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1.
J Clin Neurosci ; 66: 269-270, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31178302

RESUMO

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late onset neurodegenerative disorder associated with dysfunction of movement, memory, and the peripheral nervous system. We report an 82 years old male who presented with tremors and difficulty with balance that started at 65 years of age. His motor examination revealed decreased strength in left lower extremity. Tremors were seen in both the upper limbs at rest that worsened with movement. Bilateral lower extremities showed absent vibration and proprioception sensations, absent reflexes and upgoing toes. Electrodiagnostic studies revealed sensory predominant axonal sensory-motor peripheral polyneuropathy. Brain MRI revealed microvascular ischemic changes. The cervical and lumbar MRI showed diffuse degenerative changes. Genetic test for heritable causes of ataxia revealed a premutation in Fragile X gene (84 CGG repeats), confirming the diagnosis of FXTAS. On further genetic testing three out of his four daughters also tested positive for the FMR1 premutation. In appropriate clinical setting, Fragile X-associated tremor/ataxia syndrome (FXTAS) should be considered in every middle aged/elderly patient who presented with slowly progressive ataxia, tremor and peripheral polyneuropathy without any history of cognitive or neurological disabilities in childhood.


Assuntos
Ataxia/diagnóstico , Ataxia/genética , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/diagnóstico , Síndrome do Cromossomo X Frágil/genética , Tremor/diagnóstico , Tremor/genética , Idoso de 80 Anos ou mais , Testes Genéticos/métodos , Humanos , Masculino
3.
N Engl J Med ; 380(15): 1433-1441, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30970188

RESUMO

We report an inborn error of metabolism caused by an expansion of a GCA-repeat tract in the 5' untranslated region of the gene encoding glutaminase (GLS) that was identified through detailed clinical and biochemical phenotyping, combined with whole-genome sequencing. The expansion was observed in three unrelated patients who presented with an early-onset delay in overall development, progressive ataxia, and elevated levels of glutamine. In addition to ataxia, one patient also showed cerebellar atrophy. The expansion was associated with a relative deficiency of GLS messenger RNA transcribed from the expanded allele, which probably resulted from repeat-mediated chromatin changes upstream of the GLS repeat. Our discovery underscores the importance of careful examination of regions of the genome that are typically excluded from or poorly captured by exome sequencing.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/genética , Ataxia/genética , Deficiências do Desenvolvimento/genética , Glutaminase/deficiência , Glutaminase/genética , Glutamina/metabolismo , Repetições de Microssatélites , Mutação , Atrofia/genética , Cerebelo/patologia , Pré-Escolar , Feminino , Genótipo , Glutamina/análise , Humanos , Masculino , Fenótipo , Reação em Cadeia da Polimerase , Sequenciamento Completo do Genoma
4.
Eur J Paediatr Neurol ; 23(3): 438-447, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30928199

RESUMO

BACKGROUND: Pathogenic variants in SCN2A are associated with various neurological disorders including epilepsy, autism spectrum disorder and intellectual disability. Few reports have recently described SCN2A-associated episodic ataxia (EA). Our study identifies its broader clinical and genetic spectrum, and describes pharmacological approaches. RESULTS: We report 21 patients with SCN2A-associated EA, of which 9 are unpublished cases. The large majority of patients present with epileptic seizures (18/21, 86%), often starting within the first three months of life (12/18, 67%). In contrast, onset of episodic ataxia ranged from 10 months to 14 years of age. The frequency of EA episodes ranged from brief, daily events up to 1-2 episodes per year each lasting several weeks. Potential triggers include minor head traumas and sleep deprivation. Cognitive outcome is favorable in most patients with normal or mildly impaired cognitive development in 17/21 patients (81%). No clear genotype-phenotype correlations were identified in this cohort. However, two mutational hotspots were identified, i.e. 7/21 patients (33%) harbor the identical pathogenic variant p.A263V, whereas 5/21 (24%) carry pathogenic variants that affect the S4 segment and its cytoplasmic loop within the domain IV. In addition, we identified six novel pathogenic variants in SCN2A. While acetazolamide was previously reported as beneficial in SCN2A-associated EA in one case, our data show a conflicting response in 8 additional patients treated with acetazolamide: three of them profited from acetazolamide treatment, while 5/8 did not. CONCLUSIONS: Our study describes the heterogeneous clinical spectrum of SCN2A-associated EA, identifies two mutational hotspots and shows positive effects of acetazolamide in about 50%.


Assuntos
Ataxia/genética , Canal de Sódio Disparado por Voltagem NAV1.2/genética , Acetazolamida/uso terapêutico , Adulto , Anticonvulsivantes/uso terapêutico , Ataxia/tratamento farmacológico , Estudos de Coortes , Feminino , Humanos , Lactente , Masculino , Mutação
5.
Gene ; 704: 113-120, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30974196

RESUMO

Usher syndrome (USH) is a clinically common autosomal recessive disorder characterized by retinitis pigmentosa (RP) and sensorineural hearing loss with or without vestibular dysfunction. In this study, we identified a Hunan family of Chinese descent with two affected members clinically diagnosed with Usher syndrome type 3 (USH3) displaying hearing, visual acuity, and olfactory decline. Whole-exome sequencing (WES) identified a nonsense variant in ABHD12 gene that was confirmed to be segregated in this family by Sanger sequencing and exhibited a recessive inheritance pattern. In this family, two patients carried homozygous variant in the ABHD12 (NM_015600: c.249C>G). Mutation of ABHD12, an enzyme that hydrolyzes an endocannabinoid lipid transmitter, caused incomplete PHARC syndrome, as demonstrated in previous reports. Therefore, we also conducted a summary based on variants in ABHD12 in PHARC patients, and in PHARC patients showing that there was no obvious correlation between the genotype and phenotype. We believe that this should be considered during the differential diagnosis of USH. Our findings predicted the potential function of this gene in the development of hearing and vision loss, particularly with regard to impaired signal transmission, and identified a novel nonsense variant to expand the variant spectrum in ABHD12.


Assuntos
Códon sem Sentido , Monoacilglicerol Lipases/genética , Síndromes de Usher/genética , Adulto , Idoso , Ataxia/genética , Ataxia/patologia , Catarata/genética , Catarata/patologia , Criança , Família , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Homozigoto , Humanos , Masculino , Linhagem , Fenótipo , Polineuropatias/genética , Polineuropatias/patologia , Retinite Pigmentosa/genética , Retinite Pigmentosa/patologia , Síndromes de Usher/patologia , Sequenciamento Completo do Exoma
6.
Nat Genet ; 51(4): 649-658, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30926972

RESUMO

Late-onset ataxia is common, often idiopathic, and can result from cerebellar, proprioceptive, or vestibular impairment; when in combination, it is also termed cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). We used non-parametric linkage analysis and genome sequencing to identify a biallelic intronic AAGGG repeat expansion in the replication factor C subunit 1 (RFC1) gene as the cause of familial CANVAS and a frequent cause of late-onset ataxia, particularly if sensory neuronopathy and bilateral vestibular areflexia coexist. The expansion, which occurs in the poly(A) tail of an AluSx3 element and differs in both size and nucleotide sequence from the reference (AAAAG)11 allele, does not affect RFC1 expression in patient peripheral and brain tissue, suggesting no overt loss of function. These data, along with an expansion carrier frequency of 0.7% in Europeans, implies that biallelic AAGGG expansion in RFC1 is a frequent cause of late-onset ataxia.


Assuntos
Ataxia/genética , Íntrons/genética , Sequências Repetitivas de Ácido Nucleico/genética , Proteína de Replicação C/genética , Adulto , Idoso , Alelos , Ataxia Cerebelar/genética , Humanos , Masculino , Pessoa de Meia-Idade , Sequenciamento Completo do Genoma/métodos
7.
Mol Brain ; 12(1): 19, 2019 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-30866998

RESUMO

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS [MIM 270550]) is an early-onset neurodegenerative disorder caused by mutations in the SACS gene. Over 200 SACS mutations have been identified. Most mutations lead to a complete loss of a sacsin, a large 520 kD protein, although some missense mutations are associated with low levels of sacsin expression. We previously showed that Sacs knock-out mice demonstrate early-onset ataxic phenotype with neurofilament bundling in many neuronal populations. To determine if the preservation of some mutated sacsin protein resulted in the same cellular and behavioral alterations, we generated mice expressing an R272C missense mutation, a homozygote mutation found in some affected patients. Though SacsR272C mice express 21% of wild type brain sacsin and sacsin is found in many neurons, they display similar abnormalities to Sacs knock-out mice, including the development of an ataxic phenotype, reduced Purkinje cell firing rates, and somatodendritic neurofilament bundles in Purkinje cells and other neurons. Together our results support that Sacs missense mutation largely lead to loss of sacsin function.


Assuntos
Ataxia/genética , Ataxia/fisiopatologia , Proteínas de Choque Térmico/genética , Mutação de Sentido Incorreto/genética , Potenciais de Ação , Animais , Sequência de Bases , Encéfalo/metabolismo , Encéfalo/patologia , Dendritos/metabolismo , Marcação de Genes , Proteínas de Choque Térmico/metabolismo , Homozigoto , Humanos , Filamentos Intermediários/metabolismo , Camundongos Endogâmicos C57BL , Atividade Motora , Debilidade Muscular/patologia , Fenótipo , Células de Purkinje/metabolismo , Células de Purkinje/patologia
8.
Methods Mol Biol ; 1942: 173-189, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30900185

RESUMO

Individuals carrying an FMR1 expansion between 55 and 200 CGG repeats, are at risk of developing the Fragile X-associated tremor/ataxia syndrome (FXTAS), a late onset neurodegenerative disorder characterized by cerebellar gait ataxia, intentional tremor, neuropathy, parkinsonism, cognitive decline, and psychological disorders, such as anxiety and depression. In addition, brain atrophy, white matter disease, and hyperintensities of the middle cerebellar peduncles can also be present. The neuropathological distinct feature of FXTAS is represented by the presence of eosinophilic intranuclear inclusions in neurons and astrocytes throughout the brain and in other tissues. In this chapter, protocols for available diagnostic tools, in both humans and mice, the clinical features and the basic molecular mechanisms leading to FXTAS and the animal models proposed to study this disorder are discussed.


Assuntos
Ataxia/diagnóstico , Encéfalo/patologia , Modelos Animais de Doenças , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/diagnóstico , Mutação , Tremor/diagnóstico , Animais , Ataxia/genética , Encéfalo/metabolismo , Feminino , Síndrome do Cromossomo X Frágil/genética , Humanos , Corpos de Inclusão Intranuclear , Masculino , Camundongos , Tremor/genética , Repetições de Trinucleotídeos
9.
Nat Genet ; 51(4): 580-581, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30926965
10.
J Physiol Biochem ; 75(1): 89-99, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30759305

RESUMO

Multiple sclerosis is among the most common causes of neurological disabilities in young adults. Over the past decade, several therapeutic strategies have emerged as having potential neuroprotective and neuroregenerative properties. We investigated the effect of intranasal administration of LINGO-1-directed siRNA-loaded chitosan nanoparticles on demyelination and remyelination processes in a rat model of demyelination. Adult male Wistar rats were randomly assigned to one of 6 groups (n = 10 each) and subjected to intrapontine stereotaxic injection of ethidium bromide (EB) to induce demyelination. EB-treated rats were either left untreated or received intranasal LINGO-1-directed siRNA-chitosan nanoparticles from day 1 to day 7 (demyelination group) or from day 7 to day 21 (remyelination group) after EB injection. Chitosan nanoparticle (50 µl) was given alone after EB stereotaxic injection for both demyelination and remyelination groups. Two additional groups received 10 µl of saline by stereotaxic injection, followed by intranasal saline as controls for demyelination and remyelination groups (n = 10/group). Behavioural testing was conducted for all rats, as well as terminal biochemical assays and pathological examination of pontine tissues were done. After EB injection, rats had compromised motor performance and coordination. Pathological evidence of demyelination was observed in pontine tissue and higher levels of caspase-3 activity were detected compared to control rats. With LINGO-1-directed siRNA-chitosan nanoparticle treatment, animals performed better than controls. Remyelination-treated group showed better motor performance than demyelination group. LINGO-1 downregulation was associated with signs of repair in histopathological sections, higher expression of pontine myelin basic protein (MBP) mRNA and protein and lower levels of caspase-3 activity indicating neuroprotection and remyelination enhancement.


Assuntos
Ataxia/terapia , Doenças Desmielinizantes/terapia , Proteínas de Membrana/antagonistas & inibidores , Nanopartículas/química , Proteínas do Tecido Nervoso/antagonistas & inibidores , Fármacos Neuroprotetores/administração & dosagem , RNA Interferente Pequeno/genética , Remielinização/genética , Administração Intranasal , Animais , Ataxia/induzido quimicamente , Ataxia/genética , Ataxia/patologia , Caspase 3/genética , Caspase 3/metabolismo , Quitosana/química , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/genética , Doenças Desmielinizantes/patologia , Modelos Animais de Doenças , Portadores de Fármacos , Composição de Medicamentos/métodos , Etídio/toxicidade , Regulação da Expressão Gênica , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteína Básica da Mielina/agonistas , Proteína Básica da Mielina/genética , Proteína Básica da Mielina/metabolismo , Bainha de Mielina/metabolismo , Bainha de Mielina/patologia , Nanopartículas/administração & dosagem , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Núcleo Magno da Rafe/efeitos dos fármacos , Núcleo Magno da Rafe/metabolismo , Núcleo Magno da Rafe/patologia , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Wistar , Técnicas Estereotáxicas
11.
Psychiatr Genet ; 29(3): 91-94, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30741786

RESUMO

The sodium voltage-gated channel α subunit 2 (SCN2A) gene encodes a subunit of sodium voltage-gated channels expressed primarily in the central nervous system that are responsible for action potential initiation and propagation in excitable cells. SCN2A mutations underlie a spectrum of distinct phenotypes, including seizure disorders, neurodevelopmental disorders, and rarer instances of episodic ataxia and schizophrenia. We report on a 38-year-old patient with adult-onset psychotic symptoms on a background of infantile-onset seizures, autistic features and episodic ataxia. Whole-exome sequencing revealed a de-novo novel SCN2A mutation (c.4966T > C, p.Ser1656Pro). This and other SCN2A mutations associated with the schizophrenia phenotype overlap those seen in neurodevelopmental disorders, suggesting a common underlying mechanism. This is the first report of a patient with the entire known SCN2A phenotypic spectrum. We highlight the importance of recognizing the psychiatric phenotypes associated with SCN2A mutations and that the phenotypic spectrum is more fluid, and less categorical, than previously thought.


Assuntos
Canal de Sódio Disparado por Voltagem NAV1.2/genética , Esquizofrenia/genética , Esquizofrenia/fisiopatologia , Adulto , Ataxia/genética , Epilepsia/genética , Humanos , Masculino , Mutação/genética , Canal de Sódio Disparado por Voltagem NAV1.2/fisiologia , Transtornos do Neurodesenvolvimento/genética , Fenótipo , Psicologia do Esquizofrênico , Sequenciamento Completo do Exoma
12.
J Hum Genet ; 64(4): 297-304, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30659264

RESUMO

COQ4 mutations have recently been shown to cause a broad spectrum of mitochondrial disorders in association with CoQ10 deficiency. Herein, we report the clinical phenotype, in silico and biochemical analyses, and intervention for a novel c.370 G > A (p.G124S) COQ4 mutation in a Chinese family. This mutation is exclusively present in the East Asian population (allele frequency of ~0.001). The homozygous mutation caused CoQ10 deficiency-associated Leigh syndrome with an onset at 1-2 months of age, presenting as respiratory distress, lactic acidosis, dystonia, seizures, failure to thrive, and detectable lesions in the midbrain and basal ganglia. No renal impairment was involved. The levels of CoQ10 and mitochondrial respiratory chain complex (C) II + III activity were clearly lower in cultured fibroblasts derived from the patient than in those from unaffected carriers; the decreased CII + III activity could be increased by CoQ10 treatment. Follow-up studies suggested that our patient benefitted from the oral supplementation of CoQ10, which allowed her to maintain a relatively stable health status. Based on the genetic testing, preimplantation and prenatal diagnoses were performed, confirming that the next offspring of this family was unaffected. Our cases expand the phenotypic spectrum of COQ4 mutations and the genotypic spectrum of Leigh syndrome.


Assuntos
Ataxia/genética , Testes Genéticos , Doença de Leigh/genética , Doenças Mitocondriais/genética , Proteínas Mitocondriais/genética , Debilidade Muscular/genética , Ubiquinona/deficiência , Grupo com Ancestrais do Continente Asiático/genética , Ataxia/complicações , Pré-Escolar , Simulação por Computador , Feminino , Fibroblastos/metabolismo , Heterozigoto , Homozigoto , Humanos , Lactente , Doença de Leigh/complicações , Doença de Leigh/fisiopatologia , Masculino , Mitocôndrias/genética , Mitocôndrias/patologia , Doenças Mitocondriais/complicações , Debilidade Muscular/complicações , Mutação , Fenótipo , Ubiquinona/genética , Ubiquinona/farmacocinética
14.
Eur J Neurol ; 26(1): 66-e7, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30063100

RESUMO

BACKGROUND AND PURPOSE: CACNA1A encodes the α1 subunit of the neuronal calcium channel P/Q. CACNA1A mutations underlie three allelic disorders: familial hemiplegic migraine type 1 (FHM1), episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6). A clear-cut genotype-phenotype correlation is often lacking since clinical manifestations may overlap. Several case reports have described cognitive and behavioral features in CACNA1A disorders, but studies in larger case series are lacking. METHODS: Genetically confirmed CACNA1A cases were retrieved from the database of the ataxia outpatient clinic of the Department of Neurology at Innsbruck Medical University. Clinical charts and neuropsychological test results were retrospectively analyzed. In addition, a review of the literature including only genetically confirmed cases was performed. RESULTS: Forty-four CACNA1A cases were identified in our database. Delayed psychomotor milestones and poor school performance were described in seven (four FHM1, three EA2) and eight (three FHM1, five EA2) patients, respectively. Psychiatric comorbidities were diagnosed in eight patients (two FHM1, six EA2). Neuropsychological testing was available for 23 patients (11 FHM1, 10 EA2, two SCA6). Various cognitive deficits were documented in 21 cases (all patients except one SCA6). Impairments were predominantly seen in figural memory, visuoconstructive abilities and verbal fluency. In the literature, an early psychomotor delay is described in several children with EA2 and FHM1, whilst reports of cognitive and psychiatric findings from adult cases are scarce. CONCLUSIONS: Neuropsychiatric manifestations are common in episodic CACNA1A disorders. In the case of otherwise unexplained developmental delay and a positive family history, CACNA1A mutations should be considered in the differential diagnosis.


Assuntos
Canais de Cálcio/genética , Transtornos Mentais/genética , Doenças do Sistema Nervoso/genética , Adolescente , Adulto , Ataxia/genética , Ataxia Cerebelar/genética , Criança , Pré-Escolar , Comorbidade , Escolaridade , Feminino , Genótipo , Humanos , Masculino , Transtornos Mentais/psicologia , Transtornos de Enxaqueca/genética , Doenças do Sistema Nervoso/psicologia , Testes Neuropsicológicos , Fenótipo , Desempenho Psicomotor , Estudos Retrospectivos , Ataxias Espinocerebelares/genética , Adulto Jovem
15.
J Genet ; 97(3): 665-677, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30027902

RESUMO

The inappropriate genetic expansion of various repetitive DNA sequences underlies over 20 distinct inherited diseases. The genetic context of these repeats in exons, introns and untranslated regions has played a major role in thinking about the mechanisms by which various repeat expansions might cause disease. Repeat expansions in exons are thought to give rise to expanded toxic protein repeats (i.e. polyQ). Repeat expansions in introns and UTRs (i.e. FXTAS) are thought to produce aberrant repeat-bearing RNAs that interact with and sequester a wide variety of essential proteins, resulting in cellular toxicity. However, a new phenomenon termed 'repeat-associated nonAUG dependent (RAN) translation' paints a new and unifying picture of how distinct repeat expansion-bearing RNAs might act as substrates for this noncanonical form of translation, leading to the production of a wide range of repeat sequence-specific-encoded toxic proteins. Here, we review how the model system Caenorhabditis elegans has been utilized to model many repeat disorders and discuss how RAN translation could be a previously unappreciated contributor to the toxicity associated with these different models.


Assuntos
Ataxia/genética , Ataxia/patologia , Caenorhabditis elegans/genética , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/patologia , Tremor/genética , Tremor/patologia , Expansão das Repetições de Trinucleotídeos/genética , Animais , Modelos Animais de Doenças , Humanos
16.
Orv Hetil ; 159(28): 1163-1169, 2018 Jul.
Artigo em Húngaro | MEDLINE | ID: mdl-29983107

RESUMO

Next generation sequencing (NGS) technologies reshape the diagnostics of rare neurological diseases. In the background of certain neurological symptoms, such as ataxia, many acquired and genetic causes may be present. Variations in a given gene can present with variable phenotypes, too. Because of this phenomenon, the conventional one gene sequencing approach often fails to identify the genetic background of a disease. Next generation sequencing panels allow to sequence 50-100 genes simultaneously, and if the disease stratification is not possible based on the clinical symptoms, whole exome sequencing can help in the diagnostic of genetic disorders with atypical presentation. This case study is about the exome sequencing of a patient with cerebellar ataxia. Genetic investigations identified rare variants in the SPG11 gene in association with the clinical phenotype, which gene was originally described in the background of hereditary spastic paraparesis. Our article highlights that in certain cases the variability of the leading presenting symptom makes it hard to select the correct gene panel. In our case the variants in the gene, formerly associated to hereditary spastic paraparesis, resulted in cerebellar ataxia initially, so even an ataxia NGS gene panel would not detect those. Orv Hetil. 2018; 159(28): 1163-1169.


Assuntos
Ataxia/genética , Testes Genéticos/métodos , Paraplegia Espástica Hereditária/genética , Sequenciamento Completo do Exoma , Ataxia/diagnóstico , Genes Recessivos/genética , Predisposição Genética para Doença , Humanos , Doenças do Sistema Nervoso/genética , Doenças Raras , Paraplegia Espástica Hereditária/diagnóstico
17.
Handb Clin Neurol ; 155: 175-189, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29891057

RESUMO

X-linked cerebellar ataxias (XLCA) are an expanding group of genetically heterogeneous and clinically variable conditions characterized by cerebellar dysgenesis (hypoplasia, atrophy, or dysplasia) caused by gene mutations or genomic imbalances on the X chromosome. The neurologic features of XLCA include hypotonia, developmental delay, intellectual disability, ataxia, and other cerebellar signs. Normal cognitive development has also been reported. Cerebellar defects may be isolated or associated with other brain malformations or extraneurologic involvement. More than 20 genes on the X chromosome, mainly encoding for proteins involved in brain development and synaptic function that have been constantly or occasionally associated with a pathologic cerebellar phenotype, and several families with X-linked inheritance have been reported. Given the excess of males with ataxia, this group of conditions is probably underestimated and families of patients with neuroradiologic and clinical evidence of a cerebellar disorder should be counseled for high risk of X-linked inheritance.


Assuntos
Ataxia/genética , Doenças Cerebelares/genética , Cerebelo/anormalidades , Genes Ligados ao Cromossomo X/genética , Ataxia/fisiopatologia , Humanos
18.
Handb Clin Neurol ; 155: 205-215, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29891059

RESUMO

Primary episodic ataxias (EAs) are a group of dominantly inherited disorders characterized by transient recurrent incoordination and truncal instability, often triggered by physical exertion and emotional stress, variably associated with progressive baseline ataxia. There are now eight designated subtypes based largely on genetic loci. Mutations have been identified in multiple individuals and families with EA1, EA2, and EA6, mostly with onset before adulthood. EA1 and EA2 are prototypical neurologic channelopathies. EA1 is caused by heterozygous mutations in KCNA1, which encodes the α1 subunit of a neuronal voltage-gated potassium channel, Kv1.1. EA2, the most common and best characterized, is caused by heterozygous mutations in CACNA1A, which encodes the α1A subunit of a neuronal voltage-gated calcium channel, Cav2.1. EA6 is caused by heterozygous mutations in SLC1A3, which encodes a subunit of a glial excitatory amino acid transporter, EAAT1. The other EA subtypes were defined in single families awaiting gene identification and further confirmation. This chapter focuses on the best-characterized EA syndromes, the clinical assessment and genetic diagnosis of EA, and the management of EA, as well as newly recognized allelic disorders that have greatly expanded the clinical spectrum of EA2. Illustrative cases are discussed, with a focus on sporadic patients with congenital features without episodic ataxia who present diagnostic and therapeutic challenges.


Assuntos
Ataxia/genética , Canal de Potássio Kv1.1/genética , Mutação/genética , Ataxia/classificação , Canalopatias/etiologia , Canalopatias/genética , Transportador 1 de Aminoácido Excitatório/genética , Humanos
19.
Handb Clin Neurol ; 155: 73-89, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29891078

RESUMO

Recessive ataxias (spinocerebellar ataxias, recessive or SCARs) are a heterogeneous group of rare, mostly neurodegenerative genetic disorders which usually start in childhood or early adult life. They can be subdivided into two major groups: predominant sensory or afferent ataxias, which are disorders mainly of the peripheral input to the cerebellum, and predominant cerebellar ataxias, in which the cerebellum is primarily affected. Next-generation sequencing technology has enabled the identification of >100 novel SCAR genes in the last 5 years, although most of them are ultrarare. To guide clinical workup and management in SCARs, we provide an up-to-date overview of the most frequent SCARs and their phenotypic features. These include Friedreich ataxia, spastic paraplegia type 7-related ataxia, autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) and spectrin repeat-containing nuclear envelope protein (SYNE)-related ataxia. In some restricted populations ARSACS or ataxia with vitamin E deficiency (AVED) is most common. All require a high index of suspicion in patients who present with an early-onset disorder of balance, especially children, in whom normal development and the lack of typical clinical characteristics seen in later stages of the respective SCARs can confuse the clinical picture. We summarize the diagnostic features which can help guide diagnosis, the natural history for common SCARs, and the approach to therapy, both in current use and in ongoing clinical trials. We also provide a summary table for other clinically relevant SCARs. Based on the frequency data, phenotypes, and the cost-effectiveness of recent next-generation sequencing approaches, we conclude with a diagnostic algorithm for the workup of patients with unexplained SCAR.


Assuntos
Genes Recessivos/genética , Ataxias Espinocerebelares/genética , Ataxia/complicações , Ataxia/genética , Transtornos Heredodegenerativos do Sistema Nervoso/diagnóstico por imagem , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Humanos , Técnicas de Diagnóstico Molecular , Mutação/genética , Proteínas do Tecido Nervoso/genética , Neuroimagem , Proteínas Nucleares/genética , Ataxias Espinocerebelares/classificação , Ataxias Espinocerebelares/diagnóstico por imagem , Deficiência de Vitamina E/complicações , Deficiência de Vitamina E/genética
20.
Handb Clin Neurol ; 155: 91-103, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29891079

RESUMO

The terminology of nonprogressive congenital ataxia (NPCA) refers to a clinically and genetically heterogeneous group of disorders characterized by congenital or early-onset ataxia, but no progression or even improvement on follow-up. Ataxia is preceded by muscular hypotonia and delayed motor (and usually language) milestones. We exclude children with prenatal, perinatal, and postnatal acquired diseases, malformations other than cerebellar hypoplasia, and defined syndromic disorders. Patients with NPCA have a high prevalence of cognitive and language impairments, in addition to increased occurrence of seizures, ocular signs (nystagmus, strabismus), behavior changes, and microcephaly. Neuroimaging is variable, ranging from normal cerebellar anatomy to reduced cerebellar volume (hypoplasia in the proper sense), and enlarged interfolial spaces, potentially mimicking atrophy. The latter appearance is often called "hypoplasia" as well, in view of the static clinical course. Some patients had progressive enlargement of cerebellar fissures, but a nonprogressive course. There is no imaging-clinical-genetic correlation. Dominant, recessive, and X-linked inheritance is documented for NPCA. Here, we focus on the still rather short list of dominant and recessive genes associated with NPCA, identified in the last few years. With future advances in genetics, we expect a rapid expansion of knowledge in this field.


Assuntos
Ataxia , Cerebelo/anormalidades , Transtornos Cognitivos/etiologia , Ataxia/diagnóstico por imagem , Ataxia/genética , Ataxia/fisiopatologia , Cerebelo/diagnóstico por imagem , Transtornos Cognitivos/diagnóstico por imagem , Transtornos Cognitivos/genética , Humanos , Neuroimagem
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