“Rigid spine syndrome is a rare childhood-onset myopathy characterised by neck and spine contractures. Mutations in SEPN1 account for most cases of rigid spine syndrome, however in some patients the underlying genetic cause remains unexplained.
By WES, we identified biallelic missense variants (p.Gly297Val and p.Arg430Lys) in HMGCS1, encoding 3-hydroxy-3-methylglutaryl-coenzyme-A-synthase of the mevalonate pathway, in an Italian patient affected by undiagnosed myopathy with rigid spine.
A 35 years old man, presented since age 5 years with raised CK and proximal hypotonia. Muscle biopsy revealed abnormalities of the myofibrillar network, dotted glycogen accumulation and increased acid phoshatase. Patient developed over the years diffuse muscle atrophy, mild proximal weakness preserving ambulation, severe spine stiffness and respiratory restrictive disorder.
Within a collaborative international study, further HMGCS1 variants have been characterised in a total of 5 patients from 4 families. All patients presented with spinal rigidity primarily affecting the cervical and dorsolumbar regions, scoliosis, and respiratory insufficiency later in life. CK levels were elevated. Muscle biopsies revealed irregularities in oxidative enzyme staining with occasional internal nuclei and rimmed vacuoles.
To our knowledge, HMGCS1 has not been previously associated with disease, though disturbance of the mevalonate pathway are involved in the HMGCR inflammatory myopathy and GGPS1-muscular dystrophy.
To support the pathogenicity of HMGCS1 defect, a zebrafish hmgcs1 null mutant was generated which displayed severe early defects, including immobility at 2 days and subsequent death.
We suggest that biallelic variants in HMGCS1 should be considered in patients presenting with an unresolved rigid spine phenotype and respiratory involvement.”