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1.
Am J Hum Genet ; 110(4): 663-680, 2023 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-36965478

RESUMO

The vast majority of human genes encode multiple isoforms through alternative splicing, and the temporal and spatial regulation of those isoforms is critical for organismal development and function. The spliceosome, which regulates and executes splicing reactions, is primarily composed of small nuclear ribonucleoproteins (snRNPs) that consist of small nuclear RNAs (snRNAs) and protein subunits. snRNA gene transcription is initiated by the snRNA-activating protein complex (SNAPc). Here, we report ten individuals, from eight families, with bi-allelic, deleterious SNAPC4 variants. SNAPC4 encoded one of the five SNAPc subunits that is critical for DNA binding. Most affected individuals presented with delayed motor development and developmental regression after the first year of life, followed by progressive spasticity that led to gait alterations, paraparesis, and oromotor dysfunction. Most individuals had cerebral, cerebellar, or basal ganglia volume loss by brain MRI. In the available cells from affected individuals, SNAPC4 abundance was decreased compared to unaffected controls, suggesting that the bi-allelic variants affect SNAPC4 accumulation. The depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing. Analysis of available fibroblasts from affected individuals showed decreased snRNA expression and global dysregulation of alternative splicing compared to unaffected cells. Altogether, these data suggest that these bi-allelic SNAPC4 variants result in loss of function and underlie the neuroregression and progressive spasticity in these affected individuals.


Assuntos
Processamento Alternativo , Proteínas de Ligação a DNA , Paraparesia Espástica , Fatores de Transcrição , Paraparesia Espástica/genética , Humanos , Proteínas de Ligação a DNA/genética , Fatores de Transcrição/genética , Células HeLa , Isoformas de Proteínas/genética , RNA-Seq , Masculino , Feminino , Linhagem , Alelos , Lactente , Pré-Escolar , Criança , Adolescente , Estrutura Secundária de Proteína , RNA Nuclear Pequeno/genética
2.
Dev Med Child Neurol ; 55(2): 167-172, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23121133

RESUMO

AIM: To investigate the association between magnetic resonance imaging (MRI) patterns and motor function, epileptic episodes, and IQ or developmental quotient in patients born at term with spastic diplegia. METHOD: Eighty-six patients born at term with cerebral palsy (CP) and spastic diplegia (54 males, 32 females; median age 20 y, range 7-42 y) among 829 patients with CP underwent brain MRI between 1990 and 2008. The MRI and clinical findings were analysed retrospectively. Intellectual disability was classified according to the Enjoji developmental test or the Wechsler Intelligence Scale for Children (3rd edition). RESULTS: The median ages at diagnosis of CP, assignment of Gross Motor Function Classification System (GMFCS) level, cognitive assessment, and MRI were 2 years (range 5 mo-8 y), 6 years (2 y 8 mo-19 y), 6 years (1 y 4 mo-19 y), and 7 years (10 mo-30 y) respectively. MRI included normal findings (41.9%), periventricular leukomalacia, hypomyelination, and porencephaly/periventricular venous infarction. The frequency of patients in GMFCS levels III to V and intellectual disability did not differ between those with normal and abnormal MRI findings. Patients with normal MRI findings had significantly fewer epileptic episodes than those with abnormal ones (p=0.001). INTERPRETATION: Varied MRI findings, as well as the presence of severe motor dysfunction and intellectual disability (despite normal MRI), suggest that patients born at term with spastic diplegia had heterogeneous and unidentified pathophysiology.


Assuntos
Encéfalo/patologia , Paralisia Cerebral/patologia , Inteligência/fisiologia , Destreza Motora/fisiologia , Fibras Nervosas Mielinizadas/patologia , Adolescente , Adulto , Encéfalo/fisiopatologia , Paralisia Cerebral/fisiopatologia , Criança , Epilepsia/patologia , Epilepsia/fisiopatologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino
3.
Brain Dev ; 43(2): 308-313, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33139125

RESUMO

BACKGROUND: ECHS1 is a key enzyme of the valine catabolic pathway and oxidation of fatty acids. In ECHS1 deficiency (ECHS1D), accumulation of toxic intermediates from the valine induces neurodegeneration, which presents Leigh syndrome (LS). Therefore, valine restriction is suggested as an effective therapy. Further, cysteamine may detoxify the toxic metabolites themselves and N-acetylcysteine (NAC) is a potent antioxidant preventing neurological affect. Herein, we report the therapeutic effects of dietary therapy, cysteamine, and NAC in two siblings with ECHS1D, including their clinical, neuroradiological, and chemical aspects. CASE REPORT: The elder sister was the proband and was diagnosed as LS at 13 months of age. Gene analysis identified compound heterozygous ECHS1 mutations. Her psychomotor development was regressed, and she became bedridden. At 4 years old she started a low protein diet (LPD), but with no obvious neurological change. The younger brother was confirmed early with ECHS1D and received cysteamine and NAC treatment from 5 months of age, which could not prevent him developing LS at 7 months of age. Thus, we started a LPD at 14 months of age, with which he regained his ability to roll over, then we proceeded to a valine-restricted diet. The brain magnetic resonance image hyperintensity was diminished, and the lactate peak on magnetic resonance spectroscopy decreased. His neurological outcome is better than his elder sister. In both cases, excretion of valine metabolites decreased after dietary therapy without obvious adverse effects. CONCLUSION: Early initiation of dietary therapy may reduce neurological sequelae in patients with ECHS1D.


Assuntos
Enoil-CoA Hidratase/deficiência , Valina/metabolismo , Acetilcisteína/farmacologia , Cisteamina/farmacologia , Dietoterapia/métodos , Enoil-CoA Hidratase/genética , Enoil-CoA Hidratase/metabolismo , Enoil-CoA Hidratase/fisiologia , Família , Feminino , Testes Genéticos/métodos , Humanos , Lactente , Japão , Doença de Leigh/genética , Doença de Leigh/prevenção & controle , Imageamento por Ressonância Magnética/métodos , Masculino , Mutação/genética , Linhagem , Irmãos , Resultado do Tratamento , Valina/deficiência , Valina/genética
4.
Mol Genet Metab Rep ; 29: 100809, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34667719

RESUMO

Short-chain enoyl-CoA hydratase (ECHS1) is involved in amino acid and fatty acid catabolism in mitochondria and its deficiency causes Leigh syndrome or exercise-induced dystonia. More than 60 patients with this condition have been reported till date. The accumulation of intermediate metabolites of valine is assumed to be responsible for the cytotoxicity. Since protein restriction, including valine reportedly improves neurological symptoms, it is essential to consider the possible incidence of and diagnose ECHS1 syndrome in the earlier stages. This study reported the liquid chromatography with tandem mass spectrometry (LC-MS/MS) urine and plasma metabolite analysis in six cases, including four new cases with ECHS1 deficiency. The values of urine cysteine/cysteamine conjugates from valine metabolites, S-(2-carboxypropyl) cysteine/cysteamine from methacrylyl-CoA, and S-(2-carboxyethyl) cysteine/cysteamine from acryloyl-CoA were separated between six patients and six normal controls. The LC-MS/MS analysis revealed that these metabolites can be used for the early diagnosis and evaluation of diet therapy.

6.
Brain Dev ; 35(10): 887-93, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24047572

RESUMO

The recent findings on subtraction ictal SPECT and ictal near-infrared spectroscopic topography in patients with West syndrome were summarized and its availability for presurgical evaluation was discussed. The subtraction ictal SPECT study in patients with West syndrome demonstrated the cortical epileptic region and subcortical involvement, which may consist of epilepsy networks related to the spasms. Moreover, subtraction ictal SPECT may have predictive power for short-term seizure outcome. Patients with a symmetric hyperperfusion pattern are predicted to have a better seizure outcome, whereas patients with asymmetric hyperperfusion pattern may develop poor seizure control. Importantly, asymmetric MRI findings had no predictive power for seizure outcome. Multichannel near-infrared spectroscopic topography applied to the patients with West syndrome detected an increase in regional cerebral blood volume in multiple areas which were activated either simultaneously or sequentially during spasms. Topographic changes in cerebral blood volume were closely correlated with spasm phenotype, suggesting that the cortex is involved in the generation of spasms. In conclusion, subtraction ictal SPECT may be considered as a useful tool for presurgical evaluation of patients with West syndrome and investigation of the pathophysiology of spasms. The ictal near-infrared spectroscopic topography should be more investigated to see if this is useful tool for presurgical evaluation.


Assuntos
Espasmos Infantis/diagnóstico , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Encéfalo/irrigação sanguínea , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Humanos , Lactente , Fluxo Sanguíneo Regional , Espasmos Infantis/diagnóstico por imagem , Espasmos Infantis/patologia
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