Asymptomatic pediatric presentation of S-adenosylhomocysteine hydrolase deficiency

Abstract

S-adenosylhomocysteine hydrolase deficiency is an autosomal recessive inborn error of metabolism affecting methylation by disrupting the methionine cycle. Its clinical spectrum spans from severe perinatal encephalomyopathy and liver failure to asymptomatic course in patients with isolated hypermethioninemia. We present two new cases of S-adenosylhomocysteine hydrolase deficiency from Pakistani origin clinically asymptomatic at presentation. Both siblings showed mild chronic liver failure and elevation of creatine kinase. The older patient presented at 6 years of age with isolated verbal processing difficulty and mild diffuse leukodystrophy, reversible 12 months after introduction of methionine dietary restriction. The patient showed subtle atrophy in the muscle MRI at the age of 7 years. S-adenosylhomocysteine hydrolase deficiency was confirmed with homozygous missense variant c.146G>A (p.Arg49His) in the AHCY gene, a genotype previously reported in Pakistani patients with mild presentation. Dietary methionine restriction decreased plasma methionine but not plasma S-adenosylhomocysteine and S-adenosylmethionine. This work expands the mild spectrum of S-adenosylhomocysteine hydrolase deficiency with no noticeable clinical symptoms in children, highlighting a specific hotspot variant from South Asia. This mild form of the disease is likely underdiagnosed and raises the question of therapeutic management to prevent long-term complications documented in the literature, such as hepatocellular carcinoma and myopathy in early adulthood.

Keywords: AHCY gene; S‐adenosylhomocysteine; S‐adenosylhomocysteine hydrolase deficiency; S‐adenosylmethionine; hepatocellular carcinoma; hypermethioninemia.

FIGURE 1

Schematic of the methylation cycle. Cys, cysteine; Cyst, cystathionine; Hcy, homocysteine; MAT, methionine adenosyltransferase; MeCbl, methylcobalamin; Met cycle, methionine cycle; MS, methionine synthase; MTHF, N5‐methyltetrahydrofolate; SAH, S‐adenosylhomocysteine; SAHH, S‐adenosylhomocysteine hydrolase; SAM, S‐adenosylmethionine.

FIGURE 2

Biochemical profiles of patient 1. (A) Methionine, (B) ALT, (C) PT, (D) CK, (E) Albumin, (F) Fibrinogen, and (G) SAM and SAH, the dark arrow represents commencement of methionine‐restricted diet. The gray‐shaded area in each graphic represents the normal reference range values. ALT, alanine aminotransferase; CK, creatine kinase; PT, prothrombin time; SAH, S‐adenosylhomocysteine; SAM, S‐adenosylmethionine.

FIGURE 3

Neuroimaging of patient 1. (A–F) A brain MRI from patient one performed at the age of 6.5 years before commencement of methionine‐restricted diet shows extensive and confluent hypersignal changes of deep white matter involving all the lobes (A, B; white arrows), and the anterior commissure is also engaged (B; yellow arrow) in T2 sequences. There is corresponding diffusion restriction on diffusion‐weighted imaging (DWI) (C, D) and apparent diffusion coefficient (ADC) (E, F) sequences. The optic radiation and internal capsule are spared (B; black arrows). (G–L) The brain MRI at 7.5 years (after 12 months of methionine‐restricted diet) shows resolution of all white matter changes without residual volume loss or signal change.

FIGURE 4

Biochemical profiles of patient 2. (A) Plasma methionine, (B) ALT, (C) PT, (D) CK, (E) Albumin, (F) Fibrinogen, (G) SAM and SAH. The gray‐shaded area in each graphic represents the normal reference range values. ALT, alanine aminotransferase; CK, creatine kinase; PT, prothrombin time; SAH, S‐adenosylhomocysteine; SAM, S‐adenosylmethionine.

FIGURE 5

Neuroimaging of patient 2. Normal MRI at 2 years of age.