RESUMO
BACKGROUND: Spinocerebellar ataxia 4 (SCA4), characterized in 1996, features adult-onset ataxia, polyneuropathy, and linkage to chromosome 16q22.1; its underlying mutation has remained elusive. OBJECTIVE: To explore the radiological and neuropathological abnormalities in the entire neuroaxis in SCA4 and search for its mutation. METHODS: Three Swedish families with undiagnosed ataxia went through clinical, neurophysiological, and neuroimaging tests, including PET studies and genetic investigations. In four cases, neuropathological assessments of the neuroaxis were performed. Genetic testing included short read whole genome sequencing, short tandem repeat analysis with ExpansionHunter de novo, and long read sequencing. RESULTS: Novel features for SCA4 include dysautonomia, motor neuron affection, and abnormal eye movements. We found evidence of anticipation; neuroimaging demonstrated atrophy in the cerebellum, brainstem, and spinal cord. [18F]FDG-PET demonstrated brain hypometabolism and [11C]Flumazenil-PET reduced binding in several brain lobes, insula, thalamus, hypothalamus, and cerebellum. Moderate to severe loss of Purkinje cells in the cerebellum and of motor neurons in the anterior horns of the spinal cord along with pronounced degeneration of posterior tracts was also found. Intranuclear, mainly neuronal, inclusions positive for p62 and ubiquitin were sparse but widespread in the CNS. This finding prompted assessment for nucleotide expansions. A polyglycine stretch encoding GGC expansions in the last exon of the zink finger homeobox 3 gene was identified segregating with disease and not found in 1000 controls. CONCLUSIONS: SCA4 is a neurodegenerative disease caused by a novel GGC expansion in the coding region of ZFHX3, and its spectrum is expanded to include dysautonomia and neuromuscular manifestations.
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A five-year-old girl presented with headache attacks, clumsiness, and a history of transient gait disturbances. She and her father, mother, twin sister, and brother underwent neurological evaluation, neuroimaging, and exome sequencing covering 357 genes associated with movement disorders. Sequencing revealed the new variant KCND3 c.838G>A, p.E280K in the father and sisters, but not in the mother and brother. KCND3 encodes voltage-gated potassium channel D3 (Kv4.3) and mutations have been associated with spinocerebellar ataxia type 19/22 (SCA19/22) and cardiac arrhythmias. SCA19/22 is characterized by ataxia, Parkinsonism, peripheral neuropathy, and sometimes, intellectual disability. Neuroimaging, EEG, and ECG were unremarkable. Mild developmental delay with impaired fluid reasoning was observed in both sisters, but not in the brother. None of the family members demonstrated ataxia or parkinsonism. In Xenopus oocyte electrophysiology experiments, E280K was associated with a rightward shift in the Kv4.3 voltage-activation relationship of 11 mV for WT/E280K and +17 mV for E280K/E280K relative to WT/WT. Steady-state inactivation was similarly right-shifted. Maximal peak current amplitudes were similar for WT/WT, WT/E280K, and E280K/E280K. Our data indicate that Kv4.3 E280K affects channel activation and inactivation and is associated with developmental delay. However, E280K appears to be relatively benign considering it does not result in overt ataxia.
Assuntos
Ataxia Cerebelar , Degenerações Espinocerebelares , Masculino , Feminino , Humanos , Degenerações Espinocerebelares/genética , Canais de Potássio Shal/genética , Mutação de Sentido Incorreto , Mutação , AtaxiaRESUMO
PURPOSE: Individuals with intellectual disability (ID) and/or neurodevelopment disorders (NDDs) are currently investigated with several different approaches in clinical genetic diagnostics. METHODS: We compared the results from 3 diagnostic pipelines in patients with ID/NDD: genome sequencing (GS) first (N = 100), GS as a secondary test (N = 129), or chromosomal microarray (CMA) with or without FMR1 analysis (N = 421). RESULTS: The diagnostic yield was 35% (GS-first), 26% (GS as a secondary test), and 11% (CMA/FMR1). Notably, the age of diagnosis was delayed by 1 year when GS was performed as a secondary test and the cost per diagnosed individual was 36% lower with GS first than with CMA/FMR1. Furthermore, 91% of those with a negative result after CMA/FMR1 analysis (338 individuals) have not yet been referred for additional genetic testing and remain undiagnosed. CONCLUSION: Our findings strongly suggest that genome analysis outperforms other testing strategies and should replace traditional CMA and FMR1 analysis as a first-line genetic test in individuals with ID/NDD. GS is a sensitive, time- and cost-effective method that results in a confirmed molecular diagnosis in 35% of all referred patients.
Assuntos
Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Criança , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Deficiências do Desenvolvimento/genética , Testes Genéticos/métodos , Análise em Microsséries , Transtornos do Neurodesenvolvimento/genética , Proteína do X Frágil da Deficiência Intelectual/genéticaRESUMO
Spastic ataxias are rare neurogenetic disorders involving spinocerebellar and pyramidal tracts. Many genes are involved. Among them, CAPN1, when mutated, is responsible for a complex inherited form of spastic paraplegia (SPG76). We report the largest published series of 21 novel patients with nine new CAPN1 disease-causing variants and their clinical characteristics from two European university hospitals (Paris and Stockholm). After a formal clinical examination, causative variants were identified by next-generation sequencing and confirmed by Sanger sequencing. CAPN1 variants are a rare cause (~ 1.4%) of young-adult-onset spastic ataxia; however, together with all published cases, they allowed us to better describe the clinical and genetic spectra of this form. Truncating variants are the most frequent, and missense variants lead to earlier age at onset in favor of an additional deleterious effect. Cerebellar ataxia with cerebellar atrophy, dysarthria and lower limb weakness are often associated with spasticity. We also suggest that cognitive impairment and depression should be assessed specifically in the follow-up of SPG76 cases.
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Calpaína/genética , Deficiência Intelectual/genética , Espasticidade Muscular/genética , Mutação/genética , Atrofia Óptica/genética , Paraplegia Espástica Hereditária/genética , Ataxias Espinocerebelares/genética , Adulto , Idade de Início , Ataxia Cerebelar/genética , Criança , Feminino , Estudos de Associação Genética , Humanos , Deficiência Intelectual/diagnóstico , Masculino , Espasticidade Muscular/diagnóstico , Atrofia Óptica/diagnóstico , Linhagem , Fenótipo , Ataxias Espinocerebelares/diagnóstico , Adulto JovemRESUMO
PURPOSE OF REVIEW: To provide an update on the role of Ataxin-2 gene (ATXN2) in health and neurological diseases. RECENT FINDINGS: There is a growing complexity emerging on the role of ATXN2 and its variants in association with SCA2 and several other neurological diseases. Polymorphisms and intermediate alleles in ATXN2 establish this gene as a powerful modulator of neurological diseases including lethal neurodegenerative conditions such as motor neuron disease, spinocerebellar ataxia 3 (SCA3), and peripheral nerve disease such as familial amyloidosis polyneuropathy. This role is in fact far wider than the previously described for polymorphism in the prion protein (PRNP) gene. Positive data from antisense oligo therapy in a murine model of SCA2 suggest that similar approaches may be feasible in humans SCA2 patients. SUMMARY: ATXN2 is one of the few genes where a single gene causes several diseases and/or modifies several and disparate neurological disorders. Hence, understanding mutagenesis, genetic variants, and biological functions will help managing SCA2, and several human diseases connected with dysfunctional pathways in the brain, innate immunity, autophagy, cellular, lipid, and RNA metabolism.
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Doenças do Sistema Nervoso , Ataxias Espinocerebelares , Animais , Ataxina-2/genética , Ataxina-2/metabolismo , Encéfalo/metabolismo , Humanos , Camundongos , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/terapia , Proteínas , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/terapiaRESUMO
BACKGROUND: The ataxin-2 (ATXN2) gene contains a cytosine-adenine-guanine repeat sequence ranging from 13 to 31 repeats, but when surpassing certain thresholds causes neurodegeneration. Genetic alterations in ATXN2 other than pathological cytosine adenine guanine (CAG) repeats are unknown. METHODS/RESULTS: We have identified a 9-base pair duplication in the 2-gene ATXN2 sense/antisense region. The duplication was found in a Swedish family with spinocerebellar ataxia 3 with parkinsonism, conferring a deviated age at onset unexplained by the concomitant presence of ATXN2 intermediate alleles. Similarly, C9ORF72 amyotrophic lateral sclerosis cases bearing the same duplication had earlier age at onset than those with C9ORF72 and ATXN2 intermediate alleles. No effect was evident in Parkinson's disease (PD) cases without known PD gene mutations. CONCLUSIONS: We describe the first genetic alteration other than the known intermediate-range CAG repeats in ATXN2. This 9-base pair duplication may act as an additional hit among carriers of pathological nucleotide expansions in ATXN3 and C9ORF72 with ATXN2 intermediate. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Esclerose Lateral Amiotrófica , Doença de Machado-Joseph , Ataxina-2/genética , Proteína C9orf72 , HumanosRESUMO
OBJECTIVE: Identifying molecular changes that contribute to the onset and progression of Huntington's disease (HD) is of importance for the development and evaluation of potential therapies. METHODS: We conducted an unbiased mass-spectrometry proteomic analysis on the cerebrospinal fluid of 12 manifest HD patients (ManHD), 13 pre-manifest (preHD), and 38 controls. A biologically plausible and significant possible biomarker was validated in samples from a separate cohort of patients and controls consisting of 23 ManHD patients and 23 controls. RESULTS: In ManHD compared to preHD, 10 proteins were downregulated and 43 upregulated. Decreased levels of proenkephalin (PENK) and transthyretin were closely linked to HD symptom severity, whereas levels of 15 upregulated proteins were associated with symptom severity. The decreased PENK levels were replicated in the separate cohort where absolute quantitation was performed. CONCLUSIONS: We hypothesize that declining PENK levels reflect the degeneration of medium spiny neurons (MSNs) that produce PENK and that assays for PENK may serve as a surrogate marker for the state of MSNs in HD. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Doença de Huntington , Biomarcadores , Progressão da Doença , Encefalinas , Humanos , Neurônios , Precursores de Proteínas , ProteômicaRESUMO
Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by expanded CAG repeats in the huntingtin gene (HTT). Although mutant HTT is expressed during embryonic development and throughout life, clinical HD usually manifests later in adulthood. A number of studies document neurodevelopmental changes associated with mutant HTT, but whether these are reversible under therapy remains unclear. Here, we identify very early behavioral, molecular, and cellular changes in preweaning transgenic HD rats and mice. Reduced ultrasonic vocalization, loss of prepulse inhibition, and increased risk taking are accompanied by disturbances of dopaminergic regulation in vivo, reduced neuronal differentiation capacity in subventricular zone stem/progenitor cells, and impaired neuronal and oligodendrocyte differentiation of mouse embryo-derived neural stem cells in vitro. Interventional treatment of this early phenotype with the histone deacetylase inhibitor (HDACi) LBH589 led to significant improvement in behavioral changes and markers of dopaminergic neurotransmission and complete reversal of aberrant neuronal differentiation in vitro and in vivo. Our data support the notion that neurodevelopmental changes contribute to the prodromal phase of HD and that early, presymptomatic intervention using HDACi may represent a promising novel treatment approach for HD.
Assuntos
Diferenciação Celular/efeitos dos fármacos , Doença de Huntington/fisiopatologia , Ácidos Hidroxâmicos/farmacologia , Indóis/farmacologia , Neurônios/efeitos dos fármacos , Animais , Animais Geneticamente Modificados , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Modelos Animais de Doenças , Feminino , Inibidores de Histona Desacetilases/farmacologia , Humanos , Proteína Huntingtina/genética , Doença de Huntington/genética , Ventrículos Laterais/patologia , Masculino , Camundongos Transgênicos , Mutação , Neurônios/metabolismo , Neurônios/fisiologia , Panobinostat , RatosRESUMO
BACKGROUND: Developmental dyslexia (DD) is a neurodevelopmental learning disorder with high heritability. A number of candidate susceptibility genes have been identified, some of which are linked to the function of the cilium, an organelle regulating left-right asymmetry development in the embryo. Furthermore, it has been suggested that disrupted left-right asymmetry of the brain may play a role in neurodevelopmental disorders such as DD. However, it is unknown whether there is a common genetic cause to DD and laterality defects or ciliopathies. CASE PRESENTATION: Here, we studied two individuals with co-occurring situs inversus (SI) and DD using whole genome sequencing to identify genetic variants of importance for DD and SI. Individual 1 had primary ciliary dyskinesia (PCD), a rare, autosomal recessive disorder with oto-sino-pulmonary phenotype and SI. We identified two rare nonsynonymous variants in the dynein axonemal heavy chain 5 gene (DNAH5): a previously reported variant c.7502G > C; p.(R2501P), and a novel variant c.12043 T > G; p.(Y4015D). Both variants are predicted to be damaging. Ultrastructural analysis of the cilia revealed a lack of outer dynein arms and normal inner dynein arms. MRI of the brain revealed no significant abnormalities. Individual 2 had non-syndromic SI and DD. In individual 2, one rare variant (c.9110A > G;p.(H3037R)) in the dynein axonemal heavy chain 11 gene (DNAH11), coding for another component of the outer dynein arm, was identified. CONCLUSIONS: We identified the likely genetic cause of SI and PCD in one individual, and a possibly significant heterozygosity in the other, both involving dynein genes. Given the present evidence, it is unclear if the identified variants also predispose to DD and further studies into the association between laterality, ciliopathies and DD are needed.
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Dineínas do Axonema/genética , Dislexia/genética , Situs Inversus/genética , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Criança , Transtornos da Motilidade Ciliar/genética , Transtornos da Motilidade Ciliar/patologia , Dineínas/genética , Dislexia/diagnóstico por imagem , Dislexia/patologia , Feminino , Predisposição Genética para Doença , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Polimorfismo de Nucleotídeo Único/genética , Situs Inversus/diagnóstico por imagem , Situs Inversus/patologiaRESUMO
SQSTM1 (sequestosome 1; also known as p62) encodes a multidomain scaffolding protein involved in various key cellular processes, including the removal of damaged mitochondria by its function as a selective autophagy receptor. Heterozygous variants in SQSTM1 have been associated with Paget disease of the bone and might contribute to neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Using exome sequencing, we identified three different biallelic loss-of-function variants in SQSTM1 in nine affected individuals from four families with a childhood- or adolescence-onset neurodegenerative disorder characterized by gait abnormalities, ataxia, dysarthria, dystonia, vertical gaze palsy, and cognitive decline. We confirmed absence of the SQSTM1/p62 protein in affected individuals' fibroblasts and found evidence of a defect in the early response to mitochondrial depolarization and autophagosome formation. Our findings expand the SQSTM1-associated phenotypic spectrum and lend further support to the concept of disturbed selective autophagy pathways in neurodegenerative diseases.
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Ataxia/genética , Autofagia/genética , Distonia/genética , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/fisiopatologia , Proteína Sequestossoma-1/deficiência , Paralisia Supranuclear Progressiva/genética , Adolescente , Adulto , Idade de Início , Ataxia/complicações , Autofagossomos/metabolismo , Autofagossomos/patologia , Criança , Transtornos Cognitivos/genética , Disartria/complicações , Disartria/genética , Distonia/complicações , Feminino , Fibroblastos/metabolismo , Marcha/genética , Humanos , Masculino , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Transtornos dos Movimentos/complicações , Transtornos dos Movimentos/genética , Doenças Neurodegenerativas/complicações , Linhagem , Fenótipo , RNA Mensageiro/análise , Proteína Sequestossoma-1/genética , Paralisia Supranuclear Progressiva/complicações , Adulto JovemRESUMO
BACKGROUND: Neuronopathic Gaucher disease type 3 (GD3) is frequent in northern Sweden, whereas GD1 is found throughout the country. In a nation-wide study, we examined neurological manifestations and clinical course in 12 patients with GD3 and 13 patients with GD1. METHODS: The patients were evaluated by standardized neurological assessments. Every sixth month, the GD3 patients were rated with the modified Severity Scoring Tool. At baseline and at the 3years follow-up, patients underwent University of Pennsylvania Smell Identification Test, Montreal Cognitive Assessment and Hospital Anxiety and Depression Scale. When clinical signs were present, additional examinations were undertaken. RESULTS: Marked clinical heterogeneity was evident in both GD3 and GD1 groups. Several GD3 patients had a hitherto unreported rapid and repetitive dystonia-like hyperkinetic movement disorder. Most patients with GD3 have abnormalities of horizontal gaze, ataxia and focal epilepsy, some also had cognitive impairment, anxiety and hyposmia. Six GD3 patients, all homoallelic for L444P GBA1 mutations, have lived beyond 40years of age; and none has developed Parkinsonism. Two of the GD1 patients suffer from Parkinsonism; mild to complete hyposmia was present in six GD3 and five GD1 patients. Neither the group of GD3 nor GD1 patients had detectable progression of their neurological manifestations. CONCLUSIONS: These middle-aged and older Swedish GD3 or GD1 patients are clinically stable over time. However, we have identified unusual clinical features, discordant phenotypes and a hyperkinetic dystonia-like movement disorder which appears unique to this Swedish disease variant and expands the phenotype for GD.
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Distonia/complicações , Doença de Gaucher/complicações , Hipercinese/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Ansiedade/complicações , Ansiedade/epidemiologia , Disfunção Cognitiva/complicações , Disfunção Cognitiva/epidemiologia , Depressão/complicações , Depressão/epidemiologia , Progressão da Doença , Distonia/epidemiologia , Feminino , Seguimentos , Doença de Gaucher/epidemiologia , Humanos , Hipercinese/epidemiologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Suécia/epidemiologia , Adulto JovemRESUMO
Spinocerebellar ataxia type 19 (SCA19), allelic with spinocerebellar ataxia type 22 (SCA22), is a rare syndrome caused by mutations in the KCND3 gene which encodes the potassium channel Kv4.3. Only 18 SCA19/22 families and sporadic cases of different ethnic backgrounds have been previously reported. As in other SCAs, the SCA19/22 phenotype is variable and usually consists of adult-onset slowly progressive ataxia and cognitive impairment; myoclonus and seizures; mild Parkinsonism occurs in some cases. Here we describe a Swedish SCA19/22 family spanning five generations and harboring the T377M mutation in KCND3. For the first time for this disease, 18F-fluorodeoxyglucose PET was assessed revealing widespread brain hypometabolism. In addition, we identified white matter abnormalities and found unusual features for SCA19/22 including early age of onset and fast rate of progression in the late course of disease in the oldest patient of this family.
Assuntos
Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/metabolismo , Glucose/metabolismo , Degenerações Espinocerebelares/patologia , Idoso , Córtex Cerebral/efeitos dos fármacos , Transtornos Cognitivos/diagnóstico por imagem , Transtornos Cognitivos/etiologia , Saúde da Família , Feminino , Fluordesoxiglucose F18/farmacocinética , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mutação/genética , Tomografia por Emissão de Pósitrons , Canais de Potássio Shal/genética , Degenerações Espinocerebelares/complicações , Degenerações Espinocerebelares/genética , Adulto JovemRESUMO
PURPOSE OF THE REVIEW: Imaging biomarkers for neurodegenerative disorders are primarily developed with the goal to aid diagnosis, to monitor disease progression, and to assess the efficacy of disease-modifying therapies in support to clinical outcomes that may either show limited sensitivity or need extended time for their evaluation. This article will review the most recent concepts and findings in the field of neuroimaging applied to Huntington's disease and Huntington-like syndromes. Emphasis will be given to the discussion of potential pharmacodynamic biomarkers for clinical trials in Huntington's disease (HD) and of neuroimaging tools that can be used as diagnostic biomarkers in HD-like syndromes. RECENT FINDINGS: Several magnetic resonance (MR) and positron emission tomography (PET) molecular imaging tools have been identified as potential pharmacodynamic biomarkers and others are in the pipeline after preclinical validation. MRI and 18F-fluorodeoxyglucose PET can be considered useful supportive diagnostic tools for the differentiation of other HD-like syndromes. New trials in HD have the primary goal to lower mutant huntingtin (mHTT) protein levels in the brain in order to reduce or alter the progression of the disease. MR and PET molecular imaging markers have been developed as tools to monitor disease progression and to evaluate treatment outcomes of disease-modifying trials in HD. These markers could be used alone or in combination for detecting structural and pharmacodynamic changes potentially associated with the lowering of mHTT.
Assuntos
Coreia/diagnóstico por imagem , Doença de Huntington/diagnóstico por imagem , Biomarcadores/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Coreia/metabolismo , Progressão da Doença , Humanos , Proteína Huntingtina/metabolismo , Doença de Huntington/metabolismo , Imageamento por Ressonância Magnética/métodos , Neuroimagem/métodos , Tomografia por Emissão de Pósitrons/métodosRESUMO
Spastic paraplegia type 5 (SPG5) is a rare subtype of hereditary spastic paraplegia, a highly heterogeneous group of neurodegenerative disorders defined by progressive neurodegeneration of the corticospinal tract motor neurons. SPG5 is caused by recessive mutations in the gene CYP7B1 encoding oxysterol-7α-hydroxylase. This enzyme is involved in the degradation of cholesterol into primary bile acids. CYP7B1 deficiency has been shown to lead to accumulation of neurotoxic oxysterols. In this multicentre study, we have performed detailed clinical and biochemical analysis in 34 genetically confirmed SPG5 cases from 28 families, studied dose-dependent neurotoxicity of oxysterols in human cortical neurons and performed a randomized placebo-controlled double blind interventional trial targeting oxysterol accumulation in serum of SPG5 patients. Clinically, SPG5 manifested in childhood or adolescence (median 13 years). Gait ataxia was a common feature. SPG5 patients lost the ability to walk independently after a median disease duration of 23 years and became wheelchair dependent after a median 33 years. The overall cross-sectional progression rate of 0.56 points on the Spastic Paraplegia Rating Scale per year was slightly lower than the longitudinal progression rate of 0.80 points per year. Biochemically, marked accumulation of CYP7B1 substrates including 27-hydroxycholesterol was confirmed in serum (n = 19) and cerebrospinal fluid (n = 17) of SPG5 patients. Moreover, 27-hydroxycholesterol levels in serum correlated with disease severity and disease duration. Oxysterols were found to impair metabolic activity and viability of human cortical neurons at concentrations found in SPG5 patients, indicating that elevated levels of oxysterols might be key pathogenic factors in SPG5. We thus performed a randomized placebo-controlled trial (EudraCT 2015-000978-35) with atorvastatin 40 mg/day for 9 weeks in 14 SPG5 patients with 27-hydroxycholesterol levels in serum as the primary outcome measure. Atorvastatin, but not placebo, reduced serum 27-hydroxycholesterol from 853 ng/ml [interquartile range (IQR) 683-1113] to 641 (IQR 507-694) (-31.5%, P = 0.001, Mann-Whitney U-test). Similarly, 25-hydroxycholesterol levels in serum were reduced. In cerebrospinal fluid 27-hydroxycholesterol was reduced by 8.4% but this did not significantly differ from placebo. As expected, no effects were seen on clinical outcome parameters in this short-term trial. In this study, we define the mutational and phenotypic spectrum of SPG5, examine the correlation of disease severity and progression with oxysterol concentrations, and demonstrate in a randomized controlled trial that atorvastatin treatment can effectively lower 27-hydroxycholesterol levels in serum of SPG5 patients. We thus demonstrate the first causal treatment strategy in hereditary spastic paraplegia.
Assuntos
Atorvastatina/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Paraplegia Espástica Hereditária/tratamento farmacológico , Adolescente , Adulto , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Estudos de Casos e Controles , Proliferação de Células , Estudos Transversais , Família 7 do Citocromo P450/genética , Progressão da Doença , Método Duplo-Cego , Família , Feminino , Humanos , Hidroxicolesteróis/metabolismo , Células-Tronco Pluripotentes Induzidas , Masculino , Pessoa de Meia-Idade , Mutação , Neuritos , Oxisteróis/sangue , Oxisteróis/líquido cefalorraquidiano , Linhagem , Índice de Gravidade de Doença , Paraplegia Espástica Hereditária/genética , Paraplegia Espástica Hereditária/metabolismo , Esteroide Hidroxilases/genética , Adulto JovemAssuntos
Encefalopatias/fisiopatologia , Calcinose/fisiopatologia , Ecolalia/fisiopatologia , Hipercinese/fisiopatologia , Idoso , Encefalopatias/diagnóstico por imagem , Encefalopatias/genética , Calcinose/diagnóstico por imagem , Calcinose/genética , Ataxia Cerebelar/fisiopatologia , Disartria/fisiopatologia , Distonia/fisiopatologia , Feminino , Transtornos Neurológicos da Marcha/fisiopatologia , Humanos , Transportadores de Ânions Orgânicos Dependentes de Sódio/genética , Simportadores/genética , Tomografia Computadorizada por Raios XRESUMO
Premutations in the fragile X mental retardation 1 (FMR1) gene cause fragile X-associated tremor/ataxia syndrome (FXTAS) and FMR1-related primary ovarian insufficiency (POI). Female FMR1 premutation carriers rarely develop motor features. Dual pathology is an emerging phenomenon among FMR1 premutation carriers. Here, we describe a family affected by FMR1-related disorders in which the female index case has developed a rapidly progressive and disabling syndrome of atypical parkinsonism. This syndrome consists of early onset postural instability, echolalia, dystonia, and varying types of apraxia like early onset orobuccal apraxia and oculomotor apraxia. She has also developed supranuclear gaze palsy, increased latency of saccade initiation, and slow saccades. These features are compatible with progressive supranuclear palsy (PSP) of a corticobasal syndrome (CBS) variant. Imaging displays a marked reduction of presynaptic dopaminergic uptake and cerebrospinal fluid analysis showed reduced dopamine metabolism; however, the patient is unresponsive to levodopa. Midbrain atrophy ("hummingbird sign") and mild cerebellar atrophy were found on brain MRI. Her father was affected by a typical FXTAS presentation but also displayed dopamine deficiency along with the hummingbird sign. The mechanisms by which FMR1 premutations predispose to atypical parkinsonism and dopamine deficiency await further elucidation.
Assuntos
Dopamina/deficiência , Proteína do X Frágil da Deficiência Intelectual/genética , Paralisia Supranuclear Progressiva/genética , Expansão das Repetições de Trinucleotídeos , Idoso , Encéfalo/diagnóstico por imagem , Família , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Paralisia Supranuclear Progressiva/diagnóstico por imagem , Paralisia Supranuclear Progressiva/tratamento farmacológicoRESUMO
Hyperintensities in the middle cerebellar peduncles (MCP), known as the MCP sign, and progressive late-onset ataxia constitute major characteristics of the fragile X tremor/ataxia syndrome (FXTAS). Here, we describe a 60-year-old male affected by ataxia due to biallelic mutations in the mitochondrial polymerase gamma (POLG) gene in which hyperintensities of the middle cerebellar peduncles (MCP) were found. The initial suspicion of FXTAS was however ruled out by a normal CGG expansion size in the FMR1 gene. We discuss the features of late-onset POLG-A as a phenocopy of FXTAS.
Assuntos
Ataxia/diagnóstico , Ataxia/genética , DNA Polimerase Dirigida por DNA/genética , Encéfalo/diagnóstico por imagem , DNA Polimerase gama , Diagnóstico Diferencial , Proteína do X Frágil da Deficiência Intelectual/genética , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
There is a continuous flux of the oxysterol 27-hydroxycholesterol (27-OHC) from the circulation across the blood-brain barrier (BBB) into the brain. The major metabolite of 27-OHC in the brain is 7α-hydroxy-3-oxo-4-cholestenoic acid (7-HOCA). We confirm a recent report describing the presence of this metabolite in cerebrospinal fluid (CSF) at a relatively high concentration. A simple and accurate method was developed for assay of 7-HOCA in CSF based on isotope dilution-mass spectrometry and use of (2)H4-labeled internal standard. The concentration of this metabolite was found to be markedly increased in CSF from patients with a dysfunctional BBB. There was a high correlation between the levels of 7-HOCA in CSF and the CSF/serum albumin ratio. The concentration of 7-HOCA in CSF was not significantly affected by neurodegeneration. Our findings suggest that 7-HOCA could be used as a diagnostic marker for conditions with a dysfunctional BBB.