Department of Pediatric Neurology, Klinik St. Hedwig, University Children's Hospital Regensburg (KUNO), Steinmetzstr. 1-3, 93049, Regensburg, Germany.
Center for Human Genetics, Regensburg, Germany.
Orphanet J Rare Dis. 2019 Jul 16;14(1):179. doi: 10.1186/s13023-019-1119-0.
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.
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.
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 LGMD phenotypes constantly show markedly elevated creatine kinase values in combination with microcephaly and cognitive impairment.
蛋白 O-甘露糖基转移酶 1（POMT1）基因编码的蛋白 O-甘露糖基转移酶 1 是 α- dystroglycan 糖基化的关键酶。POMT1 相关疾病属于 dystroglycanopathy 组，其特征为近端明显的肌肉营养不良，伴有脑和/或眼的结构或功能受累。表型谱范围从严重的 Walker-Warburg 综合征（WWS）到更轻微的肢带型肌营养不良（LGMD）。POMT1 相关 dystroglycanopathy 的表型严重程度取决于残留酶活性。可以假设基因型-表型相关性。
报告了 27 个独立家庭中 35 名具有双等位基因 POMT1 突变（15 例 WWS、1 例 MEB（肌肉-眼-脑疾病）、19 例 LGMD）的患者的临床、神经放射学和遗传学发现。详细描述了一名 WWS 婴儿的代表性临床过程和一名 32 岁 LGMD 患者的长期过程。定义了 15 名纯合子 founder 突变 p.Ala200Pro 患者的特定特征，作为一个明显且受影响较轻的 LGMD 亚组。鉴定了 10 种先前报道的和 8 种新的 POMT1 突变。详细评估了每种 POMT1 突变的类型和位置，并提供了迄今为止报告的所有 POMT1 突变的列表。导致蛋白质提前终止的两种突变的患者表现为 WWS 表型，而至少存在一种错义突变与更轻微的表型相关。在具有 MEB 样表型的患者中，观察到酶的催化活性域内存在两种错义突变。
我们的大型队列证实了每种 POMT1 突变的类型和位置对个体临床表现的重要性，从而扩展了 POMT1 相关 dystroglycanopathy 中基因型-表型相关性的知识。这种基因型-表型相关性进一步得到了在 5 个独立家庭中受影响的 13 个兄弟姐妹中观察到的类似家族内临床表现的支持。我们的数据证实了在更轻微的 LGMD 表型中疾病的进行性性质，最终导致在不同的年龄丧失行走能力。我们的数据定义了两种主要的临床 POMT1 表型，这应该促使包括 POMT1 基因在内的基因检测：具有严重 WWS 表现的患者主要表现为严重的新生儿肌肉张力减退和严重的进行性脑积水，伴有脑干和/或小脑受累。WWS 患者中枕骨脑膨出的存在可能表明 POMT1 是与 WWS 相关的不同基因中导致疾病的基因。更轻微的 LGMD 表型始终显示显著升高的肌酸激酶值，伴有小头畸形和认知障碍。
