Publications by authors named "Saadet Mercimek-Andrews"

50 Publications

Sorbitol Is a Severity Biomarker for PMM2-CDG with Therapeutic Implications.

Ann Neurol 2021 Dec 26;90(6):887-900. Epub 2021 Oct 26.

Department of Clinical Genomics, Mayo Clinic, Rochester, MN.

Objective: Epalrestat, an aldose reductase inhibitor increases phosphomannomutase (PMM) enzyme activity in a PMM2-congenital disorders of glycosylation (CDG) worm model. Epalrestat also decreases sorbitol level in diabetic neuropathy. We evaluated the genetic, biochemical, and clinical characteristics, including the Nijmegen Progression CDG Rating Scale (NPCRS), urine polyol levels and fibroblast glycoproteomics in patients with PMM2-CDG.

Methods: We performed PMM enzyme measurements, multiplexed proteomics, and glycoproteomics in PMM2-deficient fibroblasts before and after epalrestat treatment. Safety and efficacy of 0.8 mg/kg/day oral epalrestat were studied in a child with PMM2-CDG for 12 months.

Results: PMM enzyme activity increased post-epalrestat treatment. Compared with controls, 24% of glycopeptides had reduced abundance in PMM2-deficient fibroblasts, 46% of which improved upon treatment. Total protein N-glycosylation improved upon epalrestat treatment bringing overall glycosylation toward the control fibroblasts' glycosylation profile. Sorbitol levels were increased in the urine of 74% of patients with PMM2-CDG and correlated with the presence of peripheral neuropathy, and CDG severity rating scale. In the child with PMM2-CDG on epalrestat treatment, ataxia scores improved together with significant growth improvement. Urinary sorbitol levels nearly normalized in 3 months and blood transferrin glycosylation normalized in 6 months.

Interpretation: Epalrestat improved PMM enzyme activity, N-glycosylation, and glycosylation biomarkers in vitro. Leveraging cellular glycoproteome assessment, we provided a systems-level view of treatment efficacy and discovered potential novel biosignatures of therapy response. Epalrestat was well-tolerated and led to significant clinical improvements in the first pediatric patient with PMM2-CDG treated with epalrestat. We also propose urinary sorbitol as a novel biomarker for disease severity and treatment response in future clinical trials in PMM2-CDG. ANN NEUROL 20219999:n/a-n/a.
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http://dx.doi.org/10.1002/ana.26245DOI Listing
December 2021

Insights into the expanding phenotypic spectrum of inherited disorders of biogenic amines.

Nat Commun 2021 09 20;12(1):5529. Epub 2021 Sep 20.

University Children's Hospital Heidelberg, Dietmar-Hopp Metabolic Center, Heidelberg, Germany.

Inherited disorders of neurotransmitter metabolism are rare neurodevelopmental diseases presenting with movement disorders and global developmental delay. This study presents the results of the first standardized deep phenotyping approach and describes the clinical and biochemical presentation at disease onset as well as diagnostic approaches of 275 patients from the registry of the International Working Group on Neurotransmitter related Disorders. The results reveal an increased rate of prematurity, a high risk for being small for gestational age and for congenital microcephaly in some disorders. Age at diagnosis and the diagnostic delay are influenced by the diagnostic methods applied and by disease-specific symptoms. The timepoint of investigation was also a significant factor: delay to diagnosis has decreased in recent years, possibly due to novel diagnostic approaches or raised awareness. Although each disorder has a specific biochemical pattern, we observed confounding exceptions to the rule. The data provide comprehensive insights into the phenotypic spectrum of neurotransmitter disorders.
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http://dx.doi.org/10.1038/s41467-021-25515-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8452745PMC
September 2021

Is impaired energy production a novel insight into the pathogenesis of pyridoxine-dependent epilepsy due to biallelic variants in ALDH7A1?

PLoS One 2021 8;16(9):e0257073. Epub 2021 Sep 8.

Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada.

Background: Pyridoxine-dependent epilepsy (PDE) is due to biallelic variants in ALDH7A1 (PDE-ALDH7A1). ALDH7A1 encodes α-aminoadipic semialdehyde dehydrogenase in lysine catabolism. We investigated the gamma aminobutyric acid (GABA) metabolism and energy production pathways in human PDE-ALDH7A1 and its knock-out aldh7a1 zebrafish model.

Methods: We measured GABA pathway, and tricarboxylic acid cycle metabolites and electron transport chain activities in patients with PDE-ALDH7A1 and in knock-out aldh7a1 zebrafish.

Results: We report results of three patients with PDE-ALDH7A1: low paired complex I+II and complex II+III and individual complex IV activities in muscle biopsy in patient 1 (likely more severe phenotype); significantly elevated CSF glutamate in the GABA pathway and elevated CSF citrate, succinate, isocitrate and α-ketoglutarate in the TCA cycle in patient 3 (likely more severe phenotype); and normal CSF GABA pathway and TCA cycle metabolites on long-term pyridoxine therapy in patient 2 (likely milder phenotype). All GABA pathway metabolites (γ-hydroxybutyrate, glutamine, glutamate, total GABA, succinic semialdehyde) and TCA cycle metabolites (citrate, malate, fumarate, isocitrate, lactate) were significantly low in the homozygous knock-out aldh7a1 zebrafish compared to the wildtype zebrafish. Homozygous knock-out aldh7a1 zebrafish had decreased electron transport chain enzyme activities compared to wildtype zebrafish.

Discussion: We report impaired electron transport chain function, accumulation of glutamate in the central nervous system and TCA cycle dysfunction in human PDE-ALDH7A1 and abnormal GABA pathway, TCA cycle and electron transport chain in knock-out aldh7a1 zebrafish. Central nervous system glutamate toxicity and impaired energy production may play important roles in the disease neuropathogenesis and severity in human PDE-ALDH7A1.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0257073PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425566PMC
November 2021

Prevalence of Congenital Disorders of Glycosylation in Childhood Epilepsy and Effects of Anti-Epileptic Drugs on the Transferrin Isoelectric Focusing Test.

Genes (Basel) 2021 08 10;12(8). Epub 2021 Aug 10.

Department of Pediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.

Introduction: Childhood epilepsy is one of the most common neurological problems. The transferrin isoelectric focusing (TIEF) test is a screening test for congenital disorders of glycosylation (CDG). We identified abnormal TIEF test in children with epilepsy in our epilepsy genetics clinic. To determine if an abnormal TIEF test is associated with anti-epileptic medications or abnormal liver functions, we performed a retrospective cohort study.

Methods: This study was performed between January 2012 and March 2020. Electronic patient charts were reviewed. Standard non-parametric statistical tests were applied using R statistical software. Fischer's exact test was used for comparisons.

Results: There were 206 patients. The TIEF test was abnormal in 11% (23 out of 206) of the patients. Nine patients were diagnosed with CDG: -CDG ( = 5), -CDG ( = 1), -CDG ( = 2), -CDG ( = 1). We report 51 different genetic diseases in 84 patients. Two groups, (1) abnormal TIEF test; (2) normal TIEF test, showed statistically significant differences for abnormal liver functions and for valproic acid treatment.

Conclusion: The TIEF test guided CDG diagnosis in 2.9% of the patients. Due to the high prevalence of CDG (4.4%) in childhood epilepsy, the TIEF test might be included into the diagnostic investigations to allow earlier and cost-effective diagnosis.
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http://dx.doi.org/10.3390/genes12081227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8391492PMC
August 2021

Assessment of intellectual impairment, health-related quality of life, and behavioral phenotype in patients with neurotransmitter related disorders: Data from the iNTD registry.

J Inherit Metab Dis 2021 11 2;44(6):1489-1502. Epub 2021 Aug 2.

University Children's Hospital, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany.

Inherited disorders of neurotransmitter metabolism are a group of rare diseases, which are caused by impaired synthesis, transport, or degradation of neurotransmitters or cofactors and result in various degrees of delayed or impaired psychomotor development. To assess the effect of neurotransmitter deficiencies on intelligence, quality of life, and behavior, the data of 148 patients in the registry of the International Working Group on Neurotransmitter Related Disorders (iNTD) was evaluated using results from standardized age-adjusted tests and questionnaires. Patients with a primary disorder of monoamine metabolism had lower IQ scores (mean IQ 58, range 40-100) within the range of cognitive impairment (<70) compared to patients with a BH deficiency (mean IQ 84, range 40-129). Short attention span and distractibility were most frequently mentioned by parents, while patients reported most frequently anxiety and distractibility when asked for behavioral traits. In individuals with succinic semialdehyde dehydrogenase deficiency, self-stimulatory behaviors were commonly reported by parents, whereas in patients with dopamine transporter deficiency, DNAJC12 deficiency, and monoamine oxidase A deficiency, self-injurious or mutilating behaviors have commonly been observed. Phobic fears were increased in patients with 6-pyruvoyltetrahydropterin synthase deficiency, while individuals with sepiapterin reductase deficiency frequently experienced communication and sleep difficulties. Patients with BH deficiencies achieved significantly higher quality of life as compared to other groups. This analysis of the iNTD registry data highlights: (a) difference in IQ and subdomains of quality of life between BH deficiencies and primary neurotransmitter-related disorders and (b) previously underreported behavioral traits.
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http://dx.doi.org/10.1002/jimd.12416DOI Listing
November 2021

Disruption of NEUROD2 causes a neurodevelopmental syndrome with autistic features via cell-autonomous defects in forebrain glutamatergic neurons.

Mol Psychiatry 2021 Jun 29. Epub 2021 Jun 29.

Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT, USA.

While the transcription factor NEUROD2 has recently been associated with epilepsy, its precise role during nervous system development remains unclear. Using a multi-scale approach, we set out to understand how Neurod2 deletion affects the development of the cerebral cortex in mice. In Neurod2 KO embryos, cortical projection neurons over-migrated, thereby altering the final size and position of layers. In juvenile and adults, spine density and turnover were dysregulated in apical but not basal compartments in layer 5 neurons. Patch-clamp recordings in layer 5 neurons of juvenile mice revealed increased intrinsic excitability. Bulk RNA sequencing showed dysregulated expression of many genes associated with neuronal excitability and synaptic function, whose human orthologs were strongly associated with autism spectrum disorders (ASD). At the behavior level, Neurod2 KO mice displayed social interaction deficits, stereotypies, hyperactivity, and occasionally spontaneous seizures. Mice heterozygous for Neurod2 had similar defects, indicating that Neurod2 is haploinsufficient. Finally, specific deletion of Neurod2 in forebrain excitatory neurons recapitulated cellular and behavioral phenotypes found in constitutive KO mice, revealing the region-specific contribution of dysfunctional Neurod2 in symptoms. Informed by these neurobehavioral features in mouse mutants, we identified eleven patients from eight families with a neurodevelopmental disorder including intellectual disability and ASD associated with NEUROD2 pathogenic mutations. Our findings demonstrate crucial roles for Neurod2 in neocortical development, whose alterations can cause neurodevelopmental disorders including intellectual disability and ASD.
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http://dx.doi.org/10.1038/s41380-021-01179-xDOI Listing
June 2021

Untargeted metabolomics and infrared ion spectroscopy identify biomarkers for pyridoxine-dependent epilepsy.

J Clin Invest 2021 08;131(15)

Institute for Molecules and Materials, FELIX Laboratory and.

BackgroundPyridoxine-dependent epilepsy (PDE-ALDH7A1) is an inborn error of lysine catabolism that presents with refractory epilepsy in newborns. Biallelic ALDH7A1 variants lead to deficiency of α-aminoadipic semialdehyde dehydrogenase/antiquitin, resulting in accumulation of piperideine-6-carboxylate (P6C), and secondary deficiency of the important cofactor pyridoxal-5'-phosphate (PLP, active vitamin B6) through its complexation with P6C. Vitamin B6 supplementation resolves epilepsy in patients, but intellectual disability may still develop. Early diagnosis and treatment, preferably based on newborn screening, could optimize long-term clinical outcome. However, no suitable PDE-ALDH7A1 newborn screening biomarkers are currently available.MethodsWe combined the innovative analytical methods untargeted metabolomics and infrared ion spectroscopy to discover and identify biomarkers in plasma that would allow for PDE-ALDH7A1 diagnosis in newborn screening.ResultsWe identified 2S,6S-/2S,6R-oxopropylpiperidine-2-carboxylic acid (2-OPP) as a PDE-ALDH7A1 biomarker, and confirmed 6-oxopiperidine-2-carboxylic acid (6-oxoPIP) as a biomarker. The suitability of 2-OPP as a potential PDE-ALDH7A1 newborn screening biomarker in dried bloodspots was shown. Additionally, we found that 2-OPP accumulates in brain tissue of patients and Aldh7a1-knockout mice, and induced epilepsy-like behavior in a zebrafish model system.ConclusionThis study has opened the way to newborn screening for PDE-ALDH7A1. We speculate that 2-OPP may contribute to ongoing neurotoxicity, also in treated PDE-ALDH7A1 patients. As 2-OPP formation appears to increase upon ketosis, we emphasize the importance of avoiding catabolism in PDE-ALDH7A1 patients.FundingSociety for Inborn Errors of Metabolism for Netherlands and Belgium (ESN), United for Metabolic Diseases (UMD), Stofwisselkracht, Radboud University, Canadian Institutes of Health Research, Dutch Research Council (NWO), and the European Research Council (ERC).
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http://dx.doi.org/10.1172/JCI148272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8321577PMC
August 2021

PIGG variant pathogenicity assessment reveals characteristic features within 19 families.

Genet Med 2021 10 10;23(10):1873-1881. Epub 2021 Jun 10.

Sydney Children's Hospital, Centre for Clinical Genetics, Sydney Children's Hospital, High St, Randwick, UK.

Purpose: Phosphatidylinositol Glycan Anchor Biosynthesis, class G (PIGG) is an ethanolamine phosphate transferase catalyzing the modification of glycosylphosphatidylinositol (GPI). GPI serves as an anchor on the cell membrane for surface proteins called GPI-anchored proteins (GPI-APs). Pathogenic variants in genes involved in the biosynthesis of GPI cause inherited GPI deficiency (IGD), which still needs to be further characterized.

Methods: We describe 22 individuals from 19 unrelated families with biallelic variants in PIGG. We analyzed GPI-AP surface levels on granulocytes and fibroblasts for three and two individuals, respectively. We demonstrated enzymatic activity defects for PIGG variants in vitro in a PIGG/PIGO double knockout system.

Results: Phenotypic analysis of reported individuals reveals shared PIGG deficiency-associated features. All tested GPI-APs were unchanged on granulocytes whereas CD73 level in fibroblasts was decreased. In addition to classic IGD symptoms such as hypotonia, intellectual disability/developmental delay (ID/DD), and seizures, individuals with PIGG variants of null or severely decreased activity showed cerebellar atrophy, various neurological manifestations, and mitochondrial dysfunction, a feature increasingly recognized in IGDs. Individuals with mildly decreased activity showed autism spectrum disorder.

Conclusion: This in vitro system is a useful method to validate the pathogenicity of variants in PIGG and to study PIGG physiological functions.
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http://dx.doi.org/10.1038/s41436-021-01215-9DOI Listing
October 2021

Hyperleucinosis during infections in maple syrup urine disease post liver transplantation.

Mol Genet Metab Rep 2021 Jun 28;27:100763. Epub 2021 Apr 28.

Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada.

Maple syrup urine disease (MSUD) is due to biallelic variants in one of the three genes: , , and Branched-chain alpha-ketoacid dehydrogenase complex deficiency and elevated leucine, valine, isoleucine and alloisoleucine in body fluids are the results. We report hyperleucinosis during intercurrent illnesses in six patients with MSUD post liver transplantation. Patient charts were retrospectively reviewed. Data was entered into an Excel Database. Literature was reviewed. Six patients with MSUD were included who had post liver transplantation hyperleucinosis during an intercurrent illness. Five had encephalopathy. One received hemodialysis for the management of hyperleucinosis. All patients had unrestricted diet. Additionally, there were five patients (one patient included into the current study) reported in the literature. We suggested management considerations for the follow-up of patients with MSUD post liver transplantation after the first episode of unexplained encephalopathy or signs of acute hyperleucinosis during intercurrent illness due to our clinical experience: 1) Healthy: Unrestricted diet and monitoring of leucine levels; 2) Illness: a) home illness management: increased carbohydrate intake b) illness management at hospital: intravenous dextrose, intravenous lipid and daily plasma amino acid monitoring. We report hyperleucinosis and/or encephalopathy as a rare event post liver transplantation in MSUD as a multicenter case series. Hyperleucinosis and/or encephalopathy may occur in both related and unrelated donor liver transplantation. Based on the long-term follow-up of those patients, these suggested management considerations may be revised as per the patients' needs.
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http://dx.doi.org/10.1016/j.ymgmr.2021.100763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102797PMC
June 2021

PPP3CA truncating variants clustered in the regulatory domain cause early-onset refractory epilepsy.

Clin Genet 2021 08 1;100(2):227-233. Epub 2021 Jun 1.

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

PPP3CA encodes the catalytic subunit of calcineurin, a calcium-calmodulin-regulated serine-threonine phosphatase. Loss-of-function (LoF) variants in the catalytic domain have been associated with epilepsy, while gain-of-function (GoF) variants in the auto-inhibitory domain cause multiple congenital abnormalities. We herein report five new patients with de novo PPP3CA variants. Interestingly, the two frameshift variants in this study and the six truncating variants reported previously are all located within a 26-amino acid region in the regulatory domain (RD). Patients with a truncating variant had more severe earlier onset seizures compared to patients with a LoF missense variant, while autism spectrum disorder was a more frequent feature in the latter. Expression studies of a truncating variant showed apparent RNA expression from the mutant allele, but no detectable mutant protein. Our data suggest that PPP3CA truncating variants clustered in the RD, causing more severe early-onset refractory epilepsy and representing a type of variants distinct from LoF or GoF missense variants.
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http://dx.doi.org/10.1111/cge.13979DOI Listing
August 2021

Lysinuric protein intolerance mimicking -acetylglutamate synthase deficiency in a nine-year-old boy.

Mol Genet Metab Rep 2021 Jun 13;27:100741. Epub 2021 Mar 13.

Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada.

We report a 9-year-old boy with lysinuric protein intolerance (LPI). He had developmental delay, short stature, failure to thrive, high-protein food aversion, hypothyroidism, growth hormone deficiency, features of hemophagocytic lymphohistiocytosis (HLH), decreased bone mineral density and multiple thoracic spine compression fractures on X-ray. LPI was suspected, but urine amino acid profile and normal orotic acid did not suggest biochemical diagnosis of LPI. Targeted next generation sequencing panel for HLH (including ) was organized. Due to elevated glutamine in plasma amino acid analysis, a metabolic consultation was initiated and his asymptomatic post-prandial ammonia was 295 μmol/L. We then suspected -acetylglutamate synthase or carbamoyl-phosphate synthase I deficiency due to marked hyperammonemia, elevated glutamine level, normal orotic acid, and normalization of ammonia at 2 h of carglumic acid (200 mg/kg/d). His targeted next generation sequencing panel for HLH revealed homozygous pathogenic variant in ((NM_001126106.2): c.726G>A (p.Trp242*)) and confirmed the diagnosis of LPI. We emphasize the importance of genetic investigations in the diagnosis of LPI.
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http://dx.doi.org/10.1016/j.ymgmr.2021.100741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973239PMC
June 2021

Outcomes of patients with cobalamin C deficiency: A single center experience.

JIMD Rep 2021 Jan 8;57(1):102-114. Epub 2020 Nov 8.

Division of Clinical and Metabolic Genetics, Department of Pediatrics The Hospital for Sick Children Toronto Ontario Canada.

Biallelic variants in results in the combined methylmalonic aciduria and homocystinuria, called cobalamin (cbl) C (cblC) deficiency. We report 26 patients with cblC deficiency with their phenotypes, genotypes, biochemical parameters, and treatment outcomes, who were diagnosed and treated at our center. We divided all cblC patients into two groups: group 1: SX group: identified after manifestations of symptoms (n = 11) and group 2: NB group: identified during the asymptomatic period via newborn screening (NBS) or positive family history of cblC deficiency (n = 15). All patients in the SX group had global developmental delay and/or cognitive dysfunction at the time of the diagnosis and at the last assessment. Seizure, stroke, retinopathy, anemia, cerebral atrophy, and thin corpus callosum in brain magnetic resonance imaging (MRI) were common in patients in the SX group. Global developmental delay and cognitive dysfunction was present in nine patients in the NB group at the last assessment. Retinopathy, anemia, and cerebral atrophy and thin corpus callosum in brain MRI were less frequent. We report favorable outcomes in patients identified in the neonatal period and treated pre-symptomatically. Identification of cblC deficiency by NBS is crucial to improve neurodevelopmental outcomes.
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http://dx.doi.org/10.1002/jmd2.12179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802631PMC
January 2021

Brain MR patterns in inherited disorders of monoamine neurotransmitters: An analysis of 70 patients.

J Inherit Metab Dis 2021 07 28;44(4):1070-1082. Epub 2021 Jan 28.

Inborn Errors of Metabolism Unit, Department of Neurology, Institut de Recerca Sant Joan de Déu and CIBERER-ISCIII, Barcelona, Spain.

Inherited monoamine neurotransmitter disorders (iMNDs) are rare disorders with clinical manifestations ranging from mild infantile hypotonia, movement disorders to early infantile severe encephalopathy. Neuroimaging has been reported as non-specific. We systematically analyzed brain MRIs in order to characterize and better understand neuroimaging changes and to re-evaluate the diagnostic role of brain MRI in iMNDs. 81 MRIs of 70 patients (0.1-52.9 years, 39 patients with tetrahydrobiopterin deficiencies, 31 with primary disorders of monoamine metabolism) were retrospectively analyzed and clinical records reviewed. 33/70 patients had MRI changes, most commonly atrophy (n = 24). Eight patients, six with dihydropteridine reductase deficiency (DHPR), had a common pattern of bilateral parieto-occipital and to a lesser extent frontal and/or cerebellar changes in arterial watershed zones. Two patients imaged after acute severe encephalopathy had signs of profound hypoxic-ischemic injury and a combination of deep gray matter and watershed injury (aromatic l-amino acid decarboxylase (AADCD), tyrosine hydroxylase deficiency (THD)). Four patients had myelination delay (AADCD; THD); two had changes characteristic of post-infantile onset neuronal disease (AADCD, monoamine oxidase A deficiency), and nine T2-hyperintensity of central tegmental tracts. iMNDs are associated with MRI patterns consistent with chronic effects of a neuronal disorder and signs of repetitive injury to cerebral and cerebellar watershed areas, in particular in DHPRD. These will be helpful in the (neuroradiological) differential diagnosis of children with unknown disorders and monitoring of iMNDs. We hypothesize that deficiency of catecholamines and/or tetrahydrobiopterin increase the incidence of and the CNS susceptibility to vascular dysfunction.
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http://dx.doi.org/10.1002/jimd.12360DOI Listing
July 2021

SCYL1 disease and liver transplantation diagnosed by reanalysis of exome sequencing and deletion/duplication analysis of SCYL1.

Am J Med Genet A 2021 04 14;185(4):1091-1097. Epub 2021 Jan 14.

Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada.

SCYL1 disease results from biallelic pathogenic variants in SCYL1. We report two new patients with severe hepatic phenotype requiring liver transplantation. Patient charts reviewed. DNA samples and skin fibroblasts were utilized. Literature was reviewed. 13-year-old boy and 9-year-old girl siblings had acute liver insufficiency and underwent living related donor liver transplantation in infancy with no genetic diagnosis. Both had tremor, global developmental delay, and cognitive dysfunction during their follow-up in the medical genetic clinic for diagnostic investigations after their liver transplantation. Exome sequencing identified a likely pathogenic variant (c.399delC; p.Asn133Lysfs*136) in SCYL1. Deletion/duplication analysis of SCYL1 identified deletions of exons 7-8 in Patient 1. Both variants were confirmed in Patient 2 and the diagnosis of SCYL1 disease was confirmed in both patients at the age of 13 and 9 years, respectively. SCYL1 protein was not expressed in both patients' fibroblast using western blot analysis. Sixteen patients with SCYL1 disease reported in the literature. Liver phenotype (n = 16), neurological phenotype (n = 13) and skeletal phenotype (n = 11) were present. Both siblings required liver transplantation in infancy and had variable phenotypes. Exome sequencing may miss the diagnosis and phenotyping of patients can help to diagnose patients.
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http://dx.doi.org/10.1002/ajmg.a.62079DOI Listing
April 2021

Phenotypic and Genotypic Spectrum of Glucose Transporter-1 Deficiency Syndrome.

Can J Neurol Sci 2021 Jan 12:1-5. Epub 2021 Jan 12.

Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada.

Background: Glucose Transporter-1 (GLUT1) Deficiency Syndrome (GLUT1DS) is caused by defective transport of glucose across the blood-brain barrier into brain cells resulting in hypoglycorrhachia due to the heterozygous pathogenic variants in SLC2A1. We report on the phenotypic spectrum of patients with pediatric GLUT1DS as well as their diagnostic methods from a single center in Canada.

Methods: We reviewed patient charts for clinical features, biochemical and molecular genetic investigations, neuroimaging, treatment modalities, and outcomes of patients with GLUT1DS at our institution.

Results: There were 13 patients. The most common initial symptom was seizures, with the most common seizure type being absence seizures (85%). Seventy-seven percent of the patients had movement disorders, and dystonia and ataxia were the most common movement disorders. Fifty-four percent of the patients did not have a history of developmental delay during their initial presentation, whereas all patients had developmental delay, intellectual disability, or cognitive dysfunction during their follow-up. All patients had a pathogenic or likely pathogenic variant in SLC2A1 and missense variants were the most common variant type.

Conclusion: We present 13 patients with GLUT1DS in the pediatric patient population. Atypical clinical features such as hemiplegia and hemiplegic migraine were present in an infant; there was a high prevalence of absence seizures and movement disorders in our patient population. We report an increased number of patients with GLUT1DS since the introduction of next-generation sequencing in the clinical settings. We believe that GLUT1DS should be included in the differential diagnosis of seizures, movement disorders, and hemiplegic migraine.
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http://dx.doi.org/10.1017/cjn.2021.3DOI Listing
January 2021

Histone H3.3 beyond cancer: Germline mutations in cause a previously unidentified neurodegenerative disorder in 46 patients.

Sci Adv 2020 Dec 2;6(49). Epub 2020 Dec 2.

Institut für Neurogenomik, Helmholtz Zentrum München, Munich, Germany.

Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A () or with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation.
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http://dx.doi.org/10.1126/sciadv.abc9207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821880PMC
December 2020

Urine creatine metabolite panel as a screening test in neurodevelopmental disorders.

Orphanet J Rare Dis 2020 12 2;15(1):339. Epub 2020 Dec 2.

Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, USA.

Background: Cerebral creatine deficiency disorders (CCDD) are inherited metabolic disorders of creatine synthesis and transport. Urine creatine metabolite panel is helpful to identify these disorders.

Methods: We reviewed electronic patient charts for all patients that underwent urine creatine metabolite panel testing in the metabolic laboratory at our institution.

Results: There were 498 tests conducted on 413 patients. Clinical, molecular genetics and neuroimaging features were available in 318 patients. Two new patients were diagnosed with creatine transporter deficiency: one female and one male, both had markedly elevated urine creatine. Urine creatine metabolite panel was also used as a monitoring test in our metabolic laboratory. Diagnostic yield of urine creatine metabolite panel was 0.67% (2/297). There were six known patients with creatine transporter deficiency. The prevalence of creatine transporter deficiency was 2.64% in our study in patients with neurodevelopmental disorders who underwent screening or monitoring of CCDS at our institution.

Conclusion: Even though the diagnostic yield of urine creatine metabolite panel is low, it can successfully detect CCDD patients, despite many neurodevelopmental disorders are not a result of CCDD. To the best of our knowledge, this study is the first Canadian study to report diagnostic yield of urine creatine metabolite panel for CCDD from a single center.
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http://dx.doi.org/10.1186/s13023-020-01617-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709238PMC
December 2020

Person Ability Scores as an Alternative to Norm-Referenced Scores as Outcome Measures in Studies of Neurodevelopmental Disorders.

Am J Intellect Dev Disabil 2020 11;125(6):475-480

Judith S. Miller, University of Pennsylvania.

Although norm-referenced scores are essential to the identification of disability, they possess several features which affect their sensitivity to change. Norm-referenced scores often decrease over time among people with neurodevelopmental disorders who exhibit slower-than-average increases in ability. Further, the reliability of norm-referenced scores is lower at the tails of the distribution, resulting in floor effects and increased measurement error for people with neurodevelopmental disorders. In contrast, the person ability scores generated during the process of constructing a standardized test with item response theory are designed to assess change. We illustrate these limitations of norm-referenced scores, and relative advantages of ability scores, using data from studies of autism spectrum disorder and creatine transporter deficiency.
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http://dx.doi.org/10.1352/1944-7558-125.6.475DOI Listing
November 2020

Fosmetpantotenate Randomized Controlled Trial in Pantothenate Kinase-Associated Neurodegeneration.

Mov Disord 2021 06 16;36(6):1342-1352. Epub 2020 Nov 16.

Research and Development, Retrophin, Inc., San Diego, California, USA.

Background: Pantothenate kinase-associated neurodegeneration (PKAN) currently has no approved treatments.

Objectives: The Fosmetpantotenate Replacement Therapy pivotal trial examined whether treatment with fosmetpantotenate improves PKAN symptoms and stabilizes disease progression.

Methods: This randomized, double-blind, placebo-controlled, multicenter study evaluated fosmetpantotenate, 300 mg oral dose three times daily, versus placebo over a 24-week double-blind period. Patients with pathogenic variants of PANK2, aged 6 to 65 years, with a score ≥6 on the PKAN-Activities of Daily Living (PKAN-ADL) scale were enrolled. Patients were randomized to active (fosmetpantotenate) or placebo treatment, stratified by weight and age. The primary efficacy endpoint was change from baseline at week 24 in PKAN-ADL.

Results: Between July 23, 2017, and December 18, 2018, 84 patients were randomized (fosmetpantotenate: n = 41; placebo: n = 43); all 84 patients were included in the analyses. Six patients in the placebo group discontinued treatment; two had worsening dystonia, two had poor compliance, and two died of PKAN-related complications (aspiration during feeding and disease progression with respiratory failure, respectively). Fosmetpantotenate and placebo group PKAN-ADL mean (standard deviation) scores were 28.2 (11.4) and 27.4 (11.5) at baseline, respectively, and were 26.9 (12.5) and 24.5 (11.8) at week 24, respectively. The difference in least square mean (95% confidence interval) at week 24 between fosmetpantotenate and placebo was -0.09 (-1.69 to 1.51; P = 0.9115). The overall incidence of treatment-emergent serious adverse events was similar in the fosmetpantotenate (8/41; 19.5%) and placebo (6/43; 14.0%) groups.

Conclusions: Treatment with fosmetpantotenate was safe but did not improve function assessed by the PKAN-ADL in patients with PKAN. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246547PMC
June 2021

Homozygous GLUL deletion is embryonically viable and leads to glutamine synthetase deficiency.

Clin Genet 2020 12 1;98(6):613-619. Epub 2020 Oct 1.

Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Canada.

Glutamine synthetase (GS) is the enzyme responsible for the biosynthesis of glutamine, providing the only source of endogenous glutamine necessary for several critical metabolic and developmental pathways. GS deficiency, caused by pathogenic variants in the glutamate-ammonia ligase (GLUL) gene, is a rare autosomal recessive inborn error of metabolism characterized by systemic glutamine deficiency, persistent moderate hyperammonemia, and clinically devastating seizures and multi-organ failure shortly after birth. The four cases reported thus far were caused by homozygous GLUL missense variants. We report a case of GS deficiency caused by homozygous GLUL gene deletion, diagnosed prenatally and likely representing the most severe end of the spectrum. We expand the known phenotype of this rare condition with novel dysmorphic, radiographic and neuropathologic features identified on post-mortem examination. The biallelic deletion identified in this case also included the RNASEL gene and was associated with immune dysfunction in the fetus. This case demonstrates that total absence of the GLUL gene in humans is viable beyond the embryonic period, despite the early embryonic lethality found in GLUL animal models.
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http://dx.doi.org/10.1111/cge.13844DOI Listing
December 2020

Inherited Metabolic Disorders Presenting with Ataxia.

Int J Mol Sci 2020 Aug 1;21(15). Epub 2020 Aug 1.

Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.

Ataxia is a common clinical feature in inherited metabolic disorders. There are more than 150 inherited metabolic disorders in patients presenting with ataxia in addition to global developmental delay, encephalopathy episodes, a history of developmental regression, coarse facial features, seizures, and other types of movement disorders. Seizures and a history of developmental regression especially are important clinical denominators to consider an underlying inherited metabolic disorder in a patient with ataxia. Some of the inherited metabolic disorders have disease specific treatments to improve outcomes or prevent early death. Early diagnosis and treatment affect positive neurodevelopmental outcomes, so it is important to think of inherited metabolic disorders in the differential diagnosis of ataxia.
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http://dx.doi.org/10.3390/ijms21155519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432519PMC
August 2020

De Novo SOX6 Variants Cause a Neurodevelopmental Syndrome Associated with ADHD, Craniosynostosis, and Osteochondromas.

Am J Hum Genet 2020 06 21;106(6):830-845. Epub 2020 May 21.

Roberts Individualized Medical Genetics Center, Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.

SOX6 belongs to a family of 20 SRY-related HMG-box-containing (SOX) genes that encode transcription factors controlling cell fate and differentiation in many developmental and adult processes. For SOX6, these processes include, but are not limited to, neurogenesis and skeletogenesis. Variants in half of the SOX genes have been shown to cause severe developmental and adult syndromes, referred to as SOXopathies. We here provide evidence that SOX6 variants also cause a SOXopathy. Using clinical and genetic data, we identify 19 individuals harboring various types of SOX6 alterations and exhibiting developmental delay and/or intellectual disability; the individuals are from 17 unrelated families. Additional, inconstant features include attention-deficit/hyperactivity disorder (ADHD), autism, mild facial dysmorphism, craniosynostosis, and multiple osteochondromas. All variants are heterozygous. Fourteen are de novo, one is inherited from a mosaic father, and four offspring from two families have a paternally inherited variant. Intragenic microdeletions, balanced structural rearrangements, frameshifts, and nonsense variants are predicted to inactivate the SOX6 variant allele. Four missense variants occur in residues and protein regions highly conserved evolutionarily. These variants are not detected in the gnomAD control cohort, and the amino acid substitutions are predicted to be damaging. Two of these variants are located in the HMG domain and abolish SOX6 transcriptional activity in vitro. No clear genotype-phenotype correlations are found. Taken together, these findings concur that SOX6 haploinsufficiency leads to a neurodevelopmental SOXopathy that often includes ADHD and abnormal skeletal and other features.
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http://dx.doi.org/10.1016/j.ajhg.2020.04.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273536PMC
June 2020

AADC deficiency from infancy to adulthood: Symptoms and developmental outcome in an international cohort of 63 patients.

J Inherit Metab Dis 2020 09 14;43(5):1121-1130. Epub 2020 May 14.

AADC Research Trust, Caterham, UK.

Aromatic l-amino acid decarboxylase deficiency (AADCD) is a rare, autosomal recessive neurodevelopmental disorder characterized by impaired synthesis of dopamine, noradrenaline, adrenaline and serotonin, leading to a complex syndrome of motor, behavioral, and autonomic symptoms. This retrospective study assessed the symptoms and developmental outcome of a large international cohort of patients with AADCD via physician and/or caregiver responses to a detailed, standardized questionnaire. Sixty-three patients (60% female; ages 6 months-36 years, median 7 years; 58 living) from 23 individual countries participated. Common symptoms at onset (median age 3 months, range 0-12 months) were hypotonia, developmental delay, and/or oculogyric crises. Oculogyric crises were present in 97% of patients aged 2 to 12 years, occurred in the majority of patients in all age groups, and tended to be most severe during early childhood. Prominent non-motor symptoms were sleep disturbance, irritable mood, and feeding difficulties. The majority of subjects (70%) had profound motor impairment characterized by absent head control and minimal voluntary movement, while 17% had mild motor impairment and were able to walk independently. Dopamine agonists were the medications most likely to produce some symptomatic benefit, but were associated with dose-limiting side effects (dyskinesia, insomnia, irritability, vomiting) that led to discontinuation 25% of the time. The age distribution of our cohort (70% of subjects under age 13 years) and the observation of a greater proportion of patients with a more severe disease phenotype in the younger compared to the older patients, both suggest a significant mortality risk during childhood for patients with severe disease.
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http://dx.doi.org/10.1002/jimd.12247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540529PMC
September 2020

Evaluation of the quality of clinical data collection for a pan-Canadian cohort of children affected by inherited metabolic diseases: lessons learned from the Canadian Inherited Metabolic Diseases Research Network.

Orphanet J Rare Dis 2020 04 10;15(1):89. Epub 2020 Apr 10.

Health Sciences Centre Winnipeg, University of Manitoba, Winnipeg, Manitoba, Canada.

Background: The Canadian Inherited Metabolic Diseases Research Network (CIMDRN) is a pan-Canadian practice-based research network of 14 Hereditary Metabolic Disease Treatment Centres and over 50 investigators. CIMDRN aims to develop evidence to improve health outcomes for children with inherited metabolic diseases (IMD). We describe the development of our clinical data collection platform, discuss our data quality management plan, and present the findings to date from our data quality assessment, highlighting key lessons that can serve as a resource for future clinical research initiatives relating to rare diseases.

Methods: At participating centres, children born from 2006 to 2015 who were diagnosed with one of 31 targeted IMD were eligible to participate in CIMDRN's clinical research stream. For all participants, we collected a minimum data set that includes information about demographics and diagnosis. For children with five prioritized IMD, we collected longitudinal data including interventions, clinical outcomes, and indicators of disease management. The data quality management plan included: design of user-friendly and intuitive clinical data collection forms; validation measures at point of data entry, designed to minimize data entry errors; regular communications with each CIMDRN site; and routine review of aggregate data.

Results: As of June 2019, CIMDRN has enrolled 798 participants of whom 764 (96%) have complete minimum data set information. Results from our data quality assessment revealed that potential data quality issues were related to interpretation of definitions of some variables, participants who transferred care across institutions, and the organization of information within the patient charts (e.g., neuropsychological test results). Little information was missing regarding disease ascertainment and diagnosis (e.g., ascertainment method - 0% missing).

Discussion: Using several data quality management strategies, we have established a comprehensive clinical database that provides information about care and outcomes for Canadian children affected by IMD. We describe quality issues and lessons for consideration in future clinical research initiatives for rare diseases, including accurately accommodating different clinic workflows and balancing comprehensiveness of data collection with available resources. Integrating data collection within clinical care, leveraging electronic medical records, and implementing core outcome sets will be essential for achieving sustainability.
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http://dx.doi.org/10.1186/s13023-020-01358-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7149838PMC
April 2020

Hypoglycemia in CDG patients due to PMM2 mutations: Follow up on hyperinsulinemic patients.

JIMD Rep 2020 Jan 25;51(1):76-81. Epub 2019 Nov 25.

Department of Clinical Genomics Mayo Clinic Rochester Rochester Minnesota.

Background: Phosphomannomutase 2 deficiency (PMM2-CDG) is the most common congenital disorder of glycosylation (CDG). Hypoglycemia has been reported in various CDG including PMM2-CDG. The frequency and etiology of hypoglycemia in PMM2-CDG are not well studied.

Methods: We conducted a systematic review of the literature on genetically and/or biochemically confirmed PMM2-CDG patients who developed hypoglycemia. Prospective follow-up information on the patients who received diazoxide therapy was collected and evaluated.

Results: A total of 165 peer-reviewed articles reporting on 933 PMM2-CDG patients were assessed. Hypoglycemia was specifically mentioned only in 23 of these patients (2.5%). Hyperinsulinism was identified in 10 patients (43% of all hypoglycemic patients). Among these 10 patients, seven were successfully treated with diazoxide. However, most patients remained on therapy longer than a year to stay free of hypoglycemia.

Conclusion: Hypoglycemia is a rarely reported finding in patients with PMM2-CDG. Diazoxide-responsive hyperinsulinism was found to have a good prognosis on medication in our PMM2-CDG patients with hypoglycemia. No genotype-phenotype correlation was observed with respect to hyperinsulinism. A prospective study should be undertaken to explore the hypothesis that hypoglycemia is underdiagnosed in PMM2-CDG and to evaluate whether hyperinsulinism is always associated with hypoglycemia.
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http://dx.doi.org/10.1002/jmd2.12085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012739PMC
January 2020

Phenotypes and genotypes of mitochondrial aminoacyl-tRNA synthetase deficiencies from a single neurometabolic clinic.

JIMD Rep 2020 Jan 18;51(1):3-10. Epub 2019 Dec 18.

Division of Clinical and Metabolic Genetics, Department of Pediatrics University of Toronto, The Hospital for Sick Children Toronto Ontario Canada.

Mitochondrial aminoacyl-tRNA synthetases play a major role in protein translation, synthesis, and oxidative phosphorylation. We reviewed all patients diagnosed with mitochondrial aminoacyl-tRNA synthetase deficiencies diagnosed in a single neurometabolic clinic. We report five patients with mitochondrial aminoacyl-tRNA synthetase deficiencies including , , , and deficiencies. Siblings with deficiency presented with global developmental delay within the first year of life. , , , and deficiencies were identified by whole exome sequencing. We report coagulation factor abnormalities in deficiency for the first time. We also report symmetric increased signal intensity in globus pallidi in FLAIR images in brain MRI in deficiency for the first time. One patient with deficiency had compound heterozygous variants in . One of those variants was an intronic variant. We confirmed the pathogenicity by mRNA studies. Mitochondrial aminoacyl-tRNA synthetase deficiencies are diagnosed by molecular genetic investigations. Clinically available non-invasive biochemical investigations are non-specific for the diagnosis of mitochondrial aminoacyl-tRNA synthetase deficiencies. A combination of brain MRI features and molecular genetic investigations should be undertaken to confirm the diagnosis of mitochondrial aminoacyl-tRNA synthetase deficiencies.
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http://dx.doi.org/10.1002/jmd2.12079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012735PMC
January 2020

Pyrroline-5-Carboxylate Reductase 2 Deficiency: A New Case and Review of the Literature.

Can J Neurol Sci 2020 03;47(2):280-282

Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.

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http://dx.doi.org/10.1017/cjn.2020.5DOI Listing
March 2020

High diagnostic yield of direct Sanger sequencing in the diagnosis of neuronal ceroid lipofuscinoses.

JIMD Rep 2019 Nov 3;50(1):20-30. Epub 2019 Sep 3.

Division of Clinical and Metabolic Genetics, Department of Paediatrics University of Toronto, The Hospital for Sick Children Toronto Ontario Canada.

Background: Neuronal ceroid lipofuscinoses are neurodegenerative disorders. To investigate the diagnostic yield of direct Sanger sequencing of the genes, we reviewed Molecular Genetics Laboratory Database for molecular genetic test results of the genes from a single clinical molecular diagnostic laboratory.

Methods: We reviewed electronic patient charts. We used consent forms and Research Electronic Data Capture questionnaires for the patients from outside of our Institution. We reclassified all variants in the genes.

Results: Six hundred and ninety three individuals underwent the direct Sanger sequencing of the genes for the diagnosis of neuronal ceroid lipofuscinoses. There were 343 symptomatic patients and 350 family members. Ninety-one symptomatic patients had molecular genetic diagnosis of neuronal ceroid lipofuscinoses including (n = 10), () (n = 33), (n = 17), (n = 7), (n = 10), () (n = 10), and (n = 4) diseases. The diagnostic yield of direct Sanger sequencing of genes was 27% in symptomatic patients. We report detailed clinical and investigation results of 33 NCL patients. Juvenile onset () and adult onset diseases were nonclassical phenotypes.

Conclusion: In our study, the diagnostic yield of direct Sanger sequencing was close to diagnostic yield of whole exome sequencing. Developmental regression, cognitive decline, visual impairment and cerebral and/or cerebellar atrophy in brain MRI are significant clinical and neuroimaging denominators to include NCL in the differential diagnosis.
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http://dx.doi.org/10.1002/jmd2.12057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6850977PMC
November 2019

Disruptive mutations in TANC2 define a neurodevelopmental syndrome associated with psychiatric disorders.

Nat Commun 2019 10 15;10(1):4679. Epub 2019 Oct 15.

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

Postsynaptic density (PSD) proteins have been implicated in the pathophysiology of neurodevelopmental and psychiatric disorders. Here, we present detailed clinical and genetic data for 20 patients with likely gene-disrupting mutations in TANC2-whose protein product interacts with multiple PSD proteins. Pediatric patients with disruptive mutations present with autism, intellectual disability, and delayed language and motor development. In addition to a variable degree of epilepsy and facial dysmorphism, we observe a pattern of more complex psychiatric dysfunction or behavioral problems in adult probands or carrier parents. Although this observation requires replication to establish statistical significance, it also suggests that mutations in this gene are associated with a variety of neuropsychiatric disorders consistent with its postsynaptic function. We find that TANC2 is expressed broadly in the human developing brain, especially in excitatory neurons and glial cells, but shows a more restricted pattern in Drosophila glial cells where its disruption affects behavioral outcomes.
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http://dx.doi.org/10.1038/s41467-019-12435-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6794285PMC
October 2019
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