S‐adenosylhomocysteine hydrolase deficiency: two siblings with fetal hydrops and fatal outcomes

Abstract

This paper reports the clinical and metabolic findings in two sibling sisters born with fetal hydrops and eventually found to have deficient S-adenosylhomocysteine hydrolase (AHCY) activity due to compound heterozygosity for two novel mutations, c.145C>T; p.Arg49Cys and c.257A>G; p.Asp86Gly. Clinically, the major abnormalities in addition to fetal hydrops (very likely due to impaired synthetic liver function) were severe hypotonia/myopathy, feeding problems, and respiratory failure. Metabolic abnormalities included elevated plasma S-adenosylhomocysteine, S-adenosylmethionine, and methionine, with hypoalbuminemia, coagulopathies, and serum transaminase elevation. The older sister died at age 25 days, but the definitive diagnosis was made only retrospectively. The underlying genetic abnormality was diagnosed in the second sister, but treatment by means of dietary methionine restriction and supplementation with phosphatidylcholine and creatine did not prevent her death at age 122 days. These cases extend the experience with AHCY deficiency in humans, based until now on only the four patients previously identified, and suggest that the deficiency in question may be a cause of fetal hydrops and developmental abnormalities of the brain.

Non-Immune Hydrops, Hypotonia, Encephalopathy, and Liver Failure with Novel Compound Heterozygous <b><i>AHCY</i></b> Mutations

“…Grubbs et al [4] described compound heterozygous AHCY mutations (p.Arg49Cys and p.Asp86Gly) in each of 2 siblings with a phenotype and outcome very similar to our case, involving hydrops and liver failure. On that basis, we deem it likely that the novel AHCY mutations we discovered were the underlying cause of the hydrops and other features in our case as well.…”

Clinical picture of S-adenosylhomocysteine hydrolase deficiency resembles phosphomannomutase 2 deficiency

“…White matter changes are typical for SAHH deficiency in contrast to PMM2-CDG Ia, for which cerebellar hypoplasia is a common sign (Table 1). However, white matter abnormalities were not present in the repeated brain MRIs in this Czech SAHH-deficient patient, and cerebellar hypoplasia was previously documented in two severely affected SAHH-deficient neonates [6]. On the other hand, MR imaging in one of the Czech PMM2-CDG Ia patients showed white matter abnormalities in addition to cerebellar hypoplasia.…”

“…fetal hydrops, hypotonia with myopathy, cerebellar hypoplasia, strabism, hepatopathy or coagulopathy [6,8,9]). White matter changes are typical for SAHH deficiency in contrast to PMM2-CDG Ia, for which cerebellar hypoplasia is a common sign (Table 1).…”

“…Deficiency of this enzyme has been reported in the literature in only six cases [2][3][4][5][6] (OMIM # 180960). Herein, we report on the seventh patient diagnosed with SAHH deficiency and highlight the remarkable resemblance of SAHH deficiency to PMM2 deficiency.…”

Liver transplantation for treatment of severe S-adenosylhomocysteine hydrolase deficiency

“…Six additional case reports appeared in the literature between 2005 and 2012 [8][9][10][11][12]. Severe AHCY deficiency presents during infancy with some combination of growth failure, microcephaly, psychomotor delay, epilepsy, hypomyelination, myopathy, hepatopathy, factor VII deficiency, and marked elevations of blood methionine, AdoMet, and AdoHcy.…”