We identified five individuals with biallelic PCYT2 variants clinically characterized by global developmental delay with regression, spastic para- or tetraparesis, epilepsy and progressive cerebral and cerebellar atrophy.
Our study supports the candidacy of CACNA2D2 as a disease gene associated with a phenotypic spectrum of neurological disease that include features of developmental and epileptic encephalopathy, ataxia, and cerebellar atrophy.
We identified five individuals with biallelic PCYT2 variants clinically characterized by global developmental delay with regression, spastic para- or tetraparesis, epilepsy and progressive cerebral and cerebellar atrophy.
Our findings should indicate that a T666M mutation of CACNA1A may be associated with more variable clinical features and that paroxysmal hemiplegic migraine attacks and progressive cerebellar atrophy should have distinct mechanisms of pathogenesis.
For the efficient screening of SCA6, we would propose testing CAG repeat expansion in CACNL1A4, in patients with one of two markers: (1) horizontal or oblique gaze nystagmus without other eye movement disorders, (2) pure cerebellar atrophy, even if occurrence is sporadic.
In SCA6, a mild reduction in the ratio of the ventral pontine area to the posterior fossa area (Pv/PF) was observed as well as obvious cerebellar atrophy.
A clinical, genetic, neuropathological study in a Japanese family with SCA 6 and a review of Japanese autopsy cases of autosomal dominant cortical cerebellar atrophy.
Infantile neuroaxonal dystrophy in a pair of Malaysian siblings with progressive cerebellar atrophy: Description of an expanded phenotype with novel PLA2G6 variants.
Mutations in PLA2G6 are known to cause Neurodegeneration with brain iron accumulation 2 (NBIA2): Our patients have some similarities with NBIA2; both are characterized by rapidly progressive psychomotor regression and cerebellar atrophy.
MRI assessment showed absence of bilateral "swallow tail sign" and cerebellar atrophy in this patient, while no obvious difference in brain iron accumulation between PLA2G6 mutant PD patient and healthy controls.
Molecular testing for PLA2G6 mutations is, therefore, indicated in childhood-onset ataxia syndromes, if neuroimaging shows cerebellar atrophy with or without evidence of iron accumulation.
We suggest that PLA2G6 should be screened in any patient exhibiting progressive gait disturbance, bradykinesia, dysarthria, tremors, mood/behavior changes or cognitive decline, especially when associated with cerebellar atrophy and/or iron accumulation and/or cerebral atrophy.