Dataset Information

Adenosine kinase deficiency presenting with tortuous cervical arteries: A risk factor for recurrent stroke.

ABSTRACT: Adenosine kinase (ADK) deficiency is a very rare inborn error of methionine and adenosine metabolism. It is characterized by developmental delay, hypotonia, epilepsy, facial dysmorphism, failure to thrive, transient liver dysfunction with cholestasis, recurrent hypoglycemia, and cardiac defects. Only 26 cases (16 families) of ADK deficiency have been published since its identification in 2011. Vascular abnormalities in cervical arteries and cerebral stroke have never been reported in this condition. Here, we describe two patients with ADK deficiency and vascular tortuosity leading to stroke in one of them. ADK deficiency is a rare inborn error of methionine metabolism with a complex phenotype that might be associated with cerebrovascular abnormalities and stroke.

SUBMITTER: Paz JA

PROVIDER: S-EPMC8574177 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Adenosine kinase deficiency presenting with tortuous cervical arteries: A risk factor for recurrent stroke.

Paz José A JA Embiruçu Emilia K EK Bueno Clarissa C Ferreira Rafaela C C L RCCL Oliveira Fernanda S FS Pereira Ane S S ASS Schwartz Ida V D IVD Paiva Anderson R B ARB Lucato Leandro T LT Kok Fernando F

JIMD reports 20210930 1

Adenosine kinase (ADK) deficiency is a very rare inborn error of methionine and adenosine metabolism. It is characterized by developmental delay, hypotonia, epilepsy, facial dysmorphism, failure to thrive, transient liver dysfunction with cholestasis, recurrent hypoglycemia, and cardiac defects. Only 26 cases (16 families) of ADK deficiency have been published since its identification in 2011. Vascular abnormalities in cervical arteries and cerebral stroke have never been reported in this condit ...[more]

PMID: 34765398

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Project description:Adenosine kinase (ADK) deficiency in human patients (OMIM:614300) disrupts the methionine cycle and triggers hypermethioninemia, hepatic encephalopathy, cognitive impairment, and seizures. To identify whether this neurological phenotype is intrinsically based on ADK deficiency in the brain or if it is secondary to liver dysfunction, we generated a mouse model with a brain-wide deletion of ADK by introducing a Nestin-Cre transgene into a line of conditional ADK deficient Adkfl/fl mice. These AdkΔbrain mice developed a progressive stress-induced seizure phenotype associated with spontaneous convulsive seizures and profound deficits in hippocampus-dependent learning and memory. Pharmacological, biochemical, and electrophysiological studies suggest enhanced adenosine levels around synapses resulting in an enhanced adenosine A1 receptor (A1R)-dependent protective tone despite lower expression levels of the receptor. Theta-burst-induced LTP was enhanced in the mutants and this was dependent on adenosine A2A receptor (A2AR) and tropomyosin-related kinase B signaling, suggesting increased activation of these receptors in synaptic plasticity phenomena. Accordingly, reducing adenosine A2A receptor activity in AdkΔbrain mice restored normal associative learning and contextual memory and attenuated seizure risk. We conclude that ADK deficiency in the brain triggers neuronal adaptation processes that lead to dysregulated synaptic plasticity, cognitive deficits, and increased seizure risk. Therefore, ADK mutations have an intrinsic effect on brain physiology and may present a genetic risk factor for the development of seizures and learning impairments. Furthermore, our data show that blocking A2AR activity therapeutically can attenuate neurological symptoms in ADK deficiency.Significance statementA novel human genetic condition (OMIM #614300) that is based on mutations in the adenosine kinase (Adk) gene has been discovered recently. Affected patients develop hepatic encephalopathy, seizures, and severe cognitive impairment. To model and understand the neurological phenotype of the human mutation, we generated a new conditional knock-out mouse with a brain-specific deletion of Adk (AdkΔbrain). Similar to ADK-deficient patients, AdkΔbrain mice develop seizures and cognitive deficits. We identified increased basal synaptic transmission and enhanced adenosine A2A receptor (A2AR)-dependent synaptic plasticity as the underlying mechanisms that govern these phenotypes. Our data show that neurological phenotypes in ADK-deficient patients are intrinsic to ADK deficiency in the brain and that blocking A2AR activity therapeutically can attenuate neurological symptoms in ADK deficiency.

Dataset Information

Adenosine kinase deficiency presenting with tortuous cervical arteries: A risk factor for recurrent stroke.

Publications

Adenosine kinase deficiency presenting with tortuous cervical arteries: A risk factor for recurrent stroke.

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