Expanding the phenotypic spectrum of CLCN2-related leucoencephalopathy and ataxia.
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Nóbrega Paulo R, R B de Paiva Anderson, Souza Katiane S, de Souza Jorge Luiz B, G S B Lima Pedro Lucas, da Silva Delson José, Pitombeira Milena Sales, Borges Viviennee K, Dias Daniel A, Bispo Luciana M, Santos Carolina F, Freua Fernando, Silva Paulo Diego S, Alves Isabela S, Portella Leonardo B, Cunha Paulina R, Salomao Rubens Paulo A, Pedroso José Luiz, Miyajima Veridiana P, Miyajima Fábio, Cali Elisa, Wade Charles, Sudarsanam Annapurna, O'Driscoll Mary, Hayton Tom, Barsottini Orlando G P, Klebe Stephan, Kok Fernando, Lucato Leandro Tavares, Houlden Henry, Depienne Christel, Lynch David S, Braga-Neto Pedro
Аннотация
Mutations in CLCN2 are a rare cause of autosomal recessive leucoencephalopathy with ataxia and specific imaging abnormalities. Very few cases have been reported to date. Here, we describe the clinical and imaging phenotype of 12 additional CLCN2 patients and expand the known phenotypic spectrum of this disorder. Informed consent was obtained for all patients. Patients underwent either whole-exome sequencing or focused/panel-based sequencing to identify variants. Twelve patients with biallelic CLCN2 variants are described. This includes three novel likely pathogenic missense variants. All patients demonstrated typical MRI changes, including hyperintensity on T2-weighted images in the posterior limbs of the internal capsules, midbrain cerebral peduncles, middle cerebellar peduncles and cerebral white matter. Clinical features included a variable combination of ataxia, headache, spasticity, seizures and other symptoms with a broad range of age of onset. This report is now the largest case series of patients with CLCN2-related leucoencephalopathy and reinforces the finding that, although the imaging appearance is uniform, the phenotypic expression of this disorder is highly heterogeneous. Our findings expand the phenotypic spectrum of CLCN2-related leucoencephalopathy by adding prominent seizures, severe spastic paraplegia and developmental delay.