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Background: Pyruvate dehydrogenase complex deficiency (PDCD) is a mitochondrial neurometabolic disorder of energy deficit, with incidence of about 1 in 42,000 live births annually in the USA. The median and mean ages of diagnosis of PDCD are about 12 and 31 months, respectively. PDCD is a major cause of primary lactic acidosis with concomitant elevation in blood alanine (Ala) and proline (Pro) concentrations depending on phenotypic severity. Alanine/Leucine (Ala/Leu) ≥4.0 and Proline/Leucine (Pro/Leu) ≥3.0 combination cutoff from dried blood spot specimens was used as a biomarker for early identification of neonates/infants with PDCD. Further investigations were needed to evaluate the sensitivity (SN), specificity (SP), and clinical utility of such amino acid (AA) ratio combination cutoffs in discriminating PDCD from other inborn errors of metabolism (IEM) for early identification of such patients. Methods: We reviewed medical records of patients seen at UPMC in the past 11 years with molecularly or enzymatically confirmed diagnosis. We collected plasma AA analysis data from samples prior to initiation of therapeutic interventions such as total parenteral nutrition and/or ketogenic diet. Conditions evaluated included organic acidemias, primary mitochondrial disorders (MtDs), fatty acid oxidation disorders (FAOD), other IEMs on current newborn screening panels, congenital cardiac great vessel anomalies, renal tubular acidosis, and non‐IEMs. The utility of specific AA ratio combinations as biomarkers were evaluated using receiver operating characteristic curves, correlation analysis, principal component analysis, and cutoff SN, SP, and positive predictive value determined from 201 subjects with broad age range. Results: Alanine/Lysine (Ala/Lys) and Ala/Leu as well as (Ala + Pro)/(Leu + Lys) and Ala/Leu ratio combinations effectively discriminated subjects with PDCD from those with other MtDs and IEMs on current newborn screening panels. Specific AA ratio combinations were significantly more sensitive in identifying PDCD than Ala alone or combinations of Ala and/or Pro in the evaluated cohort of subjects. Ala/Lys ≥3.0 and Ala/Leu ≥5.0 as well as (Ala + Pro)/(Leu + Lys) ≥2.5 and Ala/Leu ≥5.0 combination cutoffs identified patients with PDCD with 100% SN and ~85% SP. Conclusions: With the best predictor of survival and positive cognitive outcome in PDCD being age of diagnosis, PDCD patients would benefit from use of such highly SN and SP AA ratio combination cutoffs as biomarkers for early identification of at‐risk newborns, infants, and children, for early intervention(s) with known and/or novel therapeutics for this disorder. [ABSTRACT FROM AUTHOR]

Multilocus imprinting disturbances (MLID) have been associated with up to 12% of patients with Beckwith‐Wiedemann syndrome, Silver‐Russell syndrome, and pseudohypoparathyroidism type 1B (PHP1B). Single‐gene defects affecting components of the subcortical maternal complex (SCMC) have been reported in cases with multilocus hypomethylation defects. We present a patient with speech and language impairment with mild Angelman syndrome (AS) features who demonstrates maternal hypomethylation at 15q11.2 (SNRPN) as well as 11p15.5 (KCNQ1OT1) imprinted loci, but normal methylation at 6q24.2 (PLAGL1), 7p12.1 (GRB10), 7q32.2 (MEST), 11p15.5 (H19), 14q32.2 (MEG3), 19q13.43 (PEG3), and 20q13.32 (GNAS and GNAS‐AS1). The proband also has no copy number nor sequence variants within the AS imprinting center or in UBE3A. Maternal targeted next generation sequencing did not identify any pathogenic variants in ZPF57, NLRP2, NLRP5, NLRP7, KHDC3L, PADI6, TLE6, OOEP, UHRF1 or ZAR1. The presence of very delayed, yet functional speech, behavioral difficulties, EEG abnormalities but without clinical seizures, and normocephaly are consistent with the 15q11.2 hypomethylation defect observed in this patient. To our knowledge, this is the first report of MLID in a patient with mild, likely mosaic, Angelman syndrome. [ABSTRACT FROM AUTHOR]

Pyruvate dehydrogenase complex deficiency is a major cause of primary lactic acidemia resulting in high morbidity and mortality, with limited therapeutic options. PDHA1 mutations are responsible for >82% of cases. The E1 component of PDC is a symmetric dimer of heterodimers (αβ/α′β′) encoded by PDHA1 and PDHB. We measured solvent accessibility surface area (SASA), utilized nearest‐neighbor analysis, incorporated sequence changes using mutagenesis tool in PyMOL, and performed molecular modeling with SWISS‐MODEL, to investigate the impact of residues with disease‐causing missense variants (DMVs) on E1 structure and function. We reviewed 166 and 13 genetically resolved cases due to PDHA1 and PDHB, respectively, from variant databases. We expanded on 102 E1α and 13 E1β nonduplicate DMVs. DMVs of E1α Arg112‐Arg224 stretch (exons 5‐7) and of E1α Arg residues constituted 40% and 39% of cases, respectively, with invariant Arg349 accounting for 22% of arginine replacements. SASA analysis showed that 86% and 84% of residues with nonduplicate DMVs of E1α and E1β, respectively, are solvent inaccessible ("buried"). Furthermore, 30% of E1α buried residues with DMVs are deleterious through perturbation of subunit‐subunit interface contact (SSIC), with 73% located in the Arg112‐Arg224 stretch. E1α Arg349 represented 74% of buried E1α Arg residues involved in SSIC. Structural perturbations resulting from residue replacements in some matched neighboring pairs of amino acids on different subunits involved in SSIC at 2.9‐4.0 Å interatomic distance apart, exhibit similar clinical phenotype. Collectively, this work provides insight for future target‐based advanced molecular modeling studies, with implications for development of novel therapeutics for specific recurrent DMVs of E1α. [ABSTRACT FROM AUTHOR]

D,L‐3‐hydroxybutyrate (D,L‐3‐HB, a ketone body) treatment has been described in several inborn errors of metabolism, including multiple acyl‐CoA dehydrogenase deficiency (MADD; glutaric aciduria type II). We aimed to improve the understanding of enantiomer‐specific pharmacokinetics of D,L‐3‐HB. Using UPLC‐MS/MS, we analyzed D‐3‐HB and L‐3‐HB concentrations in blood samples from three MADD patients, and blood and tissue samples from healthy rats, upon D,L‐3‐HB salt administration (patients: 736‐1123 mg/kg/day; rats: 1579‐6317 mg/kg/day of salt‐free D,L‐3‐HB). D,L‐3‐HB administration caused substantially higher L‐3‐HB concentrations than D‐3‐HB. In MADD patients, both enantiomers peaked at 30 to 60 minutes, and approached baseline after 3 hours. In rats, D,L‐3‐HB administration significantly increased Cmax and AUC of D‐3‐HB in a dose‐dependent manner (controls vs ascending dose groups for Cmax: 0.10 vs 0.30‐0.35‐0.50 mmol/L, and AUC: 14 vs 58‐71‐106 minutes*mmol/L), whereas for L‐3‐HB the increases were significant compared to controls, but not dose proportional (Cmax: 0.01 vs 1.88‐1.92‐1.98 mmol/L, and AUC: 1 vs 380‐454‐479 minutes*mmol/L). L‐3‐HB concentrations increased extensively in brain, heart, liver, and muscle, whereas the most profound rise in D‐3‐HB was observed in heart and liver. Our study provides important knowledge on the absorption and distribution upon oral D,L‐3‐HB. The enantiomer‐specific pharmacokinetics implies differential metabolic fates of D‐3‐HB and L‐3‐HB. [ABSTRACT FROM AUTHOR]

Objective: Individuals with urea cycle disorders (UCDs) often present with intellectual and developmental disabilities. The major aim of this study was to evaluate the impact of diagnostic and therapeutic interventions on cognitive outcomes in UCDs.Methods: This prospective, observational, multicenter study includes data from 503 individuals with UCDs who had comprehensive neurocognitive testing with a cumulative follow-up of 702 patient-years.Results: The mean cognitive standard deviation score (cSDS) was lower in symptomatic than in asymptomatic (p < 0.001, t test) individuals with UCDs. Intellectual disability (intellectual quotient < 70, cSDS < -2.0) was associated with the respective subtype of UCD and early disease onset, whereas height of the initial peak plasma ammonium concentration was inversely associated with neurocognitive outcomes in mitochondrial (proximal) rather than cytosolic (distal) UCDs. In ornithine transcarbamylase and argininosuccinate synthetase 1 deficiencies, we did not find evidence that monoscavenger therapy with sodium or glycerol phenylbutyrate was superior to sodium benzoate in providing cognitive protection. Early liver transplantation appears to be beneficial for UCDs. It is noteworthy that individuals with argininosuccinate synthetase 1 and argininosuccinate lyase deficiencies identified by newborn screening had better neurocognitive outcomes than those diagnosed after the manifestation of first symptoms.Interpretation: Cognitive function is related to interventional and non-interventional variables. Early detection by newborn screening and early liver transplantation appear to offer greater cognitive protection, but none of the currently used nitrogen scavengers was superior with regard to long-term neurocognitive outcome. Further confirmation could determine these variables as important clinical indicators of neuroprotection for individuals with UCDs. ANN NEUROL 2019. [ABSTRACT FROM AUTHOR]

The S and LG alleles of the serotonin transporter-linked polymorphic region (5-HTTLPR) lower serotonin transporter expression. These low-expressing alleles are linked to increased risk for depression and brain activation patterns found in depression (increased amygdala activation and decreased amygdala-prefrontal cortex connectivity). Paradoxically, serotonin transporter blockade relieves depression symptoms. Rodent models suggest that decreased serotonin transporter in early life produces depression that emerges in adolescence, whereas decreased serotonin transporter that occurs later in development ameliorates depression. However, no brain imaging research has yet investigated the moderating influence of human development on the link between 5-HTTLPR and effect-related brain function. We investigated the age-related effect of 5-HTTLPR on amygdala activation and amygdala-prefrontal cortex connectivity using a well-replicated probe, an emotional face task, in children and adolescents aged 9-19 years. A significant genotype-by-age interaction predicted amygdala activation, such that the low-expressing genotype (S/S and S/LG) group showed a greater increase in amygdala activation with age compared to the higher expressing (LA/LA and S/LA) group. Additionally, compared to the higher expressing group, the low-expressing genotype group exhibited decreased connectivity between the right amygdala and ventromedial prefrontal cortex with age. Findings indicate that low-expressing genotypes may not result in the corticolimbic profile associated with depression risk until later adolescence. Hum Brain Mapp 35:646-658, 2014. © 2012 Wiley-Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Genomic rearrangements are increasingly recognized as important contributors to human disease. Here we report on an 11½-year-old child with myopia, Duane retraction syndrome, bilateral mixed hearing loss, skeletal anomalies including multiple epiphyseal dysplasia, and global developmental delay, and a complex 6p25 genomic rearrangement. We have employed oligonucleotide-based comparative genomic hybridization arrays (aCGH) of different resolutions (44 and 244K) as well as a 1 M single nucleotide polymorphism (SNP) array to analyze this complex rearrangement. Our analyses reveal a complex rearrangement involving a ∼2.21 Mb interstitial deletion, a ∼240 kb terminal deletion, and a 70-80 kb region in between these two deletions that shows maintenance of genomic copy number. The interstitial deletion contains eight known genes, including three Forkhead box containing (FOX) transcription factors ( FOXQ1, FOXF2, and FOXC1). The region maintaining genomic copy number partly overlaps the dual specificity protein phosphatase 22 ( DUSP22) gene. Array analyses suggest a homozygous loss of genomic material at the 5′ end of DUSP22, which was corroborated using TaqMan® copy number analysis. It is possible that this homozygous genomic loss may render both copies of DUSP22 or its products non-functional. Our analysis suggests a rearrangement mechanism distinct from a previously reported replication-based error-prone mechanism without template switching for a specific 6p25 rearrangement with a 1.22 Mb interstitial deletion. Our study demonstrates the utility and limitations of using oligonucleotide-based aCGH and SNP array technologies of increasing resolutions in order to identify complex DNA rearrangements and gene disruptions. © 2010 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Background The aim of this report was to present a rare case of an adolescent with multinodular goiter (MNG) found to have a DICER1 mutation. Methods and Results The methodology includes a presentation and discussion of a chart review including endocrine hormone tests, thyroid ultrasound, and genetic testing for DICER1. A 12-year-old girl presented with a diffusely enlarged thyroid gland. Family history revealed an older sister with a history of bilateral ovarian Sertoli-Leydig cell tumors and MNG. Thyroid function tests were normal. Serial thyroid ultrasounds showed enlarging multiple bilateral nodules. Fine-needle aspiration suggested MNG. Genetic testing revealed a novel heterozygous premature termination mutation (c.1525C>T p.R509X) in the DICER1 gene. Conclusions Thyroid nodules are rare in children but carry a higher risk for malignancy. It is essential to inquire about family history and refer for genetic evaluation with a family history of MNG. In patients with DICER1 mutations, tumor surveillance is critical due to the increased risk of multiple tumors, including ovarian tumors and pleuropulmonary blastoma. © 2013 Wiley Periodicals, Inc. Head Neck 35: E369-E371, 2013 [ABSTRACT FROM AUTHOR]

Submicroscopic recurrent 16p11.2 rearrangements are associated with several neurodevelopmental disorders, including autism, mental retardation, and schizophrenia. The common 16p11.2 region includes 24 known genes, of which 22 are expressed in the developing human fetal nervous system. As yet, the mechanisms leading to neurodevelopmental abnormalities and the broader phenotypes associated with deletion or duplication of 16p11.2 have not been clarified. Here we report a child with spastic quadriparesis, refractory infantile seizures, severe global developmental delay, hypotonia, and microcephaly, and a de novo 598 kb 16p11.2 microduplication. Family history is negative for any of these features in parents and immediate family members. Sequencing analyses showed no mutations in DOC2A, QPRT, and SEZ6L2, genes within the duplicated 16p11.2 region that have been implicated in neuronal function and/or seizure related phenotypes. The child's clinical course is consistent with a rare seizure disorder called malignant migrating partial seizure disorder of infancy, raising the possibility that duplication or disruption of genes in the 16p11.2 interval may contribute to this severe disorder., ((c) 2010 Wiley-Liss, Inc.)

We report on a 26-month-old boy with developmental delay and multiple congenital anomalies, including many features suggestive of either branchiootorenal syndrome (BOR) or oculoauriculovertebral spectrum (OAVS). Chromosomal microarray analysis (CMA) initially revealed a copy-number gain with a single BAC clone (RP11-79M1) mapping to 14q23.1. FISH analysis showed that the third copy of this genomic region was inserted into the long arm of one chromosome 13. The same pattern was also seen in the chromosomes of the father, who has mental retardation, short stature, hypernasal speech, and minor craniofacial anomalies, including tall forehead, and crowded dentition. Subsequent whole genome oligonucleotide microarray analysis revealed an approximately 11.79 Mb duplication of chromosome 14q22.3-q23.3 and a loss of an approximately 4.38 Mb sequence in 13q21.31-q21.32 in both the propositus and his father and FISH supported the apparent association of the two events. Chromosome 14q22.3-q23.3 contains 51 genes, including SIX1, SIX6, and OTX2. A locus for branchiootic syndrome (BOS) has been mapped to 14q21.3-q24.3, and designated as branchiootic syndrome 3 (BOS3). Interestingly, mutations in SIX1 have been reported in patients with BOR/BOS3. We propose that the increased dosage of SIX1, SIX6, or OTX2 may be responsible for the BOR and OAVS-like features in this family., (Copyright 2008 Wiley-Liss, Inc.)

Ring chromosomes are thought to be the result of breakage in both arms of a chromosome, with fusion of the points of fracture and loss of the distal fragments. Another mechanism of ring formation is believed to be the simple fusion of chromosome ends with preservation of telomeric and subtelomeric sequences. Ring chromosome 13 was first described in 1968 and its incidence estimated at 1 in 58,000 live births. Severe phenotypes associated with large deletions of 13q have been described as "ring chromosome 13 syndrome." Features of the "ring chromosome 13 syndrome" include mental retardation (often severe), growth retardation, microcephaly, facial dysmorphism, and hand, foot or toe abnormalities. We report on a case of a mother and daughter with r(13) and mild phenotypes. Our patient, IA, had chromosome analysis performed at about 4(1/2) years of age due to some developmental delay. This revealed 46,XX, r(13)(p13q34) karyotype with no loss of any chromosomal band. Her mother, EA, was subsequently found to have the same ring 13. IA's maternal grandmother had a normal karyotype while her maternal grandfather was unavailable for testing. Fluorescence in situ hybridization (FISH) analysis showed loss of a specific subtelomeric 13q region in r(13) in the mother. Clinically, IA had macular hyperpigmentation on the chin and mild delay in speech and fine motor skills. EA, 22 years of age, had mild short stature and borderline mental retardation. To our knowledge, this is the first report of a case of familial transmission of r(13). We compare phenotypes of our cases with those from other reported cases of r(13) and discuss the possible mechanism of formation of this ring chromosome.