ADH5 – AMeD syndrome

Aldehyde Degradation Deficiency (AMeD) syndrome (MONDO:0030894) is a rare digenic disorder resulting from biallelic loss-of-function variants in ADH5 combined with the heterozygous dominant-negative ALDH2*2 allele. Patients typically present in childhood with bone marrow failure, growth retardation, microcephaly, developmental delay, and non-hematologic features such as verrucae and amblyopia. Early recognition of milder dermatologic or skeletal signs can prompt genetic testing and timely management.

Eighteen unrelated probands (13 females, 5 males) with biallelic ADH5 variants and ALDH2*2 have been reported in the literature (PMID:38614309). The recurrent ADH5 frameshift c.966del (p.Gly321_Trp322insTer) has been identified in multiple cohorts. Additional cohorts include patient-derived induced pluripotent stem cells from Japanese families confirming the genotype–phenotype link (PMID:33512438).

Pedigree segregation data remain limited, with no additional affected relatives beyond the index cases formally described. The inheritance mode is digenic, combining autosomal recessive ADH5 deficiency and autosomal dominant-negative ALDH2*2 activity.

Functional studies in patient lymphocytes reveal markedly increased spontaneous sister chromatid exchanges, indicative of formaldehyde-induced DNA damage. In ADH5/ALDH2-deficient iPSCs, hematopoietic differentiation is severely impaired and DNA damage accumulates under low-dose formaldehyde exposure; treatment with an ALDH2 agonist (C1) partially rescues proliferation and genomic stability (PMID:33512438).

Hematopoietic stem cell transplantation has successfully restored hematologic function in two patients with isochromosome 1q, underscoring the value of early genetic diagnosis and intervention.

Integration of genetic and experimental data supports a Strong ClinGen-level association between ADH5 and AMeD syndrome. Key Take-home: Genetic testing for ADH5 and ALDH2 variants is critical for diagnosis, risk stratification, and guiding curative therapies in AMeD syndrome.

References

• European Journal of Medical Genetics • 2024 • Characteristic phenotypes of ADH5/ALDH2 deficiency during childhood. PMID:38614309
• Blood • 2021 • Analysis of disease model iPSCs derived from patients with a novel Fanconi anemia-like IBMFS ADH5/ALDH2 deficiency. PMID:33512438

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