Selective screening
The
clinical suspicion of S-adenosylhomocysteine hydrolase deficiency is guided by findings in ten reported patients from six families (Barić et al
2004,
2005; Buist et al
2006; Ćuk et al
2007; Grubbs et al
2010; Honzík et al
2012; Strauss et al
2015; Stender et al
2015). Two sibs presented severely with fetal hydrops, insufficient liver synthetic function and muscular hypotonia leading to respiratory failure and death in early infancy. Both sisters had cerebellar and pontine hypoplasia, hypoplastic corpus callosum and hypomyelination (Grubbs et al
2010). Muscle disease with increased CK activity was also present in all patients with a relatively milder phenotype. In addition, they had various combinations of developmental delay, behavioural disorders, microcephaly, myelination delay, strabismus, coagulopathy and liver disease. Muscle histology in several patients suggested dystrophic processes.
A novel, very recently reported dimension of the disease is the development of hepatocellular carcinoma, which occurred in a female patient at the age of 29 years and her brother, who likely had SAHH deficiency (Stender et al
2015). SAHH deficiency was diagnosed in the female
post mortem by whole exome sequencing. Her son, harbouring the same homozygous missense mutation as his mother, was diagnosed with SAHH deficiency at the age of 7 years. He was reported to be asymptomatic, although he had mildly to moderately elevated aminotransferases, decreased albumin and markedly elevated serum levels of methionine, AdoMet and AdoHcy. CK activity was not reported.
Statement #19. Grade of recommendation C-D
SAHH deficiency should be suspected in patients with any combination of myopathy with markedly increased CK activity, being the most constant feature, followed by hypotonia, developmental delay, hypomyelination, behavioural problems, liver disease (including hepatocellular carcinoma), coagulation disorders, strabismus and fetal hydrops with brain abnormalities.
Statement #20. Grade of recommendation C
SAHH patients may also be asymptomatic.
Biochemical abnormalities include elevated aminotransferases and CK activities and variable coagulation abnormalities. Repeatedly reported were: prolonged prothrombin time, low fibrinogen, antithrombin III, protein S, factor II and particularly factor VII, and increased factor V. Specific abnormalities pointing to the diagnosis are markedly elevated plasma AdoMet and particularly elevated plasma AdoHcy with normal or near normal tHcy. Plasma methionine can be normal in early infancy, but after that period in untreated patients it is probably constantly elevated. However, since hypermethioninemia is not a constant finding, it is essential to measure AdoMet and AdoHcy in all cases with clinical suspicion of the disorder. In reported patients plasma AdoMet was ∼18-50-fold elevated (up to 5109 nmol/L, reference range 91 ± 28), while AdoHcy was ∼12-200-fold elevated (up to 8139 nmol/L, reference range 27 ± 15). In early infancy these elevations can be less manifest. Biallelic pathogenic mutations in the AHCY gene have been found in all patients with SAHH deficiency.
Statement #21. Grade of recommendation C
In all cases with clinical suspicion of SAHH deficiency, plasma AdoMet and AdoHcy should be measured because their marked elevations in combination with normal or near normal tHcy are characteristic for the diagnosis. Plasma methionine may be normal in early infancy, but consequently likely to be constantly elevated in untreated patients. Diagnosis must be confirmed by either enzyme assay (possible in red blood cells, fibroblasts and liver) or by mutation analysis.
Newborn screening
Since SAHH deficiency seems to be partly treatable at least in some cases and there are indications that early diagnosis improves the outcome (Barić et al
2005; Strauss et al
2015), early identification through newborn screening could be beneficial. Currently, the only feasible way is screening for hypermethioninemia, usually done to identify CBS deficiency. Unfortunately, hypermethioninemia was present only in two out of six patients with SAHH deficiency in whom data on plasma methionine or dried blood spot methionine at the time of newborn screening was available. In two of those six patients newborn screening was performed. One of these patients had on day 3 a blood methionine level of 200 μmol/L, using the Guthrie bacterial inhibition assay (Buist et al
2006), while the other had a normal methionine level (20 μmol/L), measured by tandem mass spectrometry (Strauss et al
2015). In the remaining four patients in whom data on methionine at the time of newborn screening was available, plasma methionine was measured either because of SAHH deficiency in family members, and was normal in three patients (Barić et al
2005; I. Barić- personal communication), or because of clinical indication. In the latter case it was elevated (273 μmol/L) on day 4 (Grubbs et al
2010). A related important issue is the necessity for further diagnostic work-up following positive screening. Since increased CK activity seems to be a constant finding in SAHH deficiency, measurement of CK in dried blood spots could be an option for newborn screening, as has been used for newborn screening for Duchenne muscular dystrophy (Zellweger and Antonik
1975; Orfanos and Naylor
1984).
Statement #22. Grade of recommendation D
Since early treatment has shown a positive effect in some cases early identification through newborn screening may be beneficial.
Statement #23. Grade of recommendation C
At present, there is no sensitive screening test available to allow for newborn screening. Therefore, newborn screening is presently not possible.
Prenatal diagnosis
The only established way is the AHCY gene analysis. This is possible if the disease causing mutations are known and the carrier status of the parents has been confirmed by mutation analysis. Enzyme assay in amniocytes or chorionic villi, as well as measurement of metabolites in amniotic fluid have not been tested. The necessity for prenatal diagnosis requires thoughtful discussion, one of the reasons being the clinical variability of SAHH deficiency.
Statement #24. Grade of recommendation D
If the disease causing mutations are known, prenatal diagnosis is possible by AHCY gene analysis.