31 results on '"Peake RWA"'
Search Results
2. ME2 Deficiency Is Associated With Recessive Neurodevelopmental Disorder.
- Author
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Almontashiri NAM, Alharby E, Saleh M, Abu-Farha M, Alasmari A, Gebbia M, Hiesl C, Peake RWA, Amr SS, Boles E, Roth FP, and Abubaker J
- Abstract
Malate is an important dicarboxylic acid produced from fumarate in the tricarboxylic acid cycle. Deficiencies of fumarate hydrolase (FH) and malate dehydrogenase (MDH), responsible for malate formation and metabolism, respectively, are known to cause recessive forms of neurodevelopmental disorders (NDDs). The malic enzyme isoforms, malic enzyme 1 (ME1) and 2 (ME2), are required for the conversion of malate to pyruvate. To date, there have been no reports linking deficiency of either malic enzyme isoforms to any Mendelian disease in humans. We report a patient presenting with NDD, subtle dysmorphic features, resolved dilated cardiomyopathy, and mild blood lactate elevation. Whole exome sequencing (WES) revealed a homozygous frameshift variant (c.1379_1380delTT, p.Phe460fs*22) in the malic enzyme 2 (ME2) gene resulting in truncated and unstable ME2 protein in vitro. Subsequent deletion of the yeast ortholog of human ME2 (hME2) resulted in growth arrest, which was rescued by overexpression of hME2, strongly supporting an important role of ME2 in mitochondrial function. Our results also support the pathogenicity and candidacy of the ME2 gene and variant in association with NDD. To our knowledge, this is the first report of a Mendelian human disease resulting from a biallelic variant in the ME encoding gene. Future studies are warranted to confirm ME2-associated recessive NDD., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2024
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3. Untargeted Metabolomics for Inborn Errors of Metabolism: Development and Evaluation of a Sustainable Reference Material for Correcting Inter-Batch Variability.
- Author
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Garrett R, Ptolemy AS, Pickett S, Kellogg MD, and Peake RWA
- Abstract
Background: Untargeted metabolomics has shown promise in expanding screening and diagnostic capabilities for inborn errors of metabolism (IEMs). However, inter-batch variability remains a major barrier to its implementation in the clinical laboratory, despite attempts to address this through normalization techniques. We have developed a sustainable, matrix-matched reference material (RM) using the iterative batch averaging method (IBAT) to correct inter-batch variability in liquid chromatography-high-resolution mass spectrometry-based untargeted metabolomics for IEM screening., Methods: The RM was created using pooled batches of remnant plasma specimens. The batch size, number of batch iterations per RM, and stability compared to a conventional pool of specimens were determined. The effectiveness of the RM for correcting inter-batch variability in routine screening was evaluated using plasma collected from a cohort of phenylketonuria (PKU) patients., Results: The RM exhibited lower metabolite variability between iterations over time compared to metabolites from individual batches or individual specimens used for its creation. In addition, the mean variation across amino acid (n = 19) concentrations over 12 weeks was lower for the RM (CVtotal = 8.8%; range 4.7%-25.3%) compared to the specimen pool (CVtotal = 24.6%; range 9.0%-108.3%). When utilized in IEM screening, RM normalization minimized unwanted inter-batch variation and enabled the correct classification of 30 PKU patients analyzed 1 month apart from 146 non-PKU controls., Conclusions: Our RM minimizes inter-batch variability in untargeted metabolomics and demonstrated its potential for routine IEM screening in a cohort of PKU patients. It provides a practical and sustainable solution for data normalization in untargeted metabolomics for clinical laboratories., (© Association for Diagnostics & Laboratory Medicine 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
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- 2024
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4. Turbulent Flow Liquid Chromatography-Tandem Mass Spectrometry Methods for Antiepileptic Drug Quantitation in Serum.
- Author
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Ptolemy AS, Peake RWA, and Kellogg MD
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- Humans, Tandem Mass Spectrometry methods, Chromatography, High Pressure Liquid methods, Chromatography, Liquid methods, Drug Monitoring methods, Reproducibility of Results, Anticonvulsants, Epilepsy drug therapy
- Abstract
Epilepsy is characterized by abnormal electrical discharges in the brain that result in unprovoked seizures. Pharmacotherapy with antiepileptic drugs (AED) can help control the incidence of epileptic seizures. AED therapeutic regimens often need to be individually tailored. Therapeutic drug monitoring (TDM) of AED is required to optimize therapeutic efficacy and minimize the risk of any associated destructive toxicities. We describe a turbulent flow liquid chromatography-tandem mass spectrometry (TFC-MS/MS) method for the detection of seven different AED in human serum. TFC-MS/MS testing was performed using a TLX-2 online sample preparation liquid chromatography (SPLC) system coupled to an API 5500 Q-Trap tandem mass spectrometer. Quantification of 10,11-dihydro-10-hydroxycarbamazepine, lacosamide, lamotrigine, levetiracetam, rufinamide, topiramate, and zonisamide was, respectively, performed using calibration curves (2-60 μg/mL, R
2 > 0.99) with precisions of <10%., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)- Published
- 2024
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5. Combined targeted and untargeted high-resolution mass spectrometry analyses to investigate metabolic alterations in pompe disease.
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de Moraes MBM, de Souza HMR, de Oliveira MLC, Peake RWA, Scalco FB, and Garrett R
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- Humans, Metabolomics methods, Biomarkers urine, Phenotype, Tandem Mass Spectrometry, Glycogen Storage Disease Type II diagnosis, Glycogen Storage Disease Type II urine
- Abstract
Introduction: Pompe disease is a rare, lysosomal disorder, characterized by intra-lysosomal glycogen accumulation due to an impaired function of α-glucosidase enzyme. The laboratory testing for Pompe is usually performed by enzyme activity, genetic test, or urine glucose tetrasaccharide (Glc4) screening by HPLC. Despite being a good preliminary marker, the Glc4 is not specific for Pompe., Objective: The purpose of the present study was to develop a simple methodology using liquid chromatography-high resolution mass spectrometry (LC-HRMS) for targeted quantitative analysis of Glc
4 combined with untargeted metabolic profiling in a single analytical run to search for complementary biomarkers in Pompe disease., Methods: We collected 21 urine specimens from 13 Pompe disease patients and compared their metabolic signatures with 21 control specimens., Results: Multivariate statistical analyses on the untargeted profiling data revealed Glc4 , creatine, sorbitol/mannitol, L-phenylalanine, N-acetyl-4-aminobutanal, N-acetyl-L-aspartic acid, and 2-aminobenzoic acid as significantly altered in Pompe disease. This panel of metabolites increased sample class prediction (Pompe disease versus control) compared with a single biomarker., Conclusion: This study has demonstrated the potential of combined acquisition methods in LC-HRMS for Pompe disease investigation, allowing for routine determination of an established biomarker and discovery of complementary candidate biomarkers that may increase diagnostic accuracy, or improve the risk stratification of patients with disparate clinical phenotypes., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)- Published
- 2023
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6. Untargeted LC-HRMS metabolomics reveals candidate biomarkers for mucopolysaccharidoses.
- Author
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Torres CL, Scalco FB, de Oliveira MLC, Peake RWA, and Garrett R
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- Humans, Dermatan Sulfate urine, Tandem Mass Spectrometry methods, Glycosaminoglycans urine, Chromatography, Liquid methods, Metabolomics methods, Biomarkers urine, Heparitin Sulfate urine, Mucopolysaccharidoses diagnosis
- Abstract
Background: Mucopolysaccharidoses (MPSs) are inherited genetic diseases caused by an absence or deficiency of lysosomal enzymes responsible for catabolizing glycosaminoglycans (GAGs). Undiagnosed patients, or those without adequate treatment in early life, can be severely and irreversibly affected by the disease. In this study, we applied liquid chromatography-high resolution mass spectrometry (LC-HRMS)-based untargeted metabolomics to identify potential biomarkers for MPS disorders to better understand how MPS may affect the metabolome of patients., Methods: Urine samples from 37 MPS patients (types I, II, III, IV, and VI; untreated and treated with enzyme replacement therapy (ERT)) and 38 controls were analyzed by LC-HRMS. Data were processed by an untargeted metabolomics workflow and submitted to multivariate statistical analyses to reveal significant differences between the MPS and control groups., Results: A total of 12 increased metabolites common to all MPS types were identified. Dipeptides, amino acids and derivatives were increased in the MPS group compared to controls. N-acetylgalactosamines 4- or 6-sulfate, important constituents of GAGs, were also elevated in MPS patients, most prominently in those with MPS VI. Notably, treated patients exhibited lower levels of the aforementioned acylaminosugars than untreated patients in all MPS types., Conclusions: Untargeted metabolomics has enabled the detection of metabolites that could improve our understanding of MPS physiopathology. These potential biomarkers can be utilized in screening methods to support diagnosis and ERT monitoring., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)
- Published
- 2023
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7. Biallelic variants in HECT E3 paralogs, HECTD4 and UBE3C, encoding ubiquitin ligases cause neurodevelopmental disorders that overlap with Angelman syndrome.
- Author
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Faqeih EA, Alghamdi MA, Almahroos MA, Alharby E, Almuntashri M, Alshangiti AM, Clément P, Calame DG, Qebibo L, Burglen L, Doco-Fenzy M, Mastrangelo M, Torella A, Manti F, Nigro V, Alban Z, Alharbi GS, Hashmi JA, Alraddadi R, Alamri R, Mitani T, Magalie B, Coban-Akdemir Z, Geckinli BB, Pehlivan D, Romito A, Karageorgou V, Martini J, Colin E, Bonneau D, Bertoli-Avella A, Lupski JR, Pastore A, Peake RWA, Dallol A, Alfadhel M, and Almontashiri NAM
- Subjects
- Humans, Ubiquitin genetics, Ubiquitin-Protein Ligases genetics, Phenotype, Angelman Syndrome genetics, Neurodevelopmental Disorders genetics
- Abstract
Purpose: Pathogenic variants in genes encoding ubiquitin E3 ligases are known to cause neurodevelopmental syndromes. Additional neurodevelopmental disorders associated with the other genes encoding E3 ligases are yet to be identified., Methods: Chromosomal analysis and exome sequencing were used to identify the genetic causes in 10 patients from 7 unrelated families with syndromic neurodevelopmental, seizure, and movement disorders and neurobehavioral phenotypes., Results: In total, 4 patients were found to have 3 different homozygous loss-of-function (LoF) variants, and 3 patients had 4 compound heterozygous missense variants in the candidate E3 ligase gene, HECTD4, that were rare, absent from controls as homozygous, and predicted to be deleterious in silico. In 3 patients from 2 families with Angelman-like syndrome, paralog-directed candidate gene approach detected 2 LoF variants in the other candidate E3 ligase gene, UBE3C, a paralog of the Angelman syndrome E3 ligase gene, UBE3A. The RNA studies in 4 patients with LoF variants in HECTD4 and UBE3C provided evidence for the LoF effect., Conclusion: HECTD4 and UBE3C are novel biallelic rare disease genes, expand the association of the other HECT E3 ligase group with neurodevelopmental syndromes, and could explain some of the missing heritability in patients with a suggestive clinical diagnosis of Angelman syndrome., Competing Interests: Conflict of Interest J.R.L. has stock ownership in 23andMe, is a paid consultant for Regeneron Genetics Center, and is a coinventor on multiple US and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, genomic disorders, and bacterial genomic fingerprinting. J.R.L. serves on the Scientific Advisory Board of Baylor Genetics. Baylor College of Medicine and Miraca Holdings have formed a joint venture with shared ownership and governance of Baylor Genetics, which performs clinical microarray analysis and other genomic studies (exome sequencing, genome sequencing) for patient and family care. N.A.M.A. is a paid consultant for Noor Diagnostics and Discovery, which performs genetic and genomic studies (exome sequencing, genome sequencing) for patient and family care. All other authors declare no conflicts of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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8. Commentary on Severe Hyperhomocysteinemia in a Patient with Parkinson Disease.
- Author
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Peake RWA
- Subjects
- Humans, Hyperhomocysteinemia complications, Parkinson Disease complications
- Published
- 2022
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9. Assessment of Glucocerebrosidase Enzyme Activity in Parkinson Disease Using Multiple Approaches.
- Author
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Ortega RA, Bodamer O, Peake RWA, Raymond D, Bressman SB, and Saunders-Pullman R
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- Glucosylceramidase genetics, Humans, alpha-Synuclein, Gaucher Disease, Parkinson Disease enzymology
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- 2022
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10. Clinical characterization and further confirmation of the autosomal recessive SLC12A2 disease.
- Author
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Bilal Shamsi M, Saleh M, Almuntashri M, Alharby E, Samman M, Peake RWA, Al-Fadhli FM, Alasmari A, Faqeih EA, and Almontashiri NAM
- Subjects
- Brain diagnostic imaging, Brain pathology, Child, Child, Preschool, Deafness complications, Deafness diagnostic imaging, Deafness pathology, Exome genetics, Female, Genes, Recessive genetics, Homozygote, Humans, Infant, Intellectual Disability complications, Intellectual Disability diagnostic imaging, Intellectual Disability pathology, Male, Mutation genetics, Pedigree, Phenotype, RNA Splicing genetics, Solute Carrier Family 12, Member 2 deficiency, Exome Sequencing, Deafness genetics, Genetic Predisposition to Disease, Intellectual Disability genetics, Solute Carrier Family 12, Member 2 genetics
- Abstract
Heterozygous pathogenic variants in SLC12A2 are reported in patients with nonsyndromic hearing loss. Recently, homozygous loss-of-function variants have been reported in two patients with syndromic intellectual disability, with or without hearing loss. However, the clinical and molecular spectrum of SLC12A2 disease has yet to be characterized and confirmed. Using whole-exome sequencing, we detected a homozygous splicing variant in four patients from two independent families with severe developmental delay, microcephaly, respiratory abnormalities, and subtle dysmorphic features, with or without congenital hearing loss. We also reviewed the reported cases with pathogenic variants associated with autosomal dominant and recessive forms of the SLC12A2 disease. About 50% of the cases have syndromic and nonsyndromic congenital hearing loss. All patients harboring the recessive forms of the disease presented with severe global developmental delay. Interestingly, all reported variants are located in the c-terminal domain, suggesting a critical role of this domain for the proper function of the encoded co-transporter protein. In conclusion, our study provides an additional confirmation of the autosomal recessive SLC12A2 disease.
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- 2021
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11. A Child with Progressive Hypertrophic Cardiomyopathy and Lactic Acidosis.
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AlFaris HS, Rahbeeni ZA, Peake RWA, and Almontashiri NAM
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- Child, Humans, Mutation, Acidosis, Lactic diagnosis, Cardiomyopathy, Hypertrophic complications, Cardiomyopathy, Hypertrophic diagnosis
- Published
- 2021
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12. Biallelic loss of function variant in the unfolded protein response gene PDIA6 is associated with asphyxiating thoracic dystrophy and neonatal-onset diabetes.
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Al-Fadhli FM, Afqi M, Sairafi MH, Almuntashri M, Alharby E, Alharbi G, Abdud Samad F, Hashmi JA, Zaytuni D, Bahashwan AA, Choi JH, Peake RWA, Beutler B, and Almontashiri NAM
- Subjects
- Abnormalities, Multiple genetics, Alleles, Animals, Consanguinity, Ellis-Van Creveld Syndrome diagnostic imaging, Gene Knockout Techniques, Gestational Age, Humans, Magnetic Resonance Imaging, Male, Mice, Pedigree, Ellis-Van Creveld Syndrome genetics, Infant, Premature, Diseases genetics, Loss of Function Mutation, Protein Disulfide-Isomerases genetics, Unfolded Protein Response genetics
- Abstract
Protein disulfide isomerase A6 (PDIA6) is an unfolded protein response (UPR)-regulating protein. PDIA6 regulates the UPR sensing proteins, Inositol requiring enzyme 1, and EIF2AK3. Biallelic inactivation of the two genes in mice and humans resulted in embryonic lethality, diabetes, skeletal defects, and renal insufficiency. We recently showed that PDIA6 inactivation in mice caused embryonic and early lethality, diabetes and immunodeficiency. Here, we present a case with asphyxiating thoracic dystrophy (ATD) syndrome and infantile-onset diabetes. Whole exome sequencing revealed a homozygous frameshift variant in the PDIA6 gene. RNA expression was reduced in a gene dosage-dependent manner, supporting a loss-of-function effect of this variant. Phenotypic correlation with the mouse model recapitulated the growth defect and delay, early lethality, coagulation, diabetes, immunological, and polycystic kidney disease phenotypes. In general, the phenotype of the current patient is consistent with phenotypes associated with the disruption of PDIA6 and the sensors of UPR in mice and humans. This is the first study to associate ATD to the UPR gene, PDIA6. We recommend screening ATD cases with or without insulin-dependent diabetes for variants in PDIA6., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
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- 2021
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13. Progressive Ataxia and Neurologic Regression in RFXANK -Associated Bare Lymphocyte Syndrome.
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Alharby E, Obaid M, Elamin MAO, Almuntashri M, Bakhsh I, Samman M, Peake RWA, Alasmari A, and Almontashiri NAM
- Abstract
Objective: To identify the genetic cause of a late-onset immunodeficiency and subacute progressive neurodegenerative disease affecting cognition, motor, visual, and cerebellar systems in a patient with a family history of 2 younger siblings with an early-onset immunodeficiency disease., Methods: Physical examinations, immunologic, brain MRI, whole-exome sequencing, and segregation studies were used to identify the genetic and neuroimmunologic etiology of disease in this family., Results: We identified a homozygous loss-of-function (LOF) mutation (c.271+1G>C) in the RFXANK gene in the index patient and one of his younger affected siblings. Biallelic mutations in the RFXANK gene are known to cause bare lymphocyte syndrome (BLS) type II, complementation group B. The clinical and immunologic investigations were consistent with a clinical diagnosis of BLS type II. MRI demonstrated global cerebral and cerebellar atrophy with white matter signal changes in the index case., Conclusions: In addition to BLS type II, our study has expanded and further characterized the phenotype associated with the LOF of RFXANK to include progressive neurodegenerative disease. Our study also provides evidence for the impact of LOF on brain development and function. Thus, early bone marrow transplantation, as a standard of care for BLS, could prove to be protective against the neurologic phenotypes in this group of patients., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
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- 2021
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14. New paradigms of USP53 disease: normal GGT cholestasis, BRIC, cholangiopathy, and responsiveness to rifampicin.
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Alhebbi H, Peer-Zada AA, Al-Hussaini AA, Algubaisi S, Albassami A, AlMasri N, Alrusayni Y, Alruzug IM, Alharby E, Samman MA, Ayoub SZ, Maddirevula S, Peake RWA, Alkuraya FS, Wali S, and Almontashiri NAM
- Subjects
- Adolescent, Adult, Child, Cholangitis genetics, Cholangitis pathology, Cholestasis genetics, Cholestasis pathology, Female, Humans, Infant, Male, Nucleic Acid Synthesis Inhibitors pharmacology, Pedigree, Prognosis, Exome Sequencing, Cholangitis drug therapy, Cholestasis drug therapy, Homozygote, Mutation, Rifampin pharmacology, Ubiquitin-Specific Proteases genetics, gamma-Glutamyltransferase metabolism
- Abstract
Biallelic variants in the USP53 gene have recently been reported to segregate with normal gamma glutamyltransferase (GGT) cholestasis. Using whole-exome sequencing (WES), we detected two USP53 homozygous variants (c.951delT; p. Phe317fs and c.1744C>T; p. Arg582*) in five additional cases, including an unpublished cousin of a previously described family with intractable itching and normal GGT cholestasis. Three patients, a child and two adults, presented with recurrent episodes of normal GGT cholestasis, consistent with a diagnosis of benign recurrent intrahepatic cholestasis (BRIC). Cholangiopathic changes, possibly autoimmune in origin, were recognized in some patients. Additional phenotypic details in one patient included an enlarged left kidney, and speech/developmental delay. Notably, two patients exhibited a complete response to rifampicin, and one responded to ursodeoxycholic acid (UDCA). Two adult patients were suspected to have autoimmune liver disease and treated with steroids. This report describes new cases of USP53 disease presenting with normal GGT cholestasis or BRIC in three children and two adults. We also describe the novel finding of a dramatic response to rifampicin. The association of cholangiopathy with normal GGT cholestasis provides a diagnostic challenge and remains poorly understood.
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- 2021
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15. Hyperammonemia, Lactic Acidosis, and Arrhythmia in a Newborn.
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Almannai M, Aldehaimi A, Peake RWA, and Almontashiri NAM
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- Acidosis, Lactic blood, Acidosis, Lactic diagnosis, Arrhythmias, Cardiac blood, Arrhythmias, Cardiac diagnosis, Carnitine analogs & derivatives, Carnitine blood, Female, Humans, Hyperammonemia blood, Hyperammonemia diagnosis, Infant, Newborn, Lipid Metabolism, Inborn Errors blood, Lipid Metabolism, Inborn Errors complications, Lipid Metabolism, Inborn Errors genetics, Membrane Transport Proteins genetics, Mutation, Acidosis, Lactic etiology, Arrhythmias, Cardiac etiology, Hyperammonemia etiology, Lipid Metabolism, Inborn Errors diagnosis
- Published
- 2021
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16. Clinical, molecular, and biochemical delineation of asparagine synthetase deficiency in Saudi cohort.
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Alharby E, Faqeih EA, Saleh M, Alameer S, Almuntashri M, Pastore A, Samman MA, Alnawfal AM, Hashem M, Zaytuni D, Alharbi G, Almannai M, Alasmari A, Mahmoud AA, Alwadei AH, Jad L, AlOtaibi A, Al-Hakami F, Eyaid W, Alkuraya FS, Alfadhel M, Peake RWA, and Almontashiri NAM
- Subjects
- Humans, Retrospective Studies, Saudi Arabia epidemiology, Aspartate-Ammonia Ligase genetics, Intellectual Disability diagnosis, Intellectual Disability genetics, Microcephaly
- Abstract
Purpose: Asparagine synthetase deficiency (ASNSD) is a rare neurometabolic disease. Patients may not demonstrate low asparagine levels, which highlights the advantage of molecular over biochemical testing in the initial work-up of ASNSD. We aimed to further delineate the ASNSD variant and phenotypic spectrum and determine the value of biochemical testing as a frontline investigation in ASNSD., Methods: We retrospectively collected the clinical and molecular information on 13 families with ASNSD from the major metabolic clinics in Saudi Arabia., Results: The major phenotypes included congenital microcephaly (100%), facial dysmorphism (100%), global developmental delay (100%), brain abnormalities (100%), spasticity (86%), and infantile-onset seizures (93%). Additional unreported phenotypes included umbilical hernia, osteopenia, eczema, lung hypoplasia, and hearing loss. Overall, seven homozygous variants accounted for ASNSD. The p.Tyr398Cys and p.Asn75Ile variants accounted for 54% of the cases. The clinical sensitivity and specificity of the proposed biochemical analysis of cerebrospinal fluid (CSF) for the detection of patients with ASNSD were 83% and 98%, respectively., Conclusion: Our study describes the largest reported ASNSD cohort with clinical, molecular, and biochemical characterization. Taking into consideration the suboptimal sensitivity of biochemical screening, the delineation of the phenotype variant spectrum is of diagnostic utility for accurate diagnosis, prognosis, counseling, and carrier screening.
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- 2020
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17. Author Correction: Clinical Validation of Targeted and Untargeted Metabolomics Testing for Genetic Disorders: A 3 Year Comparative Study.
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Almontashiri NAM, Zha L, Young K, Law T, Kellogg MD, Bodamer OA, and Peake RWA
- Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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- 2020
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18. Clinical Validation of Targeted and Untargeted Metabolomics Testing for Genetic Disorders: A 3 Year Comparative Study.
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Almontashiri NAM, Zha L, Young K, Law T, Kellogg MD, Bodamer OA, and Peake RWA
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- Adolescent, Biomarkers metabolism, Child, Child, Preschool, Cohort Studies, Female, Genetic Testing, Humans, Male, Phenotype, Syndrome, Genetic Diseases, Inborn genetics, Metabolism, Inborn Errors genetics, Metabolomics methods
- Abstract
Global untargeted metabolomics (GUM) has entered clinical diagnostics for genetic disorders. We compared the clinical utility of GUM with traditional targeted metabolomics (TM) as a screening tool in patients with established genetic disorders and determined the scope of GUM as a discovery tool in patients with no diagnosis under investigation. We compared TM and GUM data in 226 patients. The first cohort (n = 87) included patients with confirmed inborn errors of metabolism (IEM) and genetic syndromes; the second cohort (n = 139) included patients without diagnosis who were undergoing evaluation for a genetic disorder. In patients with known disorders (n = 87), GUM performed with a sensitivity of 86% (95% CI: 78-91) compared with TM for the detection of 51 diagnostic metabolites. The diagnostic yield of GUM in patients under evaluation with no established diagnosis (n = 139) was 0.7%. GUM successfully detected the majority of diagnostic compounds associated with known IEMs. The diagnostic yield of both targeted and untargeted metabolomics studies is low when assessing patients with non-specific, neurological phenotypes. GUM shows promise as a validation tool for variants of unknown significance in candidate genes in patients with non-specific phenotypes.
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- 2020
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19. Consolidation of vitamin A and E methods onto a multiplexing liquid chromatography tandem mass spectrometry platform simplifies laboratory workflow.
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Zha L, Law T, MacDonald C, Kodgis I, Kellogg MD, and Peake RWA
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- 25-Hydroxyvitamin D 2 analysis, Anticonvulsants analysis, Busulfan analysis, Humans, Immunosuppressive Agents analysis, Laboratories organization & administration, Reference Standards, Reproducibility of Results, Workflow, Chromatography, High Pressure Liquid methods, Tandem Mass Spectrometry methods, Vitamin A blood, Vitamin E blood
- Abstract
Background: Vitamin A and E are routinely monitored to assess nutritional status. The most commonly used approach for their measurement involves laborious liquid-liquid extraction followed by high-performance liquid chromatography (HPLC) analysis on dedicated instrumentation. We describe a simple, rapid protocol for measurement of vitamin A and E and their integration into an existing online sample preparation liquid chromatography tandem mass spectrometry (SPLC-MS/MS) workflow., Methods: We performed a method comparison between the SPLC-MS/MS and HPLC methods for vitamin A and E by measuring patient specimens across the concentration range 11-81 µg/dL for vitamin A and 1-18 mg/L for vitamin E. The analysis times on each platform were also compared., Results: SPLC-MS/MS and HPLC methods were comparable with regards to analytical performance; mean bias across the measured range was 2.54% (95% CL: -11.56-16.64%) for vitamin A and -2.04% (95% CL: -18.20-14.12%) for vitamin E. Total analysis times were 7 min and 15 min for SPLC-MS/MS and HPLC respectively., Conclusions: The development of a simplified sample preparation protocol and the use of multiplexing SPLC-MS/MS have reduced sample analysis times for vitamin A and E. This method has also optimized clinical workflow through consolidation of previously independent benches., (Copyright © 2020 Elsevier B.V. All rights reserved.)
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- 2020
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20. Metabolic Acidosis and Hypoglycemia in a Child with Leigh-Like Phenotype.
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Alayed AM, Faqeih EA, Aldehaimi A, Peake RWA, and Almontashiri ANAM
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- Abnormalities, Multiple genetics, Acidosis genetics, Amino Acid Metabolism, Inborn Errors complications, Amino Acid Metabolism, Inborn Errors genetics, Female, Humans, Hypoglycemia genetics, Infant, Mutation, Phenotype, Thiolester Hydrolases genetics, Abnormalities, Multiple diagnosis, Acidosis etiology, Amino Acid Metabolism, Inborn Errors diagnosis, Hypoglycemia etiology, Thiolester Hydrolases deficiency
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- 2020
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21. Abnormal Glycerol Metabolism in a Child with Global Developmental Delay, Adrenal Insufficiency, and Intellectual Disability.
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Almontashiri NAM, Berry GT, Majzoub J, and Peake RWA
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- Adrenal Insufficiency metabolism, Child, Preschool, DAX-1 Orphan Nuclear Receptor genetics, Developmental Disabilities metabolism, Glycerol Kinase genetics, Glycerol Kinase metabolism, Humans, Infant, Newborn, Intellectual Disability metabolism, Male, Adrenal Insufficiency etiology, Developmental Disabilities etiology, Glycerol metabolism, Glycerol Kinase deficiency, Intellectual Disability etiology
- Published
- 2018
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22. Recurrent heteroplasmy for the MT-ATP6 p.Ser148Asn (m.8969G>A) mutation in patients with syndromic congenital sideroblastic anemia of variable clinical severity.
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Berhe S, Heeney MM, Campagna DR, Thompson JF, White EJ, Ross T, Peake RWA, Hanrahan JD, Rodriguez V, Renaud DL, Patnaik MS, Chang E, Bottomley SS, and Fleming MD
- Subjects
- Adolescent, Anemia, Sideroblastic metabolism, Anemia, Sideroblastic pathology, Child, DNA Mutational Analysis methods, Female, Genetic Association Studies, Genetic Diseases, X-Linked metabolism, Genetic Diseases, X-Linked pathology, Humans, Infant, Male, Mitochondrial Proton-Translocating ATPases metabolism, Point Mutation, Recurrence, Syndrome, Anemia, Sideroblastic genetics, DNA, Mitochondrial genetics, Genetic Diseases, X-Linked genetics, Mitochondrial Proton-Translocating ATPases genetics, Mutation, Missense
- Published
- 2018
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23. Arginine does not rescue p.Q188R mutation deleterious effect in classic galactosemia.
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Haskovic M, Derks B, van der Ploeg L, Trommelen J, Nyakayiru J, van Loon LJC, Mackinnon S, Yue WW, Peake RWA, Zha L, Demirbas D, Qi W, Huang X, Berry GT, Achten J, Bierau J, Rubio-Gozalbo ME, and Coelho AI
- Subjects
- Aspartic Acid therapeutic use, Cells, Cultured, Fibroblasts drug effects, Fibroblasts metabolism, Galactose metabolism, Humans, Metabolism, Inborn Errors drug therapy, Metabolism, Inborn Errors genetics, Retrospective Studies, Arginine therapeutic use, Galactosemias drug therapy, Galactosemias genetics, Mutation genetics
- Abstract
Background: Classic galactosemia is a rare genetic metabolic disease with an unmet treatment need. Current standard of care fails to prevent chronically-debilitating brain and gonadal complications. Many mutations in the GALT gene responsible for classic galactosemia have been described to give rise to variants with conformational abnormalities. This pathogenic mechanism is highly amenable to a therapeutic strategy based on chemical/pharmacological chaperones. Arginine, a chemical chaperone, has shown beneficial effect in other inherited metabolic disorders, as well as in a prokaryotic model of classic galactosemia. The p.Q188R mutation presents a high prevalence in the Caucasian population, making it a very clinically relevant mutation. This mutation gives rise to a protein with lower conformational stability and lower catalytic activity. The aim of this study is to assess the potential therapeutic role of arginine for this mutation., Methods: Arginine aspartate administration to four patients with the p.Q188R/p.Q188R mutation, in vitro studies with three fibroblast cell lines derived from classic galactosemia patients as well as recombinant protein experiments were used to evaluate the effect of arginine in galactose metabolism. This study has been registered at https://clinicaltrials.gov (NCT03580122) on 09 July 2018. Retrospectively registered., Results: Following a month of arginine administration, patients did not show a significant improvement of whole-body galactose oxidative capacity (p = 0.22), erythrocyte GALT activity (p = 0.87), urinary galactose (p = 0.52) and urinary galactitol levels (p = 0.41). Patients' fibroblasts exposed to arginine did not show changes in GALT activity. Thermal shift analysis of recombinant p.Q188R GALT protein in the presence of arginine did not exhibit a positive effect., Conclusions: This short pilot study in four patients homozygous for the p.Q188R/p.Q188R mutation reveals that arginine has no potential therapeutic role for galactosemia patients homozygous for the p.Q188R mutation.
- Published
- 2018
- Full Text
- View/download PDF
24. Hyperammonemia in a Child Presenting with Growth Delay, Short Stature, and Diarrhea.
- Author
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Almontashiri NAM, Demirbas D, Berry GT, and Peake RWA
- Subjects
- Child, Preschool, Humans, Male, Diarrhea complications, Growth Disorders complications, Hyperammonemia complications, Hyperammonemia diagnosis
- Published
- 2018
- Full Text
- View/download PDF
25. Serine Deficiency in a Child with Neurological Presentation, Hearing Loss, and Multiple Congenital Anomalies.
- Author
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Almontashiri NAM, Rodan LH, and Peake RWA
- Subjects
- Child, Preschool, Humans, Male, Congenital Abnormalities metabolism, Hearing Loss metabolism, Serine deficiency
- Published
- 2018
- Full Text
- View/download PDF
26. Beta-Ketothiolase Deficiency Presenting with Metabolic Stroke After a Normal Newborn Screen in Two Individuals.
- Author
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Wojcik MH, Wierenga KJ, Rodan LH, Sahai I, Ferdinandusse S, Genetti CA, Towne MC, Peake RWA, James PM, Beggs AH, Brownstein CA, Berry GT, and Agrawal PB
- Abstract
Beta-ketothiolase (mitochondrial acetoacetyl-CoA thiolase) deficiency is a genetic disorder characterized by impaired isoleucine catabolism and ketone body utilization that predisposes to episodic ketoacidosis. It results from biallelic pathogenic variants in the ACAT1 gene, encoding mitochondrial beta-ketothiolase. We report two cases of beta-ketothiolase deficiency presenting with acute ketoacidosis and "metabolic stroke." The first patient presented at 28 months of age with metabolic acidosis and pallidal stroke in the setting of a febrile gastrointestinal illness. Although 2-methyl-3-hydroxybutyric acid and trace quantities of tiglylglycine were present in urine, a diagnosis of glutaric acidemia type I was initially suspected due to the presence of glutaric and 3-hydroxyglutaric acids. A diagnosis of beta-ketothiolase deficiency was ultimately made through whole exome sequencing which revealed compound heterozygous variants in ACAT1. Fibroblast studies for beta-ketothiolase enzyme activity were confirmatory. The second patient presented at 6 months of age with ketoacidosis, and was found to have elevations of urinary 2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid, and tiglylglycine. Sequencing of ACAT1 demonstrated compound heterozygous presumed causative variants. The patient exhibited choreoathethosis 2 months after the acute metabolic decompensation. These cases highlight that, similar to a number of other organic acidemias and mitochondrial disorders, beta-ketothiolase deficiency can present with metabolic stroke. They also illustrate the variability in clinical presentation, imaging, and biochemical evaluation that make screening for and diagnosis of this rare disorder challenging, and further demonstrate the value of whole exome sequencing in the diagnosis of metabolic disorders.
- Published
- 2018
- Full Text
- View/download PDF
27. Ethylmalonic Aciduria in an Infant with Neurological and Skin Presentation.
- Author
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Peake RWA and Rodan LH
- Subjects
- Brain Diseases, Metabolic, Inborn genetics, Child, Preschool, Female, Humans, Mitochondrial Proteins genetics, Nucleocytoplasmic Transport Proteins genetics, Purpura genetics, Brain Diseases, Metabolic, Inborn diagnosis, Malonates urine, Purpura diagnosis
- Published
- 2017
- Full Text
- View/download PDF
28. A Case of Severe Neonatal Hyperammonemia.
- Author
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Peake RWA and Neilan EG
- Subjects
- Humans, Infant, Male, Ornithine Carbamoyltransferase Deficiency Disease blood, Hyperammonemia blood, Ornithine Carbamoyltransferase Deficiency Disease diagnosis
- Published
- 2017
- Full Text
- View/download PDF
29. Towards a random-access LC-MS/MS model for busulfan analysis.
- Author
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Peake RWA, Law T, Esposito CL, and Kellogg MD
- Subjects
- Gas Chromatography-Mass Spectrometry, Humans, Vitamin D blood, Busulfan blood, Chromatography, High Pressure Liquid, Tandem Mass Spectrometry
- Published
- 2017
- Full Text
- View/download PDF
30. Raised Anion Gap Metabolic Acidosis in a 4-Day-Old Child.
- Author
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Peake RWA and Rodan LH
- Subjects
- Acid-Base Equilibrium, Gas Chromatography-Mass Spectrometry, Humans, Infant, Newborn, Male, Acidosis metabolism, Acidosis urine, Anions metabolism, Anions urine
- Published
- 2017
- Full Text
- View/download PDF
31. Hyperammonemia as a Presenting Feature in Two Siblings with FBXL4 Variants.
- Author
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Morton SU, Neilan EG, Peake RWA, Shi J, Schmitz-Abe K, Towne M, Markianos K, Prabhu SP, and Agrawal PB
- Abstract
Early-onset mitochondrial encephalomyopathy is a rare disorder that presents in the neonatal period with lactic acidosis, hypotonia, and developmental delay. Sequence variants in the nuclear-encoded gene FBXL4 have been previously demonstrated to be a cause of early-onset mitochondrial encephalomyopathy in several unrelated families. We have identified a pair of siblings with mutations in FBXL4 who each presented in the neonatal period with hyperammonemia, low plasma levels of aspartate, low urine levels of tricarboxylic acid cycle intermediates suggesting a defect in anaplerosis, and cerebellar hypoplasia in addition to lactic acidosis and other classic signs of mitochondrial encephalomyopathy. After initial clinical stabilization, both subjects continued to have episodic exacerbations characterized by lactic acidosis and hyperammonemia. Previously reported cases of FBXL4 mutations are reviewed and compared with these affected siblings. These two new cases add to the spectrum of disease caused by mutations in FBLX4 and suggest possible benefit from anaplerotic therapies.
- Published
- 2017
- Full Text
- View/download PDF
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