ABSTRACT
The nuclear-encoded glycyl-tRNA synthetase gene (GARS) is essential for protein translation in both cytoplasm and mitochondria. In contrast, different genes encode the mitochondrial and cytosolic forms of most other tRNA synthetases. Dominant GARS mutations were described in inherited neuropathies, while recessive mutations cause severe childhood-onset disorders affecting skeletal muscle and heart. The downstream events explaining tissue-specific phenotype-genotype relations remained unclear. We investigated the mitochondrial function of GARS in human cell lines and in the GarsC210R mouse model. Human-induced neuronal progenitor cells (iNPCs) carrying dominant and recessive GARS mutations showed alterations of mitochondrial proteins, which were more prominent in iNPCs with dominant, neuropathy-causing mutations. Although comparative proteomic analysis of iNPCs showed significant changes in mitochondrial respiratory chain complex subunits, assembly genes, Krebs cycle enzymes and transport proteins in both recessive and dominant mutations, proteins involved in fatty acid oxidation were only altered by recessive mutations causing mitochondrial cardiomyopathy. In contrast, significant alterations of the vesicle-associated membrane protein-associated protein B (VAPB) and its downstream pathways such as mitochondrial calcium uptake and autophagy were detected in dominant GARS mutations. The role of VAPB has been supported by similar results in the GarsC210R mice. Our data suggest that altered mitochondria-associated endoplasmic reticulum (ER) membranes (MAM) may be important disease mechanisms leading to neuropathy in this condition.
Subject(s)
Endoplasmic Reticulum/genetics , Glycine-tRNA Ligase/genetics , Mitochondria/genetics , Vesicular Transport Proteins/genetics , Animals , Humans , Mice , Mitochondria/metabolism , Mutation , Neurons/metabolism , Neurons/pathology , Signal Transduction , Stem Cells/metabolismABSTRACT
PURPOSE: To understand the role of the mitochondrial oxodicarboxylate carrier (SLC25A21) in the development of spinal muscular atrophy-like disease. METHODS: We identified a novel pathogenic variant in a patient by whole-exome sequencing. The pathogenicity of the mutation was studied by transport assays, computer modeling, followed by targeted metabolic testing and in vitro studies in human fibroblasts and neurons. RESULTS: The patient carries a homozygous pathogenic variant c.695A>G; p.(Lys232Arg) in the SLC25A21 gene, encoding the mitochondrial oxodicarboxylate carrier, and developed spinal muscular atrophy and mitochondrial myopathy. Transport assays show that the mutation renders SLC25A21 dysfunctional and 2-oxoadipate cannot be imported into the mitochondrial matrix. Computer models of central metabolism predicted that impaired transport of oxodicarboxylate disrupts the pathways of lysine and tryptophan degradation, and causes accumulation of 2-oxoadipate, pipecolic acid, and quinolinic acid, which was confirmed in the patient's urine by targeted metabolomics. Exposure to 2-oxoadipate and quinolinic acid decreased the level of mitochondrial complexes in neuronal cells (SH-SY5Y) and induced apoptosis. CONCLUSION: Mitochondrial oxodicarboxylate carrier deficiency leads to mitochondrial dysfunction and the accumulation of oxoadipate and quinolinic acid, which in turn cause toxicity in spinal motor neurons leading to spinal muscular atrophy-like disease.
Subject(s)
Adipates/metabolism , DNA, Mitochondrial/genetics , Dicarboxylic Acid Transporters/genetics , Mitochondrial Membrane Transport Proteins/genetics , Muscular Atrophy, Spinal/genetics , Adipates/pharmacology , Apoptosis/drug effects , Cell Line , DNA, Mitochondrial/metabolism , Dicarboxylic Acid Transporters/metabolism , Fibroblasts/drug effects , Homozygote , Humans , Mitochondria/genetics , Mitochondria/metabolism , Mitochondrial Membrane Transport Proteins/metabolism , Motor Neurons/drug effects , Muscular Atrophy, Spinal/metabolism , Muscular Atrophy, Spinal/physiopathology , Mutation , Pipecolic Acids/metabolism , Quinolinic Acid/metabolismABSTRACT
Synaptotagmin 2 is a synaptic vesicle protein that functions as a calcium sensor for neurotransmission but has not been previously associated with human disease. Via whole-exome sequencing, we identified heterozygous missense mutations in the C2B calcium-binding domain of the gene encoding Synaptotagmin 2 in two multigenerational families presenting with peripheral motor neuron syndromes. An essential calcium-binding aspartate residue, Asp307Ala, was disrupted by a c.920A>C change in one family that presented with an autosomal-dominant presynaptic neuromuscular junction disorder resembling Lambert-Eaton myasthenic syndrome. A c.923C>T variant affecting an adjacent residue (p.Pro308Leu) produced a presynaptic neuromuscular junction defect and a dominant hereditary motor neuropathy in a second family. Characterization of the mutation homologous to the human c.920A>C variant in Drosophila Synaptotagmin revealed a dominant disruption of synaptic vesicle exocytosis using this transgenic model. These findings indicate that Synaptotagmin 2 regulates neurotransmitter release at human peripheral motor nerve terminals. In addition, mutations in the Synaptotagmin 2 C2B domain represent an important cause of presynaptic congenital myasthenic syndromes and link them with hereditary motor axonopathies.
Subject(s)
Genes, Dominant/genetics , Lambert-Eaton Myasthenic Syndrome/genetics , Motor Neuron Disease/genetics , Mutation/genetics , Peripheral Nervous System Diseases/genetics , Synaptotagmin II/genetics , Adolescent , Adult , Aged , Animals , Child , Drosophila/genetics , Drosophila/growth & development , Drosophila/metabolism , Electrophysiology , Exocytosis/physiology , Female , Humans , Male , Middle Aged , Pedigree , Synaptic Transmission , Young AdultABSTRACT
Using a combination of exome sequencing and linkage analysis, we investigated an English family with two affected siblings in their 40s with recessive Charcot-Marie Tooth disease type 2 (CMT2). Compound heterozygous mutations in the immunoglobulin-helicase-µ-binding protein 2 (IGHMBP2) gene were identified. Further sequencing revealed a total of 11 CMT2 families with recessively inherited IGHMBP2 gene mutations. IGHMBP2 mutations usually lead to spinal muscular atrophy with respiratory distress type 1 (SMARD1), where most infants die before 1 year of age. The individuals with CMT2 described here, have slowly progressive weakness, wasting and sensory loss, with an axonal neuropathy typical of CMT2, but no significant respiratory compromise. Segregating IGHMBP2 mutations in CMT2 were mainly loss-of-function nonsense in the 5' region of the gene in combination with a truncating frameshift, missense, or homozygous frameshift mutations in the last exon. Mutations in CMT2 were predicted to be less aggressive as compared to those in SMARD1, and fibroblast and lymphoblast studies indicate that the IGHMBP2 protein levels are significantly higher in CMT2 than SMARD1, but lower than controls, suggesting that the clinical phenotype differences are related to the IGHMBP2 protein levels.
Subject(s)
Charcot-Marie-Tooth Disease/genetics , Exome/genetics , Models, Molecular , Mutation, Missense/genetics , Phenotype , Adult , Base Sequence , Charcot-Marie-Tooth Disease/pathology , Chromosome Mapping , Female , Haplotypes/genetics , Humans , Molecular Sequence Data , Pedigree , Protein Interaction Mapping , Sequence Analysis, DNA , Sural Nerve/pathologyABSTRACT
Mitochondrial diseases are usually severe and progressive conditions; however, there are rare forms that show remarkable spontaneous recoveries. Two homoplasmic mitochondrial tRNA mutations (m.14674T>C/G in mt-tRNA(Glu)) have been reported to cause severe infantile mitochondrial myopathy in the first months of life. If these patients survive the first year of life by extensive life-sustaining measures they usually recover and develop normally. Another mitochondrial disease due to deficiency of the 5-methylaminomethyl-2-thiouridylate methyltransferase (TRMU) causes severe liver failure in infancy, but similar to the reversible mitochondrial myopathy, within the first year of life these infants may also recover completely. Partial recovery has been noted in some other rare forms of mitochondrial disease due to deficiency of mitochondrial tRNA synthetases and mitochondrial tRNA modifying enzymes. Here we summarize the clinical presentation of these unique reversible mitochondrial diseases and discuss potential molecular mechanisms behind the reversibility. Understanding these mechanisms may provide the key to treatments of potential broader relevance in mitochondrial disease, where for the majority of the patients no effective treatment is currently available.
Subject(s)
Liver Failure/genetics , Mitochondrial Diseases/genetics , Mitochondrial Myopathies/genetics , RNA, Transfer/genetics , Thionucleotides/deficiency , Thionucleotides/genetics , Uracil Nucleotides/deficiency , Uracil Nucleotides/genetics , Gene Expression , Humans , Infant , Infant, Newborn , MutationABSTRACT
PURPOSE: Psychogenic nonepileptic seizure (PNES) is an important differential diagnostic problem in patients with or without epilepsy. There are many studies that have analyzed PNES in adults; currently, however, there is no systematic assessment of purely childhood PNES semiology. Our study based on a large pediatric video-electroencephalography (EEG) monitoring (VEM) cohort, provides a detailed analysis of childhood PNES and assesses the usability of the current classification system described in adults. METHODS: Medical and video-EEG records of 568 consecutive children (younger than 18 years) who underwent video-EEG monitoring (VEM) at our hospital were reviewed. Aura, type of movement, anatomic distribution, synchrony, symmetry, eye movement, responsiveness, vocalization, hyperventilation, vegetative and emotional signs, presence of eyewitness, and duration of the event were recorded among children with the diagnosis of PNES. We also compared our data with those of earlier adult studies. KEY FINDINGS: Seventy-five archived PNES of 27 children (21 girls; age 8-18 years) were reanalyzed. Nine children (33%) had the diagnosis of epilepsy currently or in the past. Mean age at the time of PNES onset was 11.6 (standard deviation 3.2) years. Mean duration of PNES was longer (269 s) compared to seizures of the epileptic group (83 s; p = 0.002). Eyewitnesses (mostly parents) were present in 89% of cases. Eighty percent of PNES had an abrupt start, with 68% also ending abruptly. In only 15% of events were the patients eyes closed at the beginning of the attack. Patients were unresponsive in 34%. The most frequent motor sign was tremor (25%) with the upper, rather than lower limbs more frequently involved. Pelvic thrusting was seen in only two attacks. Emotional-mostly negative-signs were observed during 32 PNES (43%). Based on Seneviratne et al.'s classification, 18 events (24%) were classified as rhythmic motor PNES, only half the frequency of that previously described in adults. No hypermotor PNES was found. The frequency of complex motor PNES (13%) and mixed PNES (4%) showed similar frequency in children as in adults. Dialeptic PNES was found more frequently among younger children. All PNES belonged to the same semiologic type in 23 patients (85%). SIGNIFICANCE: Because homogeneity of PNES within a patient was high in the pediatric population, we found it useful to classify PNES into different semiologic categories. Dialeptic PNES seems to be more frequent among younger children. Tremor is the most frequent motor sign and usually accompanied by preserved responsiveness in childhood. Negative emotion is commonly seen in pediatric PNES, but pelvic thrusting is a rare phenomenon. We, therefore, suggest a modification of the present classification system in which PNES with motor activity is divided into minor and major motor PNES, and the latter group is subdivided into synchron rhythmic motor and asynchron motor PNES. We believe that our study, a detailed analysis on the semiology and classification of purely childhood PNES might assist the early and precise diagnosis of nonepileptic paroxysmal events.
Subject(s)
Conversion Disorder/diagnosis , Electroencephalography/methods , Epilepsy/diagnosis , Video Recording/methods , Adolescent , Child , Cohort Studies , Conversion Disorder/psychology , Epilepsy/classification , Female , Humans , Male , Retrospective StudiesABSTRACT
BACKGROUND: Behr syndrome is a clinically distinct, but genetically heterogeneous disorder characterized by optic atrophy, progressive spastic paraparesis, and motor neuropathy often associated with ataxia. The molecular diagnosis is based on gene panel testing or whole-exome/genome sequencing. METHODS: Here, we report the clinical presentation of two siblings with a novel genetic form of Behr syndrome. We performed whole-exome sequencing in the two patients and their mother. RESULTS: Both patients had a childhood-onset, slowly progressive disease resembling Behr syndrome, starting with visual impairment, followed by progressive spasticity, weakness, and atrophy of the lower legs and ataxia. They also developed scoliosis, leading to respiratory problems. In their late 30's, both siblings developed a hypertrophic cardiomyopathy and died of sudden cardiac death at age 43 and 40, respectively. Whole-exome sequencing identified the novel homozygous c.627_629del; p.(Gly210del) deletion in UCHL1. CONCLUSIONS: The presentation of our patients raises the possibility that hypertrophic cardiomyopathy may be an additional feature of the clinical syndrome associated with UCHL1 mutations, and highlights the importance of cardiac follow-up and treatment in neurodegenerative disease associated with UCHL1 mutations.
Subject(s)
Cardiomyopathy, Hypertrophic , Neurodegenerative Diseases , Optic Atrophy , Spastic Paraplegia, Hereditary , Ataxia , Child , Hearing Loss , Humans , Intellectual Disability , Mutation/genetics , Optic Atrophy/congenital , Optic Atrophy/genetics , Pedigree , Spasm , Ubiquitin ThiolesteraseABSTRACT
OBJECTIVE: To describe a patient with a multifocal demyelinating motor neuropathy with onset in childhood and a mutation in phosphatase and tensin homolog (PTEN), a tumor suppressor gene associated with inherited tumor susceptibility conditions, macrocephaly, autism, ataxia, tremor, and epilepsy. Functional implications of this protein have been investigated in Parkinson and Alzheimer diseases. METHODS: We performed whole-exome sequencing in the patient's genomic DNA validated by Sanger sequencing. Immunoblotting, in vitro enzymatic assay, and label-free shotgun proteomic profiling were performed in the patient's fibroblasts. RESULTS: The predominant clinical presentation of the patient was a childhood onset, asymmetric progressive multifocal motor neuropathy. In addition, he presented with macrocephaly, autism spectrum disorder, and skin hamartomas, considered as clinical criteria for PTEN-related hamartoma tumor syndrome. Extensive tumor screening did not detect any malignancies. We detected a novel de novo heterozygous c.269T>C, p.(Phe90Ser) PTEN variant, which was absent in both parents. The pathogenicity of the variant is supported by altered expression of several PTEN-associated proteins involved in tumorigenesis. Moreover, fibroblasts showed a defect in catalytic activity of PTEN against the secondary substrate, phosphatidylinositol 3,4-trisphosphate. In support of our findings, focal hypermyelination leading to peripheral neuropathy has been reported in PTEN-deficient mice. CONCLUSION: We describe a novel phenotype, PTEN-associated multifocal demyelinating motor neuropathy with a skin hamartoma syndrome. A similar mechanism may potentially underlie other forms of Charcot-Marie-Tooth disease with involvement of the phosphatidylinositol pathway.
Subject(s)
Hamartoma/genetics , Hereditary Central Nervous System Demyelinating Diseases/genetics , Hereditary Sensory and Motor Neuropathy/genetics , PTEN Phosphohydrolase/genetics , Adult , Genetic Predisposition to Disease , Hamartoma/complications , Hereditary Central Nervous System Demyelinating Diseases/complications , Hereditary Sensory and Motor Neuropathy/complications , Humans , Male , Mutation , Exome SequencingABSTRACT
OBJECTIVE: To study the prevalence, molecular cause, and clinical presentation of hereditary motor neuropathies in a large cohort of patients from the North of England. METHODS: Detailed neurologic and electrophysiologic assessments and next-generation panel testing or whole exome sequencing were performed in 105 patients with clinical symptoms of distal hereditary motor neuropathy (dHMN, 64 patients), axonal motor neuropathy (motor Charcot-Marie-Tooth disease [CMT2], 16 patients), or complex neurologic disease predominantly affecting the motor nerves (hereditary motor neuropathy plus, 25 patients). RESULTS: The prevalence of dHMN is 2.14 affected individuals per 100,000 inhabitants (95% confidence interval 1.62-2.66) in the North of England. Causative mutations were identified in 26 out of 73 index patients (35.6%). The diagnostic rate in the dHMN subgroup was 32.5%, which is higher than previously reported (20%). We detected a significant defect of neuromuscular transmission in 7 cases and identified potentially causative mutations in 4 patients with multifocal demyelinating motor neuropathy. CONCLUSIONS: Many of the genes were shared between dHMN and motor CMT2, indicating identical disease mechanisms; therefore, we suggest changing the classification and including dHMN also as a subcategory of Charcot-Marie-Tooth disease. Abnormal neuromuscular transmission in some genetic forms provides a treatable target to develop therapies.
Subject(s)
Charcot-Marie-Tooth Disease/epidemiology , Genetic Heterogeneity , Hereditary Sensory and Motor Neuropathy/epidemiology , Hereditary Sensory and Motor Neuropathy/genetics , Mutation/genetics , Adolescent , Adult , Aged , Analysis of Variance , Charcot-Marie-Tooth Disease/genetics , Charcot-Marie-Tooth Disease/physiopathology , Cohort Studies , Connexins/genetics , DNA Mutational Analysis , Electromyography , England/epidemiology , Family Health , Female , GTP Phosphohydrolases/genetics , Hereditary Sensory and Motor Neuropathy/physiopathology , Humans , Male , Middle Aged , Mitochondrial Proteins/genetics , Myelin Proteins/genetics , Neural Conduction/genetics , Young Adult , Gap Junction beta-1 ProteinABSTRACT
Menkes disease is an X-linked multisystem disorder with epilepsy, kinky hair, and neurodegeneration caused by mutations in the copper transporter ATP7A. Other ATP7A mutations have been linked to juvenile occipital horn syndrome and adult-onset hereditary motor neuropathy.1,2 About 5%-10% of the patients present with "atypical Menkes disease" characterized by longer survival, cerebellar ataxia, and developmental delay.2 The intracellular copper transport is regulated by 2 P type ATPase copper transporters ATP7A and ATP7B. These proteins are expressed in the trans-Golgi network that guides copper to intracellular compartments, and in copper excess, it relocates copper to the plasma membrane to pump it out from the cells.3ATP7B mutations cause Wilson disease with dystonia, ataxia, tremor, and abnormal copper accumulation in the brain, liver, and other organs.4.
ABSTRACT
Mutations in the transient receptor potential vanilloid 4 (TRPV4) gene have been associated with autosomal dominant skeletal dysplasias and peripheral nervous system syndromes (PNSS). PNSS include Charcot-Marie-Tooth disease (CMT) type 2C, congenital spinal muscular atrophy and arthrogryposis and scapuloperoneal spinal muscular atrophy. We report the clinical, electrophysiological and muscle biopsy findings in two unrelated patients with two novel heterozygous missense mutations in the TRPV4 gene. Whole exome sequencing was carried out on genomic DNA using Illumina Truseq(TM) 62Mb exome capture. Patient 1 harbours a de novo c.805C > T (p.Arg269Cys) mutation. Clinically, this patient shows signs of both scapuloperoneal spinal muscular atrophy and skeletal dysplasia. Patient 2 harbours a novel c.184G > A (p.Asp62Asn) mutation. While the clinical phenotype is compatible with CMT type 2C with the patient's muscle harbours basophilic inclusions. Mutations in the TRPV4 gene have a broad phenotypic variability and disease severity and may share a similar pathogenic mechanism with Heat Shock Protein related neuropathies.
Subject(s)
Charcot-Marie-Tooth Disease/genetics , Dwarfism/genetics , Muscular Atrophy, Spinal/genetics , Osteochondrodysplasias/genetics , TRPV Cation Channels/genetics , Charcot-Marie-Tooth Disease/pathology , Child , Dwarfism/pathology , Female , Humans , Male , Middle Aged , Muscular Atrophy, Spinal/pathology , Mutation, Missense , Osteochondrodysplasias/pathology , PhenotypeABSTRACT
Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy with heterogeneous clinical presentation and genetic background. The axonal form (CMT2) is characterised by decreased action potentials indicating primary axonal damage. The underlying pathology involves axonal degeneration which is supposed to be related to axonal protein dysfunction caused by various gene mutations. The overlapping clinical manifestation of CMT2 with distal hereditary motor neuropathy (dHMN) and intermediate CMT causes further diagnostic difficulties. Aminoacyl-tRNA synthetases have been implicated in the pathomechanism of CMT2. They have an essential role in protein translation by attaching amino acids to their cognate tRNAs. To date six families have been reported worldwide with dominant missense alanyl-tRNA synthetase (AARS) mutations leading to clinically heterogeneous axonal neuropathies. The pathomechanism of some variants could be explained by impaired amino acylation activity while other variants implicating an editing defect need to be further investigated. Here, we report a cohort of six additional families originating from the United Kingdom and Ireland with dominant AARS-related neuropathies. The phenotypic manifestation was distal lower limb predominant sensorimotor neuropathy but upper limb impairment with split hand deformity occasionally associated. Nerve conduction studies revealed significant demyelination accompanying the axonal lesion in motor and sensory nerves. Five families have the c.986G>A, p.(Arg329His) variant, further supporting that this is a recurrent loss of function variant. The sixth family, of Irish origin, had a novel missense variant, c.2063A>G, p.(Glu688Gly). We discuss our findings and the associated phenotypic heterogeneity in these families, which expands the clinical spectrum of AARS-related neuropathies.
Subject(s)
Amino Acyl-tRNA Synthetases/genetics , Hereditary Sensory and Motor Neuropathy/genetics , Hereditary Sensory and Motor Neuropathy/physiopathology , Adult , Aged , Axons/pathology , Charcot-Marie-Tooth Disease/genetics , Charcot-Marie-Tooth Disease/physiopathology , Child , Child, Preschool , Cohort Studies , Female , Genotype , Humans , Ireland , Male , Middle Aged , Mutation, Missense , Pedigree , Phenotype , United Kingdom , Young AdultABSTRACT
OBJECTIVES: To describe the clinical and electrophysiologic features of synaptotagmin II (SYT2) mutations, a novel neuromuscular syndrome characterized by foot deformities and fatigable ocular and lower limb weakness, and the response to modulators of acetylcholine release. METHODS: We performed detailed clinical and neurophysiologic assessment in 2 multigenerational families with dominant SYT2 mutations (c.920T>G [p.Asp307Ala] and c.923G>A [p.Pro308Leu]). Serial clinical and electrophysiologic assessments were performed in members of one family treated first with pyridostigmine and then with 3,4-diaminopyridine. RESULTS: Electrophysiologic testing revealed features indicative of a presynaptic deficit in neurotransmitter release with posttetanic potentiation lasting up to 60 minutes. Treatment with 3,4-diaminopyridine produced both a clinical benefit and an improvement in neuromuscular transmission. CONCLUSION: SYT2 mutations cause a novel and potentially treatable complex presynaptic congenital myasthenic syndrome characterized by motor neuropathy causing lower limb wasting and foot deformities, with reflex potentiation following exercise and a uniquely prolonged period of posttetanic potentiation.
Subject(s)
Mutation , Myasthenic Syndromes, Congenital/physiopathology , Synaptic Transmission/physiology , Synaptotagmin II/genetics , 4-Aminopyridine/analogs & derivatives , 4-Aminopyridine/pharmacology , 4-Aminopyridine/therapeutic use , Adolescent , Adult , Aged , Amifampridine , Child , Electrophysiological Phenomena , Female , Humans , Male , Middle Aged , Myasthenic Syndromes, Congenital/drug therapy , Myasthenic Syndromes, Congenital/genetics , Potassium Channel Blockers/pharmacology , Potassium Channel Blockers/therapeutic use , Pyridostigmine Bromide/pharmacology , Pyridostigmine Bromide/therapeutic use , Reflex/drug effects , Reflex/physiology , Synaptic Transmission/drug effects , Young AdultABSTRACT
Animal models of fragile X syndrome (FXS) suggest the impairment of the intracellular AKT messenger system, which is activated by neuregulin 1 (NRG1), a key regulator of neurodevelopment. We investigated NRG1-induced activation of the AKT and extracellular signal-regulated kinase (ERK) systems by the measurement of the phosphorylated AKT/ERK to total AKT/ERK ratio in peripheral B lymphoblasts of patients with FXS, IQ-matched controls with intellectual disability (obstetric complications, preterm birth, perinatal hypoxia, and low birth weight), and typically developed healthy participants. Results revealed that patients with FXS displayed decreased AKT but normal ERK activation after the administration of NRG1. IQ-matched controls with intellectual disability displayed intact AKT/ERK activation. In conclusion, FXS, but not intellectual disability associated with obstetric complications, is associated with decreased NRG1-induced AKT phosphorylation.
Subject(s)
Fragile X Syndrome/metabolism , Intellectual Disability/metabolism , MAP Kinase Signaling System , Neuregulin-1/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Adult , B-Lymphocytes/metabolism , Case-Control Studies , Female , Humans , Intellectual Disability/etiology , Male , Neuregulin-1/genetics , Obstetric Labor Complications/metabolism , Phosphorylation , Pregnancy , Proto-Oncogene Proteins c-akt/geneticsABSTRACT
Inherited ataxias are heterogeneous disorders affecting both children and adults, with over 40 different causative genes, making molecular genetic diagnosis challenging. Although recent advances in next-generation sequencing have significantly improved mutation detection, few treatments exist for patients with inherited ataxia. In two patients with adult-onset cerebellar ataxia and coenzyme Q10 (CoQ10) deficiency in muscle, whole exome sequencing revealed mutations in ANO10, which encodes anoctamin 10, a member of a family of putative calcium-activated chloride channels, and the causative gene for autosomal recessive spinocerebellar ataxia-10 (SCAR10). Both patients presented with slowly progressive ataxia and dysarthria leading to severe disability in the sixth decade. Epilepsy and learning difficulties were also present in one patient, while retinal degeneration and cataract were present in the other. The detection of mutations in ANO10 in our patients indicate that ANO10 defects cause secondary low CoQ10 and SCAR10 patients may benefit from CoQ10 supplementation.