Clinical long-time course, novel mutations and genotype-phenotype correlation in a cohort of 27 families with POMT1-related disorders

Abstract

Background The protein O-mannosyltransferase 1, encoded by the POMT1 gene, is a key enzyme in the glycosylation of α-dystroglycan. POMT1 –related disorders belong to the group of dystroglycanopathies characterized by a proximally pronounced muscular dystrophy with structural or functional involvement of the brain and/or the eyes. The phenotypic spectrum ranges from the severe Walker-Warburg syndrome (WWS) to milder forms of limb girdle muscular dystrophy (LGMD). The phenotypic severity of POMT1 -related dystroglycanopathies depends on the residual enzyme activity. A genotype-phenotype correlation can be assumed. Results The clinical, neuroradiological, and genetic findings of 35 patients with biallelic POMT1 mutations (15 WWS, 1 MEB (muscle-eye-brain disease), 19 LGMD) from 27 independent families are reported. The representative clinical course of an infant with WWS and the long-term course of a 32 years old patient with LGMD are described in more detail. Specific features of 15 patients with the homozygous founder mutation p.Ala200Pro are defined as a distinct and mildly affected LGMD subgroup. Ten previously reported and 8 novel POMT1 mutations were identified. Type and location of each of the POMT1 mutations are evaluated in detail and a list of all POMT1 mutations reported by now is provided. Patients with two mutations leading to premature protein termination had a WWS phenotype, while the presence of at least one missense mutation was associated with milder phenotypes. In the patient with MEB-like phenotype two missense mutations were observed within the catalytic active domain of the enzyme. Conclusions Our large cohort confirms the importance of type and location of each POMT1 mutation for the individual clinical manifestation and thereby expands the knowledge on the genotype-phenotype correlation in POMT1 -related dystroglycanopathies. This genotype-phenotype correlation is further supported by the observation of an intrafamiliar analogous clinical manifestation observed in all affected 13 siblings from 5 independent families. Our data confirm the progressive nature of the disease also in milder LGMD phenotypes, ultimately resulting in loss of ambulation at a variable age. Our data define two major clinical POMT1 phenotypes, which should prompt genetic testing including the POMT1 gene: patients with a severe WWS manifestation predominantly present with profound neonatal muscular hypotonia and a severe and progressive hydrocephalus with involvement of brainstem and/or cerebellum. The presence of an occipital encephalocele in a WWS patient might point to POMT1 as causative gene within the different genes associated with WWS. The milder LG...

Further evidence for POMK as candidate gene for WWS with meningoencephalocele

“…Investigation of a muscle biopsy obtained from one patient revealed normal histological findings whereas the biopsy from the sibling showed moderate chronic myopathic changes with small groups of regenerating fibers and sparse inflammatory cell infiltrates [7]. Based on our findings as well as previous findings of meningoencephaloceles in patients with POMT1 and ISPD mutations, we recommend an initial laboratory analysis of CK in newborns which present clinically with the combined symptoms of muscular weakness and meningoencephalocele [3,4].…”

“…Based on our findings as well as previous findings of meningoencephaloceles in patients with POMT1 and ISPD mutations, we recommend an initial laboratory analysis of CK in newborns which present clinically with the combined symptoms of muscular weakness and meningoencephalocele [ 3 , 4 ].…”

“…Given that encephaloceles are occasionally associated with other genetic defects causative of alpha-dystroglycanopathies, including genes encoding for proteins involved in O-mannosylation of α-DG such as POMT1 [ 3 ], the presence of a meningoencephalocele in our POMK patients supports the concept that perturbed post-translational modification of α-DG has a detrimental impact on α-DG-function and affects correct maturation of the neural tube during fetal development. Our combined clinical and genetic findings thus expand the clinical spectrum of POMK patients and classify POMK as candidate gene for meningoencephalocele.…”

“…Encephalocele is characteristic for some syndromal diseases, such as Knobloch syndrome ( COL18A1 ), as well as certain ciliopathies such as Meckel-Gruber and Joubert syndromes, and several chromosomal aberrations [ 2 ]. Regarding diseases affecting proper glycosylation of alpha-dystroglycan, the manifestation of a meningoencephalocele has only rarely been associated with defects in known genes such as POMT1 and ISPD [ 3 , 4 ]. Geis and colleagues discussed the presence of an encephalocele as possibly an indicator of the presence of pathogenic POMT1 mutations in terms of a phenotype-genotype correlation [ 3 ].…”

Genetic variations and clinical spectrum of dystroglycanopathy in a large cohort of Chinese patients

“…However, c.1814G > A 15 was identified as common mutation in Turkey and c.1539 + 1G > A 30 in European countries and the USA. In POMT1 gene, c.1457G > C was identified in 5 CMD patients in our cohort while c.598G > C, c.193G > A, c.280 + 1G > T were identified as hotspots and founder mutations in other cohorts in European countries or the USA, seperately 31,32 . In the ISPD gene, c.1251G > A was detected as frequent mutations in CMD patients and c.1114_1116delGTT in the LGMD patients.…”