RESUMEN
The neurological phenotype of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) and short-chain enoyl-CoA hydratase (SCEH) defects is expanding and natural history studies are necessary to improve clinical management. From 42 patients with Leigh syndrome studied by massive parallel sequencing, we identified five patients with SCEH and HIBCH deficiency. Fourteen additional patients were recruited through collaborations with other centres. In total, we analysed the neurological features and mutation spectrum in 19 new SCEH/HIBCH patients. For natural history studies and phenotype to genotype associations we also included 70 previously reported patients. The 19 newly identified cases presented with Leigh syndrome (SCEH, n = 11; HIBCH, n = 6) and paroxysmal dystonia (SCEH, n = 2). Basal ganglia lesions (18 patients) were associated with small cysts in the putamen/pallidum in half of the cases, a characteristic hallmark for diagnosis. Eighteen pathogenic variants were identified, 11 were novel. Among all 89 cases, we observed a longer survival in HIBCH compared to SCEH patients, and in HIBCH patients carrying homozygous mutations on the protein surface compared to those with variants inside/near the catalytic region. The SCEH p.(Ala173Val) change was associated with a milder form of paroxysmal dystonia triggered by increased energy demands. In a child harbouring SCEH p.(Ala173Val) and the novel p.(Leu123Phe) change, an 83.6% reduction of the protein was observed in fibroblasts. The SCEH and HIBCH defects in the catabolic valine pathway were a frequent cause of Leigh syndrome in our cohort. We identified phenotype and genotype associations that may help predict outcome and improve clinical management.
Asunto(s)
Anomalías Múltiples/genética , Errores Innatos del Metabolismo de los Aminoácidos/genética , Distonía/genética , Enoil-CoA Hidratasa/genética , Enfermedad de Leigh/genética , Tioléster Hidrolasas/deficiencia , Valina/metabolismo , Encéfalo/diagnóstico por imagen , Preescolar , Distonía/diagnóstico , Enoil-CoA Hidratasa/deficiencia , Femenino , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Internacionalidad , Enfermedad de Leigh/diagnóstico , Enfermedad de Leigh/metabolismo , Imagen por Resonancia Magnética , Masculino , Redes y Vías Metabólicas/genética , Mutación , Fenotipo , Tasa de Supervivencia , Tioléster Hidrolasas/genéticaRESUMEN
BACKGROUND: Collagens are one of the major constituents of the pial membrane, which plays a crucial role in neuronal migration and cortical lamination during brain development. Type III procollagen, the chains of which are encoded by COL3A1, is the ligand of the G protein-coupled receptor 56 (GPR56), also known as adhesion G protein-coupled receptor G1. Bi-allelic mutations in GPR56 give rise to cobblestone-like malformation, white matter changes and cerebellar dysplasia. This report shows that bi-allelic mutations in COL3A1 are associated with a similar phenotype. METHODS: Exome analysis was performed in a family consisting of two affected and two non-affected siblings. Brain imaging studies of this family and of two previously reported individuals with bi-allelic mutations in COL3A1 were reviewed. Functional assays were performed on dermal fibroblasts. RESULTS: Exome analysis revealed a novel homozygous variant c.145C>G (p.Pro49Ala) in exon 2 of COL3A1. Brain MRI in the affected siblings as well as in the two previously reported individuals with bi-allelic COL3A1 mutations showed a brain phenotype similar to that associated with mutations in GPR56. CONCLUSION: Homozygous or compound heterozygous mutations in COL3A1 are associated with cobblestone-like malformation in all three families reported to date. The variability of the phenotype across patients suggests that genetic alterations in distinct domains of type III procollagen can lead to different outcomes. The presence of cobblestone-like malformation in patients with bi-allelic COL3A1 mutations emphasises the critical role of the type III collagen-GPR56 axis and the pial membrane in the regulation of brain development and cortical lamination.
Asunto(s)
Colágeno Tipo III/genética , Quistes/genética , Malformaciones del Desarrollo Cortical/genética , Receptores Acoplados a Proteínas G/genética , Sustancia Blanca/patología , Adulto , Alelos , Células Cultivadas , Enfermedades Cerebelosas/genética , Enfermedades Cerebelosas/patología , Niño , Preescolar , Quistes/patología , Exoma/genética , Exones/genética , Femenino , Fibroblastos/patología , Humanos , Ligandos , Imagen por Resonancia Magnética/métodos , Masculino , Malformaciones del Desarrollo Cortical/patología , Mutación/genética , Fenotipo , Adulto JovenRESUMEN
Encephalocraniocutaneous lipomatosis (ECCL) is a sporadically occurring neurocutaneous disorder characterized by ocular anomalies, mainly choristomas; by skin lesions consisting of hairless fatty tissue nevi (nevus psiloliparus), focal dermal hypoplasia, alopecia, and periocular skin tags; and by CNS anomalies, including intracranial and spinal lipomas and often mental retardation and seizures. Here, we report on three boys with ECCL with typical abnormalities of the eyes, skin and brain and, in addition, coarctation of the aorta. All three children developed multiple cystic bone lesions, which progressively spread throughout the skeleton in Patient 1 and was shown histologically to be non-ossifying fibromas in Patient 2. We hypothesize that ECCL may be caused by mosaicism for a mutated gene involved in benign mesenchymal tumors and in vasculogenesis.