ADK – Adenosine Kinase Deficiency

Adenosine kinase (ADK) deficiency (MONDO:0100255) is an autosomal recessive inborn error of methionine and adenosine metabolism caused by biallelic pathogenic variants in ADK (HGNC:257). It was first delineated in 2011 in two siblings and four additional individuals with developmental delay and liver dysfunction (PMID:21963049). Since then, reports have expanded the cohort to 27 patients worldwide, including three further cases from a multi‐patient series (PMID:33309011) and one Polish patient among 27 reported (PMID:36589157).

Inheritance is autosomal recessive, with segregation demonstrated in multiple families and two affected siblings confirming familial transmission (PMID:21963049). The variant spectrum comprises missense, in‐frame and frameshift alleles; representative examples include c.902C>A (p.Ala301Glu), which abolishes catalytic activity in recombinant enzyme assays (PMID:21963049).

Clinically, ADK deficiency presents in the neonatal period with sepsis‐like episodes, prolonged jaundice (HP:0006579), hypotonia (HP:0001252), dyspnea (HP:0002094), and global developmental delay (HP:0001263). Later features include dysmorphic traits, hepatopathy with cholestatic or transient liver disease, macrocytic anemia, and, in some, tall stature (HP:0000098) or short stature (HP:0004322). Rare phenotypes such as sepsis with neutrophil dysfunction (PMID:38447681) and cerebrovascular tortuosity have also been described.

Biochemically, patients exhibit hypermethioninemia with elevated S-adenosylmethionine and S-adenosylhomocysteine but normal homocysteine. Mitochondrial respiratory chain deficiencies in skeletal muscle and white matter abnormalities on brain MRI further support multisystem involvement (PMID:36589157).

Functional studies demonstrate that missense mutations such as p.Ala301Glu and p.Asp235Ala markedly reduce ADK activity in vitro and in patient cells, leading to profound enzyme deficiency and perturbation of methionine and energy pathways (PMID:21963049; PMID:38447681).

Therapeutically, a methionine‐restricted diet has shown clinical and biochemical improvement in some infants, normalizing liver function and MRI changes (PMID:34485018). Early molecular diagnosis facilitates prompt dietary management and informs prognosis.

References

• American Journal of Human Genetics | 2011 | Adenosine kinase deficiency disrupts the methionine cycle and causes hypermethioninemia, encephalopathy, and abnormal liver function. PMID:21963049
• Molecular Genetics and Metabolism | 2021 | Adenosine kinase deficiency: Three new cases and diagnostic value of hypermethioninemia. PMID:33309011
• Frontiers in Pediatrics | 2022 | Case Report: Adenosine kinase deficiency diagnosed 10 years after liver transplantation: Novel phenotypic insights. PMID:36589157
• Gene | 2024 | Novel homozygous ADK out-of-frame deletion causes adenosine kinase deficiency with rare phenotypes of sepsis, metabolites disruption and neutrophil dysfunction. PMID:38447681
• JIMD Reports | 2021 | Clinical utility of methionine restriction in adenosine kinase deficiency. PMID:34485018
• Neuropediatrics | 2019 | Adenosine Kinase Deficiency: Report and Review. PMID:30477030

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