA, Hoffer MJ, Goldstein A, Rajan DS, Narayanan V, Ramsey K, Belnap N, Schrauwen I, Richholt R, Koeleman BP, Sá J, Mendonça C, de Kovel CG, Weckhuysen S, Hardies K, De Jonghe P, De Meirleir L, Milh M, Badens C, Lebrun M, Busa T, Francannet C, Piton A, Riesch E, Biskup S, Vogt H, Dorn T, Helbig I, Michaud JL, Laube B, and Syrbe S
- Subjects
- Animals, Cohort Studies, Consanguinity, Heterozygote, Homozygote, Humans, Intellectual Disability genetics, Intellectual Disability metabolism, Movement Disorders genetics, Movement Disorders metabolism, Oocytes, Phenotype, Seizures genetics, Seizures metabolism, Xenopus laevis, Mutation, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Receptors, N-Methyl-D-Aspartate genetics, Receptors, N-Methyl-D-Aspartate metabolism
- Abstract
Objective: To determine the phenotypic spectrum caused by mutations in GRIN1 encoding the NMDA receptor subunit GluN1 and to investigate their underlying functional pathophysiology., Methods: We collected molecular and clinical data from several diagnostic and research cohorts. Functional consequences of GRIN1 mutations were investigated in Xenopus laevis oocytes., Results: We identified heterozygous de novo GRIN1 mutations in 14 individuals and reviewed the phenotypes of all 9 previously reported patients. These 23 individuals presented with a distinct phenotype of profound developmental delay, severe intellectual disability with absent speech, muscular hypotonia, hyperkinetic movement disorder, oculogyric crises, cortical blindness, generalized cerebral atrophy, and epilepsy. Mutations cluster within transmembrane segments and result in loss of channel function of varying severity with a dominant-negative effect. In addition, we describe 2 homozygous GRIN1 mutations (1 missense, 1 truncation), each segregating with severe neurodevelopmental phenotypes in consanguineous families., Conclusions: De novo GRIN1 mutations are associated with severe intellectual disability with cortical visual impairment as well as oculomotor and movement disorders being discriminating phenotypic features. Loss of NMDA receptor function appears to be the underlying disease mechanism. The identification of both heterozygous and homozygous mutations blurs the borders of dominant and recessive inheritance of GRIN1-associated disorders., (© 2016 American Academy of Neurology.)
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- 2016
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23. Outcomes of cases with 3-methylcrotonyl-CoA carboxylase (3-MCC) deficiency - Report from the Inborn Errors of Metabolism Information System.
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Forsyth R, Vockley CW, Edick MJ, Cameron CA, Hiner SJ, Berry SA, Vockley J, and Arnold GL
- Subjects
- Databases, Factual, Humans, Infant, Infant, Newborn, Neonatal Screening, Prognosis, Retrospective Studies, Acidosis, Lactic epidemiology, Carbon-Carbon Ligases deficiency, Developmental Disabilities epidemiology, Urea Cycle Disorders, Inborn pathology
- Abstract
Introduction: 3-Methyl crotonyl CoA carboxylase (3MCC) deficiency is an inborn error of leucine metabolism whose detection was increased with the advent of expanded newborn screening. While most NBS-identified infants appear clinically normal, prior studies suggest a possible increased risk for developmental or metabolic abnormalities. As yet, no predictive markers are known that can identify children at risk for biochemical or developmental abnormalities., Method: All available 3-MCC cases diagnosed by newborn screening in the Inborn Errors of Metabolism Information System (IBEM-IS) were reviewed for markers that might be predictive of outcome., Results: A limited number of cases were identified with traditional biochemical symptoms including acidosis, hyperammonemia or lactic acidosis, and 15% of those with available developmental information had recorded developmental disabilities not clearly attributable to other causes. There was no correlation between newborn screening (NBS) C5OH level and presence of metabolic, newborn, later-life or developmental abnormalities in these cases., Discussion: This sample, obtained from the IBEM-IS database, attempts to avoid some of the ascertainment bias present in retrospective studies. An increase in developmental abnormalities and in traditionally described metabolic symptoms remains apparent, although no specific biochemical markers appear predictive of outcome. The role that prevention of fasting plays in outcome cannot be ascertained. These data suggest that C5OH level found on newborn screening by itself is not sufficient for diagnostic or predictive purposes., (Copyright © 2016. Published by Elsevier Inc.)
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- 2016
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24. Newborn screening for Krabbe disease in New York State: the first eight years' experience.
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Orsini JJ, Kay DM, Saavedra-Matiz CA, Wenger DA, Duffner PK, Erbe RW, Biski C, Martin M, Krein LM, Nichols M, Kurtzberg J, Escolar ML, Adams DJ, Arnold GL, Iglesias A, Galvin-Parton P, Kronn DF, Kwon JM, Levy PA, Pellegrino JE, Shur N, Wasserstein MP, and Caggana M
- Subjects
- Algorithms, Dried Blood Spot Testing, Hematopoietic Stem Cell Transplantation adverse effects, Humans, Infant, Newborn, Leukodystrophy, Globoid Cell enzymology, Leukodystrophy, Globoid Cell therapy, Mass Spectrometry, New York, Predictive Value of Tests, Treatment Outcome, Galactosylceramidase genetics, Galactosylceramidase metabolism, Leukodystrophy, Globoid Cell diagnosis, Neonatal Screening methods, Polymorphism, Single Nucleotide
- Abstract
Purpose: Krabbe disease (KD) results from galactocerebrosidase (GALC) deficiency. Infantile KD symptoms include irritability, progressive stiffness, developmental delay, and death. The only potential treatment is hematopoietic stem cell transplantation. New York State (NYS) implemented newborn screening for KD in 2006., Methods: Dried blood spots from newborns were assayed for GALC enzyme activity using mass spectrometry, followed by molecular analysis for those with low activity (≤12% of the daily mean). Infants with low enzyme activity and one or more mutations were referred for follow-up diagnostic testing and neurological examination., Results: Of >1.9 million screened, 620 infants were subjected to molecular analysis and 348 were referred for diagnostic testing. Five had enzyme activities and mutations consistent with infantile KD and manifested clinical/neurodiagnostic abnormalities. Four underwent transplantation, two are surviving with moderate to severe handicaps, and two died from transplant-related complications. The significance of many sequence variants identified is unknown. Forty-six asymptomatic infants were found to be at moderate to high risk for disease., Conclusions: The positive predictive value of KD screening in NYS is 1.4% (5/346) considering confirmed infantile cases. The incidence of infantile KD in NYS is approximately 1 in 394,000, but it may be higher for later-onset forms.
- Published
- 2016
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25. Isolated Sagittal Synostosis in a Boy with Craniofrontonasal Dysplasia and a Novel EFNB1 Mutation.
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Chauhan BK, Hoover JM, Scanga H, Medsinge A, Arnold GL, and Nischal KK
- Abstract
Craniofrontonasal syndrome (CFNS) is a rare X-linked disorder that shows greater severity in females and is largely attributed to mutations in EFNB1. A 7-year-old boy presented with hypertelorism, broad nasal root, midfacial hypoplasia, mandibular prognathia, ptosis, and scaphocephaly was clinically diagnosed with CFNS. Three-dimensional computed tomographic scans confirmed the isolated sagittal synostosis. His mother also showed clinical features of CFNS, but less severe. Genetic tests uncovered a novel C to T mutation at nucleotide 466 (c.466C>T) in exon 1 of EFNB1 for both. To the best of our knowledge, this is the only reported incident of CFNS in a male child exhibiting isolated sagittal synostosis.
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- 2015
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26. Long-term safety and efficacy of sapropterin: the PKUDOS registry experience.
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Longo N, Arnold GL, Pridjian G, Enns GM, Ficicioglu C, Parker S, and Cohen-Pfeffer JL
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- Adolescent, Adult, Biopterins administration & dosage, Biopterins adverse effects, Biopterins pharmacology, Biopterins therapeutic use, Child, Child, Preschool, Diet, Drug-Related Side Effects and Adverse Reactions, Female, Humans, Infant, Infant, Newborn, Male, Middle Aged, Phenylalanine administration & dosage, Phenylalanine blood, Time Factors, Tyrosine blood, Young Adult, Biopterins analogs & derivatives, Phenylketonurias drug therapy, Registries
- Abstract
The Phenylketonuria (PKU) Demographics, Outcomes and Safety (PKUDOS) registry is designed to provide longitudinal safety and efficacy data on subjects with PKU who are (or have been) treated with sapropterin dihydrochloride. The PKUDOS population consists of 1189 subjects with PKU: N = 504 who were continuously exposed to sapropterin from date of registry enrollment, N = 211 who had intermittent exposure to the drug, and N = 474 with some other duration of exposure. Subjects continuously exposed to sapropterin showed an average 34% decrease in blood phenylalanine (Phe)--from 591 ± 382 μmol/L at baseline to 392 ± 239 μmol/L (p = 0.0009) after 5 years. This drop in blood Phe was associated with an increase in dietary Phe tolerance [from 1000 ± 959 mg/day (pre-sapropterin baseline) to 1539 ± 840 mg/day after 6 years]. Drug-related adverse events (AEs) were reported in 6% of subjects, were mostly considered non-serious, and were identified in the gastrointestinal, respiratory, and nervous systems. Serious drug-related AEs were reported in ≤ 1% of subjects. Similar safety and efficacy data were observed for children<4 years. Long-term data from the PKUDOS registry suggest that sapropterin has a tolerable safety profile and that continuous use is associated with a significant and persistent decrease in blood Phe and improvements in dietary Phe tolerance., (Copyright © 2015. Published by Elsevier Inc.)
- Published
- 2015
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27. Modern applications for a total sulfur reduction distillation method - what's old is new again.
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Arnold GL, Brunner B, Müller IA, and Røy H
- Abstract
Background: The use of a boiling mixture of hydriodic acid, hypophosphorous acid, and hydrochloric acid to reduce any variety of sulfur compounds has been in use in various applications since the first appearance of this method in the literature in the 1920's. In the realm of sulfur geochemistry, this method remains a useful, but under-utilized technique. Presented here is a detailed description of the distillation set-up and procedure, as well as an overview of potential applications of this method for marine sulfur biogeochemistry/isotope studies. The presented applications include the sulfur isotope analysis of extremely low amounts of sulfate from saline water, the conversion of radiolabeled sulfate into sulfide, the extraction of refractory sulfur from marine sediments, and the use of this method to assess sulfur cycling in Aarhus Bay sediments., Results: The STrongly Reducing hydrIodic/hypoPhosphorous/hydrochloric acid (STRIP) reagent is capable of rapidly reducing a wide range of sulfur compounds, including the most oxidized form, sulfate, to hydrogen sulfide. Conversion of as little as approximately 5 micromole sulfate is possible, with a sulfur isotope composition reproducibility of 0.3 permil., Conclusions: Although developed many decades ago, this distillation method remains relevant for many modern applications. The STRIP distillation quickly and quantitatively converts sulfur compounds to hydrogen sulfide which can be readily collected in a silver nitrate trap for further use. An application of this method to a study of sulfur cycling in Aarhus Bay demonstrates that we account for all of the sulfur compounds in pore-water, effectively closing the mass balance of sulfur cycling.
- Published
- 2014
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28. Development of clinical guidelines for inborn errors of metabolism: commentary.
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Vockley J, Chapman KA, and Arnold GL
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- Humans, Clinical Trials as Topic, Evidence-Based Medicine methods, Metabolism, Inborn Errors therapy, Mitochondrial Diseases therapy
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This is one of an occasional series of articles commenting on trends, advances, and challenges in understanding and treating inborn errors of metabolism (IEMs). Previously, we have called attention to the critical lack of a clinical trial infrastructure to routinely evaluate new therapies for IEMs and the adverse effect of this deficit (Vockley and Vockley, 2010 [1]). In this article, we highlight the role of therapeutic guidelines in implementing best practice for IEMs and the processes used to generate them. Current conventions for evidence-based guidelines are best applied to studies involving significantly more subjects than is feasible for IEMs, and can lead to relative weak-appearing recommendations when applied to rare disorders. We propose a guideline development process that maintains the use of conventional methodologies but adapts to unique features and inherent difficulties dealing with rare conditions such as IEMs. Such guidelines will consist of a hybrid between evidence and consensus based processes. Implementation of these recommendations and subsequent therapeutic guidelines for IEMs provides an opportunity to define current knowledge as well as starting points for future clinical trials., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
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29. Introduction: Neurodevelopmental issues in inborn errors of metabolism.
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Arnold GL and Vockley J
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- Cholesterol biosynthesis, Developmental Disabilities diagnosis, Developmental Disabilities physiopathology, Glycosylation, Humans, Lipid Metabolism, Inborn Errors diagnosis, Lipid Metabolism, Inborn Errors physiopathology, Nervous System Diseases diagnosis, Nervous System Diseases physiopathology, Neuroimaging, Neuronal Ceroid-Lipofuscinoses etiology, Neuronal Ceroid-Lipofuscinoses metabolism, Peroxisomal Disorders diagnosis, Peroxisomal Disorders etiology, Peroxisomal Disorders metabolism, Peroxisomes metabolism, Developmental Disabilities etiology, Developmental Disabilities metabolism, Lipid Metabolism, Inborn Errors complications, Lipid Metabolism, Inborn Errors metabolism, Nervous System Diseases etiology, Nervous System Diseases metabolism
- Published
- 2013
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30. Internet use by parents of infants with positive newborn screens.
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DeLuca JM, Kearney MH, Norton SA, and Arnold GL
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- Female, Health Personnel, Humans, Infant, Newborn, Male, Metabolic Diseases genetics, Neonatal Screening methods, Attitude, Health Knowledge, Attitudes, Practice, Internet, Metabolic Diseases diagnosis, Parents
- Abstract
Background: Internet searches on health topics are common, but not enough is known about online use during serious health concerns. The aim of this study was to investigate parents' internet use and responses to online information following the referral of their newborn screen-positive infants., Methods: Forty-four parents were interviewed about their internet use during their infants' evaluations for a potential metabolic disorder. Responses to open-ended questions were audio taped and transcribed. Content analysis was used in analyzing the interview data., Results: An overwhelming majority of parents (89%) accessed the internet and most went online before meeting with genetic providers at metabolic treatment centers. Primary and genetic providers did not routinely recommend websites to parents. Online descriptions of metabolic disorders increased parents' anxieties. Some parents allayed their distress by enlisting others to search and filter information for them and by seeking optimistic internet content about the disorders. Parents with fewer years of education were often baffled by complex disease information. Parents found limited information about treatments or what to expect during the clinical evaluations of their infants., Conclusions: The internet is an integral part of health care and an important source of information for newborn screening parents. Parents may benefit from recommendations of credible websites and discussions of internet information with health care providers.
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- 2012
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31. Outcome of infants diagnosed with 3-methyl-crotonyl-CoA-carboxylase deficiency by newborn screening.
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Arnold GL, Salazar D, Neidich JA, Suwannarat P, Graham BH, Lichter-Konecki U, Bosch AM, Cusmano-Ozog K, Enns G, Wright EL, Lanpher BC, Owen NN, Lipson MH, Cerone R, Levy P, Wong LJ, and Dezsofi A
- Subjects
- Adolescent, Child, Child, Preschool, Female, Humans, Infant, Infant, Newborn, Male, Urea Cycle Disorders, Inborn enzymology, Carbon-Carbon Ligases deficiency, Neonatal Screening methods, Urea Cycle Disorders, Inborn diagnosis
- Abstract
Introduction: 3-Methyl CoA carboxylase (3-MCC) deficiency is an inborn error of metabolism in the catabolism of the amino acid leucine. Original reports suggested this disorder was associated with significant neurological and biochemical effects. However newborn screening has identified a higher than expected incidence of this disorder with apparent normal outcome in most cases., Method: A retrospective analysis of thirty-five cases of 3-MCC deficiency identified by newborn screening and diagnosed by enzyme or molecular analysis., Results: There was a strong inverse correlation between initial C5OH level and residual enzyme activity. A few reports of hypoglycemia, ketosis, poor feeding/failure to thrive or fasting intolerance were reported, but there was no clear relationship between symptoms and residual enzyme activity. Developmental outcome included several children with mental retardation (including one with Down syndrome and one with schizencephaly) and two with Autism Spectrum disorders but there was no apparent relationship to residual enzyme activity. Free carnitine deficiency was relatively common., Discussion: Although residual enzyme activity was clearly related to metabolite elevation, there was no apparent relationship with other measures of outcome. The number of reports of neurologic abnormalities or metabolic symptoms (poor feeding, hypoglycemia, fasting intolerance, etc.) is concerning, but the significance is unclear in this retrospective sample., (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Published
- 2012
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32. The reversibility of dissimilatory sulphate reduction and the cell-internal multi-step reduction of sulphite to sulphide: insights from the oxygen isotope composition of sulphate.
- Author
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Brunner B, Einsiedl F, Arnold GL, Müller I, Templer S, and Bernasconi SM
- Subjects
- Chemical Fractionation, Models, Chemical, Oxidation-Reduction, Oxygen Isotopes chemistry, Sulfur Isotopes chemistry, Desulfovibrio desulfuricans metabolism, Oxygen metabolism, Sulfates metabolism, Sulfides metabolism, Sulfites metabolism
- Abstract
Dissimilatory sulphate reduction (DSR) leads to an overprint of the oxygen isotope composition of sulphate by the oxygen isotope composition of water. This overprint is assumed to occur via cell-internally formed sulphuroxy intermediates in the sulphate reduction pathway. Unlike sulphate, the sulphuroxy intermediates can readily exchange oxygen isotopes with water. Subsequent to the oxygen isotope exchange, these intermediates, e.g. sulphite, are re-oxidised by reversible enzymatic reactions to sulphate, thereby incorporating the oxygen used for the re-oxidation of the sulphur intermediates. Consequently, the rate and expression of DSR-mediated oxygen isotope exchange between sulphate and water depend not only on the oxygen isotope exchange between sulphuroxy intermediates and water, but also on cell-internal forward and backward reactions. The latter are the very same processes that control the extent of sulphur isotope fractionation expressed by DSR. Recently, the measurement of multiple sulphur isotope fractionation has successfully been applied to obtain information on the reversibility of individual enzymatically catalysed steps in DSR. Similarly, the oxygen isotope signature of sulphate has the potential to reveal complementary information on the reversibility of DSR. The aim of this work is to assess this potential. We derived a mathematical model that links sulphur and oxygen isotope effects by DSR, assuming that oxygen isotope effects observed in the oxygen isotopic composition of ambient sulphate are controlled by the oxygen isotope exchange between sulphite and water and the successive cell-internal oxidation of sulphite back to sulphate. Our model predicts rapid DSR-mediated oxygen isotope exchange for cases where the sulphur isotope fractionation is large and slow exchange for cases where the sulphur isotope fractionation is small. Our model also demonstrates that different DSR-mediated oxygen isotope equilibrium values are observed, depending on the importance of oxygen isotope exchange between sulphite and water relative to the re-oxidation of sulphite. Comparison of model results to experimental data further leads to the conclusion that sulphur isotope fractionation in the reduction of sulphite to sulphide is not a single-step process.
- Published
- 2012
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33. Thoroughly modern medicine.
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Arnold GL and Vockley J
- Subjects
- Delivery of Health Care, Evidence-Based Medicine, Humans, Mass Screening, Metabolism, Inborn Errors therapy, Statistics as Topic, Precision Medicine
- Abstract
Personalized medicine is receiving increasing attention in the medical literature and lay press as one way to optimize therapy and reduce complications of treatment for almost any disorder. However, understanding the systemic complexities necessary to implement the ambitious goals of personalized medicine is unlikely to arise from the study of common disorders. Rather, dissecting out the individual components to therapeutic response is far more feasible with defined disorders of known cause. Inborn errors of metabolism offer an attractive opportunity to better define the hyperbole surrounding development and institution of personalized medicine., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2011
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34. Parents' experiences of expanded newborn screening evaluations.
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DeLuca JM, Kearney MH, Norton SA, and Arnold GL
- Subjects
- Female, Humans, Infant, Newborn, Male, Stress, Psychological etiology, Surveys and Questionnaires, Attitude, Metabolism, Inborn Errors diagnosis, Neonatal Screening, Parents psychology
- Abstract
Objective: Abnormal results of newborn screening for common metabolic diseases are known to create substantial distress for parents. We explored parents' perceptions during diagnostic evaluations for newer disorders that are less well understood., Methods: Thirty families completed 48 open-ended interviews before and/or after parents received confirmatory test results for their infants. Qualitative content analysis was used to analyze the data., Results: Parents were shocked by the notification of the abnormal test result. Their urgent and often frustrating searches for information dominated the early phase of the screening process. Treatment center personnel were mainly informative and reassuring, but waiting for results exacerbated parents' distress. Equivocal results from diagnostic testing created uncertainties for parents regarding their infants' long-term health. After counseling, some parents reported inaccurate ideas about the disorders despite exposure to large amounts of information. Regardless of the challenges and anxieties of the evaluation, nearly every parent thought newborn screening was an important program for infant health., Conclusions: The evaluation of a newborn for an abnormal screening result was highly stressful for parents. To help reduce parents' distress, improvements in communications and clinical services are needed. Recommendations of useful Internet sites and discussions of this information may benefit parents. Tailoring counseling to meet the needs of culturally and educationally diverse families is needed. Families and infants with equivocal results are a new group of patients who merit comprehensive clinical follow-up., (Copyright © 2011 by the American Academy of Pediatrics.)
- Published
- 2011
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35. Lack of genotype-phenotype correlations and outcome in MCAD deficiency diagnosed by newborn screening in New York State.
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Arnold GL, Saavedra-Matiz CA, Galvin-Parton PA, Erbe R, Devincentis E, Kronn D, Mofidi S, Wasserstein M, Pellegrino JE, Levy PA, Adams DJ, Nichols M, and Caggana M
- Subjects
- Carnitine analogs & derivatives, Carnitine blood, Fatty Acids metabolism, Female, Genotype, Humans, Infant, Newborn, Male, Metabolism, Inborn Errors genetics, Mutation, New York, Phenotype, Prognosis, Acyl-CoA Dehydrogenases deficiency, Acyl-CoA Dehydrogenases genetics, Metabolism, Inborn Errors diagnosis, Metabolism, Inborn Errors physiopathology, Neonatal Screening methods
- Abstract
Introduction: Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is one of the most common inborn errors of metabolism. Affected patients have impaired ability to break down medium chain fatty acids during fasting, and typically present in the early years of life with hypoketotic hypoglycemia, Reye syndrome-like symptoms, brain damage or death. The development of newborn screening (NBS) for MCAD deficiency has greatly improved outcome, but some patients still appear at risk for severe complications. We reviewed the outcome of patients identified with MCAD deficiency by the New York State NBS process to identify biochemical or genotypic markers which might predict outcome., Method: All eight NBS follow-up centers in New York State contributed the cases of MCAD deficiency diagnosed by newborn screen, who received diagnostic and follow-up care in their clinic. Data reviewed included gender, age, birthweight, initial NBS octanoylcarnitine level (C8) and C8/C2 ratio, follow-up C8 and hexanoylglycine, race/ethnicity, and presence of neonatal or later symptoms., Results: We identified 53 cases of MCAD deficiency. More than one quarter of patients had a post-neonatal symptomatic admission (predominantly lethargy associated with an intercurrent illness). No genotype or C8 level was protective for neonatal or later symptoms. There was a relationship between initial C8 level or C8/C2 ratio and occurrence of later symptoms (7.3 micromol/L in the asymptomatic vs. 19.1 micromol/L in the symptomatic, p<0.0002 for C8, and 0.26 vs. 0.6, respectively, for C8/C2 ratio, p<0.012). Four infants had initial C8 level >30 micromol/L; these infants had a high rate of symptomatic or multiple symptomatic episodes or a history of sibling death from "SIDS", and typically had deletion, nonsense or splice sites mutations. Infants having a history of a symptomatic episode were more likely to have higher initial C8 on NBS and a genotype predicted to strongly affect protein function. In our ethnically diverse group of patients, the c.985A>G mutation was rarely found in non-Caucasians., Discussion: No genotype or metabolite profile is protective from symptoms. The strong relationship between initial C8 level and outcome suggests that in at least some cases neonates having high initial C8 levels may be demonstrating an increased susceptibility to catabolic stress, and may merit additional precautions. Our data also suggest that these infants are more likely to carry severe mutations including homozygosity for the common mutation, deletions, nonsense or splice site mutations. The reports of significant lethargy or hypoglycemia during intercurrent illness in over one quarter of cases even when early medical intervention is recommended (and even when initial C8 is not profoundly elevated) underscores the importance of continued vigilance to prevent stressful fasting in this disorder., (Copyright (c) 2010. Published by Elsevier Inc.)
- Published
- 2010
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36. Late onset optic neuropathy in methylmalonic and propionic acidemia.
- Author
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Williams ZR, Hurley PE, Altiparmak UE, Feldon SE, Arnold GL, Eggenberger E, and Mejico LJ
- Subjects
- Adolescent, Amino Acid Metabolism, Inborn Errors blood, Amino Acid Metabolism, Inborn Errors diet therapy, Dietary Supplements, Female, Humans, Male, Optic Nerve Diseases blood, Retrospective Studies, Scotoma blood, Visual Acuity, Visual Fields, Young Adult, Amino Acid Metabolism, Inborn Errors complications, Methylmalonic Acid blood, Optic Nerve Diseases etiology, Propionates blood, Scotoma etiology
- Abstract
Purpose: To describe 3 cases of late-onset bilateral optic neuropathy with visual dysfunction in patients with organic acidemia., Design: Retrospective case series., Methods: A total of 3 subjects, a 16-year-old male with methylmalonic acidemia (MMA), a 21-year-old male with MMA, and a 20-year-old female with propionic acidemia (PA), are included in this series. Comparison of the patients' clinical course, ophthalmologic exam, and testing are discussed. The outcome measures include visual acuity (VA), fundus appearance, visual fields, brain imaging, and genetic testing., Results: All 3 subjects had late-onset severe bilateral VA loss with bilateral optic nerve pallor, central or cecocentral scotomas on visual field testing, and negative diagnostic workups for other causes of bilateral optic neuropathy., Conclusions: Patients with organic acidemia may develop late-onset bilateral optic neuropathy with visual dysfunction despite lifelong propiogenic amino acid restriction and dietary supplementation.
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- 2009
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37. Newborn screening for Krabbe disease: the New York State model.
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Duffner PK, Caggana M, Orsini JJ, Wenger DA, Patterson MC, Crosley CJ, Kurtzberg J, Arnold GL, Escolar ML, Adams DJ, Andriola MR, Aron AM, Ciafaloni E, Djukic A, Erbe RW, Galvin-Parton P, Helton LE, Kolodny EH, Kosofsky BE, Kronn DF, Kwon JM, Levy PA, Miller-Horn J, Naidich TP, Pellegrino JE, Provenzale JM, Rothman SJ, and Wasserstein MP
- Subjects
- DNA Mutational Analysis, Evoked Potentials, Auditory, Brain Stem physiology, Evoked Potentials, Visual physiology, Follow-Up Studies, Galactosylceramidase analysis, Galactosylceramidase metabolism, Hematopoietic Stem Cell Transplantation, Humans, Infant, Newborn, Leukodystrophy, Globoid Cell genetics, Leukodystrophy, Globoid Cell therapy, Magnetic Resonance Imaging, Models, Organizational, Neural Conduction physiology, Neurologic Examination, New York, Referral and Consultation, Risk Assessment, Treatment Outcome, Leukodystrophy, Globoid Cell diagnosis, Neonatal Screening organization & administration, Neonatal Screening standards
- Abstract
Krabbe disease is a rare inherited neurologic disorder affecting the central and peripheral nervous systems. The disease has four phenotypes: early infantile, later onset, adolescent, and adult. The only known treatment is hematopoietic stem cell transplantation, which is, in the early infantile form of the disease, most beneficial if performed before onset of clinical symptoms. In August 2006, New York State began screening all newborns for Krabbe disease. A rapid and accurate technique for assessing galactocerebrosidase activity and performing DNA mutation analysis had been developed. Interpreting these results was limited, however, because neither enzyme activity nor genetic mutation reliably predicts phenotype. A series of initiatives were therefore developed by a multidisciplinary group of neurologists, geneticists, metabolic pediatricians, neurodevelopmental pediatricians, and transplant physicians (the Krabbe Consortium of New York State) to enhance the effectiveness of the newborn screening program. A standardized clinical evaluation protocol was designed based on the available literature, criteria for transplantation for the early infantile phenotype were formulated, a clinical database and registry was developed, and a study of developmental and functional outcomes was instituted. This multidisciplinary standardized approach to evaluating infants who have positive results on newborn screening may serve as a model for other states as they begin the process of screening for Krabbe disease and other lysosomal storage disorders.
- Published
- 2009
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38. Clinical outcomes after long-term treatment with alglucosidase alfa in infants and children with advanced Pompe disease.
- Author
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Nicolino M, Byrne B, Wraith JE, Leslie N, Mandel H, Freyer DR, Arnold GL, Pivnick EK, Ottinger CJ, Robinson PH, Loo JC, Smitka M, Jardine P, Tatò L, Chabrol B, McCandless S, Kimura S, Mehta L, Bali D, Skrinar A, Morgan C, Rangachari L, Corzo D, and Kishnani PS
- Subjects
- Body Height, Body Weight, Child, Preschool, Cough chemically induced, Echocardiography, Enzyme-Linked Immunosorbent Assay, Female, Glycogen metabolism, Glycogen Storage Disease Type II metabolism, Glycogen Storage Disease Type II physiopathology, Humans, Immunoglobulin G blood, Infant, Kaplan-Meier Estimate, Male, Muscle, Skeletal drug effects, Muscle, Skeletal metabolism, Skin Diseases chemically induced, Time Factors, Treatment Outcome, alpha-Glucosidases adverse effects, alpha-Glucosidases immunology, Glycogen Storage Disease Type II drug therapy, alpha-Glucosidases therapeutic use
- Abstract
Purpose: A clinical trial was conducted to evaluate the safety and efficacy of alglucosidase alfa in infants and children with advanced Pompe disease., Methods: Open-label, multicenter study of IV alglucosidase alfa treatment in 21 infants 3-43 months old (median 13 months) with minimal acid alpha-glucosidase activity and abnormal left ventricular mass index by echocardiography. Patients received IV alglucosidase alfa every 2 weeks for up to 168 weeks (median 120 weeks). Survival results were compared with an untreated reference cohort., Results: At study end, 71% (15/21) of patients were alive and 44% (7/16) of invasive-ventilator free patients remained so. Compared with the untreated reference cohort, alglucosidase alfa reduced the risk of death by 79% (P < 0.001) and the risk of invasive ventilation by 58% (P = 0.02). Left ventricular mass index improved or remained normal in all patients evaluated beyond 12 weeks; 62% (13/21) achieved new motor milestones. Five patients were walking independently at the end of the study and 86% (18/21) gained functional independence skills. Overall, 52% (11/21) of patients experienced infusion-associated reactions; 95% (19/20) developed IgG antibodies to recombinant human lysosomal acid alpha-glucosidase; no patients withdrew from the study because of safety concerns., Conclusions: In this population of infants with advanced disease, biweekly infusions with alglucosidase alfa prolonged survival and invasive ventilation-free survival. Treatment also improved indices of cardiomyopathy, motor skills, and functional independence.
- Published
- 2009
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39. A Delphi clinical practice protocol for the management of very long chain acyl-CoA dehydrogenase deficiency.
- Author
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Arnold GL, Van Hove J, Freedenberg D, Strauss A, Longo N, Burton B, Garganta C, Ficicioglu C, Cederbaum S, Harding C, Boles RG, Matern D, Chakraborty P, and Feigenbaum A
- Subjects
- Clinical Protocols, Delphi Technique, Disease Management, Female, Humans, Infant, Lipid Metabolism, Inborn Errors diagnosis, Male, Randomized Controlled Trials as Topic, Acyl-CoA Dehydrogenase, Long-Chain deficiency, Lipid Metabolism, Inborn Errors therapy
- Abstract
Introduction: Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency is a disorder of oxidation of long chain fat, and can present as cardiomyopathy or fasting intolerance in the first months to years of life, or as myopathy in later childhood to adulthood. Expanded newborn screening has identified a relatively high incidence of this disorder (1:31,500), but there is a dearth of evidence-based outcomes data to guide the development of clinical practice protocols. This consensus protocol is intended to assist clinicians in the diagnosis and management of screen-positive newborns for VLCAD deficiency until evidence-based guidelines are available., Method: The Oxford Centre for Evidence-based Medicine system was used to grade the literature review and create recommendations graded from A (evidence level of randomized clinical trials) to D (expert opinion). Delphi was used as the consensus tool. A panel of 14 experts (including clinicians, diagnostic laboratory directors and researchers) completed three rounds of survey questions and had a face-to-face meeting., Result: Panelists reviewed the initial evaluation of the screen-positive infant, diagnostic testing and management of diagnosed patients. Grade C and D consensus recommendations were made in each of these three areas. The panel did not reach consensus on all issues, particularly in the dietary management of asymptomatic infants diagnosed by newborn screening.
- Published
- 2009
- Full Text
- View/download PDF
40. Isotopic evidence for an aerobic nitrogen cycle in the latest Archean.
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Garvin J, Buick R, Anbar AD, Arnold GL, and Kaufman AJ
- Subjects
- Aerobiosis, Anaerobiosis, Australia, Biological Evolution, Nitrates chemistry, Nitrates metabolism, Nitrites chemistry, Nitrites metabolism, Nitrogen Fixation, Oceans and Seas, Oxidation-Reduction, Oxygen metabolism, Quaternary Ammonium Compounds chemistry, Quaternary Ammonium Compounds metabolism, Time, Archaea metabolism, Bacteria metabolism, Geologic Sediments chemistry, Nitrogen chemistry, Nitrogen metabolism, Nitrogen Isotopes analysis, Oxygen chemistry
- Abstract
The nitrogen cycle provides essential nutrients to the biosphere, but its antiquity in modern form is unclear. In a drill core though homogeneous organic-rich shale in the 2.5-billion-year-old Mount McRae Shale, Australia, nitrogen isotope values vary from +1.0 to +7.5 per mil (per thousand) and back to +2.5 per thousand over approximately 30 meters. These changes evidently record a transient departure from a largely anaerobic to an aerobic nitrogen cycle complete with nitrification and denitrification. Complementary molybdenum abundance and sulfur isotopic values suggest that nitrification occurred in response to a small increase in surface-ocean oxygenation. These data imply that nitrifying and denitrifying microbes had already evolved by the late Archean and were present before oxygen first began to accumulate in the atmosphere.
- Published
- 2009
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41. Universal nephroblastomatosis with bilateral hyperplastic nephromegaly in siblings.
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Katzman PJ, Arnold GL, Lagoe EC, and Huff V
- Subjects
- Female, Humans, Infant, Newborn, Male, Siblings, Kidney abnormalities, Kidney Neoplasms congenital, Kidney Neoplasms pathology
- Abstract
We present an unusual renal developmental disorder in a female infant and male sibling born in a subsequent pregnancy. Both children had prenatally diagnosed bilateral nephromegaly and survived for 6 and 10 days after birth, respectively. Both infants demonstrated the presence of bilaterally large cerebriform kidneys with numerous small lobulations containing immature glomeruli admixed with primarily intralobar nephrogenic rests without Wilms tumor. The pathology was most consistent with universal nephroblastomatosis with nephromegaly, a rare entity described in only 4 cases and in only 1 of these as a possible inherited disorder.
- Published
- 2009
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- View/download PDF
42. Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities.
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Brunetti-Pierri N, Berg JS, Scaglia F, Belmont J, Bacino CA, Sahoo T, Lalani SR, Graham B, Lee B, Shinawi M, Shen J, Kang SH, Pursley A, Lotze T, Kennedy G, Lansky-Shafer S, Weaver C, Roeder ER, Grebe TA, Arnold GL, Hutchison T, Reimschisel T, Amato S, Geragthy MT, Innis JW, Obersztyn E, Nowakowska B, Rosengren SS, Bader PI, Grange DK, Naqvi S, Garnica AD, Bernes SM, Fong CT, Summers A, Walters WD, Lupski JR, Stankiewicz P, Cheung SW, and Patel A
- Subjects
- Adolescent, Adult, Child, Child, Preschool, Female, Gene Deletion, Gene Duplication, Humans, Male, Schizophrenia genetics, Young Adult, Chromosomes, Human, Pair 1 genetics, Craniofacial Abnormalities genetics, Mental Disorders genetics, Microcephaly genetics
- Abstract
Chromosome region 1q21.1 contains extensive and complex low-copy repeats, and copy number variants (CNVs) in this region have recently been reported in association with congenital heart defects, developmental delay, schizophrenia and related psychoses. We describe 21 probands with the 1q21.1 microdeletion and 15 probands with the 1q21.1 microduplication. These CNVs were inherited in most of the cases in which parental studies were available. Consistent and statistically significant features of microcephaly and macrocephaly were found in individuals with microdeletion and microduplication, respectively. Notably, a paralog of the HYDIN gene located on 16q22.2 and implicated in autosomal recessive hydrocephalus was inserted into the 1q21.1 region during the evolution of Homo sapiens; we found this locus to be deleted or duplicated in the individuals we studied, making it a probable candidate for the head size abnormalities observed. We propose that recurrent reciprocal microdeletions and microduplications within 1q21.1 represent previously unknown genomic disorders characterized by abnormal head size along with a spectrum of developmental delay, neuropsychiatric abnormalities, dysmorphic features and congenital anomalies. These phenotypes are subject to incomplete penetrance and variable expressivity.
- Published
- 2008
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43. A Delphi-based consensus clinical practice protocol for the diagnosis and management of 3-methylcrotonyl CoA carboxylase deficiency.
- Author
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Arnold GL, Koeberl DD, Matern D, Barshop B, Braverman N, Burton B, Cederbaum S, Fiegenbaum A, Garganta C, Gibson J, Goodman SI, Harding C, Kahler S, Kronn D, and Longo N
- Subjects
- Carnitine blood, Carnitine therapeutic use, Delphi Technique, Energy Intake, Humans, Infant, Newborn, Leucine administration & dosage, Mothers, Neonatal Screening, Carbon-Carbon Ligases deficiency, Metabolism, Inborn Errors diagnosis, Metabolism, Inborn Errors therapy
- Abstract
3-MCC deficiency is among the most common inborn errors of metabolism identified on expanded newborn screening (1:36,000 births). However, evidence-based guidelines for diagnosis and management of this disorder are lacking. Using the traditional Delphi method, a panel of 15 experts in inborn errors of metabolism was convened to develop consensus-based clinical practice guidelines for the diagnosis and management of 3-MCC screen-positive infants and their mothers. The Oxford Centre for Evidence-based Medicine system was used to grade the literature review and create recommendations graded from A (evidence level of randomized clinical trials) to D (expert opinion). Panelists reviewed the initial evaluation of the screen-positive infant-mother dyad, diagnostic guidelines, and management of diagnosed patients. Grade D consensus recommendations were made in each of these three areas. The panel did not reach consensus on all issues. This consensus protocol is intended to assist clinicians in the diagnosis and management of screen-positive newborns for 3-MCC deficiency and to encourage the development of evidence-based guidelines.
- Published
- 2008
- Full Text
- View/download PDF
44. Late Archean biospheric oxygenation and atmospheric evolution.
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Kaufman AJ, Johnston DT, Farquhar J, Masterson AL, Lyons TW, Bates S, Anbar AD, Arnold GL, Garvin J, and Buick R
- Subjects
- Australia, Bacteria metabolism, Geologic Sediments microbiology, Oxidation-Reduction, Seawater, South Africa, Sulfates chemistry, Sulfates metabolism, Sulfur Isotopes analysis, Time, Atmosphere, Geologic Sediments chemistry, Oxygen, Sulfur chemistry, Sulfur metabolism
- Abstract
High-resolution geochemical analyses of organic-rich shale and carbonate through the 2500 million-year-old Mount McRae Shale in the Hamersley Basin of northwestern Australia record changes in both the oxidation state of the surface ocean and the atmospheric composition. The Mount McRae record of sulfur isotopes captures the widespread and possibly permanent activation of the oxidative sulfur cycle for perhaps the first time in Earth's history. The correlation of the time-series sulfur isotope signals in northwestern Australia with equivalent strata from South Africa suggests that changes in the exogenic sulfur cycle recorded in marine sediments were global in scope and were linked to atmospheric evolution. The data suggest that oxygenation of the surface ocean preceded pervasive and persistent atmospheric oxygenation by 50 million years or more.
- Published
- 2007
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45. A whiff of oxygen before the great oxidation event?
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Anbar AD, Duan Y, Lyons TW, Arnold GL, Kendall B, Creaser RA, Kaufman AJ, Gordon GW, Scott C, Garvin J, and Buick R
- Subjects
- Australia, Isotopes analysis, Molybdenum analysis, Oceans and Seas, Osmium analysis, Oxidation-Reduction, Rhenium analysis, Seawater chemistry, Sulfur analysis, Sulfur Isotopes analysis, Temperature, Uranium analysis, Geologic Sediments chemistry, Oxygen analysis
- Abstract
High-resolution chemostratigraphy reveals an episode of enrichment of the redox-sensitive transition metals molybdenum and rhenium in the late Archean Mount McRae Shale in Western Australia. Correlations with organic carbon indicate that these metals were derived from contemporaneous seawater. Rhenium/osmium geochronology demonstrates that the enrichment is a primary sedimentary feature dating to 2501 +/- 8 million years ago (Ma). Molybdenum and rhenium were probably supplied to Archean oceans by oxidative weathering of crustal sulfide minerals. These findings point to the presence of small amounts of O2 in the environment more than 50 million years before the start of the Great Oxidation Event.
- Published
- 2007
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- View/download PDF
46. Molybdenum isotope evidence for widespread anoxia in mid-Proterozoic oceans.
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Arnold GL, Anbar AD, Barling J, and Lyons TW
- Abstract
How much dissolved oxygen was present in the mid-Proterozoic oceans between 1.8 and 1.0 billion years ago is debated vigorously. One model argues for oxygenation of the oceans soon after the initial rise of atmospheric oxygen approximately 2.3 billion years ago. Recent evidence for H(2)S in some mid-Proterozoic marine basins suggests, however, that the deep ocean remained anoxic until much later. New molybdenum isotope data from modern and ancient sediments indicate expanded anoxia during the mid-Proterozoic compared to the present-day ocean. Consequently, oxygenation of the deep oceans may have lagged that of the atmosphere by over a billion years.
- Published
- 2004
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47. Fe isotope variations in natural materials measured using high mass resolution multiple collector ICPMS.
- Author
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Arnold GL, Weyer S, and Anbar AD
- Abstract
We present the first measurements of Fe isotope variations in chemically purified natural samples using high mass resolution multiple-collector inductively coupled plasma source mass spectrometry (MC-ICPMS). High mass resolution allows polyatomic interferences at Fe masses to be resolved (especially, (40)Ar(14)N(+), (40)Ar(16)O(+), and (40)Ar(16)OH(+)). Simultaneous detection of Fe isotope ion beams using multiple Faraday collectors facilitates high-precision isotope ratio measurements. Fe in basalt and paleosol samples was extracted and purified using a simple, single-stage anion chemistry procedure. A Cu "element spike" was used as an internal standard to correct for variations in mass bias. Using this procedure, we obtained data with an external precision of 0.03-0.11 per thousand and 0.04-0.15 per thousand for delta(56/54)Fe and delta(57/54)Fe, respectively (2sigma). Use of Cu was necessary for such reproducibility, presumably because of subtle effects of residual sample matrix on mass bias. These findings demonstrate the utility of high-resolution MC-ICPMS for high-precision Fe isotope analysis in geologic and other natural materials. They also highlight the importance of internal monitoring of mass bias, particularly when using routine methods for Fe extraction and purification.
- Published
- 2004
- Full Text
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48. Prevalence of stimulant use for attentional dysfunction in children with phenylketonuria.
- Author
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Arnold GL, Vladutiu CJ, Orlowski CC, Blakely EM, and DeLuca J
- Subjects
- Adolescent, Attention, Child, Female, Humans, Male, Phenylalanine blood, Phenylketonurias blood, Prevalence, Retrospective Studies, Tyrosine deficiency, Tyrosine therapeutic use, Attention Deficit Disorder with Hyperactivity drug therapy, Attention Deficit Disorder with Hyperactivity epidemiology, Central Nervous System Stimulants therapeutic use, Phenylketonurias epidemiology
- Abstract
Recent data suggest that children with phenylketonuria (PKU) and poor metabolic control may have an increased prevalence of attentional dysfunction. However, few formal studies have addressed this topic in detail. We reviewed the medical records of 38 school-aged children with early and continuously treated PKU to determine the prevalence of stimulant use for attentional dysfunction, and to determine the relationship between metabolic control and attentional symptoms. Twenty-six per cent of the PKU children used a stimulant medication for attentional dysfunction. This is significantly higher than in an age- and sex-matched control group consisting of children with type I diabetes mellitus (6.5%, p <0.006), and also considerably higher than population norms for attention deficit hyperactivity disorder (ADHD) (5%). We also found a significant relationship between phenylalanine levels and stimulant use or attentional symptoms. Mean plasma phenylalanine concentration was 486 micromol/L in the non-stimulant-using group and 792 micromol/L in the stimulant-using group (p <0.02). Mean phenylalanine concentration was 462 micromol/L in the group not reporting attentional symptoms, and was 702 micromol/L in the symptomatic group (p <0.05). Parents of the stimulant-using children felt that the stimulants were efficacious in treating their child's attentional symptoms. Stimulant use and parent reports of attentional dysfunction are quite common in our PKU patients and appear to be strongly related to higher phenylalanine concentrations.
- Published
- 2004
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49. Improved growth and nutrition status in children with methylmalonic or propionic acidemia fed an elemental medical food.
- Author
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Yannicelli S, Acosta PB, Velazquez A, Bock HG, Marriage B, Kurczynski TW, Miller M, Korson M, Steiner RD, Rutledge L, Bernstein L, Chinsky J, Galvin-Parton P, and Arnold GL
- Subjects
- Amino Acids administration & dosage, Ammonia blood, Child, Preschool, Female, Humans, Infant, Iron administration & dosage, Male, Nutritional Status genetics, Nutritional Support, Peroxisomal Disorders genetics, Vitamin A blood, alpha-Tocopherol blood, Body Weight physiology, Methylmalonic Acid blood, Nutritional Status physiology, Peroxisomal Disorders diet therapy, Propionates blood
- Abstract
Background: Failure-to-thrive (FTT) has been described in patients with organic acidemias treated with low protein diets., Objective: To determine if patients with methylmalonic (MMA) or propionic acidemia (PA) can achieve normal growth and nutrition status., Methods: A 6-month multicenter outpatient study was conducted with infants and toddlers treated with Propimex-1 Amino Acid-Modified Medical Food With Iron (Ross Products Division, Abbott Laboratories, Columbus, OH). Main outcome measures were anthropometrics, protein status indices, plasma retinol, and alpha-tocopherol., Results: Sixteen patients completed the study. Mean baseline age was 0.54 +/- 0.02 years (range 0.03-3.00 years). By study end, mean National Center for Health Statistics (NCHS) weight centile increased from 26 to 49%; mean crown-heel length centile from 25 to 33%; and mean head circumference centile from 43 to 54%. Mean (+/- SE) protein and energy intakes by <6-month-old, 6<12-month-old, and 1<4-year-old patients were 15.3 +/- 0.9 g and 645 +/- 10 kcal; 18.3 +/- 1.1 g and 741 +/- 92 kcal; and 25.1 +/- 2.46 g and 1062 +/- 100 kcal, respectively. Plasma glycine concentrations were significantly and negatively correlated with energy intake (r=-0.77, p<0.0005). No correlation was found between dietary protein intakes and plasma ammonia concentrations. Protein status indices, retinol and alpha-tocopherol concentrations were within reference ranges at study end., Conclusions: Propimex-1 improved growth and nutrition status in patients with MMA or PA in just 6 months when fed in sufficient amounts. Providing energy and protein for patients with FTT at intakes recommended for catch-up growth may have resulted in even better growth.
- Published
- 2003
- Full Text
- View/download PDF
50. Utility of measuring 6-methylmercaptopurine and 6-thioguanine nucleotide levels in managing inflammatory bowel disease patients treated with 6-mercaptopurine in a clinical practice setting.
- Author
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Mardini HE and Arnold GL
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Humans, Immunosuppressive Agents administration & dosage, Inflammatory Bowel Diseases metabolism, Male, Mercaptopurine administration & dosage, Middle Aged, Retrospective Studies, Guanine Nucleotides metabolism, Immunosuppressive Agents metabolism, Immunosuppressive Agents therapeutic use, Inflammatory Bowel Diseases drug therapy, Mercaptopurine analogs & derivatives, Mercaptopurine metabolism, Mercaptopurine therapeutic use, Thionucleotides metabolism
- Abstract
Background: Measuring levels of 6-mercaptopurine (6-MP) metabolites (6-thioguanine nucleotides [6-TGNs] and 6-methylmercaptopurine [6-MMP]) has been proposed as a method to adjust 6-MP dose to optimize therapeutic response while minimizing toxicity in patients with inflammatory bowel disease. A 6-TGN level of >230 pmol/8 x 108 red blood cells (RBCs) has been reported to be associated with a higher efficacy rate, and a level of >450 pmol/8 x 108 RBCs has been reported to be associated with myelotoxicity. A 6-MMP level of >5,700 pmol/8 x 108 RBCs has been reported to be associated with an increased frequency of abnormal results of liver function tests (LFTs)., Goals: To report our experience with 6-MMP and 6-TGN levels in a clinical practice setting., Study: Using outpatient clinic medical records, we identified 53 measurements. Indications for measurement, 6-MP dose, and subsequent adjustments were documented., Results: Indications for measurements included the following: persistent symptoms, 31 cases (58.5%); abnormal LFT results, 7 (13.2%); steroid dependency, 6 (11.3%); anemia, 4 (7.5%); and leukopenia, 2 (3.8%). Of the 31 cases with persistent symptoms, 12 had "therapeutic" 6-TGN levels and other interventions were undertaken. 6-TGN levels were "subtherapeutic" in 19. The 6-MP dose was increased, and remission was achieved in 10 cases after a mean period of 3.6 weeks. Among the cases with abnormal LFT results, 6-MMP levels were high in five and low in two. Among the steroid dependency cases, 6-TGN levels were "subtherapeutic" in five. The dose was increased and steroids were weaned in three cases. The 6-TGN level was high in one of the leukopenia cases and the 6-MP dose was decreased. 6-TGN levels were not above the "target range" in any of the anemia cases., Conclusion: Measuring levels of 6-MP metabolites may have a role in customizing 6-MP dosing. This role is not completely clear and needs to be explored in larger well-controlled studies.
- Published
- 2003
- Full Text
- View/download PDF
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