Progressive cerebello-cerebral atrophy and progressive encephalopathy with edema, hypsarrhythmia and optic atrophy may be allelic syndromes

In 2003, a new syndrome was described in the Sephardi Jewish population, named progressive cerebello-cerebral atrophy (PCCA) based on the typical neuroradiological findings. Following the identification of the causal genes in 2010 and 2014, two types were defined: PCCA type 1 due to SEPSECS mutations and PCCA type 2 due to VPS53 mutations. Progressive encephalopathy with edema, hypsarrhythmia and optic atrophy (PEHO) was described in 1991 in Finland. The clinical and radiological phenotype resembles PCCA. The genetic background has been elusive for many years. Recently, mutations in multiple genes including SEPSECS have been described in patients with a PEHO-like syndrome. In 2007 two siblings of Moroccan-Jewish origin were diagnosed as having PEHO due to a severe developmental encephalopathy, limb and facial edema, intractable epilepsy, optic atrophy in one sibling and dysmorphic features. Six years ago an extensive workup, including whole exome sequencing, did not reveal the cause. Recently, a clinical reevaluation of the siblings suggested the possibility that they suffer from PCCA. A reanalysis of the exome data from 2014 revealed that the siblings indeed carried the two VPS53 mutations (exon 19 c.2084A>G p.(Gln695Arg) and c.1556 + 5G>A) and the parents were found to be carriers. The discovery that mutations in both VPS53 and SEPSECS can present with a PEHO-like phenotype, place PCCA and PEHO on the same clinical spectrum and suggest they may be allelic syndromes.