Introduction: S-adenosylhomocysteine hydrolase catalyzes the reversible hydrolysis of S-adenosylhomocysteine to adenosine and homocysteine, and its deficiency results from mutations of the AHCY gene. It is a very rare autosomal recessive disease with a variable cerebrohepatomuscular phenotype.

Patients and Methods: Two siblings, an 18-year old male and 12-year old female presented with varying intellectual disability, hypotonia, myopathy, and hepatopathy with the additional novel features of bradykinesia, cerebellar ataxia, and masseter hypertrophy. The older brother had greater intellectual disability and ataxia and the younger sister manifested with additional obesity, hyperphagia, obstructive sleep apnea and visual impairment.

Results: Both had consistently marked elevations of creatine kinase up to 120-fold. Liver enzymes were elevated but liver involvement was more prominent in the obese younger sister who also had increased methionine concentrations in the blood and urine, as well as elevated serum homocysteine. Their brain imaging revealed cerebellar atrophy with decreased cerebellar N-acetyl aspartate peak on MRS and marked hypertrophy of the muscles of mastication. A novel homozygous mutation, c.142 G>A, p.Ala48Thr in the AHCYgene was detected by Whole exome sequencing in both siblings. Enzyme assay of S-adenosylhomocysteine hydrolase revealed a low residual activity in fibroblasts.

Conclusions: Increased S-adenosylhomocysteine levels may cause secondary inhibition of multiple different S-adenosylmethionine-dependent methyltransferases, and the clinical manifestations can be explained in part by the derangements in creatine and choline metabolism as well as in DNA hypermethylation. Sequencing the AHCYgene may aid in the early diagnosis and treatment of patients presenting with heterogeneous cerebrohepatomuscular manifestations.