P 307. Walker–Warburg’s Syndrome Due to Homozygous POMK Mutation in Preterm Twins: Case Report

Background: Phenotypic presentation of homozygous or compound heterozygous mutations in the protein O-mannosyl kinase or POMK gene can vary from Walker–Warburg’s syndrome to limb girdle muscular dystrophy with cognitive impairment. POMK encodes a protein that is involved in the glycosylation of the laminin-binding O-linked carbohydrate chain of α-dystroglycan, which forms transmembrane links between the extracellular matrix and the exoskeleton. Mice lacking this gene demonstrate misplaced neurons (heterotopia) in some regions of the brain, possibly as a consequence of defects in neuronal migration.

Aim: Malformations of the eye and the brain can be the leading signs of a dystroglycanopathy resembling a syndromic disease. The combination of eye and brain malformations should prompt measurement of the serum CK as a first diagnostic step.

Question: Describing the phenotype of twins with Walker–Warburg’s syndrome due to homozygous POMK mutations

Methods: We present monozygotic male twins, born at 35+2 weeks of gestation, from consanguineous parents, showing postnatal muscular hypotonia, meningoencephalocele, microphthalmia, and anophthalmia, respectively. Diagnostic investigations revealed further brain and spinal malformations (hydrocephalus internus, dysgyria with generalized polymicrogyria and bitemporo-occipital subcortical band heterotopia, hypo/-aplastic vermis, rarefication of thoracal myelon) and complex eye malformations (twin 1: microphthalmia with embryonic cleft of the right optic cup, embryonic cleft of the left optic cup or coloboma, and congenital cataract; twin 2: bilateral persisting hyperplastic primary vitreous, posterior staphyloma left eye), resulting in blindness. Additionally, a sensorineural hearing loss was confirmed in both infants. The serum CK was elevated to 7,157 U/L (twin 1) and 8,769 U/L (twin 2). At the corrected age of 10 months, the twins show severe psychomotor retardation and have not yet reached any motor milestones. In addition, both infants developed epilepsy refractory to therapy before the corrected age of 6 months.

Results: The clinical phenotype with highly elevated CK levels was suggestive for congenital muscular dystroglycanopathy with brain/eye abnormalities. Molecular panel analysis revealed a homozygous nonsense mutation in POMK (OMIM*615247) in both twins. These molecular findings confirmed the diagnosis of a POMK-associated WWS (OMIM#615247).

Conclusion: POMK mutations represent a very rare cause of α-dystrogylcanopathies with only five different POMK mutations published in three families up to date. Meningo-/encephaloceles have been reported as a rare finding and might point to a more important role of POMK in the pathogenesis of neural tube defects. The combination of central nervous system and eye malformations as predominant symptoms can be suggestive of a Walker–Warburg’s syndrome and, therefore, should always lead to measurement of the serum CK as a first diagnostic step.