A number sign (#) is used with this entry because of evidence that autosomal recessive limb-girdle muscular dystrophy-28 (LGMDR28) is caused by homozygous or compound heterozygous mutation in the HMGCR gene (142910) on chromosome 5q13.

Autosomal recessive limb-girdle muscular dystrophy-28 (LGMDR28) is characterized by progressive muscle weakness affecting the proximal and axial muscles of the upper and lower limbs. The age at onset is highly variable, usually in the first decade, although onset in the fourth decade has also been reported. The disorder can be rapidly progressive or show a slower course. Most patients have limited ambulation or become wheelchair-bound within a few decades, and respiratory insufficiency commonly occurs. Laboratory studies show increased serum creatine kinase and elevated fasting blood glucose levels, although cholesterol is normal. EMG shows a myopathic pattern; muscle biopsy is generally unremarkable, but can show nonspecific myopathic or dystrophic features (Yogev et al., 2023; Morales-Rosado et al., 2023).

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

Yogev et al. (2023) reported a large consanguineous Bedouin kindred in which 6 individuals (4 males and 2 females) presented during the fourth decade of life with muscle pain and progressive muscle fatigue and weakness, mainly affecting the proximal and axial muscles. The 3 oldest patients (49, 58, and 51 years of age) were wheelchair-bound or bedridden and showed respiratory insufficiency; 1 woman (patient V-2) had a tracheostomy. Deep tendon reflexes were diminished. There was only mild atrophy of the affected muscles, but MRI showed severe fatty replacement of the large proximal skeletal and axial muscles. None had contractures, distal or facial muscle weakness, dysphagia, or neurologic deficits, and there were no clear signs of cardiomyopathy. EMG showed a myopathic pattern. Muscle biopsies from 3 patients did not show any pathologic features; there was no fibrosis, necrosis, or inflammation; COX staining was normal. Electron microscopy was also normal. Of note, biopsy from 1 patient showed a mild deficiency of type II fibers, possibly representing muscle degeneration and regeneration. Serum creatine kinase was elevated early in the disease and declined with disease progression. All patients had elevated fasting blood glucose levels, and some had elevated transaminases; cholesterol and lipoprotein levels were normal. One severely affected patient (V-2) had low serum levels of mevalonate. The phenotype was reminiscent of statin-induced myopathy. Yogev et al. (2023) stated that the relatively benign features in histopathologic evaluation of muscle tissue in these patients hindered formal classification of this disease as a 'limb-girdle muscular dystrophy' (LGMD) based on the criteria proposed by Straub et al. (2018).

Morales-Rosado et al. (2023) reported 9 patients from 5 unrelated families with LGMDR28 who were ascertained through online matchmaking and collaborative efforts after exome sequencing identified biallelic mutations in the HMGCR gene. Seven patients were 14 to 39 years of age; 2 sibs in family 4 died at 10 and 8 years of age. Age at symptom onset in all patients ranged from 4 months to 10 years. Initial symptoms included hypotonia, delayed motor milestones, and axial and neck muscle weakness. There was progressive proximal muscle weakness of the upper and lower limbs, waddling gait, muscle atrophy, and increased serum creatine kinase. Additional variable features included calf hypertrophy, myalgias, and hyporeflexia. About half of the patients lost ambulation and most had reduced respiratory function, sometimes requiring noninvasive ventilation. None had cardiac involvement. Muscle MRI in 1 patient at 31 years of age showed replacement of almost all muscles in the upper leg with fibroadipose tissue. Muscle biopsy, performed in 5 patients, showed nonspecific dystrophic changes, including degenerating fibers with phagocytosis, fiber size variation, internal nuclei, rimmed vacuoles, and increased endomysial connective tissue. Subsarcolemmal mitochondrial clusters and myofibrillar disruption were also observed. The disease course was slowly progressive in some and rapidly progressive in others.

Yogev et al. (2023) reported a woman (patient V-2) with severe MYPLG and dependence on respiratory support who was treated with oral mevalonolactone and showed progressive significant improvement in muscle strength and respiratory function. There were minimal adverse effects (occasional gastrointestinal symptoms), although a transient pigmentation of the proximal nail fold was observed.

The transmission pattern of LGMDR28 in the family reported by Yogev et al. (2023) was consistent with autosomal recessive inheritance.

In 6 affected members of a large consanguineous Bedouin kindred with LGMDR28, Yogev et al. (2023) identified a homozygous missense mutation in the HMGCR gene (G822D; 142910.0003). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional studies in SH-SY5Y cells transfected with the mutation showed that the mutant protein had normal subcellular localization, but decreased activity. There was a 69% reduction in V(max) and a 65% increase in K(m) for the HMG-CoA substrate compared to controls. In addition, the catalytic pocket of the mutant protein had a very low affinity for pravastatin. These findings were consistent with a partial loss-of-function effect.

In 9 patients from 5 unrelated families with LGMDR28, Morales-Rosado et al. (2023) identified homozygous or compound heterozygous mutations in the HMGCR gene (see, e.g., 142910.0004-142910.0009). The mutations segregated with the disorder in the families and were absent from or present at low frequencies in the gnomAD database. There were 7 missense mutations, 1 splice site mutation, and 1 in-frame deletion. In vitro functional expression studies of 3 of the missense mutations (R443Q, Y792C, and D623N) showed that they caused variably reduced HMGCR enzyme activity and protein stability. There were no apparent genotype/phenotype correlations, but the authors noted that phenotypic variability may result from the degree of hypomorphic impairment resulting from the combined effect of the biallelic variants.

Yogev et al. (2023) found that mevalonolactone reduced muscle weakness in a mouse model of severe statin-induced myopathy.