Autosomal Recessive Spinocerebellar Ataxia Type Research Articles

Autosomal Recessive Spinocerebellar Ataxia Type 9 With a Response to Phosphate Repletion: A Case Report.

Autosomal recessive spinocerebellar ataxia type 9 (SCAR9) has received attention due to its potential response to coenzyme Q10 (CoQ10) supplementation; however, the response has so far been limited and variable. We report a SCAR9 patient with severe hypophosphatemia who responded well to CoQ10 and phosphate repletion. A 70-year-old man (the offspring of a consanguineous marriage) presented with cerebellar ataxia and intense fatigue after exercise. Whole-exome sequencing identified a novel homozygous deletion mutation (NM_020247.5:c.1218_1219del) in COQ8A. We thus diagnosed him with SCAR9. Supplementation of CoQ10 alleviated his symptoms, with the Scale for the Assessment and Rating of Ataxia (SARA) dropping from 16 to 14. During the course of the disease, he demonstrated continuous hypophosphatemia caused by renal phosphate wasting. Gait dysfunction due to weakness and eye movement was partially alleviated, and SARA dropped from 17 to 13 after phosphate repletion. Phosphate repletion should be considered for patients with severe hypophosphatemia without any apparent subjective symptoms. In this case, phosphate repletion could have improved myopathy leading to partial improvement in the patient's symptoms. Further analyses regarding the association between COQ8A mutation and phosphate wasting are required to elucidate the detailed pathogenesis. This provides Class IV evidence. This is a single observational study without controls.

Clinical, neuropathological, and genetic characterization of STUB1 variants in cerebellar ataxias: a frequent cause of predominant cognitive impairment

PurposePathogenic variants in STUB1 were initially described in autosomal recessive spinocerebellar ataxia type 16 and dominant cerebellar ataxia with cerebellar cognitive dysfunction (SCA48). MethodsWe analyzed a large series of 440 index cerebellar ataxia cases, mostly with dominant inheritance. ResultsSTUB1 variants were detected in 50 patients. Age at onset and severity were remarkably variable. Cognitive impairment, predominantly frontal syndrome, was observed in 54% of STUB1 variant carriers, including five families with Huntington or frontotemporal dementia disease–like phenotypes associated with ataxia, while no STUB1 variant was found in 115 patients with frontotemporal dementia. We report neuropathological findings of a STUB1 heterozygous patient, showing massive loss of Purkinje cells in the vermis and major loss in the cerebellar hemispheres without atrophy of the pons, hippocampus, or cerebral cortex. This screening of STUB1 variants revealed new features: (1) the majority of patients were women (70%) and (2) “second hits” in AFG3L2, PRKCG, and TBP were detected in three families suggesting synergic effects. ConclusionOur results reveal an unexpectedly frequent (7%) implication of STUB1 among dominantly inherited cerebellar ataxias, and suggest that the penetrance of STUB1 variants could be modulated by other factors, including sex and variants in other ataxia-related genes.

CHIP mutations affect the heat shock response differently in human fibroblasts and iPSC-derived neurons.

ABSTRACTC-terminus of HSC70-interacting protein (CHIP) encoded by the gene STUB1 is a co-chaperone and E3 ligase that acts as a key regulator of cellular protein homeostasis. Mutations in STUB1 cause autosomal recessive spinocerebellar ataxia type 16 (SCAR16) with widespread neurodegeneration manifesting as spastic-ataxic gait disorder, dementia and epilepsy. CHIP−/− mice display severe cerebellar atrophy, show high perinatal lethality and impaired heat stress tolerance. To decipher the pathomechanism underlying SCAR16, we investigated the heat shock response (HSR) in primary fibroblasts of three SCAR16 patients. We found impaired HSR induction and recovery compared to healthy controls. HSPA1A/B transcript levels (coding for HSP70) were reduced upon heat shock but HSP70 remained higher upon recovery in patient- compared to control-fibroblasts. As SCAR16 primarily affects the central nervous system we next investigated the HSR in cortical neurons (CNs) derived from induced pluripotent stem cells of SCAR16 patients. We found CNs of patients and controls to be surprisingly resistant to heat stress with high basal levels of HSP70 compared to fibroblasts. Although heat stress resulted in strong transcript level increases of many HSPs, this did not translate into higher HSP70 protein levels upon heat shock, independent of STUB1 mutations. Furthermore, STUB1(−/−) neurons generated by CRISPR/Cas9-mediated genome editing from an isogenic healthy control line showed a similar HSR to patients. Proteomic analysis of CNs showed dysfunctional protein (re)folding and higher basal oxidative stress levels in patients. Our results question the role of impaired HSR in SCAR16 neuropathology and highlight the need for careful selection of proper cell types for modeling human diseases.

A case of severe autosomal recessive spinocerebellar ataxia type 18 with a novel nonsense variant in GRID2

Autosomal-recessive spinocerebellar ataxia type 18 (SCAR18) is a rare neurologic disorder. It is caused by bi-allelic aberrations in the GRID2 gene, encoding an ionotropic glutamate receptor. In total, 20 affected individuals with mainly homozygous/compound heterozygous intragenic deletions/duplications, two different missense variants and one nonsense variant in GRID2 have been reported, so far. SCAR18 is characterized by delayed psychomotor development, intellectual disability, severely impaired gait due to cerebellar ataxia, ocular movement abnormalities, and cerebellar atrophy in brain imaging.By trio exome sequencing, we now identified a novel homozygous nonsense variant (c.568C > T; p.Gln190*) in GRID2 in a four year old female from a consanguineous family who presented with a particularly severe manifestation of SCAR18. The girl was born after an uneventful pregnancy and showed early-onset, profoundly delayed psychomotor development with no achieved psychomotor milestones at age 4 years. Additionally, she presented with severe muscular hypotonia, progressive truncal and appendicular ataxia, binocular vertical nystagmus, central hearing loss and incomplete loss of sight. She was dystrophic, interacted only very little and had behavioral anomalies such as eating hair and bruxism. Brain imaging showed cerebellar hypoplasia, extended cerebrospinal fluid spaces and beginning reduction of cerebral volume.Our findings further delineate the mutational and clinical spectrum of GRID2-associated spinocerebellar ataxia type 18 and indicate that homozygous nonsense variants are possibly associated with the severe end of the SCAR18 phenotypic spectrum.

The second case of dystonia associated with an autosomal recessive spinocerebellar ataxia type 16-the phenotype expanded. (948)

The second case of dystonia associated with an autosomal recessive spinocerebellar ataxia type 16-the phenotype expanded. (948)

Novel compound heterozygous mutations in the WWOX gene cause early infantile epileptic encephalopathy

Defects of WW domain-containing oxidoreductase (WWOX) has been associated with autosomal recessive spinocerebellar ataxia type 12 (SCAR12) and severe early-onset epileptic encephalopathy. The mutations in this gene can lead to global developmental delay, acquired microcephaly, and epilepsy. We report an infant with an autosomal recessive severe early-onset epileptic encephalopathy. Whole exome sequencing analysis was applied to the patient. Novel compound heterozygous mutations in the WWOX gene, c.173-2A > G and c.775 T > C (p.Ser259Pro), were identified. The present study expands our knowledge of WWOX mutations and related phenotypes, and provides new information on the genetic defects associated with this disease for clinical diagnosis.

The structural basis of lipid scrambling and inactivation in the endoplasmic reticulum scramblase TMEM16K

Membranes in cells have defined distributions of lipids in each leaflet, controlled by lipid scramblases and flip/floppases. However, for some intracellular membranes such as the endoplasmic reticulum (ER) the scramblases have not been identified. Members of the TMEM16 family have either lipid scramblase or chloride channel activity. Although TMEM16K is widely distributed and associated with the neurological disorder autosomal recessive spinocerebellar ataxia type 10 (SCAR10), its location in cells, function and structure are largely uncharacterised. Here we show that TMEM16K is an ER-resident lipid scramblase with a requirement for short chain lipids and calcium for robust activity. Crystal structures of TMEM16K show a scramblase fold, with an open lipid transporting groove. Additional cryo-EM structures reveal extensive conformational changes from the cytoplasmic to the ER side of the membrane, giving a state with a closed lipid permeation pathway. Molecular dynamics simulations showed that the open-groove conformation is necessary for scramblase activity.

WWOX-associated encephalopathies: identification of the phenotypic spectrum and the resulting genotype-phenotype correlation

Epileptic encephalopathies are a group of disorders in which epileptiform abnormalities cause progressive deterioration in cerebral function. Genetic causes have been described in several of the epileptic encephalopathies, and many previously unknown genes have been identified. WW domain-containing oxidoreductase (WWOX) has recently been implicated in autosomal recessive spinocerebellar ataxia type 12 (SCAR12) and severe early-onset epileptic encephalopathy. With whole-exome sequencing, we identified a homozygous WWOX missense mutation, p.Leu239Arg, in a girl from a consanguineous family with psychomotor developmental delay, acquired microcephaly, and epileptic seizures. WWOX-related epileptic encephalopathy is a rare condition but it should be considered in cases having early epileptic spasms and parental consanguinity.

P44. Facial onset sensory motor neuronopathy (FOSMN) syndrome – Evidence for an oligogenic entity, though no evidence of a genetic link to ALS

Facial onset sensory motor neuronopathy (FOSMN) syndrome is a rare sporadic entity which has only recently been described (Vucic et al., 2006). It is presumed to be neurodegenerative; its etiology however, remains unknown. Despite initial facial sensory symptoms, FOSMN syndrome has been linked to amyotrophic lateral sclerosis (ALS), a link which has recently been underpinned by a description of a D90A superoxide dismutase-1 (SOD-1) mutation in a case of FOSMN syndrome (Dalla Bella et al., 2014). We describe another case of a presumed FOSMN syndrome in a 70-year-old man. At the age of 56, the patient experienced facial and bulbar motor symptoms, though without prominent trigeminal sensory symptoms. He developed slow progressive mild dysarthria, dysphagia, and hoarseness, showing pronounced facial weakness, fasciculation, and myokymia, wasted furrowed tongue, but no upper or lower limb weakness or fasciculation or no upper motor neuron signs. Electrodiagnostic findings revealed an abnormal blink reflex, masseter reflex, masseteric silent period, and trigeminal SEPs. Nerve conduction studies showed a sensory-motor polyneuropathy predominantly demyelinating. A chronic neuropathy with predominant remyelination and regeneration, though without cellular infiltration or amyloid deposition, could be observed in a sural nerve biopsy. A pathologic trinucleotide CAG repeat expansion in the androgen receptor gene (spinal and bulbar muscular atrophy, Kennedy's disease) and a dynactin mutation were excluded by means of Sanger sequencing. Additionally, next-generation sequencing targeted to 242 neurodegeneration associated genes revealed a homozygous variant in the CYP2U1 gene (c.992A>G, p.N331S) and a heterozygous variant in the SYNE1 gene (c.6268G>C, p.E2090Q). These variants have yet to be described in genetic databases. No mutations could be detected among 26 screened ALS-related genes. Mutations in CYP2U1 can cause autosomal recessive inherited spastic paraplegia type 56 (SPG 56). Mutations in SYNE1 can cause either autosomal dominant Emery-Dreifuss muscular dystrophy-4 (EDMD4) or autosomal recessive spinocerebellar ataxia type 8 (SCAR8). The relationship between the CYP2U1 and SYNE1 variants and FOSMN syndrome established here requires further investigation. The genetic data presented showed no link between FOSMN syndrome and ALS, instead pointing towards evidence of an oligogenic basis for FOSMN syndrome.

WWOX-related encephalopathies: delineation of the phenotypical spectrum and emerging genotype-phenotype correlation

BackgroundHomozygous mutations in WWOX were reported in eight individuals of two families with autosomal recessive spinocerebellar ataxia type 12 and in two siblings with infantile epileptic encephalopathy (IEE), including one...

Autosomal Recessive Spinocerebellar Ataxia 7 (SCAR7) is Caused by Variants inTPP1, The Gene Involved in Classic Late-Infantile Neuronal Ceroid Lipofuscinosis 2 Disease (CLN2 Disease)

Spinocerebellar ataxias are phenotypically, neuropathologically, and genetically heterogeneous. The locus of autosomal recessive spinocerebellar ataxia type 7 (SCAR7) was previously linked to chromosome band 11p15. We have identified TPP1 as the causative gene for SCAR7 by exome sequencing. A missense and a splice site variant in TPP1, cosegregating with the disease, were found in a previously described SCAR7 family and also in another patient with a SCAR7 phenotype. TPP1, encoding the tripeptidyl-peptidase 1 enzyme, is known as the causative gene for late infantile neuronal ceroid lipofuscinosis disease 2 (CLN2 disease). CLN2 disease is characterized by epilepsy, loss of vision, ataxia, and a rapidly progressive course, leading to early death. SCAR7 patients showed ataxia and low activity of tripeptidyl-peptidase 1, but no ophthalmologic abnormalities or epilepsy. Also, the slowly progressive evolution of the disease until old age and absence of ultra structural curvilinear profiles is different from the known CLN2 phenotypes. Our findings now expand the phenotypes related to TPP1-variants to SCAR7. In spite of the limited sample size and measurements, a putative genotype-phenotype correlation may be drawn: we hypothesize that loss of function variants abolishing TPP1 enzyme activity lead to CLN2 disease, whereas variants that diminish TPP1 enzyme activity lead to SCAR7.