RESUMO
Autosomal-recessive cerebellar hypoplasia and ataxia constitute a group of heterogeneous brain disorders caused by disruption of several fundamental cellular processes. Here, we identified 10 families showing a neurodegenerative condition involving pontocerebellar hypoplasia with microcephaly (PCHM). Patients harbored biallelic mutations in genes encoding the spliceosome components Peptidyl-Prolyl Isomerase Like-1 (PPIL1) or Pre-RNA Processing-17 (PRP17). Mouse knockouts of either gene were lethal in early embryogenesis, whereas PPIL1 patient mutation knockin mice showed neuron-specific apoptosis. Loss of either protein affected splicing integrity, predominantly affecting short and high GC-content introns and genes involved in brain disorders. PPIL1 and PRP17 form an active isomerase-substrate interaction, but we found that isomerase activity is not critical for function. Thus, we establish disrupted splicing integrity and "major spliceosome-opathies" as a new mechanism underlying PCHM and neurodegeneration and uncover a non-enzymatic function of a spliceosomal proline isomerase.
Assuntos
Proteínas de Ciclo Celular/genética , Doenças Cerebelares/genética , Microcefalia/genética , Mutação/genética , Peptidilprolil Isomerase/genética , Fatores de Processamento de RNA/genética , Spliceossomos/genética , Sequência de Aminoácidos , Animais , Proteínas de Ciclo Celular/química , Doenças Cerebelares/complicações , Doenças Cerebelares/diagnóstico por imagem , Estudos de Coortes , Feminino , Técnicas de Inativação de Genes/métodos , Células HEK293 , Transtornos Heredodegenerativos do Sistema Nervoso/complicações , Transtornos Heredodegenerativos do Sistema Nervoso/diagnóstico por imagem , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microcefalia/complicações , Microcefalia/diagnóstico por imagem , Linhagem , Peptidilprolil Isomerase/química , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Fatores de Processamento de RNA/químicaAssuntos
Coreia/diagnóstico por imagem , Transtornos Cognitivos/diagnóstico por imagem , Demência/diagnóstico por imagem , Transtornos Heredodegenerativos do Sistema Nervoso/diagnóstico por imagem , Transtornos Parkinsonianos/diagnóstico por imagem , População Negra , Região do Caribe , Coreia/complicações , Transtornos Cognitivos/complicações , Disfunção Cognitiva/etiologia , Demência/complicações , Proteínas da Membrana Plasmática de Transporte de Dopamina/farmacocinética , Feminino , Transtornos Heredodegenerativos do Sistema Nervoso/complicações , Humanos , Pessoa de Meia-Idade , Transtornos Parkinsonianos/complicações , Tomografia Computadorizada de Emissão de Fóton Único , Expansão das Repetições de TrinucleotídeosRESUMO
Cerebral choline metabolism is crucial for normal brain function, and its homoeostasis depends on carrier-mediated transport. Here, we report on four individuals from three families with neurodegenerative disease and homozygous frameshift mutations (Asp517Metfs*19, Ser126Metfs*8, and Lys90Metfs*18) in the SLC44A1 gene encoding choline transporter-like protein 1. Clinical features included progressive ataxia, tremor, cognitive decline, dysphagia, optic atrophy, dysarthria, as well as urinary and bowel incontinence. Brain MRI demonstrated cerebellar atrophy and leukoencephalopathy. Moreover, low signal intensity in globus pallidus with hyperintensive streaking and low signal intensity in substantia nigra were seen in two individuals. The Asp517Metfs*19 and Ser126Metfs*8 fibroblasts were structurally and functionally indistinguishable. The most prominent ultrastructural changes of the mutant fibroblasts were reduced presence of free ribosomes, the appearance of elongated endoplasmic reticulum and strikingly increased number of mitochondria and small vesicles. When chronically treated with choline, those characteristics disappeared and mutant ultrastructure resembled healthy control cells. Functional analysis revealed diminished choline transport yet the membrane phosphatidylcholine content remained unchanged. As part of the mechanism to preserve choline and phosphatidylcholine, choline transporter deficiency was implicated in impaired membrane homeostasis of other phospholipids. Choline treatments could restore the membrane lipids, repair cellular organelles and protect mutant cells from acute iron overload. In conclusion, we describe a novel childhood-onset neurometabolic disease caused by choline transporter deficiency with autosomal recessive inheritance.
Assuntos
Antígenos CD/genética , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Proteínas de Transporte de Cátions Orgânicos/genética , Adolescente , Ataxia/genética , Ataxia/fisiopatologia , Atrofia , Cerebelo/diagnóstico por imagem , Cerebelo/patologia , Colina/farmacologia , Disfunção Cognitiva/genética , Disfunção Cognitiva/fisiopatologia , Vesículas Citoplasmáticas/efeitos dos fármacos , Vesículas Citoplasmáticas/ultraestrutura , Transtornos de Deglutição/genética , Transtornos de Deglutição/fisiopatologia , Disartria/genética , Disartria/fisiopatologia , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/ultraestrutura , Incontinência Fecal/genética , Incontinência Fecal/fisiopatologia , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/ultraestrutura , Mutação da Fase de Leitura , Globo Pálido/diagnóstico por imagem , Transtornos Heredodegenerativos do Sistema Nervoso/diagnóstico por imagem , Transtornos Heredodegenerativos do Sistema Nervoso/patologia , Transtornos Heredodegenerativos do Sistema Nervoso/fisiopatologia , Homozigoto , Humanos , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/genética , Leucoencefalopatias/fisiopatologia , Imageamento por Ressonância Magnética , Masculino , Microscopia Eletrônica , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/ultraestrutura , Nootrópicos/farmacologia , Atrofia Óptica/genética , Atrofia Óptica/fisiopatologia , Linhagem , Ribossomos/efeitos dos fármacos , Ribossomos/ultraestrutura , Substância Negra/diagnóstico por imagem , Síndrome , Tremor/genética , Tremor/fisiopatologia , Incontinência Urinária/genética , Incontinência Urinária/fisiopatologiaRESUMO
FA2H encodes fatty acid 2-hydroxylase, which plays a significant role in maintaining the neuronal myelin sheath. Previous reports have revealed that a FA2H mutation leads to spastic paraplegia, leukodystrophy, and neurodegeneration with brain iron accumulation, collectively referred to as fatty acid hydroxylase-associated neurodegeneration (FAHN). The disease severity of FAHN varies among individual patients and may be explained by the enzyme activity of FA2H mutant proteins. Here we report a 10-year-old Japanese boy with FAHN having novel heterozygous mutations in FA2H. The patient presented with a spastic gait since the age of 5 years and was unable to walk without a cane by the time he was 8 years old. Brain MRI demonstrated a partial thinning of the corpus callosum, slight reduction of cerebellar volume, and posterior dominant periventricular leukodystrophy. Whole exome sequencing revealed two novel missense mutations in FA2H with compound heterozygous inheritance (NM_024306, p.Val149Leu, and p.His260Gln mutations). The enzyme activities of the p.Val149Leu and p.His260Gln variants were 60%-80% and almost 0%, respectively. Our cell-based enzyme assay demonstrated partial functionality for one of the variants, indicating a milder phenotype. However, considered along with previous reports, there was no definite relationship between the disease severity and residual enzyme activity measured using a similar method. Further research is needed to precisely predict the phenotypic severity of this disorder.
Assuntos
Transtornos Heredodegenerativos do Sistema Nervoso/genética , Oxigenases de Função Mista/genética , Encéfalo/metabolismo , Criança , Doenças Desmielinizantes/diagnóstico por imagem , Doenças Desmielinizantes/genética , Doenças Desmielinizantes/metabolismo , Marcha/genética , Transtornos Heredodegenerativos do Sistema Nervoso/diagnóstico por imagem , Transtornos Heredodegenerativos do Sistema Nervoso/metabolismo , Heterozigoto , Humanos , Japão , Imageamento por Ressonância Magnética , Masculino , Oxigenases de Função Mista/metabolismo , Mutação , Bainha de Mielina/genética , Bainha de Mielina/metabolismo , Paraplegia Espástica Hereditária/diagnóstico por imagem , Paraplegia Espástica Hereditária/genética , Paraplegia Espástica Hereditária/metabolismoAssuntos
Calcinose/genética , Glicosídeo Hidrolases/genética , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Irmãos , Idoso , Doenças dos Gânglios da Base/diagnóstico por imagem , Doenças dos Gânglios da Base/genética , Doenças dos Gânglios da Base/fisiopatologia , Tronco Encefálico/diagnóstico por imagem , Tronco Encefálico/fisiopatologia , Calcinose/diagnóstico por imagem , Calcinose/fisiopatologia , Doenças Cerebelares/diagnóstico por imagem , Doenças Cerebelares/genética , Doenças Cerebelares/fisiopatologia , Disartria/diagnóstico por imagem , Disartria/genética , Disartria/fisiopatologia , Feminino , Transtornos Neurológicos da Marcha/diagnóstico por imagem , Transtornos Neurológicos da Marcha/genética , Transtornos Neurológicos da Marcha/fisiopatologia , Transtornos Heredodegenerativos do Sistema Nervoso/diagnóstico por imagem , Transtornos Heredodegenerativos do Sistema Nervoso/fisiopatologia , Humanos , Itália , Masculino , Mutação , Transtornos Parkinsonianos/diagnóstico por imagem , Transtornos Parkinsonianos/genética , Transtornos Parkinsonianos/fisiopatologia , LinhagemRESUMO
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 , Proteínas do Citoesqueleto , 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/genéticaRESUMO
In vivo magnetic resonance imaging (MRI) was used to investigate regional and global brain atrophy in the neurodegenerative Niemann Pick Type C1 (NPC1) disease mouse model. Imaging experiments were conducted with the most commonly studied mouse model of NPC1 disease at early and late disease states. High-resolution in vivo images were acquired at early and late stages of the disease and analyzed with atlas-based registration to obtain measurements of twenty brain region volumes. A two-way ANOVA analysis indicated eighteen of these regions were different due to genotype and thirteen showed a significant interaction with age and genotype. The ability to measure in vivo neurodegeneration evidenced by brain atrophy adds to the ability to monitor disease progression and treatment response in the mouse model.
Assuntos
Encéfalo/diagnóstico por imagem , Doença de Niemann-Pick Tipo C/diagnóstico por imagem , Animais , Atrofia/diagnóstico por imagem , Atrofia/patologia , Encéfalo/patologia , Modelos Animais de Doenças , Transtornos Heredodegenerativos do Sistema Nervoso/diagnóstico por imagem , Transtornos Heredodegenerativos do Sistema Nervoso/patologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Imageamento por Ressonância Magnética , Camundongos , Camundongos Knockout , Neuroimagem , Proteína C1 de Niemann-Pick , Doença de Niemann-Pick Tipo C/patologia , Proteínas/genéticaRESUMO
BACKGROUND: Huntington Disease-like 2 (HDL2) is a neurodegenerative disorder similar to Huntington Disease (HD) in its clinical phenotype, genetic characteristics, neuropathology and longitudinal progression. Proposed specific differences include an exclusive African ancestry, lack of eye movement abnormalities, increased Parkinsonism, and acanthocytes in HDL2. OBJECTIVE: The objective was to determine the similarities and differences between HD and HDL2 by establishing the clinical phenotype of HDL2 with the published cases. METHODS: A literature review of all clinically described cases of HDL2 until the end of 2016 was performed and a descriptive analysis was carried out. RESULTS: Sixty-nine new cases were described between 2001 and 2016. All cases had likely African ancestry, and most were found in South Africa and the USA. Many features were found to be similar to HD, including a strong negative correlation between repeat length and age of onset. Chorea was noted in 48/57 cases (84%). Dementia was reported in 74% patients, and Parkinsonism in 37%. Psychiatric features were reported in 44 out of 47 cases. Patients with chorea had lower expanded repeat lengths compared to patients without chorea. Eye movements were described in 19 cases, 8 were abnormal. Acanthocytes were detected in 4 of the 13 patients tested. Nineteen out of 20 MRIs were reported as abnormal with findings similar to HD. CONCLUSION: This review clarifies some aspects of the HDL2 phenotype and highlights others which require further investigation. Features that are unique to HDL2 have been documented in a minority of subjects and require prospective validation.
Assuntos
Coreia/genética , Coreia/fisiopatologia , Transtornos Cognitivos/genética , Transtornos Cognitivos/fisiopatologia , Demência/genética , Demência/fisiopatologia , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Transtornos Heredodegenerativos do Sistema Nervoso/fisiopatologia , Coreia/diagnóstico por imagem , Transtornos Cognitivos/diagnóstico por imagem , Demência/diagnóstico por imagem , Transtornos Heredodegenerativos do Sistema Nervoso/diagnóstico por imagem , Humanos , Doença de Huntington/diagnóstico por imagem , Doença de Huntington/genética , Doença de Huntington/fisiopatologia , FenótipoRESUMO
Neurodegeneration with brain iron accumulation (NBIA) represents a heterogeneous and complex group of inherited neurodegenerative diseases, characterized by excessive iron accumulation, particularly in the basal ganglia. Common clinical features of NBIA include movement disorders, particularly parkinsonism and dystonia, cognitive dysfunction, pyramidal signs, and retinal abnormalities. The forms of NBIA described to date include pantothenase kinase-associated neurodegeneration (PKAN), phospholipase A2 associated neurodegeneration (PLAN), neuroferritinopathy, aceruloplasminemia, beta-propeller protein-associated neurodegeneration (BPAN), Kufor-Rakeb syndrome, mitochondrial membrane protein-associated neurodegeneration (MPAN), fatty acid hydroxylase-associated neurodegeneration (FAHN), coenzyme A synthase protein-associated neurodegeneration (CoPAN) and Woodhouse-Sakati syndrome. This review is a diagnostic approach for NBIA cases, from clinical features and brain imaging findings to the genetic etiology.
Assuntos
Distúrbios do Metabolismo do Ferro/diagnóstico por imagem , Distúrbios do Metabolismo do Ferro/genética , Mutação , Distrofias Neuroaxonais/diagnóstico por imagem , Distrofias Neuroaxonais/genética , Neuroimagem/métodos , Alopecia/diagnóstico por imagem , Alopecia/genética , Arritmias Cardíacas/diagnóstico por imagem , Arritmias Cardíacas/genética , Doenças dos Gânglios da Base/diagnóstico por imagem , Doenças dos Gânglios da Base/genética , Ceruloplasmina/deficiência , Ceruloplasmina/genética , Coenzima A Ligases/genética , Diabetes Mellitus/diagnóstico por imagem , Diabetes Mellitus/genética , Transtornos Heredodegenerativos do Sistema Nervoso/diagnóstico por imagem , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Humanos , Hipogonadismo/diagnóstico por imagem , Hipogonadismo/genética , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/genética , Imageamento por Ressonância Magnética/métodos , Proteínas de Membrana/genética , Doenças Neurodegenerativas/diagnóstico por imagem , Doenças Neurodegenerativas/genética , Neurodegeneração Associada a Pantotenato-Quinase/diagnóstico por imagem , Neurodegeneração Associada a Pantotenato-Quinase/genética , Transtornos Parkinsonianos/diagnóstico por imagem , Transtornos Parkinsonianos/genética , Fosfolipases A2/genéticaRESUMO
ABSTRACT Neurodegeneration with brain iron accumulation (NBIA) represents a heterogeneous and complex group of inherited neurodegenerative diseases, characterized by excessive iron accumulation, particularly in the basal ganglia. Common clinical features of NBIA include movement disorders, particularly parkinsonism and dystonia, cognitive dysfunction, pyramidal signs, and retinal abnormalities. The forms of NBIA described to date include pantothenase kinase-associated neurodegeneration (PKAN), phospholipase A2 associated neurodegeneration (PLAN), neuroferritinopathy, aceruloplasminemia, beta-propeller protein-associated neurodegeneration (BPAN), Kufor-Rakeb syndrome, mitochondrial membrane protein-associated neurodegeneration (MPAN), fatty acid hydroxylase-associated neurodegeneration (FAHN), coenzyme A synthase protein-associated neurodegeneration (CoPAN) and Woodhouse-Sakati syndrome. This review is a diagnostic approach for NBIA cases, from clinical features and brain imaging findings to the genetic etiology.
RESUMO A neurodegeneração com acúmulo cerebral de ferro (sigla em inglês NBIA) representa um grupo heterogêneo e complexo de doenças neurodegenerativas hereditárias, caracterizada pelo acúmulo cerebral de ferro, especialmente nos núcleos da base. O quadro clínico das NBIAs em geral inclui distúrbios do movimento, particularmente parkinsonismo e distonia, disfunção cognitiva, sinais piramidais e anormalidades da retina. As formas de NBIA descritas até o momento incluem neurodegeneração associada a pantothenase kinase (PKAN), neurodegeneração associada a phospholipase A2 (PLAN), neuroferritinopatia, aceruloplasminemia, neurodegeneração associada a beta-propeller protein (BPAN), síndrome de Kufor-Rakeb, neurodegeneração associada a mitochondrial membrane protein (MPAN), neurodegeneração associada a “fatty acid hydroxylase” (FAHN), neurodegeneração associada a coenzyme A synthase protein (CoPAN) e síndrome de Woodhouse-Sakati. Esta revisão é uma orientação para o diagnóstico das NBIAs, partindo das características clínicas e achados de neuroimagem, até a etiologia genética.
Assuntos
Humanos , Distrofias Neuroaxonais/genética , Distrofias Neuroaxonais/diagnóstico por imagem , Distúrbios do Metabolismo do Ferro/genética , Distúrbios do Metabolismo do Ferro/diagnóstico por imagem , Neuroimagem/métodos , Mutação , Arritmias Cardíacas/genética , Arritmias Cardíacas/diagnóstico por imagem , Doenças dos Gânglios da Base/genética , Doenças dos Gânglios da Base/diagnóstico por imagem , Ceruloplasmina/deficiência , Ceruloplasmina/genética , Coenzima A Ligases/genética , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Transtornos Heredodegenerativos do Sistema Nervoso/diagnóstico por imagem , Diabetes Mellitus/genética , Diabetes Mellitus/diagnóstico por imagem , Alopecia/genética , Alopecia/diagnóstico por imagem , Hipogonadismo/genética , Hipogonadismo/diagnóstico por imagemRESUMO
Mutations in the synaptic nuclear envelope protein 1 (SYNE1) gene have been reported to cause a relatively pure, slowly progressive cerebellar recessive ataxia mostly identified in Quebec, Canada. Combining next-generation sequencing techniques and deep-phenotyping (clinics, magnetic resonance imaging, positron emission tomography, muscle histology), we here established the frequency, phenotypic spectrum and genetic spectrum of SYNE1 in a screening of 434 non-Canadian index patients from seven centres across Europe. Patients were screened by whole-exome sequencing or targeted panel sequencing, yielding 23 unrelated families with recessive truncating SYNE1 mutations (23/434 = 5.3%). In these families, 35 different mutations were identified, 34 of them not previously linked to human disease. While only 5/26 patients (19%) showed the classical SYNE1 phenotype of mildly progressive pure cerebellar ataxia, 21/26 (81%) exhibited additional complicating features, including motor neuron features in 15/26 (58%). In three patients, respiratory dysfunction was part of an early-onset multisystemic neuromuscular phenotype with mental retardation, leading to premature death at age 36 years in one of them. Positron emission tomography imaging confirmed hypometabolism in extra-cerebellar regions such as the brainstem. Muscle biopsy reliably showed severely reduced or absent SYNE1 staining, indicating its potential use as a non-genetic indicator for underlying SYNE1 mutations. Our findings, which present the largest systematic series of SYNE1 patients and mutations outside Canada, revise the view that SYNE1 ataxia causes mainly a relatively pure cerebellar recessive ataxia and that it is largely limited to Quebec. Instead, complex phenotypes with a wide range of extra-cerebellar neurological and non-neurological dysfunctions are frequent, including in particular motor neuron and brainstem dysfunction. The disease course in this multisystemic neurodegenerative disease can be fatal, including premature death due to respiratory dysfunction. With a relative frequency of â¼5%, SYNE1 is one of the more common recessive ataxias worldwide.
Assuntos
Ataxia Cerebelar/diagnóstico , Transtornos Heredodegenerativos do Sistema Nervoso/diagnóstico , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Adulto , Idoso , Encéfalo/metabolismo , Ataxia Cerebelar/diagnóstico por imagem , Ataxia Cerebelar/genética , Ataxia Cerebelar/fisiopatologia , Proteínas do Citoesqueleto , Potencial Evocado Motor/fisiologia , Feminino , Genes Recessivos , Transtornos Heredodegenerativos do Sistema Nervoso/diagnóstico por imagem , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Transtornos Heredodegenerativos do Sistema Nervoso/fisiopatologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Músculos/metabolismo , Mutação de Sentido Incorreto , Proteínas do Tecido Nervoso/metabolismo , Neuroimagem , Proteínas Nucleares/metabolismo , Fenótipo , Tomografia por Emissão de Pósitrons , Adulto JovemRESUMO
Neurodegeneration with brain iron accumulation (NBIA) is a group of genetic disorders with a progressive extrapyramidal syndrome and excessive iron deposition in the brain, particularly in the globus pallidus and substantia nigra. We present the case of a 31-year-old woman with mitochondrial protein associated neurodegeneration (MPAN). MPAN is a new identified subtype of NBIA, caused by mutations in C19orf12 gene. The typical features are speech and gait disturbances, dystonia, parkinsonism and pyramidal signs. Common are psychiatric symptoms such as impulsive or compulsive behavior, depression and emotional lability. In almost all cases, the optic atrophy has been noted and about 50% of cases have had a motor axonal neuropathy. In the MRI on T2- and T2*-weighted images, there are hypointense lesions in the globus palidus and substantia nigra corresponding to iron accumulation.
Assuntos
Transtornos Heredodegenerativos do Sistema Nervoso/genética , Distúrbios do Metabolismo do Ferro/genética , Proteínas Mitocondriais/genética , Adulto , Encéfalo/patologia , Distonia/patologia , Feminino , Transtornos Neurológicos da Marcha/etiologia , Transtornos Neurológicos da Marcha/genética , Transtornos Neurológicos da Marcha/fisiopatologia , Transtornos Heredodegenerativos do Sistema Nervoso/diagnóstico por imagem , Transtornos Heredodegenerativos do Sistema Nervoso/patologia , Transtornos Heredodegenerativos do Sistema Nervoso/fisiopatologia , Humanos , Imageamento por Ressonância Magnética , Transtornos Mentais/complicações , Transtornos Mentais/genética , Transtornos Mentais/psicologia , Mutação , Exame Neurológico , Atrofia Óptica/genética , Esquizofrenia Paranoide/genética , Esquizofrenia Paranoide/psicologia , UltrassonografiaRESUMO
Genetic factors represent an important etiologic group in the causation of intellectual disability. We describe a Saudi Arabian family with closley related parents in which four of six children were affected by a congenital cognitive disturbance. The four individuals (aged 18, 16, 13, and 2 years when last examined) had motor and cognitive delay with seizures in early childhood, and three of the four (sparing only the youngest child) had progressive, severe cognitive decline with spasticity. Two affected children had ocular malformations, and the three older children had progressive visual loss. The youngest had normal globes with good functional vision when last examined but exhibited the oculodigital sign, which may signify a subclinical visual deficit. A potentially deleterious nucleotide change (c.1A>G; p.Met1Val) in the C12orf57 gene was homozygous in all affected individuals, heterozygous in the parents, and absent in an unaffected sibling and >350 normal individuals. This gene has no known function. This family manifests a autosomal recessive syndrome with some phenotypic variability that includes abnormal development of brain and eyes, delayed cognitive and motor milestones, seizures, and a severe cognitive and visual decline that is associated with a homozygous variant in a newly identified gene.
Assuntos
Transtornos Cromossômicos/genética , Transtornos Cognitivos/genética , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Transtornos da Visão/genética , Adolescente , Substituição de Aminoácidos , Pré-Escolar , Transtornos Cromossômicos/diagnóstico por imagem , Mapeamento Cromossômico , Transtornos Cognitivos/diagnóstico por imagem , Feminino , Seguimentos , Genótipo , Transtornos Heredodegenerativos do Sistema Nervoso/diagnóstico por imagem , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Deficiência Intelectual/genética , Masculino , Linhagem , Mutação Puntual , Radiografia , Arábia Saudita , Análise de Sequência de DNA , IrmãosRESUMO
Several neurodegenerative disorders are known to predominantly affect the white matter of the brain including vanishing white matter disease (VWMD), an autosomal recessive disorder characterized by leukodystrophy of varying severity in addition to variable systemic involvement. We report a consanguineous Arab family with three affected children, all of whom presented with severe neonatal epilepsy and profound neurodegenerative disease characterized by marked leukodystrophy with white matter cavitation mimicking VWMD. We combined autozygome and exome analysis to identify a novel variant in the gene encoding a member of the eIF2B-related family of proteins (MRI1). This is a poorly understood family of proteins of unclear function. Our results represent the first link between a variant in a member of this family and a human disease, and suggest that it converges with the highly homologous eIF2B, known to be mutated in VWMD, on the molecular pathogenesis of neurodegeneration.
Assuntos
Aldose-Cetose Isomerases/genética , Epilepsias Mioclônicas/genética , Loci Gênicos , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Leucoencefalopatias/genética , Adulto , Aldose-Cetose Isomerases/metabolismo , Árabes , Epilepsias Mioclônicas/diagnóstico por imagem , Epilepsias Mioclônicas/enzimologia , Feminino , Transtornos Heredodegenerativos do Sistema Nervoso/diagnóstico por imagem , Transtornos Heredodegenerativos do Sistema Nervoso/enzimologia , Humanos , Lactente , Recém-Nascido , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/enzimologia , Masculino , RadiografiaRESUMO
Aicardi-Goutières syndrome (AGS) is a rare, genetically-determined encephalopathy whose importance from a neonatology perspective is magnified because of the risk of misdiagnosis as the sequelae of congenital infection. Molecular advances have shown that AGS can be caused by mutations in any one of at least five genes (four of which have been identified). A recent genotype-phenotype study has shown that a neonatal form of the disease, highly reminiscent of congenital infection, is seen particularly with TREX1 mutations. It seems likely that the enzymes defective in AGS are involved in digesting endogenous nucleic acids (DNA and RNA) produced during normal cell replication, and that a failure of this removal results in inappropriate triggering of the innate immune system. This hypothesis explains the remarkable phenotypic overlap of AGS with congenital infection, where a similar interferon alpha mediated innate immune response is triggered by viral, as opposed to self, nucleic acids.
Assuntos
Encefalite Viral/diagnóstico por imagem , Transtornos Heredodegenerativos do Sistema Nervoso/diagnóstico por imagem , Proteínas/genética , Tomografia Computadorizada por Raios X , Diagnóstico Diferencial , Encefalite Viral/congênito , Exodesoxirribonucleases , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Humanos , Lactente , Recém-Nascido , Masculino , Fenótipo , Fosfoproteínas , SíndromeAssuntos
Doenças dos Gânglios da Base/diagnóstico por imagem , Doenças dos Gânglios da Base/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Síndrome do Cromossomo X Frágil/complicações , Transtornos Heredodegenerativos do Sistema Nervoso/diagnóstico por imagem , Transtornos Heredodegenerativos do Sistema Nervoso/patologia , Idoso , Ataxia/diagnóstico por imagem , Ataxia/genética , Ataxia/patologia , Atrofia/diagnóstico por imagem , Atrofia/genética , Atrofia/patologia , Doenças dos Gânglios da Base/genética , Ligação Competitiva/fisiologia , Encéfalo/fisiopatologia , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/patologia , Corpo Estriado/fisiopatologia , Diagnóstico Diferencial , Erros de Diagnóstico/prevenção & controle , Tratos Extrapiramidais/diagnóstico por imagem , Tratos Extrapiramidais/patologia , Tratos Extrapiramidais/fisiopatologia , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Humanos , Imageamento por Ressonância Magnética , Masculino , Mesencéfalo/diagnóstico por imagem , Mesencéfalo/patologia , Mesencéfalo/fisiopatologia , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico , Doença de Parkinson/fisiopatologia , Valor Preditivo dos Testes , Radiografia , Radioisótopos , Receptores Dopaminérgicos/metabolismo , Síndrome , Tomografia Computadorizada de Emissão de Fóton Único , Tremor/diagnóstico por imagem , Tremor/genética , Tremor/patologiaRESUMO
BACKGROUND: We recently discovered an autosomal dominant disease causing a progressive dementia. The disease is caused by a point mutation in the gene coding for the serine protease inhibitor (ie, serpin) neuroserpin. The mutation results in an unstable neuroserpin protein that readily aggregates into intraneuronal inclusions that we identify as Collins bodies. The bodies are distributed throughout the cerebral hemispheres but are significantly more numerous in the cortex and the substantia nigra. We have named the disease familial encephalopathy with neuroserpin inclusion bodies (FENIB). OBJECTIVES: To describe the cognitive and neurophysiological changes exhibited by individuals with FENIB and to correlate the phenotypic expression of the disease with the neuropathological findings. DESIGN: Multiple case studies using neuropsychological assessment, electroencephalography (EEG), magnetic resonance imaging (MRI), and single-photon emission computed tomographic (SPECT) studies of family members were performed. Using these measures, we also compared family members in whom the mutation is present with family members in whom the mutation was absent to control for nonspecific familial factors. SUBJECTS: Nine individuals (5 women, aged 31-64 years; 4 men, aged 43-67 years) from 2 generations of family members related to the first reliably identified individual with symptoms of this disease. Symptoms, by self-report and reports of other family members, ranged from asymptomatic to severe dementia. Six of the 9 individuals carried the disease mutation. RESULTS: All subjects with the mutation demonstrated some cognitive changes, with the greatest demonstrated by subjects older than 40 years. The changes included restricted attention, concentration, and response regulation functions, reduced controlled oral fluency (word-list generation), and restricted visuospatial organization. In general, recall memory was not as affected as other cognitive domains. The most severely affected subject demonstrated global dementia with prominent frontal lobe features. Findings on SPECT showed anomalies limited to frontal areas in the less affected subjects and more global, patchy areas of hypoperfusion in the more severely affected subjects. The 3 oldest and most affected subjects demonstrated slowing on EEG findings. The MRI findings were noncontributory except in the 2 most severe cases, which showed global cortical atrophy. CONCLUSIONS: Cognitive changes in mildly to moderately affected subjects were characterized by deficits in frontal and frontal-subcortical area-dependent processes. Continued progressive deterioration of cerebral functions with relative sparing of recall memory suggests a unique dementia associated with this disease.