Genetic Heterogeneity Underlying Phenotypes with Early-Onset Cerebellar Atrophy

• Published in: International journal of molecular sciences Vol. 24; no. 22; p. 16400
• Main Authors: Martínez-Rubio, Dolores, Hinarejos, Isabel, Argente-Escrig, Herminia, Marco-Marín, Clara, Lozano, María Ana, Gorría-Redondo, Nerea, Lupo, Vincenzo, Martí-Carrera, Itxaso, Miranda, Concepción, Vázquez-López, María, García-Pérez, Asunción, Marco-Hernández, Ana Victoria, Tomás-Vila, Miguel, Aguilera-Albesa, Sergio, Espinós, Carmen
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 01.11.2023
• Subjects: Age; Ataxia; Atrophy; Blood tests; cerebellar atrophy; Child development; exome sequencing; Gait; gene panel; Genes; Genotype & phenotype; Intellectual disabilities; Magnetic resonance imaging; Medical imaging; Metabolism; Movement disorders; Mutation; Neuroimaging; Pediatrics; Proteins; rare disease; Spain
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms242216400

Cerebellar atrophy (CA) is a frequent neuroimaging finding in paediatric neurology, usually associated with cerebellar ataxia. The list of genes involved in hereditary forms of CA is continuously growing and reveals its genetic complexity. We investigated ten cases with early-onset cerebellar involvement with and without ataxia by exome sequencing or by a targeted panel with 363 genes involved in ataxia or spastic paraplegia. Novel variants were investigated by in silico or experimental approaches. Seven probands carry causative variants in well-known genes associated with CA or cerebellar hypoplasia: SETX, CACNA1G, CACNA1A, CLN6, CPLANE1, and TBCD. The remaining three cases deserve special attention; they harbour variants in MAST1, PI4KA and CLK2 genes. MAST1 is responsible for an ultrarare condition characterised by global developmental delay and cognitive decline; our index case added ataxia to the list of concomitant associated symptoms. PIK4A is mainly related to hypomyelinating leukodystrophy; our proband presented with pure spastic paraplegia and normal intellectual capacity. Finally, in a patient who suffers from mild ataxia with oculomotor apraxia, the de novo novel CLK2 c.1120T>C variant was found. The protein expression of the mutated protein was reduced, which may indicate instability that would affect its kinase activity.