Neuroimaging manifestations and genetic heterogeneity of Walker-Warburg syndrome in Saudi patients

Background Walker-Warburg syndrome (WWS), an autosomal recessive disease, is the most severe phenotype of congenital muscular dystrophies. Its diagnosis remains primarily clinical and radiological. Identification of its causative variants will assist genetic counseling. We aim to describe genetic and neuroimaging findings of WWS and investigate the correlation between them. Methods We retrospectively reviewed the clinical, genetic and neuroimaging findings of eleven Saudi neonates diagnosed with WWS between April 2012 and December 2018 in a single tertiary care center. Correlation between neuroimaging and genetic findings was investigated. Results All patients had macrocephaly except one who had intrauterine growth restriction. Dysmorphic features were identified in nearly half of the patients. Creatine kinase levels were available in nine patients and were always elevated. Homozygous pathogenic variants were identified in all patients spanning POMT1 (n = 5), TMEM5 (n = 3), ISPD (n = 2) and POMT2 (n = 1) including one patient who had a dual molecular diagnosis of ISPD and PGAP2. On neuroimaging, all patients showed cobblestone cortex, classical infratentorial findings, and hydrocephalus. Other cerebral cortical malformations included subependymal heterotopia, polymicrogyria and open-lip schizencephaly in four, two and one patients, respectively. Buphthalmos and microphthalmia were the most prevalent orbital findings and found in all patients either unilaterally or bilaterally. Conclusion WWS is a genetically heterogeneous disorder among Saudis. The case with an additional PGAP2-related phenotype exemplifies the increased risk of dual autosomal recessive disorders in consanguineous populations. MRI is excellent in demonstrating spectrum of WWS brain and orbital malformations; however, no definite correlation could be found between the MRI findings and the genetic variant.