Geis, Tobias and Roedl, Tanja and Topaloglu, Haluk and Balci-Hayta, Burcu and Hinreiner, Sophie and Mueller-Felber, Wolfgang and Schoser, Benedikt and Mehraein, Yasmin and Huebner, Angela and Zirn, Birgit and Hoopmann, Markus and Reutter, Heiko and Mowat, David and Schuierer, Gerhard and Schara, Ulrike and Hehr, Ute and Koelbel, Heike (2019) Clinical long-time course, novel mutations and genotype-phenotype correlation in a cohort of 27 families with POMT1-related disorders. ORPHANET JOURNAL OF RARE DISEASES, 14: 179. ISSN 1750-1172,
Full text not available from this repository. (Request a copy)Abstract
BackgroundThe protein O-mannosyltransferase 1, encoded by the POMT1 gene, is a key enzyme in the glycosylation of alpha-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.ResultsThe 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 32years 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.ConclusionsOur 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 LGMD phenotypes constantly show markedly elevated creatine kinase values in combination with microcephaly and cognitive impairment.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | WALKER-WARBURG-SYNDROME; CONGENITAL MUSCULAR-DYSTROPHY; POMT1 MUTATIONS; ALPHA-DYSTROGLYCAN; ENZYME-ACTIVITY; SUBTYPES; POMT1; Dystroglycan; Walker-Warburg syndrome; Limb girdle muscular dystrophy; Muscle-eye-brain disease; Lissencephaly; Hydrocephalus; Occipital encephalocele |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Humangenetik Medicine > Lehrstuhl für Kinder- und Jugendmedizin Medicine > Lehrstuhl für Röntgendiagnostik |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 02 Apr 2020 12:50 |
| Last Modified: | 02 Apr 2020 12:50 |
| URI: | https://pred.uni-regensburg.de/id/eprint/26630 |
Actions (login required)
 |
View Item |
