CLN7 disease: phenotypic and genotypic description of four cases of a Cordoba cohort

Abstract

Abstract: 

CLN7 disease (OMIM # 610951), caused by variants in the MFSD8/CLN7 gene, belongs to the group of neuronal ceroid lipofuscinoses (NCL). It presents mainly as a late infantile phenotype, where the first symptoms (seizures, developmental regression) usually appear between 1.5 and 6 years, followed by rapid psychomotor deterioration, behavioral changes, myoclonus, speech disorders, occasional loss of vision, and premature death. Due to the low frequency and non-specificity of symptoms, it can be confused with the most common form of NCL, CLN2 (caused by variants in the TPP1/CLN2 gene). Therefore, genomic analysis is necessary to arrive at the diagnosis, thus determining which gene is affected. In the present study, the phenotype and genotype of four suspected NCL cases in a Cordoba cohort, and their consequent confirmation among NCL variants, are analyzed.

Those responsible for the children signed an informed consent approved by CIEIS-Polo Hospitalario from the Cordoba province. Two girls and two boys developed seizures, intellectual and speech retardation, and progressive psychomotor impairment from 3-4 years of age. The boys showed behavioral changes and visual failures as well. All showed mild to severe cerebellar atrophy with compromise of the white matter. NCL was suspected, and CLN1 and CLN2 diseases were excluded by enzymology. Genetic analysis revealed DNA variants in the MFSD8/CLN7 gene. The pathogenic variant E3 c.103C>T, p.Arg35* was observed in homozygous state in one girl and one boy, while in compound heterozygosity with the pathogenic variant I9 c.863+1G>A in the other boy; and the variants E13 c.1394G>A, p.Arg465Gln (pathogenic) and I9 c.863+4A>G (possibly pathogenic) were found in compound heterozygosis in the other girl. The pathogenicity of these variants was evaluated by bioinformatics means, bibliography and public databases.

The importance of genomic analysis is emphasized when non-specific progressive neurological symptoms are present and NCL is suspected, highlighting in this work the confirmation of four CLN7 cases in a cohort from Cordoba. Precise and early diagnosis allows predicting the evolution of the patient and a correct therapeutic approach. No author declares conflicts of interest.