Muscular Dystrophy, Limb-Girdle, Autosomal Recessive 18

A number sign (#) is used with this entry because of evidence that autosomal recessive limb-girdle muscular dystrophy-18 (LGMDR18) is caused by homozygous or compound heterozygous mutation in the TRAPPC11 gene (614138) on chromosome 4q35.

Description

Autosomal recessive limb-girdle muscular dystrophy-18 is characterized by childhood-onset of proximal muscle weakness resulting in gait abnormalities and scapular winging. Serum creatine kinase is increased. A subset of patients may show a hyperkinetic movement disorder with chorea, ataxia, or dystonia and global developmental delay (summary by Bogershausen et al., 2013). Additional more variable features include alacrima, achalasia, cataracts, or hepatic steatosis (Liang et al., 2015; Koehler et al., 2017).

For discussion of genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy, see LGMDR1 (253600).

Nomenclature

At the 229th ENMC international workshop, Straub et al. (2018) reviewed, reclassified, and/or renamed forms of LGMD. The proposed naming formula was 'LGMD, inheritance (R or D), order of discovery (number), affected protein.' Under this formula, LGMD2S was renamed LGMDR18.

Clinical Features

Bogershausen et al. (2013) reported a consanguineous Syrian family in which 3 girls had progressive proximal muscle weakness resulting in impaired ambulation. The girls were 16, 20, and 26 years of age at the time of the report, but the symptoms began in childhood. The younger girls had fatigue and muscle pain, whereas the older patient was more severely affected with an inability to climb stairs. The shoulder girdle muscles were less severely affected than the hip girdle muscles. Other features included hip dysplasia, scoliosis, and increased serum creatine kinase. Two patients had myopia, 1 had mild cataracts, and another had strabismus. One had slight enlargement of the right cardiac ventricle and another had moderate restrictive pulmonary function. The oldest had mild intellectual disability.

Clinical Variability

Bogershausen et al. (2013) reported 2 Hutterite families with an autosomal recessive neuromuscular disorder. Affected individuals had early-onset psychomotor delay and evidence of a hyperkinetic movement disorder characterized mainly by choreiform movements of the trunk, limbs, and head, although athetoid movements, tremor, and dystonic posturing were also noted. All had truncal ataxia resulting in gait instability, mild muscle weakness, and increased serum creatine kinase. One patient had generalized seizures, and 2 had abnormal EEG. Neuroimaging showed mild cerebral atrophy in 2 patients. The families shared a common ancestor from the 1790s.

Liang et al. (2015) reported an 8-year-old Han Chinese girl with delayed motor development, unstable gait, delayed speech, and borderline intellectual disability associated with mild lordosis, proximal muscle weakness, hyporeflexia, and increased serum creatine kinase. Muscle biopsy showed dystrophic changes with necrotic and regenerating fibers, endomysial fibrosis, and increased lipid droplets. The patient also had infantile-onset cataracts and hepatomegaly with steatosis and abnormal liver enzymes. Brain imaging showed slightly reduced white matter volume, suggesting hypomyelination. Ataxia and abnormal movements were not observed.

Koehler et al. (2017) reported 4 teenaged patients from 2 unrelated consanguineous Turkish families with a variant of LGMD2S. The patients presented at birth or in early infancy with alacrima, and 3 had onset later in infancy of achalasia, features reminiscent of the triple A syndrome (AAAS; 231550), although none had adrenal insufficiency. All 4 patients had global developmental delay, intellectual disability with poor speech, and poor overall growth. All patients also had muscle weakness and scoliosis; 2 unrelated patients never walked. Two patients from 1 family had lower limb spasticity and cerebellar atrophy on brain imaging, whereas the 2 patients from the other family had hyperkeratosis, dental caries, seizures, and cortical atrophy on brain imaging. Muscle biopsy of 1 patient showed mild dystrophic changes with internal nuclei, fibrosis, degenerating fibers, immature myofibers, and fiber-type grouping, suggestive of denervation. Koehler et al. (2017) noted that alacrima and achalasia are thought to be due to neural degeneration, but concluded that the phenotype in these patients was consistent with expansion of LGMD2S myopathy rather than a new form of AAA syndrome.

Fee et al. (2017) reported a brother and sister, born of unrelated parents, with LGMD2S. The patients were severely affected; both were born prematurely and showed intrauterine growth retardation and hypotonia from birth necessitating placement in the intensive care unit, although they did not need intubation. Both had poor feeding, short stature, delayed psychomotor development with mild to moderate intellectual disability, language delay with speech apraxia and dysarthria, attention deficits, and impulsivity. They achieved walking between 20 and 30 months of age. Both had increased serum creatine kinase; muscle biopsy in the boy showed dystrophic changes. The boy had choking problems with eosinophilic esophagitis and constipation. He also had elevated liver enzymes, evidence of hepatic lymphocytic inflammation and early bridging fibrosis, and diffuse slowing on EEG, but no overt seizures. The girl had congenital cataracts, microcephaly, thoracic spine dysmorphism, recurrent ear infections, and onset of overt seizures at age 8 years. Her EEG also showed diffuse slowing, followed by the development of epileptiform abnormalities and focal seizures with secondary generalization that could be managed with medication. Brain imaging in the girl showed brachycephaly and cerebellar volume loss with borderline increased signal in the pons and midbrain. Her liver enzymes were increased, but liver ultrasound was normal. The patients made modest developmental progress in grade school. Exome sequencing identified compound heterozygous variants in the TRAPPC11 gene (c.513_516delTTTG and Q777P), as well as a heterozygous variant in the PGM1 gene (171900) that was inherited from the unaffected mother; transferrin studies in the mother were normal, ruling out CDG1T (614921). Functional studies of the variants were not performed.

Inheritance

The transmission pattern of LGMD2S in the Syrian family reported by Bogershausen et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

By whole-exome sequencing combined with linkage analysis of a Syrian family with LGMD, Bogershausen et al. (2013) identified a homozygous mutation in the TRAPPC11 gene (G980R; 614138.0001). The same technique revealed a different homozygous mutation in the TRAPPC11 gene (Ala372_Ser429del; 614138.0002) in affected members of 2 Hutterite families with a slightly different phenotype, but including neuromuscular dysfunction. The G980R mutation occurred in the gryzun domain, whereas the deletion occurred in the foie gras domain. Patient cells showed increased fragmentation of the Golgi apparatus and decreased amounts of the mutant proteins. Studies in yeast suggested that the mutant missense protein lost the ability to interact properly with other TRAPP proteins. Patient cells also showed altered protein transport along the secretory pathway, with a delayed exit from the Golgi and a defect in the formation and/or movement of late endosomes/lysosomes. The findings suggested that altered membrane trafficking is the underlying molecular mechanism of this disease spectrum.

In an Asian girl with LGMD2S associated with cataracts and hepatic steatosis, Liang et al. (2015) identified compound heterozygous mutations in the TRAPPC11 gene (614138.0001 and 614138.0003). The mutations, which were found by targeted next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient muscle biopsy showed absence of the normal full-length TRAPPC11 protein. Liang et al. (2015) noted that the 'foie gras' (foigr) mutant zebrafish shows lipid accumulation in hepatocytes (see ANIMAL MODEL).

In 4 patients from 2 unrelated consanguineous Turkish families with a variant of LGMD2S, Koehler et al. (2017) identified a homozygous splice site mutation in the TRAPPC11 gene (614138.0004). The mutation was found by a combination of autozygosity mapping and whole-exome sequencing and was confirmed by Sanger sequencing. The mutation segregated with the disorder in both families. Haplotype analysis suggested a founder effect. Analysis of patient cells showed about 20% of the normal transcript compared to controls, and Western blot analysis showed a dramatic decrease in levels of the full-length protein. Patient cells showed hypoglycosylation of LAMP1 (153330). In vitro studies of patient fibroblasts showed delayed exit of a marker protein through the Golgi apparatus, indicating a defect in secretory trafficking.

Animal Model

DeRossi et al. (2016) stated that 'foie gras' (foigr) mutant zebrafish exhibit lipid accumulation in hepatocytes and have a viral DNA insertion in the trappc11 gene that results in a C-terminally truncated protein. They found that trappc11 mutant larvae also had a defect in motility. Using Western blot analysis, DeRossi et al. (2016) detected mutant trappc11 at an apparent molecular mass of 56 kD and wildtype trappc11 at 129 kD. Foigr hepatocytes had a significant defect in synthesis of lipid-linked oligosaccharides, blocking protein N-glycosylation and causing protein misfolding, with chronic activation of the unfolded protein response (UPR) in ER. The block in N-glycosylation caused compensatory upregulation of nearly all genes involved in N-glycosylation and chronically stressed UPR-activated genes involved in sterol metabolism. Trappc11 mutant hepatocytes also developed abnormal ER morphology, fragmentation of the Golgi complex, and retention of secretory cargo. DeRossi et al. (2016) proposed that TRAPPC11 may function as a scaffold for enzymes of protein N-glycosylation or as a cofactor for an enzyme in lipid-linked oligosaccharide synthesis.