Adenosine Kinase Deficiency Disrupts the Methionine Cycle and Causes Hypermethioninemia, Encephalopathy, and Abnormal Liver Function

Abstract

Four inborn errors of metabolism (IEMs) are known to cause hypermethioninemia by directly interfering with the methionine cycle. Hypermethioninemia is occasionally discovered incidentally, but it is often disregarded as an unspecific finding, particularly if liver disease is involved. In many individuals the hypermethioninemia resolves without further deterioration, but it can also represent an early sign of a severe, progressive neurodevelopmental disorder. Further investigation of unclear hypermethioninemia is therefore important. We studied two siblings affected by severe developmental delay and liver dysfunction. Biochemical analysis revealed increased plasma levels of methionine, S-adenosylmethionine (AdoMet), and S-adenosylhomocysteine (AdoHcy) but normal or mildly elevated homocysteine (Hcy) levels, indicating a block in the methionine cycle. We excluded S-adenosylhomocysteine hydrolase (SAHH) deficiency, which causes a similar biochemical phenotype, by using genetic and biochemical techniques and hypothesized that there was a functional block in the SAHH enzyme as a result of a recessive mutation in a different gene. Using exome sequencing, we identified a homozygous c.902C>A (p.Ala301Glu) missense mutation in the adenosine kinase gene (ADK), the function of which fits perfectly with this hypothesis. Increased urinary adenosine excretion confirmed ADK deficiency in the siblings. Four additional individuals from two unrelated families with a similar presentation were identified and shown to have a homozygous c.653A>C (p.Asp218Ala) and c.38G>A (p.Gly13Glu) mutation, respectively, in the same gene. All three missense mutations were deleterious, as shown by activity measurements on recombinant enzymes. ADK deficiency is a previously undescribed, severe IEM shedding light on a functional link between the methionine cycle and adenosine metabolism.

Adenosine kinase deficiency: expanding the clinical spectrum and evaluating therapeutic options

“…Adapted from The American Journal of Human Genetics, Vol 89, Magnus K. Bjursell, Henk J. Blom, et al, 507-515, 2007, with permission from Elsevier initial description of ADK deficiency by Bjursell et al (Bjursell et al 2011). Apart from intellectual disability no details on the clinical course of the two patients have been published before.…”

“…Genetic confirmation has not been done in the three older sisters, but as they show a typical clinical and biochemical picture and are siblings of a genetically confirmed case of ADK deficiency, this "familial hypermethioninemia" can be considered to be ADK deficiency. Thus up to now, including the patients published by Bjursell et al, Labrune et al (Bjursell et al 2011;Labrune et al 1990) and the patients of this publication, 20 individuals with ADK deficiency are known, of whom 18 are alive at time of report. We expect ADK deficiency to be an underdiagnosed disease for several reasons: the disease is only known to a few specialists, it has a wide range of clinical phenotypes and most biochemical findings can be intermittent, especially hypermethioninaemia, and measurement of the most sensitive parameters AdoMet and AdoHcy is only performed in very few specialized metabolic laboratories.…”

“…The patients described by Bjursell et al (Bjursell et al 2011) developed epilepsy early in the disease course (mean age 18.2 months, range 10 -35). In our study, age at onset varied between 4 months to 8.1 years, and some patients have remained seizure free until now.…”

“…In patient 2 the diet was initiated during the newborn period but was discontinued after 5 days due to lack of clinical and biochemical response. Patient 5 did not tolerate (Bjursell et al 2011) and (Labrune et al 1990). n=20; d referring to failure to thrive, short stature: 54 % (7/13) methionine free formula as she developed intractable diarrhoea even with changing the diet to a different type of methionine free formula, and the parents decided to stop the dietary treatment.…”

“…1). In 2011, Bjursell et al described the first six patients from three families with autosomal-recessive ADK deficiency (OMIM #614300), that were characterized by global developmental retardation, epilepsy, liver dysfunction, dysmorphic features and hypermethioninemia (Bjursell et al 2011).…”