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J Neurosci 2022 02 18;42(8):1604-1617. Epub 2022 Jan 18.

Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109-2200

Spinocerebellar ataxia Type 3 (SCA3), the most common dominantly inherited ataxia, is a polyglutamine neurodegenerative disease for which there is no disease-modifying therapy. The polyglutamine-encoding CAG repeat expansion in the gene results in expression of a mutant form of the ATXN3 protein, a deubiquitinase that causes selective neurodegeneration despite being widely expressed. The mechanisms driving neurodegeneration in SCA3 are unclear. Read More

Neurogenetics 2021 10 2;22(4):287-295. Epub 2021 Aug 2.

Human Genetics and Genome Research Division, Clinical Genetics Department, National Research Centre, El-Tahrir Street, Dokki, Cairo, Egypt.

Fetal brain arrest is an extremely rare genetic disorder that was described in few patients and encompasses very unique findings of underdeveloped cerebral hemispheres in association with collapsed skull bones. Based on the recurrence among sibs, an autosomal recessive mode of inheritance was proposed; however, no causative gene was identified so far. Here, we report the identification of biallelic variants in the WDR81 gene in two unrelated families (4 patients) with fetal brain arrest including the originally described family and an additional new family. Read More

Neuromuscul Disord 2021 11 4;31(11):1186-1193. Epub 2021 Jun 4.

Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK; NHS Highly Specialised Services for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK; Directorate of Neurosciences, Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK. Electronic address:

Pathogenic variants in mitochondrial DNA (mtDNA) are associated with significant clinical heterogeneity with neuromuscular involvement commonly reported. Non-syndromic presentations of mtDNA disease continue to pose a diagnostic challenge and with genomic testing still necessitating a muscle biopsy in many cases. Here we describe an adult patient who presented with progressive ataxia, neuropathy and exercise intolerance in whom the application of numerous Mendelian gene panels had failed to make a genetic diagnosis. Read More

Mol Neurobiol 2021 Aug 1;58(8):4070-4106. Epub 2021 May 1.

Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057, Braga, Portugal.

Endocytosis is a fundamental process that controls protein/lipid composition of the plasma membrane, thereby shaping cellular metabolism, sensing, adhesion, signaling, and nutrient uptake. Endocytosis is essential for the cell to adapt to its surrounding environment, and a tight regulation of the endocytic mechanisms is required to maintain cell function and survival. This is particularly significant in the central nervous system (CNS), where composition of neuronal cell surface is crucial for synaptic functioning. Read More

Brain 2021 03;144(2):411-419

Dr. v. Hauner Children's Hospital, Department of Pediatric Neurology and Developmental Medicine, LMU - University of Munich, 80337, Germany.

Claudin-11, a tight junction protein, is indispensable in the formation of the radial component of myelin. Here, we report de novo stop-loss variants in the gene encoding claudin-11, CLDN11, in three unrelated individuals presenting with an early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including hypermetropia. Brain MRI showed a myelin deficit with a discrepancy between T1-weighted and T2-weighted images and some progress in myelination especially involving the central and peripheral white matter. Read More

Front Genet 2020 27;11:168. Epub 2020 Feb 27.

Department of Preventive Health Care, Children's Hospital, Capital Institute of Pediatrics, Beijing, China.

Objective: This study reports a Chinese patient with a Congenital Disorder of Glycosylation (CDG) caused by compound-heterozygous mutations in the Conserved Oligomeric Golgi 5 () gene and thereby offers concrete evidence for early diagnosis.

Methods: The clinical manifestations, the results of laboratory examinations and genetic analysis of a 4-year-old Chinese girl with CDG are reported. We also reviewed previous CDG cases that involved mutations by comparing the phenotypes and genotypes in different cases. Read More

J Inherit Metab Dis 2020 03 11;43(2):200-215. Epub 2019 Oct 11.

Department of Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.

Glutamate is involved in a variety of metabolic pathways. We reviewed the literature on genetic defects of enzymes that directly metabolise glutamate, leading to inborn errors of glutamate metabolism. Seventeen genetic defects of glutamate metabolising enzymes have been reported, of which three were only recently identified. Read More

J Hum Genet 2019 Nov 26;64(11):1117-1125. Epub 2019 Aug 26.

Department of Pediatrics, ASAN Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Whole exome sequencing (WES) is an effective tool for the genetic diagnosis of mitochondrial disorders due to various nuclear genetic defects. In this study, three patients affected by extremely rare mitochondrial disorders caused by nuclear genetic defects are described. The medical records of each patient were reviewed to obtain clinical symptoms, results of biochemical and imaging studies, and muscle biopsies. Read More

Mol Genet Genomic Med 2019 07 20;7(7):e00698. Epub 2019 May 20.

Department of Embryology, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Japan.

Background: The tricarboxylic acid (TCA) cycle is a sequence of catabolic reactions within the mitochondrial matrix, and is a central pathway for cellular energy metabolism. Genetic defects affecting the TCA cycle are known to cause severe multisystem disorders.

Methods: We performed whole exome sequencing of genomic DNA of a patient with progressive cerebellar and cerebral atrophy, hypotonia, ataxia, seizure disorder, developmental delay, ophthalmological abnormalities and hearing loss. Read More

Acta Neuropathol Commun 2019 01 3;7(1). Epub 2019 Jan 3.

Neurology V - Neuropathology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria 11, 20133, Milan, Italy.

Prion diseases are neurodegenerative disorders which are caused by an accumulation of the abnormal, misfolded prion protein known as scrapie prion protein (PrP). These disorders are unique as they occur as sporadic, genetic and acquired forms. Sporadic Creutzfeldt-Jakob Disease (CJD) is the most common human prion disease, accounting for approximately 85-90% of cases, whereas autosomal dominant genetic forms, due to mutations in the prion protein gene (PRNP), account for 10-15% of cases. Read More

J Med Genet 2019 05 28;56(5):332-339. Epub 2018 Nov 28.

Genome Research Division, Human Genetics Department, Radboud University Medical Center, Nijmegen, The Netherlands.

Background: Putative nucleotidyltransferase MAB21L1 is a member of an evolutionarily well-conserved family of the male abnormal 21 (MAB21)-like proteins. Little is known about the biochemical function of the protein; however, prior studies have shown essential roles for several aspects of embryonic development including the eye, midbrain, neural tube and reproductive organs.

Objective: A homozygous truncating variant in has recently been described in a male affected by intellectual disability, scrotal agenesis, ophthalmological anomalies, cerebellar hypoplasia and facial dysmorphism. Read More

Mov Disord Clin Pract 2018 Mar-Apr;5(2):149-155. Epub 2017 Dec 10.

Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

Background: Movement disorders are a significant clinical problem in lysosomal storage diseases (LSD) and account for substantial morbidity. The spectrum of movement disorders in childhood-onset LSD, however, remains poorly defined.

Objectives: To define the spectrum of movement disorders in a well-characterized cohort of children with LSD. Read More

JIMD Rep 2019 20;43:103-109. Epub 2018 Jun 20.

Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA.

Loss-of-function and hypomorphic ECHS1 variants are associated with mitochondrial short-chain enoyl-CoA hydratase deficiency, an inborn error of valine metabolism. We report an 8-year-old boy with developmental delay, ataxia, hemiplegia, and hearing loss with abnormalities in the basal ganglia. Biochemical studies were essentially normal except for a persistent mildly elevated CSF alanine. Read More

Mol Genet Metab 2018 01 15;123(1):28-42. Epub 2017 Nov 15.

Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.

Background: Mitochondrial diseases, a group of multi-systemic disorders often characterized by tissue-specific phenotypes, are usually progressive and fatal disorders resulting from defects in oxidative phosphorylation. MTO1 (Mitochondrial tRNA Translation Optimization 1), an evolutionarily conserved protein expressed in high-energy demand tissues has been linked to human early-onset combined oxidative phosphorylation deficiency associated with hypertrophic cardiomyopathy, often referred to as combined oxidative phosphorylation deficiency-10 (COXPD10).

Material And Methods: Thirty five cases of MTO1 deficiency were identified and reviewed through international collaboration. Read More

Am J Med Genet A 2017 Mar;173(3):712-715

BC Children's Hospital Research Institute, University of British Columbia, Vancouver, Canada.

NDST1 encodes an enzyme involved in the first steps in the synthesis of heparan sulfate chains, proteoglycans that are regulators found on the cell surface and in the extracellular matrix. Eight individuals homozygous for one of four family-specific missense mutations in the sulfotransferase domain of the enzyme have been described. They have intellectual disability. Read More

Mol Genet Metab 2016 09 25;119(1-2):68-74. Epub 2016 Jul 25.

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

Deficiency of the TCA cycle enzyme Succinyl-CoA Synthetase/Ligase (SCS), due to pathogenic variants in subunits encoded by SUCLG1 and SUCLA2, causes mitochondrial encephalomyopathy, methylmalonic acidemia, and mitochondrial DNA (mtDNA) depletion. In this study, we report an 11year old patient who presented with truncal ataxia, chorea, hypotonia, bilateral sensorineural hearing loss and preserved cognition. Whole exome sequencing identified a heterozygous known pathogenic variant and a heterozygous novel missense variant of uncertain clinical significance (VUS) in SUCLG1. Read More

Mol Syndromol 2016 May 15;7(2):62-71. Epub 2016 Apr 15.

N.N. Petrov Institute of Oncology, St. Petersburg, Russia; St. Petersburg Pediatric Medical University, St. Petersburg, Russia; I.I. Mechnikov North-Western Medical University, St. Petersburg, Russia; St. Petersburg State University, St. Petersburg, Russia.

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive genetic disorder. It is characterized by heterogeneous clinical manifestations including primary features of the disease (rod-cone dystrophy, polydactyly, obesity, genital abnormalities, renal defects, and learning difficulties) and secondary BBS characteristics (developmental delay, speech deficit, brachydactyly or syndactyly, dental defects, ataxia or poor coordination, olfactory deficit, diabetes mellitus, congenital heart disease, etc.); most of these symptoms may not be present at birth but appear and progressively worsen during the first and second decades of life. Read More

Pediatr Neurol 2016 07 1;60:79-82. Epub 2016 Apr 1.

Departments of Neurology and Pediatrics, University of Washington, Division of Neurology, Seattle Children's Hospital, Seattle Washington.

Background: Channelopathies are a group of monogenic disorders that affect a single ion channel and can result in neurological disease. While a rare cause of epilepsy, channelopathies offer unique insight to the molecular basis of epilepsy and treatment opportunities. Calcium homeostasis is tightly regulated by a series of interacting subunits. Read More

Mol Genet Metab 2016 Jan 17;117(1):42-8. Epub 2015 Nov 17.

Division of Biochemical Diseases, Dept of Pediatrics, B.C. Children's Hospital, University of British Columbia, Vancouver, Canada; Center for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, Canada. Electronic address:

We describe neurotransmitter abnormalities in two patients with drug-resistant epilepsy resulting from deleterious de novo mutations in sodium channel genes. Whole exome sequencing identified a de novo SCN2A splice-site mutation (c.2379+1G>A, p. Read More

Hum Mol Genet 2015 Aug 14;24(16):4516-29. Epub 2015 May 14.

Department of Neurology,

Ataxia oculomotor apraxia type 1 (AOA1) is an autosomal recessive disease caused by mutations in APTX, which encodes the DNA strand-break repair protein aprataxin (APTX). CoQ10 deficiency has been identified in fibroblasts and muscle of AOA1 patients carrying the common W279X mutation, and aprataxin has been localized to mitochondria in neuroblastoma cells, where it enhances preservation of mitochondrial function. In this study, we show that aprataxin deficiency impairs mitochondrial function, independent of its role in mitochondrial DNA repair. Read More

Orphanet J Rare Dis 2015 Mar 28;10:38. Epub 2015 Mar 28.

Department of Anesthesiology, Stony Brook University, Stony Brook, NY, 11794-8480, USA.

Background: Fatty acid amide hydrolase 2 (FAAH2) is a hydrolase that mediates the degradation of endocannabinoids in man. Alterations in the endocannabinoid system are associated with a wide variety of neurologic and psychiatric conditions, but the phenotype and biochemical characterization of patients with genetic defects of FAAH2 activity have not previously been described. We report a male with autistic features with an onset before the age of 2 years who subsequently developed additional features including anxiety, pseudoseizures, ataxia, supranuclear gaze palsy, and isolated learning disabilities but was otherwise cognitively intact as an adult. Read More

J Inherit Metab Dis 2015 Jan 21;38(1):65-76. Epub 2014 Aug 21.

Centre de Recherches en Cancérologie de Toulouse (CRCT), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR1037, Team n 4, CHU Rangueil, BP, 84225, 31432, Toulouse, France.

Monogenic defects of sphingolipid biosynthesis have been recently identified in human patients. These enzyme deficiencies affect the synthesis of sphingolipid precursors, ceramides or complex glycosphingolipids. They are transmitted as autosomal recessive or dominant traits, and their resulting phenotypes often replicate the abnormalities seen in murine models deficient for the corresponding enzymes. Read More

J Neurol Sci 2014 Jul 12;342(1-2):173-7. Epub 2014 Apr 12.

Department of Neuropathology (The Brain Bank for Aging Research), Tokyo Metropolitan Geriatric Hospital, 35-2 Sakae-cho, Itabashi City, Tokyo 173-0015, Japan; Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi City, Tokyo 173-0015, Japan.

Neuroferritinopathy or hereditary ferritinopathy is an inherited neurodegenerative disease caused by mutations in ferritin light chain (FTL) gene. The clinical features of the disease are highly variable, and include a movement disorder, behavioral abnormalities, and cognitive impairment. Neuropathologically, the disease is characterized by abnormal iron and ferritin depositions in the central nervous system. Read More

J Inherit Metab Dis 2014 Jul 1;37(4):577-85. Epub 2014 May 1.

Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK,

Thiamine, in the form of thiamine pyrophosphate, is a cofactor for a number of enzymes which play important roles in energy metabolism. Although dietary thiamine deficiency states have long been recognised, it is only relatively recently that inherited defects in thiamine uptake, activation and the attachment of the active cofactor to target enzymes have been described, and the underlying genetic defects identified. Thiamine is transported into cells by two carriers, THTR1 and THTR2, and deficiency of these results in thiamine-responsive megaloblastic anaemia and biotin-responsive basal ganglia disease respectively. Read More

Neurology 2014 Mar 19;82(11):963-8. Epub 2014 Feb 19.

From Metabolics and Newborn Screening (M.A.L.), University of Ottawa, Children's Hospital of Eastern Ontario; Clinical and Metabolic Genetics (R.J.), and The Centre for Applied Genomics and Program in Genetics and Genome Biology (C.R.M., S.W.S.), The Hospital for Sick Children, Toronto; Neuromuscular and Neuorometabolic Disorders (L.B., M.A.T.), and Department of Ophthalmology (A.R.R.), McMaster University, Hamilton; Department of Molecular Genetics, McLaughlin Centre (C.R.M., S.W.S.), and Division of Neurology, Sunnybrook Health Sciences Centre (L.L.), University of Toronto; Morton and Gloria Shulman Movement Disorders Centre and the Edmond J. Safra Program in Parkinson's Disease (A.E.L., T.A.M.), Toronto Western Hospital, Canada; and Laboratory Genetic Metabolic Diseases (R.J.A.W., S.F.), Academic Medical Center, University of Amsterdam, the Netherlands.

Objective: To determine the causative genetic lesion in 3 adult siblings with a slowly progressive, juvenile-onset phenotype comprising cerebellar atrophy and ataxia, intellectual decline, hearing loss, hypogonadism, hyperreflexia, a demyelinating sensorimotor neuropathy, and (in 2 of 3 probands) supratentorial white matter changes, in whom numerous prior investigations were nondiagnostic.

Methods: The patients' initial clinical assessment included history and physical examination, cranial MRI, and nerve conduction studies. We performed whole-exome sequencing of all 3 probands, followed by variant annotation and selection of rare, shared, recessive coding changes to identify the gene responsible. Read More

Nat Genet 2014 Feb 12;46(2):166-70. Epub 2014 Jan 12.

1] Institute for Cancer Genetics, Columbia University, New York, New York, USA. [2] Department of Pathology, Columbia University Medical Center, New York, New York, USA. [3] Department of Pediatrics, Columbia University Medical Center, New York, New York, USA.

Peripheral T cell lymphomas (PTCLs) are a heterogeneous and poorly understood group of non-Hodgkin lymphomas. Here we combined whole-exome sequencing of 12 tumor-normal DNA pairs, RNA sequencing analysis and targeted deep sequencing to identify new genetic alterations in PTCL transformation. These analyses identified highly recurrent epigenetic factor mutations in TET2, DNMT3A and IDH2 as well as a new highly prevalent RHOA mutation encoding a p. Read More