Biallelic MYORG mutation carriers exhibit primary brain calcification with a distinct phenotype

Area of Science:

• Neurogenetics
• Neurology
• Radiology

Background:

• Primary familial brain calcification (PFBC) is a rare neurogenetic disorder.
• Mutations in SLC20A2, XPR1, PDGFB, and PDGFRB cause autosomal dominant PFBC.
• Biallelic MYORG mutations are a newly identified cause of autosomal recessive PFBC.

Purpose of the Study:

• To investigate MYORG as a causative gene for PFBC in patients negative for autosomal dominant PFBC genes.
• To characterize the clinical and radiological phenotype of MYORG-associated PFBC.
• To compare the phenotype of MYORG-PFBC with autosomal dominant PFBC.

Main Methods:

• Screening of the MYORG gene in 29 unrelated probands.
• Clinical and radiological assessment of 16 patients from 11 families with biallelic MYORG variants.
• Comparison with 102 patients with autosomal dominant PFBC.

Main Results:

• Identified biallelic MYORG variants in 11 families.
• MYORG-PFBC shows high penetrance with early motor impairment (median age 52), notably dysarthria.
• MYORG-PFBC patients exhibit severe calcifications (including brainstem/pontine) and cerebellar atrophy, distinct from autosomal dominant PFBC.
• Potential phenotypic expression in heterozygous MYORG carriers.

Conclusions:

• MYORG is confirmed as a significant gene causing PFBC.
• MYORG-associated PFBC has a recognizable phenotype characterized by specific clinical and radiological features.
• This expands the genetic landscape of PFBC and aids in differential diagnosis.