AHCY – Hypermethioninemia with S-Adenosylhomocysteine Hydrolase Deficiency

S-Adenosylhomocysteine hydrolase (AHCY) catalyzes the reversible hydrolysis of S-adenosylhomocysteine to adenosine and homocysteine, a critical step in the methionine cycle. Loss of AHCY function leads to accumulation of S-adenosylhomocysteine and secondary hypermethioninemia, manifesting as multisystem neurometabolic disease (AHCY; Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase).

Genetic evidence supports an autosomal recessive inheritance pattern with biallelic AHCY variants identified in at least 15 patients from 12 unrelated families (PMID:35789945). Reported pathogenic alleles include missense changes (e.g., p.Tyr328Asp, p.Thr57Ile, p.Val217Met) and loss-of-function truncations, consistent with enzyme insufficiency as the disease mechanism.

Segregation has been demonstrated in sib-pairs from a Croatian kindred (PMID:16435181) and asymptomatic Pakistani siblings (PMID:39512434), yielding two additional affected relatives. A representative variant, c.982T>G (p.Tyr328Asp), was reported in the original index patient with early-onset growth failure, microcephaly, developmental delay, myopathy, hepatopathy, and coagulopathy (PMID:26095522).

The clinical spectrum spans severe neonatal encephalopathy, hypotonia, areflexia, delayed myelination, global developmental delay, muscle weakness (myopathy), liver dysfunction, coagulopathy (reduced factor VII activity), and persistent hypermethioninemia. Some patients exhibit only isolated hypermethioninemia with minimal symptoms, underscoring variable expressivity.

Functional studies of mutant AHCY proteins confirm a loss-of-function mechanism: the p.Tyr143Cys enzyme shows a 65–75% reduction in catalytic rates and thermosensitivity (PMID:16872278); the p.Arg49Cys and p.Asp86Gly mutants form inactive aggregates or aberrant disulfide-linked oligomers, dramatically reducing activity and stability (PMID:19177456).

Integration of robust genetic segregation, multiple unrelated probands, and concordant biochemical and structural data supports a Strong gene–disease association. Dietary methionine restriction and liver transplantation have yielded biochemical and clinical improvements. Key take-home: AHCY deficiency should be considered in patients with unexplained hypermethioninemia and neuromuscular or hepatic manifestations to guide timely therapeutic intervention.

References

• Molecular genetics and metabolism reports • 2022 • The biochemical profile and dietary management in S-adenosylhomocysteine hydrolase deficiency. PMID:35789945
• Journal of inherited metabolic disease • 2005 • S-Adenosylhomocysteine hydrolase deficiency: a second patient, the younger brother of the index patient, and outcomes during therapy. PMID:16435181
• JIMD reports • 2024 • Asymptomatic pediatric presentation of S-adenosylhomocysteine hydrolase deficiency. PMID:39512434
• Molecular genetics and metabolism • 2015 • Liver transplantation for treatment of severe S-adenosylhomocysteine hydrolase deficiency. PMID:26095522
• The Biochemical journal • 2006 • A single mutation at Tyr143 of human S-adenosylhomocysteine hydrolase renders the enzyme thermosensitive and affects the oxidation state of bound cofactor nicotinamide-adenine dinucleotide. PMID:16872278
• Human Mutation • 2009 • S-adenosylhomocysteine hydrolase (AHCY) deficiency: two novel mutations with lethal outcome. PMID:19177456

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