SLC25A15 – Ornithine Translocase Deficiency (HHH Syndrome)

Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare autosomal recessive disorder of the urea cycle characterized by hyperornithinemia, hyperammonemia and urinary homocitrullinuria, with clinical features including episodic confusion, seizures, ataxia and intellectual disability (PMID:11814739). Affected individuals often present in infancy or early childhood, although adult-onset cases have been reported.

The SLC25A15 gene (HGNC:10985) encodes the mitochondrial ornithine transporter ORC1, essential for ornithine uptake into mitochondria in exchange for citrulline. Biallelic pathogenic variants result in ORC1 deficiency and urea cycle dysfunction. To date, fewer than 100 patients have been documented worldwide, spanning multiple ethnicities (PMID:30187369).

Genetic studies have identified over 70 distinct SLC25A15 variants, including missense, nonsense, frameshift, splice-site and small indels. A French-Canadian founder allele, p.Phe188del, accounts for the majority of cases in that population (PMID:18978333). Other recurrent alleles include p.Arg179Ter in Japanese patients and p.Gly220Arg globally.

Segregation analyses in more than 30 unrelated families demonstrate autosomal recessive inheritance with both homozygous and compound heterozygous presentations. The common p.Arg179Ter allele segregates in multiple Japanese kindreds, confirmed by RT-PCR showing exon 4 skipping in affected fibroblasts (PMID:11355015).

Functional assays in reconstituted liposomes and yeast complementation confirm loss of ornithine transport activity for numerous missense variants. For example, p.Ala15Val abolishes mitochondrial uptake of ornithine in yeast ORT1Δ cells (PMID:24721342), and p.Gly27Arg fails to complement ORT1Δ growth, indicating severe functional impairment (PMID:25818551).

Despite broad phenotype variability and limited genotype–phenotype correlations, the concordance of genetic and functional data across populations establishes SLC25A15 as a definitive cause of HHH syndrome. Early molecular diagnosis enables targeted dietary management and ammonia-scavenger therapy, which are critical for preventing irreversible neurological damage.

Key Take-Home: Biallelic loss-of-function variants in SLC25A15 underlie HHH syndrome; genetic testing should be pursued in all unexplained hyperammonemia and hyperornithinemia cases.

References

• Pediatric neurology • 2002 • A novel mutation, P126R, in a Japanese patient with HHH syndrome. PMID:11814739
• JIMD reports • 2019 • Hyperornithinemia, Hyperammonemia, and Homocitrullinuria Syndrome Causing Severe Neonatal Hyperammonemia. PMID:30187369
• Journal of medical genetics • 2008 • Phenotypic variability among patients with hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome homozygous for the delF188 mutation in SLC25A15. PMID:18978333
• Journal of human genetics • 2001 • Diagnosis of Japanese patients with HHH syndrome by molecular genetic analysis: a common mutation, R179X. PMID:11355015
• Molecular genetics and metabolism • 2014 • A novel mutation in the SLC25A15 gene in a Turkish patient with HHH syndrome: functional analysis of the mutant protein. PMID:24721342
• Molecular genetics and metabolism • 2015 • Pathogenic potential of SLC25A15 mutations assessed by transport assays and complementation of Saccharomyces cerevisiae ORT1 null mutant. PMID:25818551

Evidence Based Scoring (AI generated)