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Approximately 15 cases of S-adenosylhomocysteine hydrolase (SAHH) deficiency have been described to date.

Disease onset is typically in infancy, but may occur in utero or in adult age. In infancy, the clinical picture is typically comprised of developmental delay and hypotonia due to myopathy with markedly increased creatine kinase (CK) plasma levels, and more variably with cerebral hypomyelination, coagulation abnormalities and hepatopathy. Microcephaly, strabismus and behavioral changes are frequent. Severe cases may present in utero with fetal hydrops, congenital brain anomalies (pontine and cerebellar hypoplasia, hypoplastic corpus callosum), synthetic liver failure, respiratory insufficiency due to severe muscle weakness and death in early infancy. Specific biochemical findings include markedly increased plasma S-adenosylhomocysteine (AdoHyc) and S-adenosylmethionine (AdoMet) in combination with normal or near normal total homocysteine (tHcy) and hypermethioninemia which is not always present, particularly not in early infancy. Whilst the disease is typically severe with poor developmental outcomes, the phenotype can vary from mild to asymptomatic (one report). The milder phenotype includes later disease onset and milder weakness and developmental delay. Hepatocellular carcinoma was reported in one patient and was possibly present in another.

The disease is due to mutations in the gene encoding S-adenosylhomocysteine hydrolase, AHCY (20q11.22), an enzyme involved in methionine metabolism.

Diagnosis should be suspected in patients with any combination of the clinical symptoms and in all patients with unexplained hypermethioninemia. Marked elevations of AdoMet and AdoHcy, in combination with normal or near normal tHcy are characteristic for the disease, thus plasma AdoMet and AdoHcy should be measured where there is clinical suspicion for the disease. Since these biochemical assays are poorly available, gene analysis could be a better choice. The latter , as well as enzyme assay of AdoHcy hydrolase, serves also for confirmation of the diagnosis.

Based on the multiorgan clinical presentation, SAHH deficiency has a very wide differential diagnosis, with chronic myopathies, muscular dystrophies, floppy infant syndrome and group of isolated persistent hypermethioninemias being the most important.

Prenatal testing is possible if a genetic mutation has been previously identified in a family member.

The pattern of inheritance is autosomal recessive. Where both parents are unaffected carriers of the disease, the risk of transmission to offspring is 25%. There is variable disease severity between different families. Intrafamilial variability is also possible.

Whilst there is little evidence to support specific treatment strategies, the current consensus is on a methionine-restricted diet (with methionine-free amino acid mixture supplementation), which can decrease and sometimes even normalize plasma AdoMet and AdoHcy. Subsequent close clinical and biochemical monitoring seem mandatory. Phosphatidylcholine, creatine and cysteine supplementation may be beneficial. Liver transplantation has resulted in clinical and biochemical improvement in a single case.

Prognosis depends on the severity of the disease and ranges from death during the neonatal period to survival into adulthood and possibly normal life span. Functional outcomes in surviving patients are frequently severe, with the most common impact on neurodevelopment and mobility. Long term follow-up is missing in most patients and accurate and precise prognosis is not possible. Whilst dietary management is promising in some cases, it is not effective in all (improving metabolic parameters but not functional outcomes). Evidence on liver graft is limited.