Liver transplantation for treatment of severe S-adenosylhomocysteine hydrolase deficiency

Strauss, Kevin A.; Ferreira, Carlos R.; Bottiglieri, Teodoro; Zhao, Xueqing; Arning, Erland; Zhang, Shucha; Zeisel, Steven H.; Escolar, Maria L.; Presnick, Nancy; Puffenberger, Erik G.; Vugrek, Oliver; Kovačević, Lucija; Wagner, Conrad; Mazariegos, George; Mudd, S. Harvey; Soltys, Kyle

doi:10.1016/j.ymgme.2015.06.005

Cited by 35 publications

(40 citation statements)

References 42 publications

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“…Elevated levels of muscle enzymes such as CK, LDH, and AST have been also reported in a few cases [30]. Importantly, dietary methionine restriction and dietary supplements of creatine and phosphatidylcholine can substantially lower circulating levels of methionine in SAH hydrolase-deficient patients [29, 31], though its long-term clinical benefits are still unknown.…”

Section: Discussionmentioning

confidence: 99%

Exome sequencing in Jewish and Arab patients with rhabdomyolysis reveals single-gene etiology in 43% of cases

et al. 2017

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Background Rhabdomyolysis is a clinical emergency that may cause acute kidney injury (AKI). It can be acquired or due to monogenic mutations. Around 60 different rare monogenic forms of rhabdomyolysis have been reported to date. In the clinical setting, identifying the underlying molecular diagnosis is challenging, due to nonspecific presentation, the high number of causative genes, and current lack of data on the prevalence of monogenic forms. Methods We employed whole exome sequencing (WES) to reveal the percentage of rhabdomyolysis cases explained by single-gene (monogenic) mutations in one of 58 candidate genes. We investigated a cohort of 21 unrelated families with rhabdomyolysis. in whom no underlying etiology had been previously established. Results Using WES, we identified causative mutations in candidate genes in nine of the 21 families (43%). We detected disease-causing mutations in eight of 58 candidate genes, grouped into the following categories: 1) disorders of fatty acid metabolism (CPT2), 2) disorders of glycogen metabolism (PFKM and PGAM2), 3) disorders of abnormal skeletal muscle relaxation and contraction (CACNA1S, MYH3, RYR1 and SCN4A), and 4) disorders of purine metabolism (AHCY). Conclusions Our findings demonstrate a very high detection rate for monogenic etiologies using WES and reveal broad genetic heterogeneity for rhabdomyolysis. These results highlight the importance of molecular genetic diagnostics for establishing an etiologic diagnosis. Because these patients are at risk for recurrent episodes of rhabdomyolysis and subsequent risk for AKI, WES allows adequate prophylaxis and treatment for these patients and their family members and enables a personalized medicine approach.

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Section: Discussionmentioning

confidence: 99%

Exome sequencing in Jewish and Arab patients with rhabdomyolysis reveals single-gene etiology in 43% of cases

et al. 2017

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“…We are aware of a total of five patients with GNMT deficiency, four reported in extenso in three publications (Mudd et al 2001b; Augoustides-Savvopoulou et al 2003; Barić et al 2016), nine patients with SAHH deficiency reported in seven publications in detail (Barić et al 2004, 2005; Buist et al 2006; Grubbs et al 2010; Honzík et al 2012; Strauss et al 2015; Stender et al 2015) and 21 patients with ADK deficiency, 20 of them reported in four articles in extenso (Bjursell et al 2011; Labrune et al 1990; Staufner et al 2016a, b). Very recently, almost all known patients with MAT I/III deficiency (in total 64 patients) were extensively described (Chien et al 2015).…”

Section: Methodsmentioning

confidence: 99%

Consensus recommendations for the diagnosis, treatment and follow‐up of inherited methylation disorders

Barić

Staufner

Augoustides‐Savvopoulou

et al. 2016

J of Inher Metab Disea

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Inherited methylation disorders are a group of rarely reported, probably largely underdiagnosed disorders affecting transmethylation processes in the metabolic pathway between methionine and homocysteine. These are methionine adenosyltransferase I/III, glycine N-methyltransferase, S-adenosylhomocysteine hydrolase and adenosine kinase deficiencies. This paper provides the first consensus recommendations for the diagnosis and management of methylation disorders. Following search of the literature and evaluation according to the SIGN-methodology of all reported patients with methylation defects, graded recommendations are provided in a structured way comprising diagnosis (clinical presentation, biochemical abnormalities, differential diagnosis, newborn screening, prenatal diagnosis), therapy and follow-up. Methylation disorders predominantly affect the liver, central nervous system and muscles, but clinical presentation can vary considerably between and within disorders. Although isolated hypermethioninemia is the biochemical hallmark of this group of disorders, it is not always present, especially in early infancy. Plasma S-adenosylmethionine and S-adenosylhomocysteine are key metabolites for the biochemical clarification of isolated hypermethioninemia. Mild hyperhomocysteinemia can be present in all methylation disorders. Methylation disorders do not qualify as primary targets of newborn screening. A low-methionine diet can be beneficial in patients with methionine adenosyltransferase I/III deficiency if plasma methionine concentrations exceed 800 μmol/L. There is some evidence that this diet may also be beneficial in patients with S-adenosylhomocysteine hydrolase and adenosine kinase deficiencies. S-adenosylmethionine supplementation may be useful in patients with methionine adenosyltransferase I/III deficiency. Recommendations given in this article are based on general principles and in practice should be adjusted individually according to patient’s age, severity of the disease, clinical and laboratory findings.Electronic supplementary materialThe online version of this article (doi:10.1007/s10545-016-9972-7) contains supplementary material, which is available to authorized users.

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“…Recently, an 8 month-old girl (#7, Table 2) with developmental delay, hypotonia, and elevated aminotransferase levels due to SAH hydrolase deficiency was reported. Dietary methionine restriction reduced, but failed to normalize the levels of SAH and SAM in her serum so she underwent liver transplantation at 40 months of age [7]. Within six months, her serum SAH and SAM levels had normalized and her growth and development had appeared to accelerate.…”

Section: Discussionmentioning

confidence: 99%

“…Liver transplantation may be another treatment option for SAH hydrolase deficiency [7]. Only one patient with SAH hydrolase deficiency has undergone liver transplantation.…”

Section: Discussionmentioning

confidence: 99%

“…Only one patient with SAH hydrolase deficiency has undergone liver transplantation. In that patient, serum SAH and SAM levels were normalized within 6 months of transplantation, but further observation will be required to assess the effects of liver transplantation on the course of the disease [7]. The early development and fatal course of hepatocellular carcinoma in the proband and her brother raises the possibility that prophylactic screening of the liver may be indicated in these patients and that the possibility of developing a hepatic malignancy may be a further indication for liver transplantation.…”

Section: Discussionmentioning

confidence: 99%

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Adult-onset liver disease and hepatocellular carcinoma in S-adenosylhomocysteine hydrolase deficiency

Stender

Chakrabarti

Xing

et al. 2015

Molecular Genetics and Metabolism

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Background The etiology of liver disease remains elusive in some adults presenting with severe hepatic dysfunction. Methods and results Here we describe a woman of Pakistani descent who had elevated aminotransferases at age 23. She developed muscle weakness in her mid-20s, and was diagnosed with hepatocellular carcinoma at age 29. She died without a diagnosis at age 32 after having a liver transplant. Exome sequencing revealed that she was homozygous for a missense mutation (R49H) in AHCY, the gene encoding S-adenosylhomocysteine (SAH) hydrolase. SAH hydrolase catalyzes the final step in conversion of methionine to homocysteine and inactivating mutations in this enzyme cause a rare autosomal recessive disorder, SAH hydrolase deficiency, that typically presents in infancy. An asymptomatic 7-year old son of the proband is also homozygous for the AHCY-R49H mutation and has elevated serum aminotransferase levels, as well as markedly elevated serum levels of SAH, S-adenosylmethionine (SAM), and methionine, which are hallmarks of SAH hydrolase deficiency. Conclusion This report reveals several new aspects of SAH hydrolase deficiency. Affected women with SAH hydrolase deficiency can give birth to healthy children. SAH hydrolase deficiency can remain asymptomatic in childhood, and the disorder can be associated with early onset hepatocellular carcinoma. The measurement of serum amino acids should be considered in patients with liver disease or hepatocellular carcinoma of unknown etiology.

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Liver transplantation for treatment of severe S-adenosylhomocysteine hydrolase deficiency

Cited by 35 publications

References 42 publications

Exome sequencing in Jewish and Arab patients with rhabdomyolysis reveals single-gene etiology in 43% of cases

Exome sequencing in Jewish and Arab patients with rhabdomyolysis reveals single-gene etiology in 43% of cases

Consensus recommendations for the diagnosis, treatment and follow‐up of inherited methylation disorders

Adult-onset liver disease and hepatocellular carcinoma in S-adenosylhomocysteine hydrolase deficiency

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