HACD1 – Congenital Myopathy

Congenital myopathies are heterogeneous inherited muscle diseases characterized by early-onset hypotonia and weakness. HACD1 (HGNC:9639) encodes 3-hydroxyacyl-CoA dehydratase 1, the third enzyme in very long-chain fatty acid elongation vital for membrane integrity. Recessive loss-of-function variants in HACD1 underlie a distinct form of congenital myopathy (MONDO:0019952).

In a consanguineous family with autosomal recessive congenital myopathy, a homozygous nonsense variant c.599G>A (p.Trp200Ter) led to nonsense-mediated decay of HACD1 mRNA to 31% of control levels and complete loss of enzymatic activity in patient muscle (PMID:23933735). Three additional unrelated patients presenting with neonatal-onset generalized muscle weakness and motor delay carried homozygous HACD1 variants: a nonsense change c.458G>A (p.Trp153Ter) and two splice-site variants c.373_375+2del and c.785-1G>T, all absent from population databases (PMID:33354762).

These findings define an autosomal recessive inheritance pattern with a variant spectrum dominated by nonsense and splice-site mutations. Segregation analysis confirmed biallelic transmission in affected individuals and heterozygous carrier status in parents. The consistency of clinical improvement over time and shared histologic features further support a distinct HACD1-related myopathy phenotype.

Functional studies demonstrate that loss of HACD1 activity abolishes 3-hydroxyacyl-CoA dehydration, disrupting VLCFA synthesis and muscle membrane composition. The resultant haploinsufficiency mechanism aligns with the observed neonatal hypotonia and progressive muscle weakness, and rescue of enzymatic activity in vitro confirms pathogenicity.

No conflicting evidence has been reported to date; the reproducibility of genetic and functional data across independent cohorts solidifies the gene–disease link. Further natural history studies may elucidate long-term outcomes and potential therapeutic strategies.

Key Take-home: Biallelic HACD1 loss-of-function variants cause a clinically recognizable autosomal recessive congenital myopathy, warranting inclusion of HACD1 in genetic diagnostic panels.

References

• Human molecular genetics • 2013 • Congenital myopathy is caused by mutation of HACD1. PMID:23933735
• Clinical Genetics • 2021 • Biallelic loss-of-function HACD1 variants are a bona fide cause of congenital myopathy. PMID:33354762

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