Publications by authors named "Elsea S"

157 Publications

Improved clinical outcome following liver transplant in patients with ethylmalonic encephalopathy.

Am J Med Genet A 2019 06 12;179(6):1015-1019. Epub 2019 Mar 12.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.

Ethylmalonic encephalopathy (EE) is a rapidly progressive autosomal recessive mitochondrial disease caused by biallelic pathogenic variants in the ETHE1 gene that encodes the mitochondrial sulfur dioxygenase. It is characterized by neurodevelopmental delay and regression, pyramidal and extrapyramidal signs, recurrent petechiae, chronic diarrhea, and orthostatic acrocyanosis. Laboratory findings include elevated serum levels of lactate and C4-C5 acylcarnitines, and elevated urinary excretion of ethylmalonic acid and C4-C6 acylglycines, notably isobutyrylglycine and 2-methylbutyrylglycine. These findings are attributed to deficiency of the mitochondrial sulfur dioxygenase resulting in toxic accumulation of hydrogen sulfide metabolites in vascular endothelium and mucosal cells of the large intestine. Medical management has thus far been directed toward decreasing the accumulation of hydrogen sulfide metabolites using a combination of metronidazole and N-acetylcysteine. More recently, orthotopic liver transplant (OLT) has been reported as a new therapeutic option for EE. Here, we report two additional cases of EE who achieved psychomotor developmental improvement after 7- and 22-months following OLT. The second case serves as the longest developmental outcome follow-up reported, thus far, following OLT for EE. This report provides additional evidence to validate OLT as a promising therapeutic approach for what was considered to be a fatal disease.
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http://dx.doi.org/10.1002/ajmg.a.61104DOI Listing
June 2019

De novo missense variant in the GTPase effector domain (GED) of leads to static encephalopathy and seizures.

Cold Spring Harb Mol Case Stud 2019 06 3;5(3). Epub 2019 Jun 3.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.

encodes a GTPase of the dynamin superfamily, which plays a crucial role in mitochondrial and peroxisomal fission. Pathogenic variants affecting the middle domain and the GTPase domain of have been implicated in encephalopathy because of defective mitochondrial and peroxisomal fission 1 (EMPF1, MIM #614388). Patients show variable phenotypes ranging from severe hypotonia leading to death in the neonatal period to developmental delay/regression, with or without seizures. Familial pathogenic variants in the GTPase domain have also been associated with isolated optic atrophy. We present a 27-yr-old woman with static encephalopathy, a history of seizures, and nystagmus, in whom a novel de novo heterozygous variant was detected in the GTPase effector domain (GED) of (c.2072A>G, p.Tyr691Cys). Functional studies in demonstrate large, abnormally distributed peroxisomes and mitochondria, an effect very similar to that of middle domain missense alleles observed in pediatric subjects with EMPF1. To our knowledge, not only is this the first report of a disease-causing variant in the GED domain in humans, but this is also the oldest living individual reported with EMPF1. Longitudinal data of this kind helps to expand our knowledge of the natural history of a growing list of -related disorders.
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http://dx.doi.org/10.1101/mcs.a003673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549558PMC
June 2019

Case report and novel treatment of an autosomal recessive Leigh syndrome caused by short-chain enoyl-CoA hydratase deficiency.

Am J Med Genet A 2019 05 7;179(5):803-807. Epub 2019 Mar 7.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.

Short chain enoyl-CoA hydratase (SCEH) deficiency leads to a severe form of autosomal recessive Leigh syndrome with inevitable neurological decline and early mortality. SCEH is most notably involved in valine catabolism, a deficiency of which results in various metabolic alterations, including increased levels of the highly reactive metabolite 2-methacrylyl-CoA. With no proven treatments available to date, it has been speculated that patients may respond to a valine restricted diet and/or N-acetylcysteine supplementation, as suggested by early studies of a very similar inborn error of metabolism, 3-hydroxyisobutyryl-CoA hydrolase deficiency. We describe a patient with typical Leigh syndrome clinical findings and identified compound heterozygous variants in ECSH1. Valine-restricted diet was initiated at 6 months of age and N-acetylcysteine supplementation at 9 months with subsequent improvement in growth and slow progress in developmental milestones. However, at 15 months, the patient aspirated during a breakthrough seizure from which he did not recover and died soon after from related complications. This report highlights some of the challenges that remain in the management and treatment of SCEH deficiency, while demonstrating that a valine restricted diet and N-acetylcysteine can be safely administered with the potential for clinical improvement.
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http://dx.doi.org/10.1002/ajmg.a.61074DOI Listing
May 2019

Genotype and phenotype correlation in 103 individuals with 2q37 deletion syndrome reveals incomplete penetrance and supports HDAC4 as the primary genetic contributor.

Am J Med Genet A 2019 05 7;179(5):782-791. Epub 2019 Mar 7.

Department of Pediatrics, Virginia Commonwealth University School of Medicine, Richmond, Virginia.

The 2q37 deletion syndrome, also described in the literature as brachydactyly-mental retardation syndrome (MIM 600430), is caused by deletion or haploinsufficiency of the HDAC4 gene, which encodes the histone deacetylase 4 protein. Although the most commonly described hallmark features of the 2q37 deletion syndrome include brachydactyly type E, developmental delay, obesity, autistic features, and craniofacial or skeletal dysmorphism, a literature review of 101 published cases plus two newly reported individuals indicates that there is a high degree of variability in the presence of some of the features that are considered the most characteristic of the syndrome: overweight and obesity (34%), cognitive-behavioral issues (79%), dysmorphic craniofacial features (86%), and type E brachydactyly (48%). These features overlap with other neurodevelopmental conditions, including Smith-Magenis syndrome (SMS), and may be incompletely penetrant or demonstrate variable expressivity, depending on the specific chromosomal anomaly. With the advent of fluorescence in situ hybridization (FISH), array-based comparative genomic hybridization, and next-generation DNA sequencing, more detailed molecular diagnoses are possible than in years past, enabling refined characterization of the genotype-phenotype correlation for subjects with 2q37 deletions. In addition, investigations into molecular and gene expression networks are expanding in neurodevelopmental conditions, and we surveyed HDAC4 downstream gene expression by quantitative real-time polymerase chain reaction, further implicating HDAC4 in its role in the regulation of RAI1. Correlation of clinical data defining the impact on downstream gene expression and the potential clinical associations across neurodevelopment will improve our understanding of these complex conditions and potentially lead to common therapeutic approaches.
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http://dx.doi.org/10.1002/ajmg.a.61089DOI Listing
May 2019

De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith-Magenis syndrome.

Genome Med 2019 02 28;11(1):12. Epub 2019 Feb 28.

Centre de Génétique Humaine, Université de Franche-Comté, Besançon, France.

Background: Neurodevelopmental disorders are genetically and phenotypically heterogeneous encompassing developmental delay (DD), intellectual disability (ID), autism spectrum disorders (ASDs), structural brain abnormalities, and neurological manifestations with variants in a large number of genes (hundreds) associated. To date, a few de novo mutations potentially disrupting TCF20 function in patients with ID, ASD, and hypotonia have been reported. TCF20 encodes a transcriptional co-regulator structurally related to RAI1, the dosage-sensitive gene responsible for Smith-Magenis syndrome (deletion/haploinsufficiency) and Potocki-Lupski syndrome (duplication/triplosensitivity).

Methods: Genome-wide analyses by exome sequencing (ES) and chromosomal microarray analysis (CMA) identified individuals with heterozygous, likely damaging, loss-of-function alleles in TCF20. We implemented further molecular and clinical analyses to determine the inheritance of the pathogenic variant alleles and studied the spectrum of phenotypes.

Results: We report 25 unique inactivating single nucleotide variants/indels (1 missense, 1 canonical splice-site variant, 18 frameshift, and 5 nonsense) and 4 deletions of TCF20. The pathogenic variants were detected in 32 patients and 4 affected parents from 31 unrelated families. Among cases with available parental samples, the variants were de novo in 20 instances and inherited from 4 symptomatic parents in 5, including in one set of monozygotic twins. Two pathogenic loss-of-function variants were recurrent in unrelated families. Patients presented with a phenotype characterized by developmental delay, intellectual disability, hypotonia, variable dysmorphic features, movement disorders, and sleep disturbances.

Conclusions: TCF20 pathogenic variants are associated with a novel syndrome manifesting clinical characteristics similar to those observed in Smith-Magenis syndrome. Together with previously described cases, the clinical entity of TCF20-associated neurodevelopmental disorders (TAND) emerges from a genotype-driven perspective.
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http://dx.doi.org/10.1186/s13073-019-0623-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393995PMC
February 2019

Opening a window on lysosomal acid lipase deficiency: Biochemical, molecular, and epidemiological insights.

J Inherit Metab Dis 2019 05 5;42(3):509-518. Epub 2019 Mar 5.

Department of Translational Medical Sciences, Section of Pediatrics, Federico II University, Naples, Italy.

Lysosomal acid lipase deficiency (LAL-D) is a multi-organ autosomal recessive disease caused by mutations in LIPA. We reviewed data from 681 samples (white blood cells [WBC] n = 625, fibroblasts = 30, liver = 4, amniocytes = 13, chorionic villus = 9) received for analysis of lysosomal acid lipase (LAL) activity over a 15-year period. LIPA sequencing was performed in 49 patients with reduced (n = 26) or deficient (n = 23) LAL activity. The Exome Aggregation Consortium and Genome Aggregation Database dataset were used for LAL-D prevalence calculations. LAL WBC activity was reduced in 67 patients (10.72%) and deficient in 37 (5.92%). The average of LAL activity ± margin of error (CI 95%) was 19.32 ± 0.86 pmol/min/mg for reduced activity patients and 5.90 ± 1.42 pmol/min/mg for deficient patients. The average age at diagnosis for LAL-D was 23.6 years with several patients older than age 30. The correlation between the age at diagnosis and LAL activity showed a significant moderate direct correlation (Pearson's r = 0.46, P < 0.005). Homozygous or compound heterozygous mutations were identified in 9 out of 23 patients with deficient results (detection rate 39.1%). The average LAL activity in molecularly confirmed patients was 4.02 ± 2.02 pmol/min/mg protein, while in molecularly negative patients was 13.886 ± 1.49 pmol/min/mg (P < 0.0001). Twenty-two different mutations were identified including two novel variants (c.309C>A and c.856G>C). A carrier frequency of approximately 1 in 350 was inferred. LAL activity in WBC is a validated tool for LAL-D diagnosis. Higher residual enzymatic activity might result in a milder phenotype leading to diagnosis delay. A cut-off below 12 pmol/min/mg protein might be useful to discriminate patients with LIPA mutations.
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http://dx.doi.org/10.1002/jimd.12057DOI Listing
May 2019

Diagnosis and management in Pitt-Hopkins syndrome: First international consensus statement.

Clin Genet 2019 04 18;95(4):462-478. Epub 2019 Feb 18.

Behavioral Science Institute, Radboud University Nijmegen, Nijmegen, The Netherlands.

Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder characterized by intellectual disability, specific facial features, and marked autonomic nervous system dysfunction, especially with disturbances of regulating respiration and intestinal mobility. It is caused by variants in the transcription factor TCF4. Heterogeneity in the clinical and molecular diagnostic criteria and care practices has prompted a group of international experts to establish guidelines for diagnostics and care. For issues, for which there was limited information available in international literature, we collaborated with national support groups and the participants of a syndrome specific international conference to obtain further information. Here, we discuss the resultant consensus, including the clinical definition of PTHS and a molecular diagnostic pathway. Recommendations for managing particular health problems such as dysregulated respiration are provided. We emphasize the need for integration of care for physical and behavioral issues. The recommendations as presented here will need to be evaluated for improvements to allow for continued optimization of diagnostics and care.
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http://dx.doi.org/10.1111/cge.13506DOI Listing
April 2019

Untargeted metabolomic profiling reveals multiple pathway perturbations and new clinical biomarkers in urea cycle disorders.

Genet Med 2019 09 23;21(9):1977-1986. Epub 2019 Jan 23.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Purpose: Untargeted metabolomic analysis is increasingly being used in the screening and management of individuals with inborn errors of metabolism (IEM). We aimed to test whether untargeted metabolomic analysis in plasma might be useful for monitoring the disease course and management of urea cycle disorders (UCDs).

Methods: Untargeted mass spectrometry-based metabolomic analysis was used to generate z-scores for more than 900 metabolites in plasma from 48 individuals with various UCDs. Pathway analysis was used to identify common pathways that were perturbed in each UCD.

Results: Our metabolomic analysis in plasma identified multiple potentially neurotoxic metabolites of arginine in arginase deficiency and, thus, may have utility in monitoring the efficacy of treatment in arginase deficiency. In addition, we were also able to detect multiple biochemical perturbations in all UCDs that likely reflect clinical management, including metabolite alterations secondary to dietary and medication management.

Conclusion: In addition to utility in screening for IEM, our results suggest that untargeted metabolomic analysis in plasma may be beneficial for monitoring efficacy of clinical management and off-target effects of medications in UCDs and potentially other IEM.
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http://dx.doi.org/10.1038/s41436-019-0442-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6650380PMC
September 2019

Untargeted metabolomics identifies unique though benign biochemical changes in patients with pathogenic variants in .

Mol Genet Metab Rep 2019 Mar 29;18:14-18. Epub 2018 Dec 29.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Urocanic aciduria is caused by a deficiency in the enzyme urocanase (E.C. 4.2.1.49) encoded by the gene . In the past, deficiency of urocanase has been associated with intellectual disability in a few case studies with some suggestion that the enzyme deficiency was the causative etiology. Here, we describe two phenotypically normal siblings with compound heterozygous pathogenic variants in and characteristic biochemical evidence of urocanase deficiency collected utilizing untargeted metabolomic analysis. These findings suggest that urocanic aciduria may represent an otherwise benign biochemical phenotype and that those individuals with concurrent developmental delay should continue to be evaluated for other underlying causes for their symptoms.
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http://dx.doi.org/10.1016/j.ymgmr.2018.12.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312870PMC
March 2019

Behavior and sleep disturbance in Smith-Magenis syndrome.

Curr Opin Psychiatry 2019 03;32(2):73-78

Department of Molecular and Human Genetics, Baylor College of Medicine.

Purpose Of Review: To provide an update of the most recent studies on Smith-Magenis syndrome (SMS) with a focus on the unique pattern of behavioral and sleep disturbances associated with the condition.

Recent Findings: The recent literature on SMS has focused on the characteristic severe behavioral and sleep disturbances. A better understanding of the underlying pathophysiological mechanisms and common clinical course has helped further characterize SMS, while much is left to be discovered in regard to effective treatment/management.

Summary: SMS is a difficult to manage genetic condition defined by pervasive and progressive behavioral and sleep disturbances with a unique pattern that can often be easily discerned from other neurodevelopmental disorders. Common behavioral features include maladaptive/self-injurious, aggressive, stereotypic, and the newly appreciated food seeking behaviors associated with SMS. In addition, there is a sleep disturbance defined by an altered circadian rhythm with frequent nighttime waking and daytime sleepiness, causing patients and families significant distress. Small studies have suggested some treatment/management approaches to the behavioral and sleep disturbances, however, much remains to be discovered.
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http://dx.doi.org/10.1097/YCO.0000000000000474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6362978PMC
March 2019

Metabolomics in the clinic: A review of the shared and unique features of untargeted metabolomics for clinical research and clinical testing.

J Mass Spectrom 2018 Nov;53(11):1143-1154

Metabolon, Morrisville, NC, USA.

Metabolomics is the untargeted measurement of the metabolome, which is composed of the complement of small molecules detected in a biological sample. As such, metabolomic analysis produces a global biochemical phenotype. It is a technology that has been utilized in the research setting for over a decade. The metabolome is directly linked to and is influenced by genetics, epigenetics, environmental factors, and the microbiome-all of which affect health. Metabolomics can be applied to human clinical diagnostics and to other fields such as veterinary medicine, nutrition, exercise, physiology, agriculture/plant biochemistry, and toxicology. Applications of metabolomics in clinical testing are emerging, but several aspects of its use as a clinical test differ from applications focused on research or biomarker discovery and need to be considered for metabolomics clinical test data to have optimum impact, be meaningful, and be used responsibly. In this review, we deconstruct aspects and challenges of metabolomics for clinical testing by illustrating the significance of test design, accurate and precise data acquisition, quality control, data processing, n-of-1 comparison to a reference population, and biochemical pathway analysis. We describe how metabolomics technology is integral to defining individual biochemical phenotypes, elaborates on human health and disease, and fits within the precision medicine landscape. Finally, we conclude by outlining some future steps needed to bring metabolomics into the clinical space and to be recognized by the broader medical and regulatory fields.
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http://dx.doi.org/10.1002/jms.4292DOI Listing
November 2018

Rapid Disruption of Genes Specifically in Livers of Mice Using Multiplex CRISPR/Cas9 Editing.

Gastroenterology 2018 12 28;155(6):1967-1970.e6. Epub 2018 Aug 28.

Center for Cell and Gene Therapy, Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, Texas; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas. Electronic address:

Background & Aims: Despite advances in gene editing technologies, generation of tissue-specific knockout mice is time-consuming. We used CRISPR/Cas9-mediated genome editing to disrupt genes in livers of adult mice in just a few months, which we refer to as somatic liver knockouts.

Methods: In this system, Fah mice are given hydrodynamic tail vein injections of plasmids carrying CRISPR/Cas9 designed to excise exons in Hpd; the Hpd-edited hepatocytes have a survival advantage in these mice. Plasmids that target Hpd and a separate gene of interest can therefore be used to rapidly generate mice with liver-specific deletion of nearly any gene product.

Results: We used this system to create mice with liver-specific knockout of argininosuccinate lyase, which develop hyperammonemia, observed in humans with mutations in this gene. We also created mice with liver-specific knockout of ATP binding cassette subfamily B member 11, which encodes the bile salt export pump. We found that these mice have a biochemical phenotype similar to that of Abcb11 mice. We then used this system to knock out expression of 5 different enzymes involved in drug metabolism within the same mouse.

Conclusions: This approach might be used to develop new models of liver diseases and study liver functions of genes that are required during development.
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http://dx.doi.org/10.1053/j.gastro.2018.08.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420307PMC
December 2018

Development of a rapid UPLC-MS/MS determination of urine sulfocysteine for diagnosis of sulfocysteinuria and molybdenum co-factor deficiencies.

Bioanalysis 2018 May 18;10(10):747-756. Epub 2018 May 18.

Division of Biochemical Genetics, Baylor Genetics, Houston, TX 77021, USA.

Aim: Molybdenum co-factor deficiencies and isolated sulfite oxidase deficiency are rare autosomal recessively inherited diseases characterized by severe psychomotor impairment, intractable seizures, dislocated lens and dysmorphic facial features. The biochemical diagnosis of these diseases requires the determination of urine sulfocysteine.

Materials & Methods: Urine sulfocysteine was quantified by an ultra-high performance liquid chromatography-MS/MS assay. The method was validated for linearity, accuracy, precision, recovery and stability.

Results & Conclusion: Total imprecision of accuracy was less than 6%. Intra-assay and inter-assay precisions were less than 5%. The recovery was higher than 98%. The method is inexpensive, fast, accurate and has been successfully used for identifying five molybdenum co-factor deficient and six sulfite oxidase deficient patients since deployed.
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http://dx.doi.org/10.4155/bio-2017-0278DOI Listing
May 2018

LIPT1 deficiency presenting as early infantile epileptic encephalopathy, Leigh disease, and secondary pyruvate dehydrogenase complex deficiency.

Am J Med Genet A 2018 05;176(5):1184-1189

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.

Lipoic acid is an essential cofactor for the mitochondrial 2-ketoacid dehydrogenase complexes and the glycine cleavage system. Lipoyltransferase 1 catalyzes the covalent attachment of lipoate to these enzyme systems. Pathogenic variants in LIPT1 gene have recently been described in four patients from three families, commonly presenting with severe lactic acidosis resulting in neonatal death and/or poor neurocognitive outcomes. We report a 2-month-old male with severe lactic acidosis, refractory status epilepticus, and brain imaging suggestive of Leigh disease. Exome sequencing implicated compound heterozygous LIPT1 pathogenic variants. We describe the fifth case of LIPT1 deficiency, whose phenotype progressed to that of an early infantile epileptic encephalopathy, which is novel compared to previously described patients whom we will review. Due to the significant biochemical and phenotypic overlap that LIPT1 deficiency and mitochondrial energy cofactor disorders have with pyruvate dehydrogenase deficiency and/or nonketotic hyperglycinemia, they are and have been presumptively under-diagnosed without exome sequencing.
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http://dx.doi.org/10.1002/ajmg.a.38654DOI Listing
May 2018

A metabolomic map of Zellweger spectrum disorders reveals novel disease biomarkers.

Genet Med 2018 10 8;20(10):1274-1283. Epub 2018 Feb 8.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.

Purpose: Peroxisome biogenesis disorders-Zellweger spectrum disorders (PBD-ZSD) are metabolic diseases with multisystem manifestations. Individuals with PBD-ZSD exhibit impaired peroxisomal biochemical functions and have abnormal levels of peroxisomal metabolites, but the broader metabolic impact of peroxisomal dysfunction and the utility of metabolomic methods is unknown.

Methods: We studied 19 individuals with clinically and molecularly characterized PBD-ZSD. We performed both quantitative peroxisomal biochemical diagnostic studies in parallel with untargeted small molecule metabolomic profiling in plasma samples with detection of >650 named compounds.

Results: The cohort represented intermediate to mild PBD-ZSD subjects with peroxisomal biochemical alterations on targeted analysis. Untargeted metabolomic profiling of these samples revealed elevations in pipecolic acid and long-chain lysophosphatidylcholines, as well as an unanticipated reduction in multiple sphingomyelin species. These sphingomyelin reductions observed were consistent across the PBD-ZSD samples and were rare in a population of >1,000 clinical samples. Interestingly, the pattern or "PBD-ZSD metabolome" was more pronounced in younger subjects suggesting studies earlier in life reveal larger biochemical changes.

Conclusion: Untargeted metabolomics is effective in detecting mild to intermediate cases of PBD-ZSD. Surprisingly, dramatic reductions in plasma sphingomyelin are a consistent feature of the PBD-ZSD metabolome. The use of metabolomics in PBD-ZSD can provide insight into novel biomarkers of disease.
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http://dx.doi.org/10.1038/gim.2017.262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605708PMC
October 2018

Genetic diagnosis of Down syndrome in an underserved community.

Am J Med Genet A 2018 02 26;176(2):483-486. Epub 2017 Dec 26.

Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.

It is a matter of course that in high-income countries, infants born with features suggestive of Down syndrome (DS) are offered genetic testing for confirmation of a clinical diagnosis. Benefits of a definitive diagnosis include an end to the diagnostic odyssey, informed prognosis, opportunities for caregiver support, inclusion to social support networks, and more meaningful genetic counseling. The healthcare experience for families of children born with DS in low- and middle-income nations is in stark contrast with such a level of care. Barriers to obtaining genetic diagnosis might include economic disparities, geographical isolation, and lack of access to health care professionals trained in genetic medicine. As part of a combined research and community outreach effort, we provided genetic testing for several patients with DS. These individuals and their families live on several resource-limited Caribbean islands and have either limited or virtually no access to medical genetics services. Within this group were three families with recurrent DS. Karyotype established that translocation events were not involved in the DS in any of these families. This information enabled genetic counseling to help family members understand their recurrent DS. A definitive diagnosis of DS is beneficial to families in resource-limited communities and may help to provide such families with genetic counseling, reassurance, and peace of mind.
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http://dx.doi.org/10.1002/ajmg.a.38573DOI Listing
February 2018

Disturbed phospholipid metabolism in serine biosynthesis defects revealed by metabolomic profiling.

Mol Genet Metab 2018 03 12;123(3):309-316. Epub 2017 Dec 12.

Division of Clinical Genetic and Metabolic Disorders, Tawam Hospital, Al-Ain, United Arab Emirates. Electronic address:

Serine biosynthesis defects are autosomal recessive metabolic disorders resulting from the deficiency of any of the three enzymes involved in de novo serine biosynthesis, specifically phosphoglycerate dehydrogenase (PGDH), phosphoserine aminotransferase (PSAT), and phosphoserine phosphatase (PSP). In this study, we performed metabolomic profiling on 4 children with serine biosynthesis defects; 3 with PGDH deficiency and 1 with PSAT deficiency. The evaluations were performed at baseline and with serine and glycine supplementation. Metabolomic profiling performed at baseline showed low phospholipid species, including glycerophosphocholine, glycerophosphoethanolamine, and sphingomyelin. All children had low serine and glycine as expected. Low glycerophosphocholine compounds were found in 4 children, low glycerophosphoethanolamine compounds in 3 children, and low sphingomyelin species in 2 children. Metabolic profiling with serine and glycine supplementation showed normalization of most of the low phospholipid compounds in the 4 children. Phospholipids are the major component of plasma and intracellular membranes, and phosphatidylcholine is the most abundant phospholipid of all mammalian cell types and subcellular organelles. Phosphatidylcholine is of particular importance for the nervous system, where it is essential for neuronal differentiation. The observed low phosphatidylcholine species in children with serine biosynthesis defects that improved after serine supplementation, supports the role of serine as a significant precursor for phosphatidylcholine. The vital role that phosphatidylcholine has during neuronal differentiation and the pronounced neurological manifestations in serine biosynthesis defects suggest that phosphatidylcholine deficiency occurring secondary to serine deficiency may have a significant contribution to the development of the neurological manifestations in individuals with serine biosynthesis defects.
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http://dx.doi.org/10.1016/j.ymgme.2017.12.009DOI Listing
March 2018

Biochemical phenotyping unravels novel metabolic abnormalities and potential biomarkers associated with treatment of GLUT1 deficiency with ketogenic diet.

PLoS One 2017 29;12(9):e0184022. Epub 2017 Sep 29.

Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, United States of America.

Global metabolomic profiling offers novel opportunities for the discovery of biomarkers and for the elucidation of pathogenic mechanisms that might lead to the development of novel therapies. GLUT1 deficiency syndrome (GLUT1-DS) is an inborn error of metabolism due to reduced function of glucose transporter type 1. Clinical presentation of GLUT1-DS is heterogeneous and the disorder mirrors patients with epilepsy, movement disorders, or any paroxysmal events or unexplained neurological manifestation triggered by exercise or fasting. The diagnostic biochemical hallmark of the disease is a reduced cerebrospinal fluid (CSF)/blood glucose ratio and the only available treatment is ketogenic diet. This study aimed at advancing our understanding of the biochemical perturbations in GLUT1-DS pathogenesis through biochemical phenotyping and the treatment of GLUT1-DS with a ketogenic diet. Metabolomic analysis of three CSF samples from GLUT1-DS patients not on ketogenic diet was feasible inasmuch as CSF sampling was used for diagnosis before to start with ketogenic diet. The analysis of plasma and urine samples obtained from GLUT1-DS patients treated with a ketogenic diet showed alterations in lipid and amino acid profiles. While subtle, these were consistent findings across the patients with GLUT1-DS on ketogenic diet, suggesting impacts on mitochondrial physiology. Moreover, low levels of free carnitine were present suggesting its consumption in GLUT1-DS on ketogenic diet. 3-hydroxybutyrate, 3-hydroxybutyrylcarnitine, 3-methyladipate, and N-acetylglycine were identified as potential biomarkers of GLUT1-DS on ketogenic diet. This is the first study to identify CSF, plasma, and urine metabolites associated with GLUT1-DS, as well as biochemical changes impacted by a ketogenic diet. Potential biomarkers and metabolic insights deserve further investigation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0184022PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5621665PMC
November 2017

Functional analysis of novel DEAF1 variants identified through clinical exome sequencing expands DEAF1-associated neurodevelopmental disorder (DAND) phenotype.

Hum Mutat 2017 12 23;38(12):1774-1785. Epub 2017 Sep 23.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.

Deformed epidermal autoregulatory factor-1 (DEAF1), a transcription factor essential for central nervous system and early embryonic development, has recently been implicated in a series of intellectual disability-related neurodevelopmental anomalies termed, in this study, as DEAF1-associated neurodevelopmental disorder (DAND). We identified six potentially deleterious DEAF1 variants in a cohort of individuals with DAND via clinical exome sequencing (CES) and in silico analysis, including two novel de novo variants: missense variant c.634G > A p.Gly212Ser in the SAND domain and deletion variant c.913_915del p.Lys305del in the NLS domain, as well as c.676C > T p.Arg226Trp, c.700T > A p.Trp234Arg, c.737G > C p.Arg246Thr, and c.791A > C p.Gln264Pro. Luciferase reporter, immunofluorescence staining, and electrophoretic mobility shift assays revealed that these variants had decreased transcriptional repression activity at the DEAF1 promoter and reduced affinity to consensus DEAF1 DNA binding sequences. In addition, c.913_915del p.K305del localized primarily to the cytoplasm and interacted with wild-type DEAF1. Our results demonstrate that variants located within the SAND or NLS domains significantly reduce DEAF1 transcriptional regulatory activities and are thus, likely to contribute to the underlying clinical concerns in DAND patients. These findings illustrate the importance of experimental characterization of variants with uncertain significance identified by CES to assess their potential clinical significance and possible use in diagnosis.
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http://dx.doi.org/10.1002/humu.23339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5679464PMC
December 2017

Quantitation of phenylbutyrate metabolites by UPLC-MS/MS demonstrates inverse correlation of phenylacetate:phenylacetylglutamine ratio with plasma glutamine levels.

Mol Genet Metab 2017 11 31;122(3):39-45. Epub 2017 Aug 31.

Division of Biochemical Genetics, Baylor Genetics Laboratories, Houston, TX, United States; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States. Electronic address:

Urea cycle disorders (UCDs) are genetic conditions characterized by nitrogen accumulation in the form of ammonia and caused by defects in the enzymes required to convert ammonia to urea for excretion. UCDs include a spectrum of enzyme deficiencies, namely n-acetylglutamate synthase deficiency (NAGS), carbamoyl phosphate synthetase I deficiency (CPS1), ornithine transcarbamylase deficiency (OTC), argininosuccinate lyase deficiency (ASL), citrullinemia type I (ASS1), and argininemia (ARG). Currently, sodium phenylbutyrate and glycerol phenylbutyrate are primary medications used to treat patients with UCDs, and long-term monitoring of these compounds is critical for preventing drug toxic levels. Therefore, a fast and simple ultra-performance liquid chromatography (UPLC-MS/MS) method was developed and validated for quantification of phenylbutyrate (PB), phenylacetate (PA), and phenylacetylglutamine (PAG) in plasma and urine. The separation of all three analytes was achieved in 2min, and the limits of detection were <0.04μg/ml. Intra-precision and inter-precision were <8.5% and 4% at two quality control concentrations, respectively. Average recoveries for all compounds ranged from 100% to 106%. With the developed assay, a strong correlation between PA and the PA/PAG ratio and an inverse correlation between PA/PAG ratio and plasma glutamine were observed in 35 patients with confirmed UCDs. Moreover, all individuals with a ratio ≥0.6 had plasma glutamine levels<1000μmol/l. Our data suggest that a PA/PAG ratio in the range of 0.6-1.5 will result in a plasma glutamine level<1000μmol/l without reaching toxic levels of PA.
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http://dx.doi.org/10.1016/j.ymgme.2017.08.011DOI Listing
November 2017

Clinical Metabolomics to Segregate Aromatic Amino Acid Decarboxylase Deficiency From Drug-Induced Metabolite Elevations.

Pediatr Neurol 2017 Oct 29;75:66-72. Epub 2017 Jun 29.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas. Electronic address:

Background: Phenotyping technologies featured in the diagnosis of inborn errors of metabolism, such as organic acid, amino acid, and acylcarnitine analyses, recently have been supplemented by broad-scale untargeted metabolomic phenotyping. We investigated the analyte changes associated with aromatic amino acid decarboxylase (AADC) deficiency and dopamine medication treatment.

Methods: Using an untargeted metabolomics platform, we analyzed ethylenediaminetetraacetic acid plasma specimens, and biomarkers were identified by comparing the biochemical profile of individual patient samples to a pediatric-centric population cohort.

Results: Elevated 3-methoxytyrosine (average z score 5.88) accompanied by significant decreases of dopamine 3-O-sulfate (-2.77), vanillylmandelate (-2.87), and 3-methoxytyramine sulfate (-1.44) were associated with AADC deficiency in three samples from two patients. In five non-AADC patients treated with carbidopa-levodopa, levels of 3-methoxytyrosine were elevated (7.65); however, the samples from non-AADC patients treated with DOPA-elevating drugs had normal or elevated levels of metabolites downstream of aromatic l-amino acid decarboxylase, including dopamine 3-O-sulfate (2.92), vanillylmandelate (0.33), and 3-methoxytyramine sulfate (5.07). In one example, a plasma metabolomic phenotype pointed to a probable AADC deficiency and prompted the evaluation of whole exome sequencing data, identifying homozygosity for a known pathogenic variant, whereas whole exome analysis in a second patient revealed compound heterozygosity for two variants of unknown significance.

Conclusions: These data demonstrate the power of combining broad-scale genotyping and phenotyping technologies to diagnose inherited neurometabolic disorders and suggest that metabolic phenotyping of plasma can be used to identify AADC deficiency and to distinguish it from non-AADC patients with elevated 3-methoxytyrosine caused by DOPA-raising medications.
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http://dx.doi.org/10.1016/j.pediatrneurol.2017.06.014DOI Listing
October 2017

Overexpression Promotes Altered Circadian Gene Expression and Dyssomnia in Potocki-Lupski Syndrome.

J Pediatr Genet 2017 Sep 7;6(3):155-164. Epub 2017 Mar 7.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States.

( ) encodes a dosage-sensitive gene that when haploinsufficient results in Smith-Magenis syndrome (SMS) and when overexpressed results in Potocki-Lupski syndrome (PTLS). Phenotypic and molecular evidence illustrates that haploinsufficiency of disrupts circadian rhythm through the dysregulation of the master circadian regulator, ( , and other core circadian components, contributing to prominent sleep disturbances in SMS. However, the phenotypic and molecular characterization of sleep features in PTLS has not been elucidated. Using the Pittsburgh Sleep Quality Index (PSQI), caregivers of 15 school-aged children with PTLS reported difficulties in initiating sleep. Indeed, more than 70% of individuals manifested moderate to severe sleep latency, as defined by the PSQI. Moreover, these individuals manifested difficulties in sleep maintenance, with middle of the night and early morning awakenings. When assessing daytime sleepiness through the Epworth Sleepiness Scale, approximately 21% of the individuals manifested excessive daytime somnolence. This indicates that mild dyssomnia characterizes the majority of the sleep phenotype, with occasionally problematic daytime somnolence, a phenotype different than that expressed by individuals with SMS, where daytime sleepiness is a chronic problem. Gene expression analysis of the core circadian machinery in the hypothalamus of the PTLS mouse model ( -Tg) found significant dysregulation of the transcriptional activators, and , and the transcriptional repressors, and , during both light and dark phases. These findings suggest a partial loss of circadian entrainment typically evoked by environmental photic cues. Examination of circadian clock gene expression in the Tg mouse heart, liver, and kidney found unchanged expression of and most of its downstream targets during both light and dark phases, suggesting an asynchronized circadian rhythm. Furthermore, examination of circadian gene expression in synchronized PTLS lymphoblasts revealed reduced transcripts of the Period ( ) family and normal expression of . The finding that central circadian gene expression was altered while many peripheral circadian components were intact suggests a tissue-specific circadian uncoupling of the circadian machinery due to overexpression. Overall, our results demonstrate that overexpression of results in sleep deficiencies in individuals with PTLS due to a lack of properly regulated circadian machinery gene expression and highlight the importance of evaluating sleep concerns in individuals with PTLS.
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http://dx.doi.org/10.1055/s-0037-1599147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5548529PMC
September 2017

Analyses of SLC13A5-epilepsy patients reveal perturbations of TCA cycle.

Mol Genet Metab 2017 08 24;121(4):314-319. Epub 2017 Jun 24.

Dept. of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States. Electronic address:

Objective: To interrogate the metabolic profile of five subjects from three families with rare, nonsense and missense mutations in SLC13A5 and Early Infantile Epileptic Encephalopathies (EIEE) characterized by severe, neonatal onset seizures, psychomotor retardation and global developmental delay.

Methods: Mass spectrometry of plasma, CSF and urine was used to identify consistently dysregulated analytes in our subjects.

Results: Distinctive elevations of citrate and dysregulation of citric acid cycle intermediates, supporting the hypothesis that loss of SLC13A5 function alters tricarboxylic acid cycle (TCA) metabolism and may disrupt metabolic compartmentation in the brain.

Significance: Our results indicate that analysis of plasma citrate and other TCA analytes in SLC13A5 deficient patients define a diagnostic metabolic signature that can aid in diagnosing children with this disease.
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http://dx.doi.org/10.1016/j.ymgme.2017.06.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539367PMC
August 2017

Elucidation of the complex metabolic profile of cerebrospinal fluid using an untargeted biochemical profiling assay.

Mol Genet Metab 2017 06 9;121(2):83-90. Epub 2017 Apr 9.

Dept. of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. Electronic address:

We sought to determine the molecular composition of human cerebrospinal fluid (CSF) and identify the biochemical pathways represented in CSF to understand the potential for untargeted screening of inborn errors of metabolism (IEMs). Biochemical profiles for each sample were obtained using an integrated metabolomics workflow comprised of four chromatographic techniques followed by mass spectrometry. Secondarily, we wanted to compare the biochemical profile of CSF with those of plasma and urine within the integrated mass spectrometric-based metabolomic workflow. Three sample types, CSF (N=30), urine (N=40) and EDTA plasma (N=31), were analyzed from retrospectively collected pediatric cohorts of equivalent age and gender characteristics. We identified 435 biochemicals in CSF representing numerous biological and chemical/structural families. Sixty-three percent (273 of 435) of the biochemicals detected in CSF also were detected in urine and plasma, another 32% (140 of 435) were detected in either plasma or urine, and 5% (22 of 435) were detected only in CSF. Analyses of several metabolites showed agreement between clinically useful assays and the metabolomics approach. An additional set of CSF and plasma samples collected from the same patient revealed correlation between several biochemicals detected in paired samples. Finally, analysis of CSF from a pediatric case with dihydropteridine reductase (DHPR) deficiency demonstrated the utility of untargeted global metabolic phenotyping as a broad assessment to screen samples from patients with undifferentiated phenotypes. The results indicate a single CSF sample processed with an integrated metabolomics workflow can be used to identify a large breadth of biochemicals that could be useful for identifying disrupted metabolic patterns associated with IEMs.
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http://dx.doi.org/10.1016/j.ymgme.2017.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6200411PMC
June 2017

Smith-Magenis Syndrome Patients Often Display Antibody Deficiency but Not Other Immune Pathologies.

J Allergy Clin Immunol Pract 2017 Sep - Oct;5(5):1344-1350.e3. Epub 2017 Mar 9.

Division of Allergy Immunology, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Penn. Electronic address:

Background: Smith-Magenis syndrome (SMS) is a complex neurobehavioral disorder associated with recurrent otitis. Most SMS cases result from heterozygous interstitial chromosome 17p11.2 deletions that encompass not only the intellectual disability gene retinoic acid-induced 1 but also other genes associated with immunodeficiency, autoimmunity, and/or malignancy.

Objectives: The goals of this study were to describe the immunological consequence of 17p11.2 deletions by determining the prevalence of immunological diseases in subjects with SMS and by assessing their immune systems via laboratory methods.

Methods: We assessed clinical histories of 76 subjects with SMS with heterozygous 17p11.2 deletions and performed in-depth immunological testing on 25 representative cohort members. Laboratory testing included determination of serum antibody concentrations, vaccine titers, and lymphocyte subset frequencies. Detailed reactivity profiles of SMS serum antibodies were performed using custom-made antigen microarrays.

Results: Of 76 subjects with SMS, 74 reported recurrent infections including otitis (88%), pneumonia (47%), sinusitis (42%), and gastroenteritis (34%). Infections were associated with worsening SMS-related neurobehavioral symptoms. The prevalence of autoimmune and atopic diseases was not increased. Malignancy was not reported. Laboratory evaluation revealed most subjects with SMS to be deficient of isotype-switched memory B cells and many to lack protective antipneumococcal antibodies. SMS antibodies were not more reactive than control antibodies to self-antigens.

Conclusions: Patients with SMS with heterozygous 17p.11.2 deletions display an increased susceptibility to sinopulmonary infections, but not to autoimmune, allergic, or malignant diseases. SMS sera display an antibody reactivity profile favoring neither recognition of pathogen-associated antigens nor self-antigens. Prophylactic strategies to prevent infections may also provide neurobehavioral benefits to selected patients with SMS.
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http://dx.doi.org/10.1016/j.jaip.2017.01.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5591748PMC
May 2018

Analytes related to erythrocyte metabolism are reliable biomarkers for preanalytical error due to delayed plasma processing in metabolomics studies.

Clin Chim Acta 2017 Mar 6;466:105-111. Epub 2017 Jan 6.

Dept. of Molecular and Human Genetics, Medical Genetics Laboratory, Baylor College of Medicine, Houston, TX, United States. Electronic address:

Background: Delaying plasma separation after phlebotomy (processing delay) can cause perturbations of numerous small molecule analytes. This poses a major challenge to the clinical application of metabolomics analyses. In this study, we further define the analyte changes that occur during processing delays and generate a model for the post hoc detection of this preanalytical error.

Methods: Using an untargeted metabolomics platform we analyzed EDTA-preserved plasma specimens harvested after processing delays lasting from minutes to days. Identified biomarkers were tested on (i) a test-set of samples exposed to either minimal (n=28) or long delays (n=40) and (ii) samples collected in a clinical setting for metabolomics analysis (n=141).

Results: A total of 149 of 803 plasma analytes changed significantly during processing delays lasting 0-20h. Biomarkers related to erythrocyte metabolism, e.g., 5-oxoproline, lactate, and an ornithine/arginine ratio, were the strongest predictors of plasma separation delays, providing 100% diagnostic accuracy in the test set. Together these biomarkers could accurately predict processing delays >2h in a pilot study and we found evidence of sample mishandling in 4 of 141 clinically derived specimens.

Conclusions: Our study highlights the widespread effects of processing delays and proposes that erythrocyte metabolism creates a reproducible signal that can identify mishandled specimens in metabolomics studies.
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http://dx.doi.org/10.1016/j.cca.2017.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5321821PMC
March 2017

Expansion of the Phenotypic Spectrum of Propionic Acidemia with Isolated Elevated Propionylcarnitine.

JIMD Rep 2017 30;35:33-37. Epub 2016 Nov 30.

Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.

We report three patients with elevations of propionylcarnitine (C3), one without elevations of 2-methylcitrate and 3-hydroxypropionate in urine organic acid analysis, and the other two showing only mild elevations, all of whom were subsequently confirmed to have propionic acidemia by molecular analysis of PCCA and PCCB genes. To date, they have had a mild clinical course. These cases illustrate the importance of considering high C3 as the only biochemical abnormality in a diagnosis of propionic acidemia. Since mild C3 elevations may be overlooked and considered non-diagnostic in isolation, we advise considering a diagnosis of propionic acidemia even in the absence of significant elevations 2-methylcitrate or 3-hydroxypropionate in urine organic acid analysis.
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http://dx.doi.org/10.1007/8904_2016_21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5585109PMC
November 2016

Homozygous variants in pyrroline-5-carboxylate reductase 2 (PYCR2) in patients with progressive microcephaly and hypomyelinating leukodystrophy.

Am J Med Genet A 2017 Feb 11;173(2):460-470. Epub 2016 Nov 11.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.

Pyrroline-5-carboxylate reductase 2, encoded by PYCR2, is one of the three homologous enzymes that catalyze the last step of proline synthesis. Homozygous variants in PYCR2 have been reported in patients from multiple consanguineous families with hypomyelinating leukodystrophy 10 (HLD10) (MIM: 616420). Here, we report five additional patients from three families with homozygous nonsense or missense variants in PYCR2, identified through clinical exome sequencing. All patients presented with postnatally acquired microcephaly, moderate to profound global developmental delay, and failure to thrive. Brain MRI in these patients showed thin corpus callosum, delayed myelination, and generalized white-matter volume loss. Additional phenotypes that were less consistent among patients included seizures or seizure-like movements, spasticity and ataxic gait, recurrent vomiting, cortical blindness, dysmorphic features, joint contractures, and irritability. Exome sequencing identified homozygous variants in PYCR2 in the proband from each family: c.28C>T (p.(Glu10Ter)), c.796C>T (p.(Arg266Ter)), and c.577G>A (p.(Val193Met)). Subsequent targeted analyses demonstrated co-segregation of the disease with the variant in the family. Despite the metabolic role of PYCR2, routine serum metabolic test in these patients were normal. To further understand the disease etiology and functions of PYCR2, small molecule metabolomics profiling was performed in plasma from three severely affected patients. No significant changes were identified in proline biosynthesis pathway or related metabolites. Studying the clinical features and the metabolic profiles of the PYCR2-deficient patients provides a more comprehensive picture for this newly identified disorder and facilitates further research on the gene function and disease etiology. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.38049DOI Listing
February 2017

Simultaneous determination of plasma total homocysteine and methionine by liquid chromatography-tandem mass spectrometry.

Clin Chim Acta 2017 Jan 12;464:93-97. Epub 2016 Nov 12.

Division of Biochemical Genetics, Baylor Genetics, Houston, TX, United States; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States. Electronic address:

The sulfur-containing amino acid homocysteine is a cardiac risk factor and a biomarker for several inborn errors of metabolism in methionine synthesis. A simple LC-MS/MS method was developed and validated for determination of homocysteine and methionine in human plasma. Rapid separation was achieved using a reverse phase liquid chromatography. Mass spectrometry identification was performed in positive electrospray ionization mode for homocysteine and methionine. Accuracy, precision, linearity, recovery and sample stability were evaluated in the method validation. The test is applied in diagnosis of homocystinuria and monitoring total homocysteine levels. Moreover, simultaneous measurement of methionine helps in the differentiation of homocystinuria and some cobalamin disorders (such as cblC and cblD defects) without additional amino acid testing. Lastly, this assay is sensitive to detect reduced total homocysteine levels that are possibly seen in sulfocysteinuria and molybdenum cofactor deficiencies.
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http://dx.doi.org/10.1016/j.cca.2016.11.017DOI Listing
January 2017