Two Novel Mutations in the HMGCR Gene Causing Autosomal Recessive Limb-girdle Muscular Dystrophy
Taylor Stevens1, Jordan Bontrager1, Johanna Hamel2
1Neurology, University of Rochester, 2University of Rochester, Neurology
Objective:
To describe two novel genetic variants in HMGCR leading to Limb-Girdle Muscular Dystrophy.
Background:
The 3-Hydroxy-3-Methylglutaryl-CoA Reductase gene (HMGCR) encodes for an important enzyme involved in cholesterol synthesis and has been widely implicated in a variety of disease states from dysregulation-induced hypercholesterolemia to autoimmune anti-HMGCR protein immune mediated necrotizing myopathy (with and without statin exposure). However, only more recently have genetic variants in HMGCR been described as causing an autosomal recessive Limb-Girdle Muscular Dystrophy (LGMD) (Morales-Rosado et al., 2023; Yogev et al., 2023). We report two novel variants in HMGCR in one individual leading to a LGMD phenotype.
Results:
A 34 year old woman presented initially with recurrent episodes of proximal limb-girdle weakness during the first trimester of pregnancies at 14, 23, and 26 years of age. At age 27 painful weakness recurred and became persistent and progressive. Physical exam disclosed progressive proximal arm and leg weakness, neck flexor weakness, left winged scapula, and paraspinal muscle atrophy. Needle EMG was consistent with underlying myopathy with marked muscle fiber irritability, and rare, higher frequency myotonic discharges in proximal arm and thoracic paraspinal muscles. Initial CK was 4415 IU/L. Left rectus femoris biopsy showed chronic and active myopathy with significant interstitial fibrosis and several rimmed vacuoles with few containing congophilic myofibrillar amyloid. On whole exome sequencing biallelic variants were identified in HMGCR, one missense and one splice site, both novel: c.1378 A>G (p.Lys460Glu); c.1723-1 G>T.
Conclusions:
This case expands the known genotype spectrum of the only recently described autosomal recessive HMGCR-associated limb girdle muscular dystrophy with associated rimmed vacuoles on biopsy. Broader recognition of genetic forms of HMGCR-related myopathy may lead to increased testing and diagnosis of a potentially treatable condition (Yogev et al., 2023).
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