HTRA2 – 3-Methylglutaconic Aciduria Type 8

HTRA2 encodes a mitochondrial serine protease whose loss-of-function underlies autosomal recessive 3-methylglutaconic aciduria type 8 (MGCA8) (MONDO:0044723). Clinically, affected infants present with hypotonia, global developmental delay, and ocular abnormalities such as nystagmus. A single report describes an infant male with compound heterozygous HTRA2 variants: c.1037A>T (p.Glu346Val) (maternal) and c.1172T>A (p.Val391Glu) (paternal); both are absent from population databases and predicted to be deleterious (PMID:38304066). To date, fewer than ten unrelated families have been reported with MGCA8 (PMID:38304066).

Functional modeling in the murine mnd2 mutant, which harbors the orthologous Ser276Cys change, demonstrates a profound loss of Omi/HTRA2 protease activity, leading to early neuromuscular degeneration and lethality; rescue with a wild-type transgene restores protease function and survival (PMID:14534547). These data support a recessive loss-of-function mechanism for MGCA8. Genetic testing of HTRA2 should be considered in patients with unexplained neonatal hypotonia, developmental delay, and 3-methylglutaconic aciduria.

References

• Frontiers in Genetics • 2023 • Biallelic variants in HTRA2 cause 3-methylglutaconic aciduria mitochondrial disorder: case report and literature review. PMID:38304066
• Nature • 2003 • Loss of Omi mitochondrial protease activity causes the neuromuscular disorder of mnd2 mutant mice. PMID:14534547

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