Objective: Following the MDSGene protocol, we here present the clinical and mutational spectrum of SLC20A2 mutations, thereby adding the first gene found to be mutated in patients with primary familial brain calcification (PFBC) to MDSGene.

Background: The recently launched MDSGene database (www.mdsgene.org) currently summarizes genetic and phenotypic information on >500 mutations found in >1000 patients with various movement disorders reported in the literature.

Methods: A systematic literature screen for SLC20A2 in PubMed yielded 57 original articles. We identified 29 articles that reported at least one mutation-positive individual with PFBC and provided clinical information on mutation carriers. Mutations were included if they had a minor allele frequency <1% (based on the ExAC Browser, dbSNP or unaffected control individuals screened in the publication). We extracted radiological data and 70 other phenotypic features for 134 clinically affected and unaffected mutation carriers.

Results: 134 mutation-positive, symptomatic or asymptomatic individuals with PFBC from 41 families were included in our review. They carried 36 different heterozygous SLC20A2 mutations (17 missense and 9 frameshift). General motor signs were the most frequently reported clinical feature in 63 individuals (47%) including parkinsonism and dystonia (both 13%) and speech disturbance (12%). A considerable proportion of patients also displayed non-motor signs, such as cognitive deficits (26%) or headache (10%). Examples of other rare manifestations are seizures, chorea, and ataxia (6-7%).

Thirty-seven mutation carriers were described as clinically asymptomatic (28%). The age of onset (AOO) of clinical features ranged from 1-82 years with a mean of 32.2 years. Detailed cranial computed tomography (CCT) data was available for 82 patients (62%), showing that brain calcification was most common in the basal ganglia (80%). Overall, there was a large percentage of missing (unspecified) data (e.g. parkinsonism 35%; seizures 43%; headache 51%; AOO 62%).

Conclusions: SLC20A2 mutations lead to PFBC of mostly the basal ganglia with high phenotypic variability and reduced penetrance of clinical signs. Our review will complement the PFBC section of MDSGene by adding the most common known gene for this condition and, as for previous entries, identifies major data gaps in the present literature, especially for non-motor symptoms.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/reviewing-the-clinical-and-mutational-spectrum-of-slc20a2-mutations-in-primary-familial-brain-calcification-pfbc-for-mdsgene/