Muscular Dystrophy-Dystroglycanopathy (Limb-Girdle), Type C, 14

A number sign (#) is used with this entry because this form of limb-girdle muscular dystrophy-dystroglycanopathy (type C14; MDDGC14), also known as LGMDR19 and LGMD2T, is caused by homozygous or compound heterozygous mutation in the GMPPB gene (615320), which encodes the beta subunit of GDP-mannose pyrophosphorylase, on chromosome 3p21.

Mutation in the GMPPB gene can also cause a more severe congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A14; MDDGA14; 615350) and a congenital muscular dystrophy-dystroglycanopathy with mental retardation (type B14; MDDGB14; 615351).

Description

MDDGC14 is an autosomal recessive form of muscular dystrophy characterized by onset in early childhood of mild proximal muscle weakness. Some patients may have additional features, such as mild intellectual disability or seizures. It is part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239), collectively known as 'dystroglycanopathies' (summary by Carss et al., 2013). Some patients with GMPPB mutations may show features consistent with a congenital myasthenic syndrome (see, e.g., CMS1A; 601462), such as fatigability and decremental compound muscle action potential response to repetitive nerve stimulation; these patients may show a positive therapeutic response to treatment with pyridostigmine (Belaya et al., 2015).

For a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type C, see MDDGC1 (609308).

Clinical Features

Carss et al. (2013) reported 3 unrelated patients with limb-girdle muscular dystrophy. The patients were of Indian, English, and Egyptian descent, and the phenotype was variable. A 12-year-old girl (P2) presented at birth with hypotonia and microcephaly. She had mild intellectual delay and seizures, but was able to run. An 18-year-old Egyptian boy (P8) presented at age 2.5 years with microcephaly and difficulty climbing stairs. He also had mild intellectual delay and seizures, but was able to run. Other features included cataracts, nystagmus, cardiomyopathy, and respiratory insufficiency. Brain MRI in both patients was normal. The patient with the mildest phenotype (P7) presented at age 4 years with mild exercise intolerance. He had normal cognition, and brain MRI was not performed. All 3 patients had increased serum creatine kinase and dystrophic findings on muscle biopsy. Muscle biopsy showed hypoglycosylation of DAG1.

Belaya et al. (2015) reported 4 patients, including 2 sibs, with onset of variable features of MDDGC14 in the first years of life. The sibs presented with global developmental delay, but one had no detectable muscle weakness at age 36 years. A third patient presented at age 2.5 years with seizures and later showed proximal muscle weakness and moderate cognitive delay. The fourth patient presented at age 1.5 years with an episode of muscle weakness; she did not have cognitive delay at age 17 years. This patient showed a decremental compound muscle action potential response on repetitive nerve stimulation, and another patient who reported fatigability showed a positive response to pyridostigmine. Muscle biopsies from the 3 symptomatic patients showed dystrophic changes and reduced immunostaining for alpha-DAG. Molecular analysis identified biallelic mutations in the GMPPB gene in all patients.

Clinical Variability

Belaya et al. (2015) reported 7 patients from 5 unrelated families who were diagnosed with a muscle disorder consistent with a congenital myasthenic syndrome. The patients presented in adolescence or adulthood with proximal muscle weakness causing decreased walking tolerance and inability to run and lift weights. Most of the patients retrospectively reported delayed motor milestones or being slower than their peers in school. The patients reported activity-dependent fatigability and improvement with rest, as well as fluctuating muscle strength. Electromyography showed decremental responses on repetitive nerve stimulation, although this did not affect all muscles. Muscle biopsy from 3 patients showed dystrophic features, and 2 had reduced alpha-DAG immunostaining. The patients had increased serum creatine kinase, which Belaya et al. (2015) noted was an unusual finding for a congenital myasthenic syndrome. None had cognitive impairment. Treatment with pyridostigmine and/or salbutamol resulted in increased muscle strength. Belaya et al. (2015) noted that the pathogenic mechanism may involve abnormal glycosylation of acetylcholine receptor (AChR) subunits, which could result in reduced postsynaptic responses to acetylcholine.

Inheritance

The transmission pattern of MDDGC14 in the families reported by Carss et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 unrelated patients with MDDGC14, Carss et al. (2013) identified homozygous or compound heterozygous mutations in the GMPPB gene (615320.0001, 615320.0003, 615320.0004, and 615320.0007-615320.0008). The initial mutations were found by exome sequencing.

In 7 patients from 5 unrelated families with MDDGC14 with features of congenital myasthenic syndrome, Belaya et al. (2015) identified homozygous or compound heterozygous mutations in the GMPPB gene (see, e.g., 615320.0007; 615320.0009-615320.0011). The mutations in the first patient were found by whole-exome sequencing; mutations in subsequent patients were found by screening of the GMPPB gene in a cohort of patients diagnosed with congenital myasthenic syndrome. The patients with GMPPB mutations showed decrement of compound muscle action potentials on repetitive nerve stimulation as well as myopathic findings on muscle biopsy and increased serum creating kinase. The findings indicated that GMPPB mutations can lead to a wide spectrum of clinical features including defects in neuromuscular transmission.