Search Our Scientific Publications & Authors

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 2018 Jun 20. 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.

Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada; Centre for Molecular Medicine and Therapeutics, Vancouver, BC, Canada; BC Children's Hospital Research Institute, University of British Columbia, Vancouver, Canada; Departments of Pediatrics and Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands. Electronic address:

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

Neurochem Int 2014 Jul 30;73:192-203. Epub 2013 Sep 30.

Department of Physiology, McGill University, Montreal, Canada. Electronic address:

Na(+)/H(+) exchanger NHE6/SLC9A6 is an X-linked gene that is widely expressed and especially abundant in brain, heart and skeletal muscle where it is implicated in endosomal pH homeostasis and trafficking as well as maintenance of cell polarity. Recent genetic studies have identified several mutations in the coding region of NHE6 that are linked with severe intellectual disability, autistic behavior, ataxia and other abnormalities. One such defect consists of an in-frame deletion of three amino acids ((370)Trp-Ser-Thr(372), ΔWST) that adjoin the predicted ninth transmembrane helix of the exchanger. Read More

Neurology 2013 Aug 19;81(7):681-7. Epub 2013 Jul 19.

Department of Pediatrics, Medizinische Hochschule Hannover, Germany.

Objective: To identify the underlying genetic defect in a patient with intellectual disability, seizures, ataxia, macrothrombocytopenia, renal and cardiac involvement, and abnormal protein glycosylation.

Methods: Genetic studies involved homozygosity mapping by 250K single nucleotide polymorphism array and SLC35A1 sequencing. Functional studies included biochemical assays for N-glycosylation and mucin-type O-glycosylation and SLC35A1-encoded cytidine 5'-monophosphosialic acid (CMP-sialic acid) transport after heterologous expression in yeast. Read More

Glycoconj J 2013 Jan 16;30(1):77-84. Epub 2012 Sep 16.

Center for Child and Adolescent Medicine, Center for Metabolic Diseases Heidelberg, Kinderheilkunde I Im Neuenheimer Feld 433, 69120, Heidelberg, Germany.

Inborn errors in glycoconjugate biosynthesis termed 'Congenital Disorders of Glycosylation' (CDG) comprise a rapidly expanding group of metabolic diseases in man. Up till now more than 60 different inherited disorders in N- and O-glycosylation pathways have been identified. They affect the biosynthesis of glycan moieties linked to proteins as well as lipids. Read More

Pediatr Neurol 2011 Nov;45(5):311-8

Genetic Health, Victorian Clinical Genetics Service, Melbourne, Victoria, Australia.

Alpers syndrome is a rare autosomal recessive hepatocerebral degenerative disorder. Seventeen patients with Alpers syndrome or polymerase-γ gene mutations were identified. Case records of 12 patients with Alpers syndrome and polymerase-γ mutations in both alleles were reviewed. Read More

Neurogenetics 2011 Aug 5;12(3):193-201. Epub 2011 Apr 5.

SOSD Genetics of Neurodegenerative and Metabolic Diseases, Fondazione-IRCCS, Istituto Neurologico Carlo Besta, via Celoria11, 20133 Milan, Italy.

Ataxia with oculomotor apraxia type1 (AOA1, MIM 208920) is a rare autosomal recessive disease caused by mutations in the APTX gene. We screened a cohort of 204 patients with cerebellar ataxia and 52 patients with early-onset isolated chorea. APTX gene mutations were found in 13 ataxic patients (6%). Read More

Brain 2010 Nov 17;133(11):3210-20. Epub 2010 Sep 17.

Radboud University Nijmegen Medical Centre, Institute for Genetic and Metabolic Disease, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.

Cerebellar hypoplasia and slowly progressive ophthalmological symptoms are common features in patients with congenital disorders of glycosylation type I. In a group of patients with congenital disorders of glycosylation type I with unknown aetiology, we have previously described a distinct phenotype with severe, early visual impairment and variable eye malformations, including optic nerve hypoplasia, retinal coloboma, congenital cataract and glaucoma. Some of the symptoms overlapped with the phenotype in other congenital disorders of glycosylation type I subtypes, such as vermis hypoplasia, anaemia, ichtyosiform dermatitis, liver dysfunction and coagulation abnormalities. Read More

J Med Genet 2010 Sep 20;47(9):608-15. Epub 2010 Jul 20.

Academic Medical Centre, University of Amsterdam, Laboratory Genetic Metabolic Diseases, Department of Paediatrics/Emma Children's Hospital, Amsterdam, The Netherlands.

Background: Zellweger syndrome spectrum disorders are caused by mutations in any of at least 12 different PEX genes. This includes PEX16, which encodes an integral peroxisomal membrane protein involved in peroxisomal membrane assembly. PEX16-defective patients have been reported to have a severe clinical presentation. Read More

Brain 2010 May 15;133(Pt 5):1391-402. Epub 2010 Apr 15.

Department of Neurology, Wayne State University School of Medicine, Detroit, MI 48201, USA.

We have studied a family with severe mental retardation characterized by the virtual absence of speech, autism spectrum disorder, epilepsy, late-onset ataxia, weakness and dystonia. Post-mortem examination of two males revealed widespread neuronal loss, with the most striking finding being neuronal and glial tau deposition in a pattern reminiscent of corticobasal degeneration. Electron microscopic examination of isolated tau filaments demonstrated paired helical filaments and ribbon-like structures. Read More

Handb Clin Neurol 2010 ;95:445-76

Department of Neurology, Veterans Affairs Medical Center, Tomah, WI 54660, USA.

This historical review addresses major neurological disorders associated with deficiencies of water-soluble B vitamins: beriberi, Wernicke-Korsakoff syndrome, pellagra, neural tube defects, and subacute combined degeneration of the spinal cord. Beriberi: Beriberi was known for millennia in Asia, but was not described by a European until the 17th century when Brontius in the Dutch East Indies reported the progressive sensorimotor polyneuropathy. The prevalence of beriberi increased greatly in Asia with a change in the milling process for rice in the late 19th century. Read More

Hum Mol Genet 2010 Jan 29;19(2):374-86. Epub 2009 Oct 29.

Weill Medical College of Cornell University, New York, NY 10065, USA.

Mutations in the mitochondrial DNA (mtDNA) encoded subunit 6 of ATPase (ATP6) are associated with variable disease expression, ranging from adult onset neuropathy, ataxia and retinitis pigmentosa (NARP) to fatal childhood maternally inherited Leigh's syndrome (MILS). Phenotypical variations have largely been attributed to mtDNA heteroplasmy. However, there is often a discrepancy between the levels of mutant mtDNA and disease severity. Read More

Am J Hum Genet 2003 Feb 9;72(2):471-7. Epub 2003 Jan 9.

Department of Clinical Chemistry, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Patients affected with Refsum disease (RD) have elevated levels of phytanic acid due to a deficiency of the peroxisomal enzyme phytanoyl-CoA hydroxylase (PhyH). In most patients with RD, disease-causing mutations in the PHYH gene have been identified, but, in a subset, no mutations could be found, indicating that the condition is genetically heterogeneous. Linkage analysis of a few patients diagnosed with RD, but without mutations in PHYH, suggested a second locus on chromosome 6q22-24. Read More

Nihon Rinsho 2001 Nov;59(11):2278-84

Department of Inherited Metabolic Disease, National Institute of Neuroscience, National Center of Neurology and Psychiatry.

Mitochondrial ornithine transporter deficiency has been called HHH syndrome, because this disorder is characterized by three biochemical abnormalities; hyperornithinemia, hyperammonemia, and homocitrullinuria, and presents with various neurological symptoms; mental retardation, spastic paraparesis with pyramidal signs, cerebellar ataxia and episodic disturbance of consciousness or coma due to hyperammonemia. We identified four mutations in the mitochondrial ornithine transporter gene (ORNT1) of Japanese patients with HHH syndrome. These include a nonsense mutation (R179X), associated with exon skipping, missense mutations (G27E, P126R), and an insertion of AAC between codons 228 and 229, leading to an insertion of amino acid Asn. Read More

Neuroscience 2001 ;105(3):599-617

Department of Physiology and Biophysics, Case Western Reserve University, School of Medicine, Cleveland, OH 44106-4970, USA.

Inherited forms of ataxia and absence seizures in mice have been linked to defects in voltage-dependent calcium channel subunits. However, a correlation between the sites of neuronal dysfunction and the impact of the primary lesion upon calcium channel subunit expression or function has not been clearly established. For example, the mutation in stargazer mice has pleiotropic consequences including synaptic alterations in cerebellar granule cells, hippocampal CA3/mossy fibers, and cortical neurons in layer V that, presumably, lead to ataxia and seizures. Read More

J Inherit Metab Dis 2000 May;23(3):247-63

Division of Biochemistry and Genetics, Istituto Nazionale Neurologico C. Besta, Milan, Italy.

Faulty oxidative phosphorylation (OXPHOS) is observed in a number of mitochondrial disorders, and may be associated with single or multiple defects of the five complexes of the respiratory chain. From the genetic standpoint, the respiratory chain is unique as it is formed by means of the complementation of two separate genetic systems: the nuclear genome and the mitochondrial genome. The nuclear genome encodes most of the protein subunits of the respiratory complexes and most of the mtDNA replication and expression systems, whereas the mitochondrial genome encodes only 13 OXPHOS subunits and some RNA components of the mitochondrial translation apparatus. Read More

Neuron 2000 Feb;25(2):359-71

Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, New York 10021, USA.

We have combined genetic and biochemical approaches to analyze the function of the RNA-binding protein Nova-1, the paraneoplastic opsoclonus-myoclonus ataxia (POMA) antigen. Nova-1 null mice die postnatally from a motor deficit associated with apoptotic death of spinal and brainstem neurons. Nova-1 null mice show specific splicing defects in two inhibitory receptor pre-mRNAs, glycine alpha2 exon 3A (GlyRalpha2 E3A) and GABA(A) exon gamma2L. Read More

J Child Neurol 1999 Oct;14(10):660-6; discussion 669-72

Department of Pediatrics, University of Washington School of Medicine and Children's Hospital and Regional Medical Center, Seattle 98195, USA.

Joubert syndrome is an autosomal-recessive disorder characterized by cerebellar hypoplasia, hypotonia, developmental delay, abnormal respiratory patterns, and abnormal eye movements. The biochemical and genetic basis of Joubert syndrome is unknown and a specific chromosomal locus for this disorder has not been identified. Review of this disorder and related syndromes suggests that (1) hypoplasia of the cerebellar vermis in Joubert syndrome is frequently associated with a complex brain stem malformation represented as the "molar tooth sign" on magnetic resonance imaging, (2) the "molar tooth sign" could be present in association with the Dandy-Walker malformation and occipital encephalocele, (3) cerebellar hypoplasia is present in conditions related to Joubert syndrome such as Arima syndrome; Senior-Loken syndrome; cerebellar vermian hypoplasia, oligophrenia, congenital ataxia, coloboma, and hepatic fibrosis syndrome; and juvenile nephronophthisis due to NPH1 mutations, and (4) the brainstem-vermis malformation spectrum is probably caused by at least two and probably several genetic loci. Read More

Mol Cell Endocrinol 1998 Oct;145(1-2):75-80

Service d'Endocrinologie, Hôpital Saint-Antoine, Paris, France.

Premature ovarian failure (POF) is an heterogeneous syndrome. Among genetic causes, X monosomy as in Turner syndrome or X deletions and translocations are known to be responsible for POF. The genes involved in ovarian function, located on the X chromosome are still unknown. Read More

Oncogene 1998 Dec;17(25):3301-8

St Jude Children's Research Hospital, Department of Hematology and Oncology, Memphis, Tennessee 38105-2794, USA.

Ataxia-telangiectasia (AT) is a complex, autosomal recessive disorder characterized by cerebellar ataxia, believed to result from progressive neurodegeneration, and telangiectasia, dilation of blood vessels within the eyes and parts of the facial region. AT patients suffer from recurrent infections caused by both cellular and humoral immune deficiencies and as a population, are significantly predisposed to cancer, particularly lymphomas and leukemias. Early attempts at treating these malignancies with radiotherapy revealed another hallmark of AT, a profound hypersensitivity to the cytotoxic effects of ionizing radiation (IR) which is recapitulated at the cellular level in culture. Read More

Adv Genet 1998 ;38:31-68

Centre de Recherche Louis-Charles Simard, Montréal, Québec, Canada.

One of us (MP) learned about the mapping of Huntington disease gene to chromosome 4 from the late Dr. Anita Harding. She got the news over the phone from her London office during a visit to Italy for a meeting on hereditary ataxias. Read More

Biochim Biophys Acta 1995 May;1271(1):135-40

University Department of Clinical Neurology, Institute of Neurology, London, UK.

This study examines the relationship of genotype to phenotype in 14 unselected patients who were found to harbour the A3243G transition in the mitochondrial transfer RNALeu(UUR) gene commonly associated with the syndrome of mitochondrial encephalopathy, lactic acidosis and strokes (MELAS). Only 6 of the 14 cases (43%) had seizures and recurrent strokes, the core clinical features of the MELAS phenotype. Of the remaining cases, four had an encephalomyopathy with deafness, ataxia and dementia, two had syndromes with progressive external ophthalmoplegia and two had limb weakness alone. Read More