LIMB GIRDLE MUSCULAR DYSTROPHIES: P.136 POMT2 homozygous mutation presenting as intellectual deficiency and isolated elevated CK in siblings

Abstract

Recessive mutations in the gene coding for protein O-mannosyl-transferase 2 (POMT2) are known to cause severe congenital muscular dystrophies (CMD), such as Walker-Warburg syndrome and muscle–eye–brain disease. They have also been described in a milder muscular dystrophy (LGMD2N). We report the case of two non-identical twins (one male, one female), of Tunisian origin, born of consanguineous parents, presenting with psychomotor acquisitions delay and elevated CK. Both parents had normal CK levels, one brother presented with a similar phenotype. They started walking at 20 months, and language was acquired late (2.5 years old). Both children could practice sport, with very mild dyspnea on exertion. They followed specialized schooling. On examination, there was no muscle deficiency, a moderate hyperlaxity in the brother. At age 12 head circumference was -2.6 SD for the boy, -3.5 SD for the girl. CK were between 1000 and 2500 UI/l, ophthalmologic examination showed a possible retinitis pigmentosa, cerebral MRI revealed a microcephaly. Electroneuromyography displayed a moderate myogenic proximal syndrome, muscular MRI was normal for the sister, and showed less than 30% fatty replacement in the hamstrings for the brother. Muscular biopsy in the brother showed some nuclear internalisations, a variability of fiber size, and numerous 2C fibers. Immunostainings were normal, Western-Blot displayed a reduction in calpain expression. NGS showed a homozygous mutation in the POMT2 gene (c.1709G>T (p.W570L)), consistent with an alpha-dystroglycanopathy. It was found in all three siblings, and familial segregation is ongoing. This diagnostic is compatible with the phenotype, considering the central nervous system abnormalities of the patients. This broadens, however, the phenotype of POMT2-related diseases, with intellectual deficiency and elevated CK as main presenting symptoms, without clear clinic muscular deficiency.