RESUMEN
The present study aimed to characterize clinical and molecular data of a large cohort of subjects with childhood-onset hereditary spastic paraplegias (HSPs). A multicenter historical cohort was performed at five centers in Brazil, in which probands and affected relatives' data from consecutive families with childhood-onset HSP (onset < 12 years-old) were reviewed from 2011 to 2020. One hundred and six individuals (83 families) with suspicion of childhood-onset HSP were evaluated, being 68 (50 families) with solved genetic diagnosis, 6 (5 families) with candidate variants in HSP-related genes and 32 (28 families) with unsolved genetic diagnosis. The most common childhood-onset subtype was SPG4, 11/50 (22%) families with solved genetic diagnosis; followed by SPG3A, 8/50 (16%). Missense pathogenic variants in SPAST were found in 54.5% of probands, favoring the association of this type of variant to childhood-onset SPG4. Survival curves to major handicap and cross-sectional Spastic Paraplegia Rating Scale progressions confirmed the slow neurological deterioration in SPG4 and SPG3A. Most common complicating features and twenty variants not previously described in HSP-related genes were reported. These results are fundamental to understand the molecular and clinical epidemiology of childhood-onset HSP, which might help on differential diagnosis, patient care and guiding future collaborative trials for these rare diseases.
Asunto(s)
Paraplejía Espástica Hereditaria/diagnóstico , Paraplejía Espástica Hereditaria/etiología , Adolescente , Adulto , Edad de Inicio , Alelos , Brasil/epidemiología , Niño , Estudios de Cohortes , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Imagen por Resonancia Magnética , Masculino , Fenotipo , Vigilancia de la Población , Paraplejía Espástica Hereditaria/epidemiología , Espastina/genética , Evaluación de Síntomas , Adulto JovenRESUMEN
AIMS: To investigate hereditary spastic paraplegia (HSP) in a pediatric Brazilian sample. METHODS: Epidemiological, clinical, radiological and laboratory data were analyzed in 35 patients. RESULTS: Simple HSP (HSP-S) was detected in 12 patients, and complicated HSP (HSP-C) was detected in 23 patients. The mean age of onset of symptoms was 2.9 years in HSP-S and 1.6 years in HSP-C (p = 0.023). The disease was more severe in HSP-C. There were no differences in sex, ethnic background, or family history between groups. Intellectual disability was the most frequent finding associated with HSP-C. Peripheral axonal neuropathy was found in three patients. In the HSP-C group, MRI was abnormal in 13 patients. The MRI abnormalities included nonspecific white matter lesions, cerebellar atrophy, thinning of the corpus callosum and the "ear of the lynx sign". CONCLUSIONS: In children with spastic paraplegia, HSP must be considered whenever similar pathologies, mainly diplegic cerebral palsy, are ruled out.
Asunto(s)
Paraplejía Espástica Hereditaria/epidemiología , Paraplejía Espástica Hereditaria/patología , Adolescente , Distribución por Edad , Edad de Inicio , Brasil/epidemiología , Niño , Preescolar , Cuerpo Calloso/diagnóstico por imagen , Cuerpo Calloso/patología , Femenino , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Distribución por Sexo , Paraplejía Espástica Hereditaria/diagnóstico por imagen , Estadísticas no Paramétricas , Factores de TiempoRESUMEN
ABSTRACT Aims: To investigate hereditary spastic paraplegia (HSP) in a pediatric Brazilian sample. Methods: Epidemiological, clinical, radiological and laboratory data were analyzed in 35 patients. Results: Simple HSP (HSP-S) was detected in 12 patients, and complicated HSP (HSP-C) was detected in 23 patients. The mean age of onset of symptoms was 2.9 years in HSP-S and 1.6 years in HSP-C (p = 0.023). The disease was more severe in HSP-C. There were no differences in sex, ethnic background, or family history between groups. Intellectual disability was the most frequent finding associated with HSP-C. Peripheral axonal neuropathy was found in three patients. In the HSP-C group, MRI was abnormal in 13 patients. The MRI abnormalities included nonspecific white matter lesions, cerebellar atrophy, thinning of the corpus callosum and the "ear of the lynx sign". Conclusions: In children with spastic paraplegia, HSP must be considered whenever similar pathologies, mainly diplegic cerebral palsy, are ruled out.
RESUMO Objetivo: Investigar paraplegia espástica hereditária (PEH) em uma amostra brasileira de pacientes pediátricos. Métodos: Foram colhidos dados clínicos, epidemiológicos, radiológicos e laboratoriais de 35 pacientes. Resultados: Doze pacientes foram classificados como PEH simples (PEH-S), e 23 como PEH complicada (PEH-C). A média de idade de início dos sintomas foi de 2,9 anos na PEH-S e 1,6 anos na PEH-C (p = 0,023). A doença foi mais grave na PEH-C. Não houve diferença de sexo, etnia e histórico familial entre os dois grupos. Deficiência intelectual foi a associação clínica mais frequente na PEH-C. Neuropatia periférica axonal foi encontrada em três pacientes. A RM foi normal em 13 casos de PEH-C. Anormalidades de RM incluiram alterações inespecíficas da substância branca, atrofia de cerebelo, afilamento de corpo caloso e o "sinal da orelha de lince". Conclusões: PEH deve ser considerada em crianças com paraparesia espástica sempre que descartadas condições patológicas similares, principalmente paralisia cerebral.
Asunto(s)
Humanos , Masculino , Femenino , Lactante , Preescolar , Niño , Adolescente , Paraplejía Espástica Hereditaria/patología , Paraplejía Espástica Hereditaria/epidemiología , Factores de Tiempo , Brasil/epidemiología , Imagen por Resonancia Magnética , Paraplejía Espástica Hereditaria/diagnóstico por imagen , Distribución por Sexo , Edad de Inicio , Distribución por Edad , Estadísticas no Paramétricas , Cuerpo Calloso/patología , Cuerpo Calloso/diagnóstico por imagenRESUMEN
The most common causes of congenital myasthenic syndromes (CMS) are CHRNE mutations, and some pathogenic allelic variants in this gene are especially frequent in certain ethnic groups. In the southern region of Brazil, a study found the c.130dupG CHRNE mutation in up to 33% of families with CMS. Here, we aimed to verify the frequency of this mutation among individuals with CMS in a larger cohort of CMS patients from different areas of Brazil and to characterize clinical features of these patients. Eighty-four patients with CMS, from 72 families, were clinically evaluated and submitted to direct sequencing of the exon 2 of CHRNE. The c.130dupG mutation was found in 32 patients (23 families), with 26 patients (19 families, 26.3%) in homozygosis, confirming its high prevalence in different regions of Brazil. Among the homozygous patients, the following characteristics were frequent: onset of symptoms before 2 years of age (92.3%), little functional restriction (92.3%), fluctuating symptoms (100%), ocular muscle impairment (96.1%), ptosis (100%), limb weakness (88.4%), response to pyridostigmine (100%), facial involvement (77%), and bulbar symptoms (70.8%). The pretest probability of finding at least one allele harbouring the c.130dupG mutation was 38.1%. Selecting only patients with impaired eye movement together with limb weakness and improvement with pyridostigmine, the probability increases to 72.2%. This clinical pre-selection of patients is likely a useful tool for regions where CHRNE mutations have a founder effect. In conclusion, the CHRNE mutation c.130dupG leads to fairly benign natural course of the disease with relative homogeneity.