Disequilibrium syndrome caused by an unusual constellation of VLDLR mutations

Dysequilibrium syndrome (DES) is caused by an unusual constellation of VLDLR mutations. DES is an autosomal recessively inherited rare neurological disorder. DES is caused by mutations in the VLDLR gene encoding the VLDL receptor. To date, eight different mutations in the VLDLR gene have been described in seven families. The VLDL receptor is part of the reelin (RELN) pathway in neurons, directing neuronal migration and organization. Patients with DES are affected by cerebral ataxia and instable gait, intellectual disability, and epilepsy. Brain MRI of patients shows characteristic cerebellar vermis hypoplasia and impaired foliation.

We report a German patient, who is doubly homozygous for two novel VLDLR mutations, both located at the exon 5-intron 5 splice donor consensus site causing aberrant splicing of intron 5. Despite the severe molecular defect, the clinical presentation is classical, indicating that DES caused by VLDLR mutation is not characterized by genotype-phenotype correlations.