Bi-allelic variants in HMGCR cause limb girdle muscular dystrophy and further implicate the mevalonate pathway in muscle disease

HMGCR, encoding 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the enzyme catalyzing the rate limiting step of the cholesterol synthesis pathway, is the main molecular target of statin medications. A homozygous variant in HMGCR has just been reported as causative for limb girdle muscular dystrophy with treatment response to oral mevalonolactone (Yogev et al, PNAS). We report three patients from two non-consanguineous families evaluated by our team (as part of a larger series of patients, Morales-Rosado et al, AJHG, in press) with bi-allelic pathogenic variants in the HMGCR gene. We found HMGCR variants: c.1431C>T; p.Arg443Trp and c.1626_1628del; p.Ser508del segregating in two affected children in Family 1 and c.1401C>G; p.Ile467Met in apparent homozygosity (presumed uniparental disomy, given negative deletion and duplication analyses) in one affected adult in Family 2. The clinical phenotype is notable for childhood onset, progressive proximal > distal weakness and progressive respiratory insufficiency. The oldest patient (39 years old) lost independent ambulation and started non-invasive ventilation for respiratory insufficiency at age 30 years. Serum creatine kinase was elevated in all patients (ranging: 4,203 - 18,185 U/L). Muscle MRI in one child in Family 1 was normal (at age 5 years) while in the adult patient in Family 2 (at age 31 years) demonstrated striking replacement of all upper leg muscles with fibroadipose tissue and relative sparing of the anterior and lateral muscles in the lower leg. Muscle biopsy of the tibialis anterior muscle in the adult patient (age 35 years) showed dystrophic findings. Anti-HMGCR antibodies in this individual were negative. With the finding of HMGCR as a causative gene for muscular dystrophy, following our finding of GGPS1, encoding GGPPS, another mevalonate pathway enzyme, as a causative gene for a muscular dystrophy/deafness/ovarian insufficiency syndrome, and the report of HMGCS1, encoding 3-hydroxy-3-methylglutaryl-coenzyme A synthase 1, as a causative gene for muscular dystrophy with rigid spine, the mevalonate pathway is further implicated in the etiology of muscular dystrophy. The underlying pathomechanisms of the mevalonate pathway-related muscle diseases still need to be fully understood but could lead to therapeutic targets given the rich pharmacological toolbox for this pathway. HMGCR, encoding 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the enzyme catalyzing the rate limiting step of the cholesterol synthesis pathway, is the main molecular target of statin medications. A homozygous variant in HMGCR has just been reported as causative for limb girdle muscular dystrophy with treatment response to oral mevalonolactone (Yogev et al, PNAS). We report three patients from two non-consanguineous families evaluated by our team (as part of a larger series of patients, Morales-Rosado et al, AJHG, in press) with bi-allelic pathogenic variants in the HMGCR gene. We found HMGCR variants: c.1431C>T; p.Arg443Trp and c.1626_1628del; p.Ser508del segregating in two affected children in Family 1 and c.1401C>G; p.Ile467Met in apparent homozygosity (presumed uniparental disomy, given negative deletion and duplication analyses) in one affected adult in Family 2. The clinical phenotype is notable for childhood onset, progressive proximal > distal weakness and progressive respiratory insufficiency. The oldest patient (39 years old) lost independent ambulation and started non-invasive ventilation for respiratory insufficiency at age 30 years. Serum creatine kinase was elevated in all patients (ranging: 4,203 - 18,185 U/L). Muscle MRI in one child in Family 1 was normal (at age 5 years) while in the adult patient in Family 2 (at age 31 years) demonstrated striking replacement of all upper leg muscles with fibroadipose tissue and relative sparing of the anterior and lateral muscles in the lower leg. Muscle biopsy of the tibialis anterior muscle in the adult patient (age 35 years) showed dystrophic findings. Anti-HMGCR antibodies in this individual were negative. With the finding of HMGCR as a causative gene for muscular dystrophy, following our finding of GGPS1, encoding GGPPS, another mevalonate pathway enzyme, as a causative gene for a muscular dystrophy/deafness/ovarian insufficiency syndrome, and the report of HMGCS1, encoding 3-hydroxy-3-methylglutaryl-coenzyme A synthase 1, as a causative gene for muscular dystrophy with rigid spine, the mevalonate pathway is further implicated in the etiology of muscular dystrophy. The underlying pathomechanisms of the mevalonate pathway-related muscle diseases still need to be fully understood but could lead to therapeutic targets given the rich pharmacological toolbox for this pathway.