S‐Adenosylhomocysteine hydrolase deficiency: A second patient, the younger brother of the index patient, and outcomes during therapy

Abstract

SummaryS-Adenosylhomocysteine (AdoHcy) hydrolase deficiency has been proven in a human only once, in a recently described Croatian boy. Here we report the clinical course and biochemical abnormalities of the younger brother of this proband. This younger brother has the same two mutations in the gene encoding AdoHcy hydrolase, and has been monitored since birth. We report, as well, outcomes during therapy for both patients. The information obtained suggests that the disease starts in utero and is characterized primarily by neuromuscular symptomatology (hypotonia, sluggishness, psychomotor delay, absent tendon reflexes, delayed myelination). The laboratory abnormalities are markedly increased creatine kinase and elevated aminotransferases, as well as specific amino acid aberrations that pinpoint the aetiology. The latter include, most importantly, markedly elevated plasma AdoHcy. Plasma S-adenosylmethionine (AdoMet) is also elevated, as is methionine (although the hypermethioninaemia may be absent or nonsignificant in the first weeks of life). The disease seems to be at least to some extent treatable, as shown by improved myelination and psychomotor development during dietary methionine restriction and supplementation with creatine and phosphatidylcholine.*Correspondence: Department of Pediatrics, University Hospital Center, Kišpatićeva 12, Rebro, 10000 Zagreb, Croatia. E-mail: ibaric@kbc-zagreb.hr. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptS-Adenosylhomocysteine (AdoHcy) hydrolase (adenosylhomocysteinase, EC 3.3.1.1) is the enzyme that catalyses hydrolysis of AdoHcy to adenosine and homocysteine (De La Haba and Cantoni 1959). Its deficiency (McKusick 180960) had been proven in a human only once, in a Croatian boy we reported recently (Barić et al 2004). The index patient presented with myopathy, characterized by hypotonia and delayed psychomotor development from birth, abnormally slow brain myelination (noted in MRI studies of the brain at 12.7 months) and mild hepatitis-like findings. The main biochemical abnormalities were marked increases of creatine kinase and aminotransferases, prolonged prothrombin time, low albumin, and specific amino acid aberrations indicative of the aetiology: hypermethioninaemia with almost normal total plasma homocysteine and very elevated plasma AdoHcy (up to 150 × normal) and SAdenosylmethionine (AdoMet) (up to 30 times normal). Activity of AdoHcy hydrolase was severely diminished: about 3% of control in liver and 9−15% of the mean controls in fibroblasts and red blood cells. The specific metabolic defect had been identified and the patient started on therapy by age 12.8 months. Here we report a second patient (patient 2), a brother of the proband. Patient 2 has been monitored since birth and was started on therapy at age 3.4 months, by which time the diagnosis of AdoHcy hydrolase deficiency had been clearly established. We report, also, outcomes during therapy in both patients. METHODS Metabolite assaysAmino acids were measured by i...

S‐Adenosylhomocysteine hydrolase deficiency in a 26‐year‐old man

“…Following the recent identification of AdoHcy hydrolase deficiency (Barić et al 2004), the present patient was studied by the same team. In addition to hypermethioninaemia and elevated CK, the severe elevations of plasma AdoHcy and AdoMet were similar to those in the first two patients (Barić et al 2004(Barić et al , 2005b. The elevated AdoHcy is attributed to defective removal of this compound by AdoHcy hydrolase; the elevated AdoMet to generalized inhibition by AdoHcy of AdoMetdependent methyltransferases; and the elevation of methionine to decreased flux of methionine to AdoMet when the latter accumulates abnormally (Barić et al 2004(Barić et al , 2005b).…”

“…The exon 4 p.Y143C missense mutation is paternally derived; it is identical to one of the two found in both brothers from Croatia (Barić et al 2004(Barić et al , 2005b. It seems highly likely the patient described in 1979, also from the former Yugoslavia (Gaull et al 1979(Gaull et al , 1981, had the same disorder (see further discussion below).…”

“…His behaviour was unchanged. At that time the reports by Barić and colleagues (Barić et al 2004(Barić et al , 2005b) stimulated the collaboration that has proved that this patient is also AdoHcy hydrolase-deficient.…”

“…The first was a paternally derived exon 4 mutation identical to that described in the two AdoHcy-deficient brothers (Barić et al 2004(Barić et al , 2005b) changing tyrosine to cysteine (c.428A > G; p.Y143C). The second, which was not found in either parent, was an exon 3 mutation changing alanine to valine (c.266C > T; p.A89V).…”

“…The present work was prompted by reports by Barić and co-workers of two Croatian siblings (Barić et al 2004(Barić et al , 2005b who were the first patients with proven AdoHcy hydrolase deficiency. In the proband, who was investigated because of hypotonia, psychomotor delay and elevated plasma CK, hypermethioninaemia as high as 748 μmol/L (normal 13-45 μmol/L) was first detected at age 8 months.…”