RESUMEN
BACKGROUND: Autosomal recessive spastic ataxia ofCharlevoix-Saguenay (ARSACS) is a rare neurodegenerative disorder characterizedby early-onset cerebellar ataxia, peripheral sensorimotor neuropathy, and lowerlimb spasticity. We present clinical andgenetic data of the first Bulgarian patients diagnosed with ARSACS by wholeexome sequencing (WES). METHODS: Variant filtering was performed usinglocally established pipeline and the selected variants were analysed by Sangersequencing. All patients underwent clinical examination and testingincluding the standard rating scales for spastic paraplegia and ataxia. RESULTS: Five different SACS gene variants, three of which novel, have been identified inpatients from three different ethnic groups. In addition to the classicalclinical triad, brain MRI revealed cerebellar atrophy, linear pontineT2-hypointensities, and hyperintense rim lateral tothalamus combined with retinal nerve fiber layer thickening on opticcoherence tomography (OCT). CONCLUSION: We expand the mutation, geographic, and phenotypic spectrum of ARSACS, adding Bulgaria to the world map of the disease, and drawing attention to the fact that it is still misdiagnosed. We demonstrated that brain MRI and OCT are necessary clinical tests for ARSACS diagnosis, even if one of the cardinal clinical features is lacking.
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Proteínas de Choque Térmico , Espasticidad Muscular , Ataxias Espinocerebelosas , Humanos , Masculino , Bulgaria , Ataxias Espinocerebelosas/genética , Ataxias Espinocerebelosas/patología , Ataxias Espinocerebelosas/congénito , Femenino , Espasticidad Muscular/genética , Espasticidad Muscular/patología , Espasticidad Muscular/diagnóstico , Espasticidad Muscular/diagnóstico por imagen , Proteínas de Choque Térmico/genética , Fenotipo , Niño , Adulto , Mutación , Adolescente , Imagen por Resonancia MagnéticaRESUMEN
Mutations in the SACS gene are associated with autosomal recessive spastic ataxia of Charlevoix-Saguenay disease (ARSACS) or complex clinical phenotypes of Charcot-Marie-Tooth disease (CMT). This study aimed to identify SACS mutations in a Korean CMT cohort with cerebellar ataxia and spasticity by whole exome sequencing (WES). As a result, eight pathogenic SACS mutations in four families were identified as the underlying causes of these complex phenotypes. The prevalence of CMT families with SACS mutations was determined to be 0.3%. All the patients showed sensory, motor, and gait disturbances with increased deep tendon reflexes. Lower limb magnetic resonance imaging (MRI) was performed in four patients and all had fatty replacements. Of note, they all had similar fatty infiltrations between the proximal and distal lower limb muscles, different from the neuromuscular imaging feature in most CMT patients without SACS mutations who had distal dominant fatty involvement. Therefore, these findings were considered a characteristic feature in CMT patients with SACS mutations. Although further studies with more cases are needed, our results highlight lower extremity MRI findings in CMT patients with SACS mutations and broaden the clinical spectrum. We suggest screening for SACS in recessive CMT patients with complex phenotypes of ataxia and spasticity.
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Enfermedad de Charcot-Marie-Tooth , Heterocigoto , Espasticidad Muscular , Mutación , Humanos , Masculino , Enfermedad de Charcot-Marie-Tooth/genética , Femenino , Adulto , República de Corea/epidemiología , Espasticidad Muscular/genética , Espasticidad Muscular/diagnóstico por imagen , Estudios de Cohortes , Persona de Mediana Edad , Imagen por Resonancia Magnética , Proteínas de Choque Térmico/genética , Linaje , Secuenciación del Exoma , Ataxia Cerebelosa/genética , Ataxia Cerebelosa/diagnóstico por imagen , Fenotipo , Adolescente , Adulto JovenRESUMEN
We present an infant referred to Developmental Paediatrics for delays, slow growth, hypotonia, esotropia and spasticity. Over the course of 2 months, the infant's exam progressed, demonstrating worsening spasticity and tonal changes in the setting of a normal brain MRI with acquired microcephaly. Genetic testing demonstrated a pathogenic CTNNB1 nonsense mutation. Following the discovery of the underlying cause for the child's clinical picture, the child was evaluated by therapeutic services and neurology, which was initially only available via asynchronous telehealth, due to a resource limited area. Cerebral palsy is a nonprogressive neurodevelopmental disorder and, when associated with developmental delay, qualifies for further genetic investigation into the underlying aetiology. Genetic testing recommendations exist for developmental delay, but there is no current algorithm regarding testing for cerebral palsy. Education and clear guidelines on genetic testing allow for better prognostication and potential treatment in cases of cerebral palsy, especially when associated with other disorders.
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Parálisis Cerebral , Discapacidades del Desarrollo , Espasticidad Muscular , beta Catenina , Humanos , Espasticidad Muscular/genética , Espasticidad Muscular/diagnóstico , Lactante , Discapacidades del Desarrollo/genética , Parálisis Cerebral/genética , beta Catenina/genética , Masculino , Codón sin Sentido , Femenino , Imagen por Resonancia Magnética , Pruebas GenéticasRESUMEN
Intellectual disability (ID), which affects around 2% to 3% of the population, accounts for 0.63% of the overall prevalence of neurodevelopmental disorders (NDD). ID is characterized by limitations in a person's intellectual and adaptive functioning, and is caused by pathogenic variants in more than 1000 genes. Here, we report a rare missense variant (c.350T>C; p.(Leu117Ser)) in HACE1 segregating with NDD syndrome with clinical features including ID, epilepsy, spasticity, global developmental delay, and psychomotor impairment in two siblings of a consanguineous Pakistani kindred. HACE1 encodes a HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 (HACE1), which is involved in protein ubiquitination, localization, and cell division. HACE1 is also predicted to interact with several proteins that have been previously implicated in the ID phenotype in humans. The p.(Leu117Ser) variant replaces an evolutionarily conserved residue of HACE1 and is predicted to be deleterious by various in silico algorithms. Previously, eleven protein truncating variants of HACE1 have been reported in individuals with NDD. However, to our knowledge, p.(Leu117Ser) is the second missense variant in HACE1 found in an individual with NDD.
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Mutación Missense , Trastornos del Neurodesarrollo , Ubiquitina-Proteína Ligasas , Humanos , Epilepsia/genética , Discapacidad Intelectual/genética , Espasticidad Muscular/genética , Trastornos del Neurodesarrollo/genética , Ubiquitina-Proteína Ligasas/genética , Pakistán , Consanguinidad , Masculino , Femenino , Adulto , Análisis Mutacional de ADNRESUMEN
While biallelic POLR3A loss-of-function variants are traditionally linked to hypomyelinating leukodystrophy, patients with a specific splice variant c.1909+22G>A manifest as adolescent-onset spastic ataxia without overt leukodystrophy. In this study, we reported eight new cases, POLR3A-related disorder with c.1909+22 variant. One of these patients showed expanded phenotypic spectrum of generalised dystonia and her sister remained asymptomatic except for hypodontia. Two patients with dystonic arm tremor responded to deep brain stimulation. In our systemic literature review, we found that POLR3A-related disorder with c.1909+22 variant has attenuated disease severity but frequency of dystonia and upper limb tremor did not differ among genotypes.
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Estimulación Encefálica Profunda , Distonía , ARN Polimerasa III , Humanos , Femenino , ARN Polimerasa III/genética , Distonía/genética , Distonía/terapia , Adolescente , Masculino , Espasticidad Muscular/genética , Espasticidad Muscular/terapia , Adulto , Ataxias Espinocerebelosas/genética , Ataxias Espinocerebelosas/terapia , Ataxias Espinocerebelosas/fisiopatología , Adulto Joven , Niño , Discapacidad Intelectual , Atrofia ÓpticaRESUMEN
The aim of this study was to develop a model to predict individual subject disease trajectories including parameter uncertainty and accounting for missing data in rare neurological diseases, showcased by the ultra-rare disease Autosomal-Recessive Spastic Ataxia Charlevoix Saguenay (ARSACS). We modelled the change in SARA (Scale for Assessment and Rating of Ataxia) score versus Time Since Onset of symptoms using non-linear mixed effect models for a population of 173 patients with ARSACS included in the prospective real-world multicenter Autosomal Recessive Cerebellar Ataxia (ARCA) registry. We used the Multivariate Imputation Chained Equation (MICE) algorithm to impute missing covariates, and a covariate selection procedure with a pooled p-value to account for the multiply imputed data sets. We then investigated the impact of covariates and population parameter uncertainty on the prediction of the individual trajectories up to 5 years after their last visit. A four-parameter logistic function was selected. Men were estimated to have a 25% lower SARA score at disease onset and a moderately higher maximum SARA score, and time to progression (T50) was estimated to be 35% lower in patients with age of onset over 15 years. The population disease progression rate started slowly at 0.1 points per year peaking to a maximum of 0.8 points per year (at 36.8 years since onset of symptoms). The prediction intervals for SARA scores 5 years after the last visit were large (median 7.4 points, Q1-Q3: 6.4-8.5); their size was mostly driven by individual parameter uncertainty and individual disease progression rate at that time.
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Progresión de la Enfermedad , Espasticidad Muscular , Ataxias Espinocerebelosas , Adolescente , Adulto , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Espasticidad Muscular/genética , Estudios Prospectivos , Enfermedades Raras/genética , Sistema de Registros , Índice de Severidad de la Enfermedad , Ataxias Espinocerebelosas/genética , Ataxias Espinocerebelosas/congénito , Incertidumbre , Recién Nacido , Lactante , PreescolarRESUMEN
Heterozygous RTN2 variants have been previously identified in a limited cohort of families affected by autosomal dominant spastic paraplegia (SPG12-OMIM:604805) with a variable age of onset. Nevertheless, the definitive validity of SPG12 remains to be confidently confirmed due to the scarcity of supporting evidence. In this study, we identified and validated seven novel or ultra-rare homozygous loss-of-function RTN2 variants in 14 individuals from seven consanguineous families with distal hereditary motor neuropathy (dHMN) using exome, genome and Sanger sequencing coupled with deep-phenotyping. All affected individuals (seven males and seven females, aged 9-50â years) exhibited weakness in the distal upper and lower limbs, lower limb spasticity and hyperreflexia, with onset in the first decade of life. Nerve conduction studies revealed axonal motor neuropathy with neurogenic changes in the electromyography. Despite a slowly progressive disease course, all patients remained ambulatory over a mean disease duration of 19.71 ± 13.70â years. Characterization of Caenorhabditis elegans RTN2 homologous loss-of-function variants demonstrated morphological and behavioural differences compared with the parental strain. Treatment of the mutant with an endoplasmic/sarcoplasmic reticulum Ca2+ reuptake inhibitor (2,5-di-tert-butylhydroquinone) rescued key phenotypic differences, suggesting a potential therapeutic benefit for RTN2-disorder. Despite RTN2 being an endoplasmic reticulum (ER)-resident membrane shaping protein, our analysis of patient fibroblast cells did not find significant alterations in ER structure or the response to ER stress. Our findings delineate a distinct form of autosomal recessive dHMN with pyramidal features associated with RTN2 deficiency. This phenotype shares similarities with SIGMAR1-related dHMN and Silver-like syndromes, providing valuable insights into the clinical spectrum and potential therapeutic strategies for RTN2-related dHMN.
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Linaje , Humanos , Masculino , Femenino , Niño , Adulto , Adolescente , Adulto Joven , Persona de Mediana Edad , Animales , Extremidad Inferior/fisiopatología , Caenorhabditis elegans , Espasticidad Muscular/genética , Espasticidad Muscular/fisiopatología , Paraplejía Espástica Hereditaria/genética , Paraplejía Espástica Hereditaria/fisiopatología , MutaciónRESUMEN
Objective: To explore the diagnosis and treatment of adolescence-onset methylenetetrahydrofolate reductase (MTHFR) deficiency. Methods: This was a retrospective case study. Nine patients with adolescence-onset MTHFR deficiency were diagnosed at Peking University First Hospital from January 2016 to December 2022, and followed up for more than 1 year. Their general information, clinical manifestations, laboratory tests, cranial images, MTHFR gene variants, diagnosis, treatment, and outcome were analyzed retrospectively. Results: The 9 patients came from 8 families. They had symptoms at age of 8.0 years to 17.0 years and diagnosed at 9.0 years to 17.5 years. Eight were male and 1 was female. Two patients were brothers, the elder brother developed abnormal gait at 17.0 years; and the younger brother was then diagnosed at 15.0 years of age and treated at the asymptomatic stage, who was 18.0 years old with normal condition during this study. The main manifestations of the 8 symptomatic patients included progressive dyskinesia and spastic paralysis of the lower limbs, with or without intellectual decline, cognitive impairment and behavioral abnormalities. Totally, 15 variants of MTHFR gene were identified in the 9 patients, including 8 novel variants. Five patients had brain image abnormalities. Increased plasma total homocysteine level (65-221 µmol/L) was found in all patients, and decreased to 20-70 µmol/L after treatment with betaine and calcium folinate. Besides, the 8 symptomatic patients had their behavior and cognitive problems significantly improved, with a legacy of lower limb motor disorders. Conclusions: Late-onset MTHFR deficiency can occur in adolescence. The diagnosis is usually delayed because of non-specific clinical symptoms. The test of blood total homocysteine could be used as a selective screening test. Eight novel varients of MTHFR gene were identified. Timely treatment can improve clinical condition significantly, and pre-symptomatic treatment may prevent brain damage.
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Metilenotetrahidrofolato Reductasa (NADPH2) , Espasticidad Muscular , Adolescente , Niño , Femenino , Humanos , Masculino , Homocisteína/uso terapéutico , Homocistinuria , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/deficiencia , Espasticidad Muscular/diagnóstico , Espasticidad Muscular/genética , Espasticidad Muscular/tratamiento farmacológico , Trastornos Psicóticos , Estudios RetrospectivosRESUMEN
Spastic Ataxias (SA) are a group of neurodegenerative disorders with combined pyramidal and cerebellar system affection, leading to an overlap phenotype between Hereditary Spastic Paraplegias (HSP) and Cerebellar Ataxias (CA). Here we describe the generation of iPSCs from three unrelated patients with an ultra-rare subtype of SA caused by compound heterozygous mutations in POLR3A, that encodes the largest subunit of RNA polymerase III. iPSCs were reprogrammed from normal human dermal fibroblasts (NHDFs) using episomal reprogramming with integration-free plasmid vectors: HIHRSi004-A, derived from a 44 year-old male carrying the mutations c.1909 + 22G > A/c.3944_3945delTG, HIHRSi005-A obtained from a 66 year-old male carrying the mutations c.1909 + 22G > A/c.1531C > T, and HIHRSi006-A from a 27 year-old male carrying the mutations c.1909 + 22G > A/c.2472_2472delC (ENST00000372371.8).
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Células Madre Pluripotentes Inducidas , Discapacidad Intelectual , Atrofia Óptica , Ataxias Espinocerebelosas , Adulto , Anciano , Humanos , Masculino , Línea Celular , Células Madre Pluripotentes Inducidas/metabolismo , Espasticidad Muscular/genética , Mutación , ARN Polimerasa III/genética , ARN Polimerasa III/metabolismo , Ataxias Espinocerebelosas/genéticaRESUMEN
Spasticity, affecting â¼75% of patients with spinal cord injury (SCI), leads to hyperreflexia, muscle spasms, and cocontractions of antagonist muscles, greatly affecting their quality of life. Spasticity primarily stems from the hyperexcitability of motoneurons below the lesion, driven by an upregulation of the persistent sodium current and a downregulation of chloride extrusion. This imbalance results from the post-SCI activation of calpain1, which cleaves Nav1.6 channels and KCC2 cotransporters. Our study was focused on mitigating spasticity by specifically targeting calpain1 in spinal motoneurons. We successfully transduced lumbar motoneurons in adult rats with SCI using intrathecal administration of adeno-associated virus vector serotype 6, carrying a shRNA sequence against calpain1. This approach significantly reduced calpain1 expression in transduced motoneurons, leading to a noticeable decrease in spasticity symptoms, including hyperreflexia, muscle spasms, and cocontractions in hindlimb muscles, which are particularly evident in the second month post-SCI. In addition, this decrease, which prevented the escalation of spasticity to a severe grade, paralleled the restoration of KCC2 levels in transduced motoneurons, suggesting a reduced proteolytic activity of calpain1. These findings demonstrate that inhibiting calpain1 in motoneurons is a promising strategy for alleviating spasticity in SCI patients.
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Traumatismos de la Médula Espinal , Simportadores , Animales , Ratas , Neuronas Motoras/metabolismo , Espasticidad Muscular/genética , Espasticidad Muscular/terapia , Calidad de Vida , Reflejo Anormal , Espasmo/metabolismo , Espasmo/patología , Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/complicaciones , Traumatismos de la Médula Espinal/genética , Traumatismos de la Médula Espinal/terapia , Simportadores/genéticaRESUMEN
PURPOSE: To provide an overview of outcome and complications of selective dorsal rhizotomy (SDR) and intrathecal baclofen pump implantation (ITB) for spasticity treatment in children with hereditary spastic paraplegia (HSP). METHODS: Retrospective study including children with HSP and SDR or ITB. Gross motor function measure (GMFM-66) scores and level of spasticity were assessed. RESULTS: Ten patients were included (most had mutations in ATL1 (n = 4) or SPAST (n = 3) genes). Four walked without and two with walking aids, four were non-walking children. Six patients underwent SDR, three patients ITB, and one both. Mean age at surgery was 8.9 ± 4.5 years with a mean follow-up of 3.4 ± 2.2 years. Five of the SDR patients were walking. Postoperatively spasticity in the legs was reduced in all patients. The change in GMFM-66 score was + 8.0 (0-19.7 min-max). The three ITB patients treated (SPAST (n = 2) and PNPLA6 (n = 1) gene mutation) were children with a progressive disease course. No complications of surgery occurred. CONCLUSIONS: SDR is a feasible treatment option in carefully selected children with HSP, especially in walking patients. The majority of patients benefit with respect to gross motor function, complication risk is low. ITB was used in children with severe and progressive disease.
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Parálisis Cerebral , Paraplejía Espástica Hereditaria , Niño , Humanos , Adolescente , Preescolar , Estudios Retrospectivos , Paraplejía Espástica Hereditaria/genética , Paraplejía Espástica Hereditaria/cirugía , Paraplejía Espástica Hereditaria/complicaciones , Parálisis Cerebral/complicaciones , Espasticidad Muscular/genética , Espasticidad Muscular/cirugía , Baclofeno/uso terapéutico , Rizotomía/métodos , Resultado del Tratamiento , EspastinaRESUMEN
BACKGROUND: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), classically presenting as a triad of early-onset cerebellar ataxia, lower extremity spasticity and peripheral neuropathy, is caused by mutations in SACS gene which encodes the protein sacsin. OBJECTIVE: To provide new insight into the occurrence of SACS mutations in South India. METHODS: Patients with three cardinal features of ARSACS-peripheral neuropathy, cerebellar ataxia, and pyramidal tract signs were included. Nine patients were clinically identified and genetically evaluated. Mutation screening of SACS by targeted sequencing of 40 recessive ataxia genes panel by next-generation sequencing was conducted. Additional investigations included magnetic resonance imaging (MRI), fundoscopy, optical coherence tomography (OCT) and nerve conduction studies (NCS). Functional disability was assessed by the Spinocerebellar Degeneration Functional Score. RESULTS: Two hundred and fifteen cerebellar ataxia patients were screened, and 9 patients with cerebellar ataxia with spasticity, peripheral neuropathy and MRI brain characteristics, consistent with a clinical diagnosis of ARSACS were identified, of which 7 patients were identified to have mutation in the SACS gene and are detailed hereafter. Age of presentation ranged from 20 to 55 years (29.8 ± 11.9) with a mean disease duration of 12.7 years (SD-7.65, range 5-22 years). All except one had onset of symptoms in the form of an ataxic gait noticed before 20 years of age. Additional features were subnormal intelligence (4/7), slow and hypometric saccades (1/7), seizures (1/7), kyphoscoliosis (1/7) and dysmorphic facies (1/7). SDFS was 3 in 5/7 patients signifying moderate disability with independent ambulation. MRI showed cerebellar atrophy with predominant atrophy of the superior vermis (7/7), horizontal linear T2 hypointensities in the pons(7/7), hyperintensities where lateral pons merges with the middle cerebellar peduncle (MCP) (7/7) well seen in fluid-attenuated inversion recovery (FLAIR) images, thickening of MCP (3/7), symmetric lateral thalamic hyperintensities (6/7), posterior fossa arachnoid cyst (4/7),thinning of posterior mid-body of corpus callosum (7/7), marginal mineralisation of the basal ganglia (7/7), bilateral parietal atrophy (7/7) and thinning of corticospinal tract on diffusion tensor imaging (DTI) (7/7). We identified pathogenic homozygous frameshift mutations in the SACS gene in six patients (including two siblings), while one patient had a heterozygous pathogenic deletion. CONCLUSIONS: This is the largest series of genetically confirmed ARSACS patients from India highlighting the clinical, ophthalmological, imaging and genetic features of this cohort.
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Ataxia Cerebelosa , Enfermedades del Sistema Nervioso Periférico , Ataxias Espinocerebelosas/congénito , Humanos , Adulto Joven , Adulto , Persona de Mediana Edad , Ataxia Cerebelosa/diagnóstico por imagen , Ataxia Cerebelosa/genética , Imagen de Difusión Tensora , Mutación/genética , Espasticidad Muscular/diagnóstico por imagen , Espasticidad Muscular/genética , AtrofiaRESUMEN
A 48-year-old man was referred to the movement disorders clinic for 10 years of progressive slurred speech, spasticity, limb incoordination, and wide-based gait. Extensive neurologic workup was inconclusive, including serum and CSF testing, neuroimaging, EMG/NCS, exome sequencing, and mitochondrial testing. An ataxia repeat expansion panel ultimately revealed the final diagnosis. In this report, we review the clinical characteristics of a rare, late-onset, autosomal recessive cerebellar ataxia and discuss the importance of pursuing targeted gene testing to avoid diagnostic delays, especially as new treatments for this and other genetic diseases become available.
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Ataxia Cerebelosa , Degeneraciones Espinocerebelosas , Masculino , Humanos , Persona de Mediana Edad , Ataxia Cerebelosa/diagnóstico , Ataxia Cerebelosa/genética , Ataxia , Espasticidad Muscular/diagnóstico , Espasticidad Muscular/genética , Razonamiento ClínicoRESUMEN
Tubulinopathies encompass neurodevelopmental disorders caused by mutations in genes encoding for different isotypes of α- and ß-tubulins, the structural components of microtubules. Less frequently, mutations in tubulins may underlie neurodegenerative disorders. In the present study, we report two families, one with 11 affected individuals and the other with a single patient, carrying a novel, likely pathogenic, variant (p. Glu415Lys) in the TUBA4A gene (NM_006000). The phenotype, not previously described, is that of spastic ataxia. Our findings widen the phenotypic and genetic manifestations of TUBA4A variants and add a new type of spastic ataxia to be taken into consideration in the differential diagnosis.
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Discapacidad Intelectual , Atrofia Óptica , Paraplejía Espástica Hereditaria , Ataxias Espinocerebelosas , Humanos , Ataxias Espinocerebelosas/genética , Ataxias Espinocerebelosas/patología , Atrofia Óptica/genética , Espasticidad Muscular/genética , Espasticidad Muscular/patología , Discapacidad Intelectual/genética , Mutación/genética , Fenotipo , Paraplejía Espástica Hereditaria/genéticaRESUMEN
OBJECTIVE: To explore the clinical feature and genetic variant of a child with autosomal recessive Charlevoix-Saguenay type spastic ataxia (ARSACS). METHODS: Clinical data of a child who was admitted to the West China Second Hospital of Sichuan University on April 30, 2021 was collected. Whole exome sequencing (WES) was carried out for the child and his parents. Candidate variants were verified by Sanger sequencing and bioinformatic analysis based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). RESULTS: The child, a 3-year-and-3-month-old female, had a complain of "walking instability for over a year". Physical and laboratory examination revealed progressive and aggravated gait instability, increased muscle tone of the right limbs, peripheral neuropathy of the lower limbs, and thickening of retinal nerve fiber layer. The results of WES revealed that she has harbored a maternally derived heterozygous deletion of exons 1 to 10 of the SACS gene, in addition with a de novo heterozygous c.3328dupA variant in exon 10 of the SACS gene. Based on the ACMG guidelines, the exons 1-10 deletion was rated as likely pathogenic (PVS1+PM2_Supporting), and the c.3328dupA was rated as a pathogenic variant (PVS1_Strong+PS2+PM2_Supporting). Neither variant was recorded in the human population databases. CONCLUSION: The c.3328dupA variant and the deletion of exons 1-10 of the SACS gene probably underlay the ARSACS in this patient.
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Proteínas de Choque Térmico , Ataxias Espinocerebelosas , Femenino , Humanos , Proteínas de Choque Térmico/genética , Espasticidad Muscular/genética , Mutación , Ataxias Espinocerebelosas/genética , Ataxias Espinocerebelosas/patología , PreescolarRESUMEN
ATP1A3 encodes the α3 subunit of the sodium-potassium ATPase, one of two isoforms responsible for powering electrochemical gradients in neurons. Heterozygous pathogenic ATP1A3 variants produce several distinct neurological syndromes, yet the molecular basis for phenotypic variability is unclear. We report a novel recurrent variant, ATP1A3(NM_152296.5):c.2324C>T; p.(Pro775Leu), in nine individuals associated with the primary clinical features of progressive or non-progressive spasticity and developmental delay/intellectual disability. No patients fulfil diagnostic criteria for ATP1A3-associated syndromes, including alternating hemiplegia of childhood, rapid-onset dystonia-parkinsonism or cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss (CAPOS), and none were suspected of having an ATP1A3-related disorder. Uniquely among known ATP1A3 variants, P775L causes leakage of sodium ions and protons into the cell, associated with impaired sodium binding/occlusion kinetics favouring states with fewer bound ions. These phenotypic and electrophysiologic studies demonstrate that ATP1A3:c.2324C>T; p.(Pro775Leu) results in mild ATP1A3-related phenotypes resembling complex hereditary spastic paraplegia or idiopathic spastic cerebral palsy. Cation leak provides a molecular explanation for this genotype-phenotype correlation, adding another mechanism to further explain phenotypic variability and highlighting the importance of biophysical properties beyond ion transport rate in ion transport diseases.
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Ataxia Cerebelosa , Discapacidad Intelectual , Humanos , Mutación/genética , Síndrome , Discapacidad Intelectual/genética , Ataxia Cerebelosa/genética , Fenotipo , Espasticidad Muscular/genética , Cationes , ATPasa Intercambiadora de Sodio-Potasio/genéticaRESUMEN
Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS) is now increasingly identified from all countries over the world, possibly rendering it one of the most common autosomal recessive ataxias. Here, we selected patients harboring SACS variants, the causative gene for ARSACS, in a large cohort of 137 patients with early-onset ataxia recruited from May 2019 to May 2021 and were referred to the ataxia clinic. Genetic studies were performed for 111 out of 137 patients (81%) which led to a diagnostic rate of 72.9% (81 out of 111 cases). Ten patients with the molecular diagnosis of ARSACS were identified. We investigated the phenotypic and imaging spectra of all confirmed patients with ARSACS. We also estimated the frequency of ARSACS in this cohort and described their clinical and genetic findings including seven novel variants as well as novel neuroimaging findings. While the classic clinical triad of ARSACS is progressive cerebellar ataxia, spasticity, and sensorimotor polyneuropathy, it is not a constant feature in all patients. Sensorimotor axonal-demyelinating neuropathy was detected in all of our patients, but spasticity and extensor plantar reflex were absent in 50% (5/10). In all patients, brain magnetic resonance imaging (MRI) showed symmetric linear hypointensities in the pons (pontine stripes) and anterior superior cerebellar atrophy as well as a hyperintense rim around the thalami (thalamic rim). Although infratentorial arachnoid cyst has been reported in ARSACS earlier, we report anterior temporal arachnoid cyst in two patients for the first time, indicating that arachnoid cyst may be an associated imaging feature of ARSACS. We also extended molecular spectrum of ARSACS by presenting 8 pathogenic and one variant of unknown significance (VUS) sequence variants, which 7 of them have not been reported previously. MetaDome server confirmed that the identified VUS variant was in the intolerant regions of sacsin protein encoded by SACS.
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Ataxia Cerebelosa , Quistes , Ataxias Espinocerebelosas , Humanos , Irán , Mutación/genética , Ataxias Espinocerebelosas/diagnóstico por imagen , Ataxias Espinocerebelosas/genética , Espasticidad Muscular/diagnóstico por imagen , Espasticidad Muscular/genética , NeuroimagenRESUMEN
This case report describes the optic nerve features of a male patient aged 23 years with a diagnosis of autosomal recessive spastic ataxia of Charlevoix-Saguenay.
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Ataxias Espinocerebelosas , Humanos , Ataxias Espinocerebelosas/diagnóstico por imagen , Ataxias Espinocerebelosas/genética , Espasticidad Muscular/diagnóstico por imagen , Espasticidad Muscular/genética , Nervio Óptico/diagnóstico por imagenRESUMEN
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare and early-onset neurodegenerative disease caused by variants of the SACS gene which maps to chromosome 13q11 and encodes sacsin protein. Sacsin is highly expressed in large motor neurons, in particular cerebellar Purkinje cells. This article has provided a review for the structure and function of sacsin protein and the mechanisms underlying abnormalities of sacsin in ARSACS disease.
Asunto(s)
Humanos , Ataxias Espinocerebelosas/patología , Ataxia/genética , Espasticidad Muscular/genéticaRESUMEN
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare and early-onset neurodegenerative disease caused by variants of the SACS gene which maps to chromosome 13q11 and encodes sacsin protein. Sacsin is highly expressed in large motor neurons, in particular cerebellar Purkinje cells. This article has provided a review for the structure and function of sacsin protein and the mechanisms underlying abnormalities of sacsin in ARSACS disease.