Adenosine Kinase Deficiency

Mendelian MONDO:0100255 Pathograph 27 Inborn error of purine metabolism Inborn error of metabolism

Adenosine kinase deficiency is a rare autosomal recessive inborn error of purine and methionine metabolism caused by loss of ADK function. The disorder disrupts adenosine salvage, lowers AMP production, perturbs the methionine cycle, and produces a combined hepatic, neurologic, and cerebrovascular phenotype.

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1
Inheritance
7
Pathophys.
14
Phenotypes
27
Pathograph
1
Genes
2
Treatments
2
Differentials
1
Deep Research
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
autosomal recessive inheritance
⚙

Pathophysiology

7
ADK Loss of Function
Biallelic loss of ADK activity reduces phosphorylation of adenosine to AMP, impairing adenosine salvage and disturbing intracellular adenine nucleotide balance.
hepatocyte link astrocyte link neuron link
ADK link
adenosine metabolic process link ↓ DECREASED AMP biosynthetic process link ↓ DECREASED methionine metabolic process link ⚠ ABNORMAL methionine cycle link ⚠ ABNORMAL
adenosine kinase activity link
liver link
Downstream
Adenosine Accumulation and AMP Depletion Loss of ADK activity shifts adenosine away from AMP generation and raises intracellular and extracellular adenosine.
Cerebrovascular Abnormalities ADK deficiency has been reported with cervical arterial tortuosity and stroke, but the intervening vascular mechanism is unresolved.
Mitochondrial Respiratory Chain Abnormality ADK-deficient patients can show combined respiratory-chain complex defects in liver or skeletal muscle, producing a mitochondrial-disease-like energy-stress branch downstream of the primary purine and methionine metabolic defect.
Facial dysmorphism Dysmorphic facial features are part of the recurrent syndromic phenotype, although the developmental intermediates connecting ADK loss to craniofacial findings are not established.
Cardiac defects Cardiac abnormalities have been reported in ADK deficiency, but the path from the metabolic defect to cardiac development or function remains unresolved.
Short stature Short stature has been documented on long-term follow-up after liver transplantation in ADK deficiency, with unresolved causal intermediates.
Cortisol deficiency Cortisol deficiency has been reported in long-term follow-up, but the connection between ADK loss and adrenal steroid physiology is unresolved.
Show evidence (1 reference)
PMID:33309011 SUPPORT Human Clinical
"Adenosine kinase (ADK) deficiency is characterized by liver disease, dysmorphic features, epilepsy and developmental delay. This defect disrupts the adenosine/AMP futile cycle and interferes with the upstream methionine cycle."
The abstract directly identifies the core biochemical lesion and the major organ systems affected by ADK loss of function.
Adenosine Accumulation and AMP Depletion
Excess adenosine and reduced AMP availability alter purine homeostasis, disturb adenosine receptor signaling, and contribute to downstream neuronal and hepatic stress.
astrocyte link neuron link
adenosine metabolic process link ↑ INCREASED
Downstream
Transmethylation Cycle Disruption and Hypermethioninemia Adenosine accumulation drives the S-adenosylhomocysteine hydrolase reaction backward and impairs methylation flux.
Neurodevelopmental Impairment and Seizures Elevated brain adenosine alters adenosine receptor signaling and synaptic plasticity, contributing to cognitive impairment and seizure risk.
Show evidence (1 reference)
PMID:27903722 SUPPORT Model Organism
"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."
The model shows elevated synaptic adenosine after ADK deficiency.
Transmethylation Cycle Disruption and Hypermethioninemia
Accumulation of adenosine and S-adenosylhomocysteine perturbs one-carbon metabolism, producing elevated methionine, elevated AdoMet/AdoHcy, and a biochemical pattern that is diagnostically useful.
hepatocyte link
methionine metabolic process link ↑ INCREASED methionine cycle link ↑ INCREASED
Downstream
Hepatic Dysfunction and Cholestasis The biochemical block is most evident in the liver and can present as neonatal or early infantile liver disease.
Neurodevelopmental Impairment and Seizures Methionine cycle disruption and excess adenosine also affect the central nervous system.
Hypermethioninemia Disrupted methionine-cycle flux produces the characteristic elevated plasma methionine phenotype.
Elevated S-adenosyl-L-homocysteine Disturbed transmethylation produces elevated S-adenosylhomocysteine, a diagnostically useful one-carbon metabolite abnormality.
Macrocytic anemia Macrocytic anemia has been documented with the ADK transmethylation phenotype, including persistence after liver transplantation, but the causal intermediates remain unresolved.
Show evidence (3 references)
PMID:33309011 SUPPORT Human Clinical
"In addition, we retrospectively analyzed methionine plasma concentration, a hallmark of ADK deficiency, in a cohort of children and showed that methionine level in patients with ADK deficiency was strongly increased compared with patients with other liver diseases."
This directly supports hypermethioninemia as a hallmark biochemical feature.
PMID:36589157 SUPPORT Human Clinical
"Whole exome sequencing revealed the patient to be affected with two novel ADK variants, which pathogenicity was confirmed biochemically by demonstration of elevated concentration of S-adenosylhomocysteine."
Confirms the AdoHcy elevation that accompanies the disturbed transmethylation state.
PMID:30477030 SUPPORT Human Clinical
"Biochemically, methionine is elevated with normal homocysteine levels and the diagnosis is confirmed through molecular analysis of the ADK gene."
Establishes the expected biochemical profile of ADK deficiency.
Mitochondrial Respiratory Chain Abnormality
ADK deficiency can secondarily reduce mitochondrial respiratory-chain activity in liver or skeletal muscle, with reported combined liver complex defects and reduced complex II/III activity in skeletal muscle.
hepatocyte link skeletal muscle cell link
respiratory electron transport chain link ↓ DECREASED oxidative phosphorylation link ↓ DECREASED
Downstream
Hepatic Dysfunction and Cholestasis Respiratory-chain defects in liver tissue are part of the mitochondrial-disease-like presentation accompanying ADK-related neonatal liver disease.
Show evidence (2 references)
PMID:33309011 SUPPORT Human Clinical
"As the phenotype was consistent with a mitochondrial disorder, we studied liver mitochondrial respiratory chain activities in two patients and revealed a combined defect of several complexes."
Human liver tissue testing showed combined mitochondrial respiratory-chain defects in ADK deficiency.
PMID:36589157 SUPPORT Human Clinical
"A decrease of mitochondrial respiratory chain complex II and III activity were found in the postnuclear supernatants obtained from skeletal muscle biopsy."
A later human case supports reduced respiratory-chain complex activity in skeletal muscle.
Hepatic Dysfunction and Cholestasis
Patients may present with neonatal jaundice, cholestasis, transaminase elevation, transient liver dysfunction, or even liver failure.
hepatocyte link
liver link
Downstream
Cholestasis Hepatic involvement in ADK deficiency commonly presents as transient liver dysfunction with cholestasis.
Hypoglycemia Recurrent hypoglycemia occurs as part of the liver-centered metabolic phenotype in ADK deficiency.
Failure to Thrive Failure to thrive is reported in the same infantile multisystem metabolic presentation as hepatic dysfunction and recurrent hypoglycemia.
Show evidence (3 references)
PMID:34765398 SUPPORT Human Clinical
"It is characterized by developmental delay, hypotonia, epilepsy, facial dysmorphism, failure to thrive, transient liver dysfunction with cholestasis, recurrent hypoglycemia, and cardiac defects."
Supports the hepatic phenotype and the variability of organ involvement in ADK deficiency.
PMID:33309011 SUPPORT Human Clinical
"Adenosine kinase (ADK) deficiency is characterized by liver disease, dysmorphic features, epilepsy and developmental delay."
The abstract identifies liver disease as a defining clinical feature.
PMID:36589157 SUPPORT Human Clinical
"Six-month-old patient presented with cholestatic liver disease, macrocytic anemia, developmental delay, generalized hypotonia, delayed brain myelination, and elevated levels of serum methionine."
Demonstrates cholestatic liver disease in a long-followed patient.
Neurodevelopmental Impairment and Seizures
ADK deficiency causes hypotonia, global developmental delay, epilepsy, and cognitive impairment; brain-specific deficiency can directly drive seizure susceptibility and learning deficits, and neurologic disease may persist despite liver transplantation.
neuron link astrocyte link
chemical synaptic transmission link ⚠ ABNORMAL
Downstream
Global Developmental Delay Neurodevelopmental impairment manifests clinically as global developmental delay.
Hypotonia The neurologic disease includes generalized hypotonia.
Seizure Brain ADK deficiency increases seizure susceptibility and epilepsy risk.
Delayed brain myelination Delayed myelination is a reported neuroimaging manifestation in affected patients.
Show evidence (3 references)
PMID:27903722 SUPPORT Model Organism
"We conclude that ADK deficiency in the brain triggers neuronal adaptation processes that lead to dysregulated synaptic plasticity, cognitive deficits, and increased seizure risk."
Directly links brain ADK deficiency to the neurologic phenotype.
PMID:34765398 SUPPORT Human Clinical
"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."
Summarizes the recurring human neurologic phenotype.
PMID:30477030 SUPPORT Human Clinical
"Subsequently, patients demonstrate hypotonia and global developmental delay."
Confirms the common developmental and tone abnormalities.
Cerebrovascular Abnormalities
Vascular tortuosity of the cervical arteries and recurrent stroke have been reported as additional complications of ADK deficiency.
blood vessel endothelial cell link
Downstream
Stroke Cervical artery tortuosity and related cerebrovascular abnormalities can lead to stroke in a subset of patients.
Show evidence (2 references)
PMID:34765398 SUPPORT Human Clinical
"Here, we describe two patients with ADK deficiency and vascular tortuosity leading to stroke in one of them."
Directly documents the cerebrovascular complication.
PMID:34765398 SUPPORT Human Clinical
"ADK deficiency is a rare inborn error of methionine metabolism with a complex phenotype that might be associated with cerebrovascular abnormalities and stroke."
Supports vascular involvement as part of the broader phenotype.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Adenosine Kinase Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

14
Blood 1
Macrocytic anemia OCCASIONAL Macrocytic anemia (HP:0001972)
Show evidence (1 reference)
PMID:36589157 SUPPORT Human Clinical
"Six-month-old patient presented with cholestatic liver disease, macrocytic anemia, developmental delay, generalized hypotonia, delayed brain myelination, and elevated levels of serum methionine."
Directly supports macrocytic anemia in a well-described human case.
Cardiovascular 2
Cardiac defects OCCASIONAL Abnormality of the cardiovascular system (HP:0001626)
Show evidence (1 reference)
PMID:34765398 SUPPORT Human Clinical
"It is characterized by developmental delay, hypotonia, epilepsy, facial dysmorphism, failure to thrive, transient liver dysfunction with cholestasis, recurrent hypoglycemia, and cardiac defects."
Directly supports cardiac defects as part of the ADK deficiency phenotype.
Stroke Stroke (HP:0001297)
Show evidence (1 reference)
PMID:34765398 SUPPORT Human Clinical
"vascular tortuosity leading to stroke in one of them."
The case report documents stroke in a patient with ADK deficiency and vascular tortuosity.
Digestive 1
Cholestasis FREQUENT Cholestasis (HP:0001396)
Show evidence (1 reference)
PMID:34765398 SUPPORT Human Clinical
"transient liver dysfunction with cholestasis"
Confirms cholestasis as part of the reported phenotype.
Endocrine 1
Cortisol deficiency OCCASIONAL Adrenal insufficiency (HP:0000846)
Show evidence (1 reference)
PMID:36589157 SUPPORT Human Clinical
"Ten-year follow-up after LTx revealed a preserved good liver function, persistent regenerative macrocytic anemia, progressive neurological disease but disappearance of brain MR changes, short stature, and cortisol deficiency."
The long-term follow-up case directly documents cortisol deficiency, mapped to the adrenal insufficiency HPO term.
Metabolism 1
Hypoglycemia FREQUENT Hypoglycemia (HP:0001943)
Show evidence (1 reference)
PMID:34765398 SUPPORT Human Clinical
"It is characterized by developmental delay, hypotonia, epilepsy, facial dysmorphism, failure to thrive, transient liver dysfunction with cholestasis, recurrent hypoglycemia, and cardiac defects."
Directly supports hypoglycemia as part of the reported clinical spectrum.
Musculoskeletal 1
Hypotonia VERY_FREQUENT Generalized hypotonia (HP:0001290)
Show evidence (2 references)
PMID:34765398 SUPPORT Human Clinical
"It is characterized by developmental delay, hypotonia, epilepsy, facial dysmorphism, failure to thrive, transient liver dysfunction with cholestasis, recurrent hypoglycemia, and cardiac defects."
Confirms generalized hypotonia as a common presenting feature.
PMID:36589157 SUPPORT Human Clinical
"generalized hypotonia"
The follow-up case report explicitly lists generalized hypotonia.
Nervous System 3
Global Developmental Delay VERY_FREQUENT Global developmental delay (HP:0001263)
Show evidence (2 references)
PMID:33309011 SUPPORT Human Clinical
"Adenosine kinase (ADK) deficiency is characterized by liver disease, dysmorphic features, epilepsy and developmental delay."
Supports developmental delay as a core phenotype.
PMID:30477030 SUPPORT Human Clinical
"Subsequently, patients demonstrate hypotonia and global developmental delay."
Confirms global developmental delay in the clinical description.
Seizure FREQUENT Seizure (HP:0001250)
Show evidence (2 references)
PMID:27903722 SUPPORT Model Organism
"Similar to ADK-deficient patients, AdkΔbrain mice develop seizures and cognitive deficits."
Demonstrates a direct mechanistic link between ADK deficiency and seizure susceptibility.
PMID:34765398 SUPPORT Human Clinical
"epilepsy"
Confirms seizure/epilepsy as a recurring clinical feature.
Delayed brain myelination OCCASIONAL Delayed myelination (HP:0012448)
Show evidence (1 reference)
PMID:36589157 SUPPORT Human Clinical
"Six-month-old patient presented with cholestatic liver disease, macrocytic anemia, developmental delay, generalized hypotonia, delayed brain myelination, and elevated levels of serum methionine."
Directly supports delayed brain myelination in a human case with ADK deficiency.
Growth 2
Failure to Thrive FREQUENT Failure to thrive (HP:0001508)
Show evidence (1 reference)
PMID:34765398 SUPPORT Human Clinical
"failure to thrive"
Confirms failure to thrive as part of the clinical spectrum.
Short stature OCCASIONAL Short stature (HP:0004322)
Show evidence (1 reference)
PMID:36589157 SUPPORT Human Clinical
"Ten-year follow-up after LTx revealed a preserved good liver function, persistent regenerative macrocytic anemia, progressive neurological disease but disappearance of brain MR changes, short stature, and cortisol deficiency."
The long-term follow-up case directly documents short stature in ADK deficiency.
Other 2
Hypermethioninemia VERY_FREQUENT Hypermethioninemia (HP:0003235)
Show evidence (2 references)
PMID:33309011 SUPPORT Human Clinical
"methionine level in patients with ADK deficiency was strongly increased compared with patients with other liver diseases."
Demonstrates the strong diagnostic signal of hypermethioninemia.
PMID:30477030 SUPPORT Human Clinical
"Biochemically, methionine is elevated with normal homocysteine levels and the diagnosis is confirmed through molecular analysis of the ADK gene."
Confirms the biochemical phenotype.
Facial dysmorphism FREQUENT Abnormality of the face (HP:0000271)
Show evidence (1 reference)
PMID:34765398 SUPPORT Human Clinical
"It is characterized by developmental delay, hypotonia, epilepsy, facial dysmorphism, failure to thrive, transient liver dysfunction with cholestasis, recurrent hypoglycemia, and cardiac defects."
Directly supports facial dysmorphism as part of the core clinical presentation.
🧬

Genetic Associations

1
ADK (Pathogenic Variants)
Show evidence (1 reference)
CGGV:assertion_c2319ca2-652d-411e-ab6d-5b7fb7e185ea-2021-04-08T160000.000Z SUPPORT Other
"ADK | HGNC:257 | adenosine kinase deficiency | MONDO:0100255 | AR | Definitive"
ClinGen classifies the ADK-adenosine kinase deficiency gene-disease relationship as definitive with autosomal recessive inheritance.
💊

Treatments

2
Methionine-Restricted Diet
Action: dietary methionine intake avoidance MAXO:0010092
Dietary methionine intake restriction has been tried, but outcomes are variable and it is not curative.
Mechanism Target:
MODULATES Transmethylation Cycle Disruption and Hypermethioninemia — Methionine restriction is intended to reduce the hypermethioninemia component of the disturbed methionine cycle, though outcomes are variable.
Show evidence (1 reference)
PMID:30477030 SUPPORT Human Clinical
"There is no curative treatment; however, a methionine-restricted diet has been tried with variable outcomes."
The clinical review supports methionine restriction as a management approach but notes variable outcomes, so the target effect is modeled as modulation rather than correction.
Show evidence (1 reference)
PMID:30477030 SUPPORT Human Clinical
"There is no curative treatment; however, a methionine-restricted diet has been tried with variable outcomes."
Directly supports methionine restriction as a tried management strategy.
Liver transplantation
Action: organ transplantation MAXO:0010039
Liver transplantation can correct the hepatic component, although neurologic disease may continue to progress.
Mechanism Target:
INHIBITS Hepatic Dysfunction and Cholestasis — Liver transplantation can correct the hepatic dysfunction component while neurologic disease may persist.
Show evidence (1 reference)
PMID:36589157 SUPPORT Human Clinical
"Ten-year follow-up after LTx revealed a preserved good liver function, persistent regenerative macrocytic anemia, progressive neurological disease but disappearance of brain MR changes, short stature, and cortisol deficiency."
Long-term follow-up supports improvement of liver function after transplantation while distinguishing persistent non-hepatic disease.
Show evidence (1 reference)
PMID:36589157 SUPPORT Human Clinical
"The patient underwent living-donor liver transplantation (LTx) at 14 months of age. Ten-year follow-up after LTx revealed a preserved good liver function, persistent regenerative macrocytic anemia, progressive neurological disease but disappearance of brain MR changes, short stature, and..."
Supports liver transplantation as a major intervention that improves liver disease while not fully correcting the neurologic phenotype.
🔬

Biochemical Markers

3
Elevated plasma methionine (INCREASED)
Context: Plasma methionine is a high-signal diagnostic biochemical readout of ADK deficiency and distinguishes it from nonspecific liver disease.
Pathograph Readouts
Readout Of Transmethylation Cycle Disruption and Hypermethioninemia Positive Diagnostic
Higher plasma methionine reflects the ADK-related methionine-cycle disturbance.
Show evidence (1 reference)
PMID:33309011 SUPPORT Human Clinical
"methionine level in patients with ADK deficiency was strongly increased compared with patients with other liver diseases."
The cohort shows methionine elevation as a diagnostic readout of ADK deficiency.
Show evidence (2 references)
PMID:33309011 SUPPORT Human Clinical
"methionine level in patients with ADK deficiency was strongly increased compared with patients with other liver diseases."
The clinical cohort supports elevated plasma methionine as a recurring ADK deficiency biomarker.
PMID:30477030 SUPPORT Human Clinical
"Biochemically, methionine is elevated with normal homocysteine levels and the diagnosis is confirmed through molecular analysis of the ADK gene."
The review confirms the characteristic elevated-methionine profile.
Elevated S-adenosyl-L-homocysteine (INCREASED)
Context: S-adenosylhomocysteine elevation provides a more specific transmethylation-cycle readout alongside hypermethioninemia.
Pathograph Readouts
Readout Of Transmethylation Cycle Disruption and Hypermethioninemia Positive Diagnostic
Elevated S-adenosylhomocysteine reflects disruption of the adenosine-sensitive transmethylation cycle.
Show evidence (1 reference)
PMID:36589157 SUPPORT Human Clinical
"elevated concentration of S-adenosylhomocysteine."
The report uses elevated S-adenosylhomocysteine as biochemical confirmation of pathogenic ADK variants.
Show evidence (1 reference)
PMID:36589157 SUPPORT Human Clinical
"elevated concentration of S-adenosylhomocysteine."
The case report directly supports elevated S-adenosylhomocysteine in ADK deficiency.
Normal plasma homocysteine (NORMAL)
Context: Normal homocysteine paired with elevated methionine helps define the ADK biochemical pattern and distinguishes it from hyperhomocysteinemic methionine-cycle disorders.
Pathograph Readouts
Readout Of Transmethylation Cycle Disruption and Hypermethioninemia Present Absent Diagnostic
Normal homocysteine is part of the diagnostic biochemical signature when interpreted together with elevated methionine.
Show evidence (1 reference)
PMID:30477030 SUPPORT Human Clinical
"Biochemically, methionine is elevated with normal homocysteine levels and the diagnosis is confirmed through molecular analysis of the ADK gene."
The review explicitly states the elevated-methionine, normal- homocysteine biochemical pattern.
Show evidence (1 reference)
PMID:30477030 SUPPORT Human Clinical
"Biochemically, methionine is elevated with normal homocysteine levels and the diagnosis is confirmed through molecular analysis of the ADK gene."
The review confirms normal homocysteine as part of the ADK deficiency biochemical profile.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Adenosine Kinase Deficiency:

Primary Mitochondrial Disease Not Yet Curated MONDO:0044970
Overlapping Features ADK deficiency can mimic a primary mitochondrial disorder because it may present with neonatal liver disease, hypotonia, developmental delay, and respiratory-chain abnormalities on tissue testing.
Distinguishing Features
  • Elevated plasma methionine and elevated S-adenosylhomocysteine favor ADK deficiency.
  • ADK sequencing identifies biallelic pathogenic variants in ADK.
  • Mitochondrial disease may show broader respiratory chain defects without the ADK biochemical signature.
Show evidence (1 reference)
PMID:33309011 SUPPORT Human Clinical
"ADK deficiency is a cause of neonatal or early infantile liver disease that may mimic primary mitochondrial disorders."
Directly identifies mitochondrial disease as an important mimic.
Other Hypermethioninemic Disorders
Overlapping Features The differential diagnosis of elevated methionine includes CBS deficiency, MAT1A deficiency, GNMT deficiency, AHCY deficiency, citrin deficiency, and FAH deficiency/tyrosinemia type I.
Distinguishing Features
  • CBS deficiency usually produces homocystinuria with elevated homocysteine.
  • MAT1A, GNMT, and AHCY deficiencies are alternative methionine-cycle disorders with overlapping hypermethioninemia.
  • Citrin deficiency and tyrosinemia type I can also present with hypermethioninemia, but the broader metabolic context differs.
  • ADK deficiency is distinguished by the combination of hypermethioninemia with elevated S-adenosylhomocysteine and ADK variants.
Show evidence (1 reference)
PMID:21308989 SUPPORT Human Clinical
"This review covers briefly the major conditions, genetic and non-genetic, sometimes leading to abnormally elevated methionine, with emphasis on recent developments. A major aim is to assist in the differential diagnosis of hypermethioninemia."
The review explicitly frames these disorders as the differential for hypermethioninemia.
{ }

Source YAML

click to show 
name: Adenosine Kinase Deficiency
creation_date: "2026-04-16T00:00:00Z"
updated_date: "2026-05-21T00:27:23Z"
category: Mendelian
description: >-
  Adenosine kinase deficiency is a rare autosomal recessive inborn error of
  purine and methionine metabolism caused by loss of ADK function. The disorder
  disrupts adenosine salvage, lowers AMP production, perturbs the methionine
  cycle, and produces a combined hepatic, neurologic, and cerebrovascular
  phenotype.
disease_term:
  preferred_term: adenosine kinase deficiency
  term:
    id: MONDO:0100255
    label: adenosine kinase deficiency
parents:
- Inborn error of purine metabolism
- Inborn error of metabolism
synonyms:
- hypermethioninemia due to adenosine kinase deficiency
- ADK deficiency
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
pathophysiology:
- name: ADK Loss of Function
  description: >-
    Biallelic loss of ADK activity reduces phosphorylation of adenosine to
    AMP, impairing adenosine salvage and disturbing intracellular adenine
    nucleotide balance.
  genes:
  - preferred_term: ADK
    term:
      id: hgnc:257
      label: ADK
  molecular_functions:
  - preferred_term: adenosine kinase activity
    term:
      id: GO:0004001
      label: adenosine kinase activity
  biological_processes:
  - preferred_term: adenosine metabolic process
    term:
      id: GO:0046085
      label: adenosine metabolic process
    modifier: DECREASED
  - preferred_term: AMP biosynthetic process
    term:
      id: GO:0006167
      label: AMP biosynthetic process
    modifier: DECREASED
  - preferred_term: methionine metabolic process
    term:
      id: GO:0006555
      label: L-methionine metabolic process
    modifier: ABNORMAL
  - preferred_term: methionine cycle
    term:
      id: GO:0033353
      label: L-methionine cycle
    modifier: ABNORMAL
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  chemical_entities:
  - preferred_term: adenosine
    term:
      id: CHEBI:16335
      label: adenosine
    modifier: INCREASED
  - preferred_term: adenosine 5'-monophosphate
    term:
      id: CHEBI:16027
      label: adenosine 5'-monophosphate
    modifier: DECREASED
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: PMID:33309011
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Adenosine kinase (ADK) deficiency is characterized by liver disease,
      dysmorphic features, epilepsy and developmental delay. This defect
      disrupts the adenosine/AMP futile cycle and interferes with the
      upstream methionine cycle.
    explanation: >-
      The abstract directly identifies the core biochemical lesion and the
      major organ systems affected by ADK loss of function.
  downstream:
  - target: Adenosine Accumulation and AMP Depletion
    description: >-
      Loss of ADK activity shifts adenosine away from AMP generation and
      raises intracellular and extracellular adenosine.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33309011
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This defect disrupts the adenosine/AMP futile cycle and interferes
        with the upstream methionine cycle.
      explanation: >-
        The human case-series abstract directly links ADK deficiency to
        disruption of the adenosine/AMP cycle.
  - target: Cerebrovascular Abnormalities
    description: >-
      ADK deficiency has been reported with cervical arterial tortuosity and
      stroke, but the intervening vascular mechanism is unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34765398
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        cerebrovascular abnormalities and stroke.
      explanation: >-
        The case report explicitly associates ADK deficiency with
        cerebrovascular abnormalities and stroke, supporting a connected
        vascular branch while leaving the intermediates unspecified.
  - target: Mitochondrial Respiratory Chain Abnormality
    description: >-
      ADK-deficient patients can show combined respiratory-chain complex
      defects in liver or skeletal muscle, producing a mitochondrial-disease-like
      energy-stress branch downstream of the primary purine and methionine
      metabolic defect.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33309011
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        As the phenotype was consistent with a mitochondrial disorder, we
        studied liver mitochondrial respiratory chain activities in two
        patients and revealed a combined defect of several complexes.
      explanation: >-
        The patient series reports combined liver respiratory-chain defects in
        ADK deficiency, supporting a mitochondrial branch while not resolving
        the intervening molecular steps.
    - reference: PMID:36589157
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A decrease of mitochondrial respiratory chain complex II and III
        activity were found in the postnuclear supernatants obtained from
        skeletal muscle biopsy.
      explanation: >-
        A later human case documents reduced respiratory-chain complex II and
        III activity in skeletal muscle.
  - target: Facial dysmorphism
    description: >-
      Dysmorphic facial features are part of the recurrent syndromic phenotype,
      although the developmental intermediates connecting ADK loss to craniofacial
      findings are not established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33309011
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Adenosine kinase (ADK) deficiency is characterized by liver disease,
        dysmorphic features, epilepsy and developmental delay.
      explanation: >-
        The clinical series identifies dysmorphic features as part of the ADK
        deficiency phenotype.
  - target: Cardiac defects
    description: >-
      Cardiac abnormalities have been reported in ADK deficiency, but the
      path from the metabolic defect to cardiac development or function remains
      unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34765398
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        It is characterized by developmental delay, hypotonia, epilepsy,
        facial dysmorphism, failure to thrive, transient liver dysfunction
        with cholestasis, recurrent hypoglycemia, and cardiac defects.
      explanation: >-
        The human clinical summary lists cardiac defects among the reported
        ADK deficiency manifestations.
  - target: Short stature
    description: >-
      Short stature has been documented on long-term follow-up after liver
      transplantation in ADK deficiency, with unresolved causal intermediates.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36589157
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Ten-year follow-up after LTx revealed a preserved good liver function,
        persistent regenerative macrocytic anemia, progressive neurological
        disease but disappearance of brain MR changes, short stature, and
        cortisol deficiency.
      explanation: >-
        Long-term human follow-up documents short stature in an ADK-deficient
        patient after liver transplantation.
  - target: Cortisol deficiency
    description: >-
      Cortisol deficiency has been reported in long-term follow-up, but the
      connection between ADK loss and adrenal steroid physiology is unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36589157
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Ten-year follow-up after LTx revealed a preserved good liver function,
        persistent regenerative macrocytic anemia, progressive neurological
        disease but disappearance of brain MR changes, short stature, and
        cortisol deficiency.
      explanation: >-
        Long-term human follow-up documents cortisol deficiency in an
        ADK-deficient patient.
- name: Adenosine Accumulation and AMP Depletion
  description: >-
    Excess adenosine and reduced AMP availability alter purine homeostasis,
    disturb adenosine receptor signaling, and contribute to downstream
    neuronal and hepatic stress.
  cell_types:
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: adenosine metabolic process
    term:
      id: GO:0046085
      label: adenosine metabolic process
    modifier: INCREASED
  chemical_entities:
  - preferred_term: adenosine
    term:
      id: CHEBI:16335
      label: adenosine
    modifier: INCREASED
  - preferred_term: adenosine 5'-monophosphate
    term:
      id: CHEBI:16027
      label: adenosine 5'-monophosphate
    modifier: DECREASED
  evidence:
  - reference: PMID:27903722
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      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.
    explanation: >-
      The model shows elevated synaptic adenosine after ADK deficiency.
  downstream:
  - target: Transmethylation Cycle Disruption and Hypermethioninemia
    description: >-
      Adenosine accumulation drives the S-adenosylhomocysteine hydrolase
      reaction backward and impairs methylation flux.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33309011
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This defect disrupts the adenosine/AMP futile cycle and interferes
        with the upstream methionine cycle.
      explanation: >-
        The same clinical report connects disrupted adenosine/AMP cycling to
        upstream methionine-cycle interference.
  - target: Neurodevelopmental Impairment and Seizures
    description: >-
      Elevated brain adenosine alters adenosine receptor signaling and synaptic
      plasticity, contributing to cognitive impairment and seizure risk.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - adenosine receptor signaling
    - dysregulated synaptic plasticity
    evidence:
    - reference: PMID:27903722
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        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.
      explanation: >-
        Brain-specific ADK deficiency raises synaptic adenosine, and the same
        model links altered adenosine receptor signaling to neurologic
        phenotypes.
    - reference: PMID:27903722
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We conclude that ADK deficiency in the brain triggers neuronal
        adaptation processes that lead to dysregulated synaptic plasticity,
        cognitive deficits, and increased seizure risk.
      explanation: >-
        The same mouse model links brain ADK deficiency and downstream synaptic
        adaptation to cognitive deficits and seizure risk.
- name: Transmethylation Cycle Disruption and Hypermethioninemia
  description: >-
    Accumulation of adenosine and S-adenosylhomocysteine perturbs one-carbon
    metabolism, producing elevated methionine, elevated AdoMet/AdoHcy, and a
    biochemical pattern that is diagnostically useful.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: methionine metabolic process
    term:
      id: GO:0006555
      label: L-methionine metabolic process
    modifier: INCREASED
  - preferred_term: methionine cycle
    term:
      id: GO:0033353
      label: L-methionine cycle
    modifier: INCREASED
  chemical_entities:
  - preferred_term: L-methionine
    term:
      id: CHEBI:16643
      label: L-methionine
    modifier: INCREASED
  - preferred_term: S-adenosyl-L-homocysteine
    term:
      id: CHEBI:16680
      label: S-adenosyl-L-homocysteine
    modifier: INCREASED
  evidence:
  - reference: PMID:33309011
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, we retrospectively analyzed methionine plasma
      concentration, a hallmark of ADK deficiency, in a cohort of children
      and showed that methionine level in patients with ADK deficiency was
      strongly increased compared with patients with other liver diseases.
    explanation: >-
      This directly supports hypermethioninemia as a hallmark biochemical
      feature.
  - reference: PMID:36589157
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole exome sequencing revealed the patient to be affected with two
      novel ADK variants, which pathogenicity was confirmed biochemically
      by demonstration of elevated concentration of S-adenosylhomocysteine.
    explanation: >-
      Confirms the AdoHcy elevation that accompanies the disturbed
      transmethylation state.
  - reference: PMID:30477030
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biochemically, methionine is elevated with normal homocysteine levels
      and the diagnosis is confirmed through molecular analysis of the ADK
      gene.
    explanation: >-
      Establishes the expected biochemical profile of ADK deficiency.
  downstream:
  - target: Hepatic Dysfunction and Cholestasis
    description: >-
      The biochemical block is most evident in the liver and can present as
      neonatal or early infantile liver disease.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33309011
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        ADK deficiency is a cause of neonatal or early infantile liver disease
        that may mimic primary mitochondrial disorders.
      explanation: >-
        The clinical series directly supports ADK-related metabolic disruption
        as a cause of early liver disease.
  - target: Neurodevelopmental Impairment and Seizures
    description: >-
      Methionine cycle disruption and excess adenosine also affect the
      central nervous system.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33309011
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Adenosine kinase (ADK) deficiency is characterized by liver disease,
        dysmorphic features, epilepsy and developmental delay. This defect
        disrupts the adenosine/AMP futile cycle and interferes with the
        upstream methionine cycle.
      explanation: >-
        The human case series links ADK metabolic disruption with epilepsy and
        developmental delay, while the exact biochemical-to-neurologic
        intermediates remain incompletely resolved.
  - target: Hypermethioninemia
    description: >-
      Disrupted methionine-cycle flux produces the characteristic elevated
      plasma methionine phenotype.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33309011
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        methionine level in patients with ADK deficiency was strongly
        increased compared with patients with other liver diseases.
      explanation: >-
        The patient cohort directly supports hypermethioninemia downstream of
        ADK-related methionine-cycle disruption.
  - target: Elevated S-adenosyl-L-homocysteine
    description: >-
      Disturbed transmethylation produces elevated S-adenosylhomocysteine, a
      diagnostically useful one-carbon metabolite abnormality.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36589157
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        elevated concentration of S-adenosylhomocysteine.
      explanation: >-
        The case report biochemically confirms elevated S-adenosylhomocysteine
        in ADK deficiency.
  - target: Macrocytic anemia
    description: >-
      Macrocytic anemia has been documented with the ADK transmethylation
      phenotype, including persistence after liver transplantation, but the
      causal intermediates remain unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36589157
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Six-month-old patient presented with cholestatic liver disease,
        macrocytic anemia, developmental delay, generalized hypotonia,
        delayed brain myelination, and elevated levels of serum methionine.
      explanation: >-
        The case report places macrocytic anemia in the same ADK deficiency
        presentation as elevated methionine and cholestatic liver disease.
- name: Mitochondrial Respiratory Chain Abnormality
  description: >-
    ADK deficiency can secondarily reduce mitochondrial respiratory-chain
    activity in liver or skeletal muscle, with reported combined liver complex
    defects and reduced complex II/III activity in skeletal muscle.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  - preferred_term: skeletal muscle cell
    term:
      id: CL:0000188
      label: cell of skeletal muscle
  biological_processes:
  - preferred_term: respiratory electron transport chain
    term:
      id: GO:0022904
      label: respiratory electron transport chain
    modifier: DECREASED
  - preferred_term: oxidative phosphorylation
    term:
      id: GO:0006119
      label: oxidative phosphorylation
    modifier: DECREASED
  evidence:
  - reference: PMID:33309011
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      As the phenotype was consistent with a mitochondrial disorder, we
      studied liver mitochondrial respiratory chain activities in two
      patients and revealed a combined defect of several complexes.
    explanation: >-
      Human liver tissue testing showed combined mitochondrial respiratory-chain
      defects in ADK deficiency.
  - reference: PMID:36589157
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A decrease of mitochondrial respiratory chain complex II and III
      activity were found in the postnuclear supernatants obtained from
      skeletal muscle biopsy.
    explanation: >-
      A later human case supports reduced respiratory-chain complex activity in
      skeletal muscle.
  downstream:
  - target: Hepatic Dysfunction and Cholestasis
    description: >-
      Respiratory-chain defects in liver tissue are part of the
      mitochondrial-disease-like presentation accompanying ADK-related neonatal
      liver disease.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33309011
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We report the clinical, histological and biochemical courses of three
        ADK children carrying two new mutations and presenting with neonatal
        cholestasis and neurological disorders.
      explanation: >-
        The same case series that documents liver respiratory-chain defects
        reports neonatal cholestasis in ADK-deficient children.
- name: Hepatic Dysfunction and Cholestasis
  description: >-
    Patients may present with neonatal jaundice, cholestasis, transaminase
    elevation, transient liver dysfunction, or even liver failure.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: PMID:34765398
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is characterized by developmental delay, hypotonia, epilepsy,
      facial dysmorphism, failure to thrive, transient liver dysfunction
      with cholestasis, recurrent hypoglycemia, and cardiac defects.
    explanation: >-
      Supports the hepatic phenotype and the variability of organ
      involvement in ADK deficiency.
  - reference: PMID:33309011
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Adenosine kinase (ADK) deficiency is characterized by liver disease,
      dysmorphic features, epilepsy and developmental delay.
    explanation: >-
      The abstract identifies liver disease as a defining clinical feature.
  - reference: PMID:36589157
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Six-month-old patient presented with cholestatic liver disease,
      macrocytic anemia, developmental delay, generalized hypotonia,
      delayed brain myelination, and elevated levels of serum methionine.
    explanation: >-
      Demonstrates cholestatic liver disease in a long-followed patient.
  downstream:
  - target: Cholestasis
    description: >-
      Hepatic involvement in ADK deficiency commonly presents as transient
      liver dysfunction with cholestasis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34765398
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        transient liver dysfunction with cholestasis
      explanation: >-
        The clinical summary directly links the hepatic disease component to
        cholestasis.
  - target: Hypoglycemia
    description: >-
      Recurrent hypoglycemia occurs as part of the liver-centered metabolic
      phenotype in ADK deficiency.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34765398
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        It is characterized by developmental delay, hypotonia, epilepsy,
        facial dysmorphism, failure to thrive, transient liver dysfunction
        with cholestasis, recurrent hypoglycemia, and cardiac defects.
      explanation: >-
        The clinical summary reports recurrent hypoglycemia alongside transient
        liver dysfunction with cholestasis in ADK deficiency.
  - target: Failure to Thrive
    description: >-
      Failure to thrive is reported in the same infantile multisystem metabolic
      presentation as hepatic dysfunction and recurrent hypoglycemia.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34765398
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        It is characterized by developmental delay, hypotonia, epilepsy,
        facial dysmorphism, failure to thrive, transient liver dysfunction
        with cholestasis, recurrent hypoglycemia, and cardiac defects.
      explanation: >-
        The human clinical summary includes failure to thrive in the ADK
        deficiency presentation that also includes liver dysfunction and
        hypoglycemia.
- name: Neurodevelopmental Impairment and Seizures
  description: >-
    ADK deficiency causes hypotonia, global developmental delay, epilepsy,
    and cognitive impairment; brain-specific deficiency can directly drive
    seizure susceptibility and learning deficits, and neurologic disease may
    persist despite liver transplantation.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  biological_processes:
  - preferred_term: chemical synaptic transmission
    term:
      id: GO:0007268
      label: chemical synaptic transmission
    modifier: ABNORMAL
  evidence:
  - reference: PMID:27903722
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We conclude that ADK deficiency in the brain triggers neuronal
      adaptation processes that lead to dysregulated synaptic plasticity,
      cognitive deficits, and increased seizure risk.
    explanation: >-
      Directly links brain ADK deficiency to the neurologic phenotype.
  - reference: PMID:34765398
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      Summarizes the recurring human neurologic phenotype.
  - reference: PMID:30477030
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Subsequently, patients demonstrate hypotonia and global developmental
      delay.
    explanation: >-
      Confirms the common developmental and tone abnormalities.
  downstream:
  - target: Global Developmental Delay
    description: >-
      Neurodevelopmental impairment manifests clinically as global
      developmental delay.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30477030
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Subsequently, patients demonstrate hypotonia and global developmental
        delay.
      explanation: >-
        The clinical review directly supports developmental delay as a
        manifestation of ADK deficiency.
  - target: Hypotonia
    description: >-
      The neurologic disease includes generalized hypotonia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34765398
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        It is characterized by developmental delay, hypotonia, epilepsy,
        facial dysmorphism, failure to thrive, transient liver dysfunction
        with cholestasis, recurrent hypoglycemia, and cardiac defects.
      explanation: >-
        The human clinical summary lists hypotonia among the core neurologic
        manifestations.
  - target: Seizure
    description: >-
      Brain ADK deficiency increases seizure susceptibility and epilepsy risk.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27903722
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We conclude that ADK deficiency in the brain triggers neuronal
        adaptation processes that lead to dysregulated synaptic plasticity,
        cognitive deficits, and increased seizure risk.
      explanation: >-
        The brain-specific mouse model directly links ADK deficiency to
        increased seizure risk.
  - target: Delayed brain myelination
    description: >-
      Delayed myelination is a reported neuroimaging manifestation in affected
      patients.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36589157
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Six-month-old patient presented with cholestatic liver disease,
        macrocytic anemia, developmental delay, generalized hypotonia,
        delayed brain myelination, and elevated levels of serum methionine.
      explanation: >-
        The case report directly documents delayed brain myelination as part of
        the neurologic phenotype, though intermediates are not resolved.
- name: Cerebrovascular Abnormalities
  description: >-
    Vascular tortuosity of the cervical arteries and recurrent stroke have
    been reported as additional complications of ADK deficiency.
  cell_types:
  - preferred_term: blood vessel endothelial cell
    term:
      id: CL:0000071
      label: blood vessel endothelial cell
  evidence:
  - reference: PMID:34765398
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we describe two patients with ADK deficiency and vascular
      tortuosity leading to stroke in one of them.
    explanation: >-
      Directly documents the cerebrovascular complication.
  - reference: PMID:34765398
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ADK deficiency is a rare inborn error of methionine metabolism with a
      complex phenotype that might be associated with cerebrovascular
      abnormalities and stroke.
    explanation: >-
      Supports vascular involvement as part of the broader phenotype.
  downstream:
  - target: Stroke
    description: >-
      Cervical artery tortuosity and related cerebrovascular abnormalities can
      lead to stroke in a subset of patients.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - vascular tortuosity
    evidence:
    - reference: PMID:34765398
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Here, we describe two patients with ADK deficiency and vascular
        tortuosity leading to stroke in one of them.
      explanation: >-
        The report explicitly links vascular tortuosity to stroke in ADK
        deficiency.
phenotypes:
- category: Clinical
  name: Hypermethioninemia
  description: >-
    Elevated plasma methionine is a recurring biochemical hallmark and is
    diagnostically useful in ADK deficiency.
  phenotype_term:
    preferred_term: hypermethioninemia
    term:
      id: HP:0003235
      label: Hypermethioninemia
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:33309011
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      methionine level in patients with ADK deficiency was strongly
      increased compared with patients with other liver diseases.
    explanation: >-
      Demonstrates the strong diagnostic signal of hypermethioninemia.
  - reference: PMID:30477030
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biochemically, methionine is elevated with normal homocysteine levels
      and the diagnosis is confirmed through molecular analysis of the ADK
      gene.
    explanation: >-
      Confirms the biochemical phenotype.
- category: Clinical
  name: Cholestasis
  description: >-
    Neonatal or early infantile cholestasis is a common presentation of the
    liver disease component.
  phenotype_term:
    preferred_term: cholestasis
    term:
      id: HP:0001396
      label: Cholestasis
  frequency: FREQUENT
  evidence:
  - reference: PMID:34765398
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      transient liver dysfunction with cholestasis
    explanation: >-
      Confirms cholestasis as part of the reported phenotype.
- category: Clinical
  name: Global Developmental Delay
  description: >-
    Affected children commonly have delayed psychomotor development and
    global developmental delay.
  phenotype_term:
    preferred_term: global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:33309011
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Adenosine kinase (ADK) deficiency is characterized by liver disease,
      dysmorphic features, epilepsy and developmental delay.
    explanation: >-
      Supports developmental delay as a core phenotype.
  - reference: PMID:30477030
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Subsequently, patients demonstrate hypotonia and global developmental
      delay.
    explanation: >-
      Confirms global developmental delay in the clinical description.
- category: Clinical
  name: Hypotonia
  description: >-
    Generalized hypotonia is commonly reported in the neonatal or infantile
    presentation.
  phenotype_term:
    preferred_term: generalized hypotonia
    term:
      id: HP:0001290
      label: Generalized hypotonia
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:34765398
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is characterized by developmental delay, hypotonia, epilepsy,
      facial dysmorphism, failure to thrive, transient liver dysfunction
      with cholestasis, recurrent hypoglycemia, and cardiac defects.
    explanation: >-
      Confirms generalized hypotonia as a common presenting feature.
  - reference: PMID:36589157
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      generalized hypotonia
    explanation: >-
      The follow-up case report explicitly lists generalized hypotonia.
- category: Clinical
  name: Seizure
  description: >-
    Epilepsy and seizures are recurrent neurologic manifestations and may be
    driven directly by brain ADK deficiency.
  phenotype_term:
    preferred_term: seizure
    term:
      id: HP:0001250
      label: Seizure
  frequency: FREQUENT
  evidence:
  - reference: PMID:27903722
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Similar to ADK-deficient patients, AdkΔbrain mice develop seizures and
      cognitive deficits.
    explanation: >-
      Demonstrates a direct mechanistic link between ADK deficiency and
      seizure susceptibility.
  - reference: PMID:34765398
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      epilepsy
    explanation: >-
      Confirms seizure/epilepsy as a recurring clinical feature.
- category: Clinical
  name: Failure to Thrive
  description: >-
    Poor weight gain is described in several affected infants.
  phenotype_term:
    preferred_term: failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  frequency: FREQUENT
  evidence:
  - reference: PMID:34765398
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      failure to thrive
    explanation: >-
      Confirms failure to thrive as part of the clinical spectrum.
- category: Clinical
  name: Facial dysmorphism
  description: >-
    Dysmorphic facial features are repeatedly reported as part of the human
    ADK deficiency phenotype.
  phenotype_term:
    preferred_term: Abnormality of the face
    term:
      id: HP:0000271
      label: Abnormality of the face
  frequency: FREQUENT
  evidence:
  - reference: PMID:34765398
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is characterized by developmental delay, hypotonia, epilepsy,
      facial dysmorphism, failure to thrive, transient liver dysfunction
      with cholestasis, recurrent hypoglycemia, and cardiac defects.
    explanation: >-
      Directly supports facial dysmorphism as part of the core clinical
      presentation.
- category: Clinical
  name: Hypoglycemia
  description: >-
    Recurrent hypoglycemia is reported in affected children with the hepatic
    metabolic phenotype.
  phenotype_term:
    preferred_term: Hypoglycemia
    term:
      id: HP:0001943
      label: Hypoglycemia
  frequency: FREQUENT
  evidence:
  - reference: PMID:34765398
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is characterized by developmental delay, hypotonia, epilepsy,
      facial dysmorphism, failure to thrive, transient liver dysfunction
      with cholestasis, recurrent hypoglycemia, and cardiac defects.
    explanation: >-
      Directly supports hypoglycemia as part of the reported clinical
      spectrum.
- category: Clinical
  name: Cardiac defects
  description: >-
    Structural or other cardiac abnormalities have been reported in the human
    clinical phenotype.
  phenotype_term:
    preferred_term: Abnormality of the cardiovascular system
    term:
      id: HP:0001626
      label: Abnormality of the cardiovascular system
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:34765398
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is characterized by developmental delay, hypotonia, epilepsy,
      facial dysmorphism, failure to thrive, transient liver dysfunction
      with cholestasis, recurrent hypoglycemia, and cardiac defects.
    explanation: >-
      Directly supports cardiac defects as part of the ADK deficiency
      phenotype.
- category: Clinical
  name: Stroke
  description: >-
    Stroke has been reported in ADK deficiency in association with tortuous
    cervical arteries.
  phenotype_term:
    preferred_term: Stroke
    term:
      id: HP:0001297
      label: Stroke
  evidence:
  - reference: PMID:34765398
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      vascular tortuosity leading to stroke in one of them.
    explanation: >-
      The case report documents stroke in a patient with ADK deficiency and
      vascular tortuosity.
- category: Clinical
  name: Macrocytic anemia
  description: >-
    Persistent macrocytic anemia has been documented in long-term follow-up.
  phenotype_term:
    preferred_term: Macrocytic anemia
    term:
      id: HP:0001972
      label: Macrocytic anemia
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:36589157
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Six-month-old patient presented with cholestatic liver disease,
      macrocytic anemia, developmental delay, generalized hypotonia,
      delayed brain myelination, and elevated levels of serum methionine.
    explanation: >-
      Directly supports macrocytic anemia in a well-described human case.
- category: Clinical
  name: Delayed brain myelination
  description: >-
    Brain MRI may show delayed myelination as part of the neurologic disease
    spectrum.
  phenotype_term:
    preferred_term: Delayed myelination
    term:
      id: HP:0012448
      label: Delayed myelination
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:36589157
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Six-month-old patient presented with cholestatic liver disease,
      macrocytic anemia, developmental delay, generalized hypotonia,
      delayed brain myelination, and elevated levels of serum methionine.
    explanation: >-
      Directly supports delayed brain myelination in a human case with ADK
      deficiency.
- category: Clinical
  name: Short stature
  description: >-
    Short stature was reported during long-term follow-up after liver
    transplantation in a patient later diagnosed with ADK deficiency.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:36589157
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ten-year follow-up after LTx revealed a preserved good liver function,
      persistent regenerative macrocytic anemia, progressive neurological
      disease but disappearance of brain MR changes, short stature, and
      cortisol deficiency.
    explanation: >-
      The long-term follow-up case directly documents short stature in ADK
      deficiency.
- category: Clinical
  name: Cortisol deficiency
  description: >-
    Cortisol deficiency was documented during long-term follow-up in a patient
    with ADK deficiency.
  phenotype_term:
    preferred_term: adrenal insufficiency
    term:
      id: HP:0000846
      label: Adrenal insufficiency
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:36589157
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ten-year follow-up after LTx revealed a preserved good liver function,
      persistent regenerative macrocytic anemia, progressive neurological
      disease but disappearance of brain MR changes, short stature, and
      cortisol deficiency.
    explanation: >-
      The long-term follow-up case directly documents cortisol deficiency,
      mapped to the adrenal insufficiency HPO term.
biochemical:
- name: Elevated plasma methionine
  presence: INCREASED
  context: >-
    Plasma methionine is a high-signal diagnostic biochemical readout of ADK
    deficiency and distinguishes it from nonspecific liver disease.
  biomarker_term:
    preferred_term: L-methionine
    term:
      id: CHEBI:16643
      label: L-methionine
  readouts:
  - target: Transmethylation Cycle Disruption and Hypermethioninemia
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Higher plasma methionine reflects the ADK-related methionine-cycle
      disturbance.
    evidence:
    - reference: PMID:33309011
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        methionine level in patients with ADK deficiency was strongly
        increased compared with patients with other liver diseases.
      explanation: >-
        The cohort shows methionine elevation as a diagnostic readout of ADK
        deficiency.
  evidence:
  - reference: PMID:33309011
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      methionine level in patients with ADK deficiency was strongly
      increased compared with patients with other liver diseases.
    explanation: >-
      The clinical cohort supports elevated plasma methionine as a recurring
      ADK deficiency biomarker.
  - reference: PMID:30477030
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biochemically, methionine is elevated with normal homocysteine levels
      and the diagnosis is confirmed through molecular analysis of the ADK
      gene.
    explanation: >-
      The review confirms the characteristic elevated-methionine profile.
- name: Elevated S-adenosyl-L-homocysteine
  presence: INCREASED
  context: >-
    S-adenosylhomocysteine elevation provides a more specific
    transmethylation-cycle readout alongside hypermethioninemia.
  biomarker_term:
    preferred_term: S-adenosyl-L-homocysteine
    term:
      id: CHEBI:16680
      label: S-adenosyl-L-homocysteine
  readouts:
  - target: Transmethylation Cycle Disruption and Hypermethioninemia
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Elevated S-adenosylhomocysteine reflects disruption of the
      adenosine-sensitive transmethylation cycle.
    evidence:
    - reference: PMID:36589157
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        elevated concentration of S-adenosylhomocysteine.
      explanation: >-
        The report uses elevated S-adenosylhomocysteine as biochemical
        confirmation of pathogenic ADK variants.
  evidence:
  - reference: PMID:36589157
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      elevated concentration of S-adenosylhomocysteine.
    explanation: >-
      The case report directly supports elevated S-adenosylhomocysteine in
      ADK deficiency.
- name: Normal plasma homocysteine
  presence: NORMAL
  context: >-
    Normal homocysteine paired with elevated methionine helps define the ADK
    biochemical pattern and distinguishes it from hyperhomocysteinemic
    methionine-cycle disorders.
  biomarker_term:
    preferred_term: homocysteine
    term:
      id: CHEBI:17230
      label: homocysteine
  readouts:
  - target: Transmethylation Cycle Disruption and Hypermethioninemia
    relationship: READOUT_OF
    direction: PRESENT_ABSENT
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Normal homocysteine is part of the diagnostic biochemical signature when
      interpreted together with elevated methionine.
    evidence:
    - reference: PMID:30477030
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Biochemically, methionine is elevated with normal homocysteine levels
        and the diagnosis is confirmed through molecular analysis of the ADK
        gene.
      explanation: >-
        The review explicitly states the elevated-methionine, normal-
        homocysteine biochemical pattern.
  evidence:
  - reference: PMID:30477030
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biochemically, methionine is elevated with normal homocysteine levels
      and the diagnosis is confirmed through molecular analysis of the ADK
      gene.
    explanation: >-
      The review confirms normal homocysteine as part of the ADK deficiency
      biochemical profile.
genetic:
- name: ADK
  gene_term:
    preferred_term: ADK
    term:
      id: hgnc:257
      label: ADK
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_c2319ca2-652d-411e-ab6d-5b7fb7e185ea-2021-04-08T160000.000Z
    reference_title: "ADK / adenosine kinase deficiency (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ADK | HGNC:257 | adenosine kinase deficiency | MONDO:0100255 | AR | Definitive"
    explanation: ClinGen classifies the ADK-adenosine kinase deficiency gene-disease relationship as definitive with autosomal recessive inheritance.
diagnosis:
- name: Biochemical Screening
  diagnosis_term:
    preferred_term: biomarker analysis
    term:
      id: MAXO:0000018
      label: biomarker analysis
  description: >-
    Plasma amino acid profiling and one-carbon metabolite measurements can
    suggest ADK deficiency before molecular confirmation.
  notes: >-
    Focus on methionine, S-adenosylmethionine, S-adenosylhomocysteine, and
    homocysteine.
  evidence:
  - reference: PMID:33309011
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      methionine level in patients with ADK deficiency was strongly
      increased compared with patients with other liver diseases.
    explanation: >-
      Supports the use of methionine as a diagnostic biomarker.
  - reference: PMID:30477030
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biochemically, methionine is elevated with normal homocysteine levels
      and the diagnosis is confirmed through molecular analysis of the ADK
      gene.
    explanation: >-
      Summarizes the biochemical pattern used in diagnosis.
  - reference: PMID:36589157
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      elevated concentration of S-adenosylhomocysteine.
    explanation: >-
      Supports use of transmethylation biomarkers for diagnosis.
- name: Molecular Genetic Testing
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
  description: >-
    ADK sequencing or exome sequencing confirms the diagnosis and identifies
    pathogenic biallelic variants.
  evidence:
  - reference: PMID:30477030
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the diagnosis is confirmed through molecular analysis of the ADK gene.
    explanation: >-
      States that molecular analysis confirms ADK deficiency.
  - reference: PMID:36589157
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole exome sequencing revealed the patient to be affected with two
      novel ADK variants
    explanation: >-
      Shows exome sequencing as the confirming test in a later case.
differential_diagnoses:
- name: Primary Mitochondrial Disease
  disease_term:
    preferred_term: mitochondrial disease
    term:
      id: MONDO:0044970
      label: mitochondrial disease
  description: >-
    ADK deficiency can mimic a primary mitochondrial disorder because it may
    present with neonatal liver disease, hypotonia, developmental delay, and
    respiratory-chain abnormalities on tissue testing.
  distinguishing_features:
  - Elevated plasma methionine and elevated S-adenosylhomocysteine favor ADK deficiency.
  - ADK sequencing identifies biallelic pathogenic variants in ADK.
  - Mitochondrial disease may show broader respiratory chain defects without the ADK biochemical signature.
  evidence:
  - reference: PMID:33309011
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ADK deficiency is a cause of neonatal or early infantile liver disease
      that may mimic primary mitochondrial disorders.
    explanation: >-
      Directly identifies mitochondrial disease as an important mimic.
- name: Other Hypermethioninemic Disorders
  description: >-
    The differential diagnosis of elevated methionine includes CBS
    deficiency, MAT1A deficiency, GNMT deficiency, AHCY deficiency, citrin
    deficiency, and FAH deficiency/tyrosinemia type I.
  distinguishing_features:
  - CBS deficiency usually produces homocystinuria with elevated homocysteine.
  - MAT1A, GNMT, and AHCY deficiencies are alternative methionine-cycle disorders with overlapping hypermethioninemia.
  - Citrin deficiency and tyrosinemia type I can also present with hypermethioninemia, but the broader metabolic context differs.
  - ADK deficiency is distinguished by the combination of hypermethioninemia with elevated S-adenosylhomocysteine and ADK variants.
  evidence:
  - reference: PMID:21308989
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This review covers briefly the major conditions, genetic and
      non-genetic, sometimes leading to abnormally elevated methionine, with
      emphasis on recent developments. A major aim is to assist in the
      differential diagnosis of hypermethioninemia.
    explanation: >-
      The review explicitly frames these disorders as the differential for
      hypermethioninemia.
clinical_trials: []
datasets: []
treatments:
- name: Methionine-Restricted Diet
  description: >-
    Dietary methionine intake restriction has been tried, but outcomes are
    variable and it is not curative.
  treatment_term:
    preferred_term: dietary methionine intake avoidance
    term:
      id: MAXO:0010092
      label: dietary methionine intake avoidance
  target_mechanisms:
  - target: Transmethylation Cycle Disruption and Hypermethioninemia
    treatment_effect: MODULATES
    description: >-
      Methionine restriction is intended to reduce the hypermethioninemia
      component of the disturbed methionine cycle, though outcomes are variable.
    evidence:
    - reference: PMID:30477030
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        There is no curative treatment; however, a methionine-restricted diet
        has been tried with variable outcomes.
      explanation: >-
        The clinical review supports methionine restriction as a management
        approach but notes variable outcomes, so the target effect is modeled
        as modulation rather than correction.
  evidence:
  - reference: PMID:30477030
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There is no curative treatment; however, a methionine-restricted diet
      has been tried with variable outcomes.
    explanation: >-
      Directly supports methionine restriction as a tried management
      strategy.
- name: Liver transplantation
  description: >-
    Liver transplantation can correct the hepatic component, although
    neurologic disease may continue to progress.
  treatment_term:
    preferred_term: organ transplantation
    term:
      id: MAXO:0010039
      label: organ transplantation
  target_mechanisms:
  - target: Hepatic Dysfunction and Cholestasis
    treatment_effect: INHIBITS
    description: >-
      Liver transplantation can correct the hepatic dysfunction component while
      neurologic disease may persist.
    evidence:
    - reference: PMID:36589157
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Ten-year follow-up after LTx revealed a preserved good liver function,
        persistent regenerative macrocytic anemia, progressive neurological
        disease but disappearance of brain MR changes, short stature, and
        cortisol deficiency.
      explanation: >-
        Long-term follow-up supports improvement of liver function after
        transplantation while distinguishing persistent non-hepatic disease.
  evidence:
  - reference: PMID:36589157
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient underwent living-donor liver transplantation (LTx) at 14
      months of age. Ten-year follow-up after LTx revealed a preserved good
      liver function, persistent regenerative macrocytic anemia,
      progressive neurological disease but disappearance of brain MR changes,
      short stature, and cortisol deficiency.
    explanation: >-
      Supports liver transplantation as a major intervention that improves
      liver disease while not fully correcting the neurologic phenotype.
📚

References & Deep Research

Deep Research

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Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Adenosine Kinase Deficiency. Core disease mechanisms, molecular and cellul...
Asta Scientific Corpus Retrieval 18 citations 2026-04-16T14:41:58.839513

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Adenosine Kinase Deficiency. Core disease mechanisms, molecular and cellul...

This report is retrieval-only and is generated directly from Asta results.

  • Papers retrieved: 18
  • Snippets retrieved: 20

Relevant Papers

[1] Inborn Errors of Purine Salvage and Catabolism

  • Authors: M. Camici, M. Garcia-Gil, S. Allegrini, R. Pesi, G. Bernardini et al.
  • Year: 2023
  • Venue: Metabolites
  • URL: https://www.semanticscholar.org/paper/d148bf0d5fd4f6a8eca5ba4751391963e98d9f69
  • DOI: 10.3390/metabo13070787
  • PMID: 37512494
  • PMCID: 10383617
  • Citations: 20
  • Summary: Diagnostic tools are suggested that may indicate to clinicians that the inborn errors of purine metabolism may not be very rare diseases after all and are offered new points of view on this topic.
  • Evidence snippets:
  • Snippet 1 (score: 0.481) > Adenosine kinase (ADK) catalyzes the transfer of the γ-phosphate from ATP to adenosine, leading to the formation of AMP (Figure 1), and regulates both extracellular adenosine and intracellular adenine nucleotide levels. Human ADK consists of two alternatively spliced forms with distinct cellular and subcellular localization and functions. The overexpression of shorter, cytoplasmatic ADK in the brain resulted in spontaneous seizures and increased brain injury after ischemic stroke but the overexpression of the longer, nuclear ADK in dorsal forebrain neurons attenuated neural stem cell proliferation [210]. In addition, nuclear ADK might have a more prominent role in epigenetic mechanisms requiring transmethylation reactions than cytoplasmic ADK [211]. > ADK deficiency is a rare inborn error of methionine and adenosine metabolism, first clinically described in 2011 [212]. So far, less than 30 patients have been reported [210, [213][214][215] as showing liver dysfunction, delayed psychomotor development, mild dysmorphic features, and neurological features including generalized hypotonia and epilepsy. Vascular abnormalities have also been recently reported [216].
  • Snippet 2 (score: 0.407) > Mutations may affect different aspects of the enzyme functions, such as the kinetic parameters, or the binding of other regulating proteins or small molecules, leading to a panel of alterations in enzymatic activity and therefore to different symptoms. A complete lack of an enzyme activity may compromise vital functions resulting in life threatening diseases. Partial enzyme dysfunction may result in symptoms easily misdiagnosed as one of the many infantile syndromes characterized by neuropsychiatric, neuromotor, and neurosensorial impairments. In this regard, using metabolomic and transcriptomic approaches, dysfunctions of purine metabolism, other than the well-known ADSL deficiency, have been reported in autism spectrum disorders [304,305], such as a significant increase in ADA activity, with a reduction in UA [304], and an increase in hypoxanthine, inosine, and xanthosine [305]. Another reason for misdiagnosis is the occurrence of compensatory mechanisms, which may differ among individuals and may attenuate the effects of the purine inborn error, giving rise to various phenotypes that do not completely correlate with the genotype. > Over the years, several cell models have been developed and employed to explore the metabolic features and investigate the molecular mechanisms underpinning these rare diseases. Most studies have been initially conducted using easily available cells, such as erythrocytes and cultured fibroblasts, isolated from patients for diagnostic purposes. Other cellular models were also studied, but they quickly revealed their limitations: failing to recapitulate the different enzymatic expression or activity in different tissues or cell types, in different stages of development, or lacking several relevant pathways (e.g., protein synthesis machinery in erythrocytes). Furthermore, most of the pathologies of still unknown etiology, associated with purine inborn errors, concern the nervous system. The pathophysiology of neurological defects cannot be studied directly in the patients, because of the ethical implications of obtaining samples of brain tissue. Therefore, animal models were developed as an alternative approach, which, unfortunately, often did not completely reflect the human phenotype and failed to address many of the unresolved neurological features.

[2] Purinergic Signaling in the Pathophysiology and Treatment of Huntington’s Disease

  • Authors: M. T. Wiprich, C. Bonan
  • Year: 2021
  • Venue: Frontiers in Neuroscience
  • URL: https://www.semanticscholar.org/paper/99f1c8dc90c4f2a0ff29de57ffeac846cd1983cc
  • DOI: 10.3389/fnins.2021.657338
  • PMID: 34276284
  • PMCID: 8281137
  • Citations: 17
  • Summary: This review presents several studies describing the relationship between purinergic signaling and HD, as well as the use of purinoceptors as pharmacological targets and biomarkers for this neurodegenerative disorder.
  • Evidence snippets:
  • Snippet 1 (score: 0.436) > This review sheds light on the important regulatory role of purinergic signaling in HD pathophysiology. Notably, ATP, adenosine, and A 2A R are the main actors in HD. Although some results in animal models and HD patients are controversialdepending on the model tested, type of pharmacological treatment, and period of drug administration-pharmacological modulation of A 2A R, through agonist and antagonist drugs, has shown a neuroprotective effect by attenuating the behavioral symptoms and improving neurochemical parameters during HD progression. Besides, A 2A R in the central and peripheral nervous system might be considered a powerful biomarker for HD progression and ought to be used in clinical practice. A 2A R heterodimerizes with several other G-protein coupled receptors involved in striatal dysfunction and degeneration in HD; thus, A 2A R could be considered a target for the development of pharmacological therapies for HD patients. > Several small molecules acting as A 2A R antagonists have already been developed and tested in patients several neurological diseases, such as Parkinson's Disease. Although the efficacy of these agents in Parkinson's disease was not proved, the use of antagonists targeting A 2A R in cancer immunotherapy has been also investigated. The treatment with small molecules or mAbs aiming to block adenosine signaling, either by limiting its production or its binding to adenosine receptors, has yielded important tumor control in pre-clinical studies. Moreover, simultaneous blockade of adenosine production and receptor binding, achieved by an anti-CD73 mAb co-administered with an A 2A R antagonist, for example, have demonstrated synergy. Therefore, it is important to deepen the investigation of A 2A R as a target for the development of existing or new agents targeting this axis, along with further testing of combinatorial strategies, which may be relevant in the search for pharmacological therapies for HD patients. Moreover, the role of A 1 R and P2 receptors in HD pathogenesis needs to be reconsidered; there should be more specific investigation on these receptors, because they could provide a powerful contribution to understanding the mechanism underlying HD.

[3] The role of adenosine monophosphate-activated protein kinase in neurodegeneration in Parkinson's disease

  • Authors: Maja Jovanović-Tucović, I. Markovic
  • Year: 2019
  • Venue: Medicinski podmladak
  • URL: https://www.semanticscholar.org/paper/2dafda8123f246e45c52e099bdb60e84fdb821b6
  • DOI: 10.5937/mp70-23730
  • Citations: 1
  • Summary: The literature data regarding the role of AM PK in PD pathogenesis is summarized and some studies have shown the detrimental effect of AMPK activation in DA neurons in advanced stages of neuronal damage, where prolonged activation could inhibit protein synthesis and impair synaptic integrity and plasticity.
  • Evidence snippets:
  • Snippet 1 (score: 0.413) > Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder characterized by the chronic demise of dopaminergic neurons in the substantia nigra (SN) and the presence of intracellular inclusions called Lewy bodies (1)(2)(3)(4).Due to the loss of dopaminergic neurons, this disease is characterized by motor symptoms: bradykinesia, static tremor, muscle rigidity and postural instability (5).These motor features may be accompanied by non-motor symptoms, such as a decrease in gastrointestinal motility, loss of olfactory function, sleep dysfunction and/or neuropsychiatric disorders, which seems to occur years before the appearance of clinical manifestations of the disease (6)(7)(8)(9). > During the past 40 years, numerous studies of molecular mechanisms involved in PD pathogenesis improved our understanding of events that could lead to PD.Today we know that certain genes and environmental factors could contribute to disease development.Key molecular mechanisms that appear to be relevant for the development and progression of PD are oxidative stress, mitochondrial dysfunction, and altered proteostasis.Each of these mechanisms is, at least at some point, regulated by the enzyme adenosine-monophosphate activated protein kinase (AMPK). > The AMPK is a principal intracellular energy sensor that is activated by different types of metabolic stress that often include an increase in cellular AMP, ADP or Ca 2+ .It regulates metabolic homeostasis by stimulating catabolic processes while inhibiting anabolic ones (10).Furthermore, AMPK is a major inhibitor of mTORC1 (mechanistic target of rapamycin complex 1), another serine/threonine kinase and the main inhibitor of autophagy (11). > Compromised cellular energy homeostasis, such as disturbances in AMP/ATP ratio, is seen in patients with PD (12).Taking into account that neurons exhibit extraordinarily high energy demands, they are very vulnerable to impaired cellular energy metabolism, suggesting the importance of AMPK in the maintenance of neuronal functioning.This review will briefly summarize several functions of AMPK and their potential relevance to PD.

[4] Adenosine kinase deficiency presenting with tortuous cervical arteries: A risk factor for recurrent stroke

  • Authors: J. Paz, E. Embiruçu, Clarissa Bueno, Rafael Ferreira, F. S. Oliveira et al.
  • Year: 2021
  • Venue: JIMD Reports
  • URL: https://www.semanticscholar.org/paper/96d2eaa881deae180b14c2d064ff4c15b8963692
  • DOI: 10.1002/jmd2.12252
  • PMID: 34765398
  • PMCID: 8574177
  • Citations: 3
  • Summary: Two patients with ADK deficiency are described and vascular tortuosity leading to stroke in one of them and a complex phenotype that might be associated with cerebrovascular abnormalities and stroke is described.
  • Evidence snippets:
  • Snippet 1 (score: 0.410) > Adenosine kinase deficiency (ADK deficiency, OMIM # 614300) is a very rare autosomal recessive complex inborn error of methionine and adenosine metabolism that has a severe clinical phenotype. 1 It is caused by homozygous or compound heterozygous variant in ADK, which encodes for the enzyme ADK. Adenosine is largely metabolized through conversion to adenosine monophosphate (AMP) by ADK. The mechanisms through which ADK deficiency can be pathogenic include cellular adenosine toxicity and detrimental effects of decreased AMP levels on cellular and mitochondrial functions. 2 n addition, adenosine can inhibit the immune response and contributes to delayed neurotransmission via abnormal hormone secretion. Furthermore, adenosine is also a component of many vital enzymes. The accumulation of adenosine reverses the S-adenosylhomocysteine hydrolase (SAHH) reaction, which leads to increased levels of S-adenosyl homocysteine (AdoHcy), and impairs the methionine cycle. 1,2 DK deficiency is characterized by hypoglycemia, liver dysfunction, and hypotonia, which usually begin in the neonatal period. The liver dysfunction can be quite variable, ranging from only a few biochemical abnormalities to severe cholestasis and liver failure. Developmental delay and seizures emerge afterward. Key biochemical findings consist of elevated concentrations in plasma of Sadenosylmethionine (AdoMet) and AdoHcy; methionine might be intermittently elevated. 2 2][3][4][5][6] To the best of our knowledge, vascular abnormalities in cervical arteries and cerebral stroke have never been reported. In this report, we present two unrelated patients from the same geographic region (Vitoria da Conquista, Bahia State, Northeast Brazil) with ADK deficiency presenting enlargement and tortuosity of cervical arteries. One of them suffered recurrent strokes. Both patients were homozygous for a novel missense variant in ADK. Such findings suggest that cerebrovascular disease might be a complication of ADK deficiency and deserves careful observation.

[5] Exploring the Prognosis-Related Genetic Variation in Gastric Cancer Based on mGWAS

  • Authors: Yuling Zhang, Yanping Lyu, Liangping Chen, Kang Cao, Jingwen Chen et al.
  • Year: 2023
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/8d60bdf594030f1d41d1cc3a1fe2e20de6dc922a
  • DOI: 10.3390/ijms242015259
  • PMID: 37894938
  • PMCID: 10607287
  • Citations: 4
  • Summary: It is suggested that gastric cancer survival-related genes may influence the proliferation and infiltration of Gastric cancer cells, which provides a new idea to resolve the complex regulatory network of gastrics cancer prognosis.
  • Evidence snippets:
  • Snippet 1 (score: 0.404) > Purines also provide the necessary energy and cofactors to promote cell survival and proliferation, and their presence in the body is mainly in the form of purine nucleotides (adenosine). Adenosine-based cellular communication systems are present in almost all components of the body, and adenosine is one of the most pleiotropic biochemical components of the tumor microenvironment that affects host and tumor responses. Adenosine exerts potent immunosuppressive and anti-inflammatory activities in the body, and currently targeted purine drugs are used in the treatment of clinical cancers [2,38]. In addition, adenosine may function as a neurotransmitter, and purine signaling plays a role in neurological related diseases [39,40]. > The intestinal nervous system (ENS) is the largest component of the peripheral nervous system and is very similar to the components and functions of the central nervous system. It is a key regulator of intestinal barrier function and a regulator of intestinal homeostasis. The intestinal nervous system is a network of intestinal neurons and glial cells, which originates from neural crest stem cells. The neural callus stem cells originate from neuroectoderm and undergo the processes of proliferation, migration, and differentiation, with the participation of various cytokines and signaling molecules, forming various types of intestinal cells. These cells express different neurotransmitters and neuropeptides, respectively, which jointly regulate intestinal function. BeateNiesler et al. [41] summarized the role of ENS in gastrointestinal and systemic diseases and highlighted the interaction of ENS with key factors affecting disease phenotyping. These functional genes may play a similar role in the nervous system and gastrointestinal system because they are all composed of the same cell types and molecular mechanisms. Therefore, combined with the results of enrichment of functional genes and metabolites, this study predicts that these functional genes mainly mediate the regulation of metabolites through related pathways, such as cell signal molecule transmission, body growth and development, nervous system regulation, and immune escape, and then affect the prognosis of gastric cancer.

[6] Myotonic Dystrophy Protein Kinase: Structure, Function and Its Possible Role in the Pathogenesis of Myotonic Dystrophy Type 1

  • Authors: J. Magaña, R. Suárez-Sánchez, N. Leyva-García, B. Cisneros, O. Hernández-Hernández
  • Year: 2012
  • Venue: Unknown venue
  • URL: https://www.semanticscholar.org/paper/e76854a6ec9f44f6d8e3b256cc9e21d0fec466e2
  • DOI: 10.5772/37238
  • Citations: 3
  • Summary: An RNA-mediated dominant gain-of-function is currently accepted as the pathogenic mechanism to explain features of the myotonic dystrophy type 1 disease.
  • Evidence snippets:
  • Snippet 1 (score: 0.404) > DM1 is a neuromuscular multisystemic disease caused by the expansion of the CTG repeats in the 3'UTR of the DMPK gene. DMPK primary transcript gives rise to 6 isoforms with activity of serine/threonine kinase that differ each other in their capacity to anchor organelle membranes. DMPK is expressed mainly in heart, skeletal and smooth muscles, and brain, the most compromised tissues in DM1. Current knowledge indicates that clinical manifestations of DM1 are not due to a unique molecular mechanism; instead, it appears that different mechanisms operate in the development of the disease. In addition to the toxic RNA gain-of-function, the best-described mechanism, chromatin rearrangements of the DM1 locus, leaching of transcription factors, interference RNA pathways and altered expression of DMPK protein should be considered as contributors to DM1 biogenesis. Importantly, several partners and targets of DMPK have been reported, suggesting the involvement of DMPK in the specific cellular pathways affected in DM1. Although the physiological function of DMPK and its isoforms is not yet fully understood, growing body of experimental evidence strongly suggests a role for DMPK in DM1 pathophysiology. Future studies in different groups of DM1 patients (CDM versus classic DM1), as well as in animal and cells models with DMPK deficiency are required to define the participation of DMPK in DM1 biogenesis.

[7] Protein kinases in neurodegenerative diseases: current understandings and implications for drug discovery

  • Authors: Xiao-lei Wu, Zhang-zhong Yang, Jinjun Zou, Huile Gao, Zhenhua Shao et al.
  • Year: 2025
  • Venue: Signal Transduction and Targeted Therapy
  • URL: https://www.semanticscholar.org/paper/57c532f807605e5181ca30a675ad0d79e3625453
  • DOI: 10.1038/s41392-025-02179-x
  • PMID: 40328798
  • PMCID: 12056177
  • Citations: 34
  • Influential citations: 1
  • Summary: The role and complexity of kinase–kinase networks in the pathogenesis of neurodegenerative diseases are discussed, and the advances of clinical applications of protein kinase inhibitors or novel kinase-targeted therapeutic strategies for effective prevention and early intervention are illustrated.
  • Evidence snippets:
  • Snippet 1 (score: 0.404) > Neurodegenerative diseases (e.g., Alzheimer’s, Parkinson’s, Huntington’s disease, and Amyotrophic Lateral Sclerosis) are major health threats for the aging population and their prevalences continue to rise with the increasing of life expectancy. Although progress has been made, there is still a lack of effective cures to date, and an in-depth understanding of the molecular and cellular mechanisms of these neurodegenerative diseases is imperative for drug development. Protein phosphorylation, regulated by protein kinases and protein phosphatases, participates in most cellular events, whereas aberrant phosphorylation manifests as a main cause of diseases. As evidenced by pharmacological and pathological studies, protein kinases are proven to be promising therapeutic targets for various diseases, such as cancers, central nervous system disorders, and cardiovascular diseases. The mechanisms of protein phosphatases in pathophysiology have been extensively reviewed, but a systematic summary of the role of protein kinases in the nervous system is lacking. Here, we focus on the involvement of protein kinases in neurodegenerative diseases, by summarizing the current knowledge on the major kinases and related regulatory signal transduction pathways implicated in diseases. We further discuss the role and complexity of kinase–kinase networks in the pathogenesis of neurodegenerative diseases, illustrate the advances of clinical applications of protein kinase inhibitors or novel kinase-targeted therapeutic strategies (such as antisense oligonucleotides and gene therapy) for effective prevention and early intervention.

[8] Oxidative Stress in Healthy and Pathological Red Blood Cells

  • Authors: Florencia Orrico, Sandrine Laurance, Ana C. Lopez, S. Lefevre, L. Thomson et al.
  • Year: 2023
  • Venue: Biomolecules
  • URL: https://www.semanticscholar.org/paper/5ea67232d5288f7e47b3304da16c315738a09419
  • DOI: 10.3390/biom13081262
  • PMID: 37627327
  • PMCID: 10452114
  • Citations: 118
  • Influential citations: 3
  • Summary: The most relevant oxidant species involved in RBC damage, the enzymatic and low molecular weight antioxidant systems that protect RBCs against oxidative injury, and the role of oxidative stress in different red cell diseases are discussed, highlighting the underlying mechanisms leading to pathological RBC phenotypes are highlighted.
  • Evidence snippets:
  • Snippet 1 (score: 0.402) > Red cell diseases encompass a group of inherited or acquired erythrocyte disorders that affect the structure, function, or production of red blood cells (RBCs). These disorders can lead to various clinical manifestations, including anemia, hemolysis, inflammation, and impaired oxygen-carrying capacity. Oxidative stress, characterized by an imbalance between the production of reactive oxygen species (ROS) and the antioxidant defense mechanisms, plays a significant role in the pathophysiology of red cell diseases. In this review, we discuss the most relevant oxidant species involved in RBC damage, the enzymatic and low molecular weight antioxidant systems that protect RBCs against oxidative injury, and finally, the role of oxidative stress in different red cell diseases, including sickle cell disease, glucose 6-phosphate dehydrogenase deficiency, and pyruvate kinase deficiency, highlighting the underlying mechanisms leading to pathological RBC phenotypes.

[9] Resistance mechanisms of immune checkpoint inhibition in lymphoma: Focusing on the tumor microenvironment

  • Authors: Chunlan Zhang, Lei Wang, Caigang Xu, Heng Xu, Yu Wu
  • Year: 2023
  • Venue: Frontiers in Pharmacology
  • URL: https://www.semanticscholar.org/paper/2b6311b9447174657ec385c1fe6c676909bf59b0
  • DOI: 10.3389/fphar.2023.1079924
  • PMID: 36959853
  • PMCID: 10027765
  • Citations: 6
  • Summary: The value of multiple cell populations and metabolites in the TME as prognostic biomarkers for ICI response are highlighted, and additional potential targets in immunotherapy are underline, such as EZH2, LAG3, TIM-3, adenosine, and PI3Kδ/γ.
  • Evidence snippets:
  • Snippet 1 (score: 0.396) > clinical benefit was noted in solid cancer (Augustin et al., 2022;Chiappori et al., 2022). Similarly, adenosine pathway is also closely related to immune evasion in lymphoma. For instance in DLBCL, the numbers of CD8 + T cells with PD-1 and A2AAR expression were positively correlated with the number of dysfunctional CD8 + T cell, and worse clinical outcome . Consistently, patients with CD73 + on tumor cells as well as A2AAR + on tumor-infiltrating lymphocytes exhibited inferior survival in DLBCL (Wang et al., 2019). Moreover, pre-clinical studies have proved the anti-tumor effect of blocking adenosine pathway. For example, knocking-out A2AAR could significantly decrease tumor growth in a T cell lymphoma mouse model (Ohta et al., 2006), whereas CD73deficient mice had increased antitumor immunity against inoculated lymphoma cells compared with wild-type mice (Stagg et al., 2011). More recently, CD73 deficiency was found to significantly delay CLL progression and prolonged survival in Eµ-TCL1 transgenic mice, and was associated with increased accumulation of IFN-γ + T cells and effector-memory CD8 + T cells (Allard et al., 2022). Furthermore, adenosine pathway is also involved in drug resistance to immunotherapy for lymphoma. According to the recent study, adenosine critically impeded the therapeutic efficacy of anti-CD20 monoclonal antibodies against B cell lymphoma by impairing antibody-mediated cellular phagocytosis by macrophages and limiting the generation of anti-lymphoma CD8 + T cells (Nakamura et al., 2020). Based on these studies, it is reasonable to deduce that adenosine pathway might reduce the efficiency of ICIs in lymphoma in a manner similar to that in solid cancer. Currently, in lymphoma, the study concerning the combination of inhibitors targeting adenosine and ICIs in pre-clinical or clinical settings is scarce, and further investigation is in urgent need.

[10] Global and Targeted Metabolomics for Revealing Metabolomic Alteration in Niemann-Pick Disease Type C Model Cells

  • Authors: Masahiro Watanabe, Masamitsu Maekawa, Keitaro Miyoshi, Toshihiro Sato, Yu Sato et al.
  • Year: 2024
  • Venue: Metabolites
  • URL: https://www.semanticscholar.org/paper/27c7aa8f74e2997a59b92b38aec1fb9ff9cbb608
  • DOI: 10.3390/metabo14100515
  • PMID: 39452896
  • PMCID: 11509386
  • Citations: 2
  • Summary: Several metabolite characteristics of Niemann-Pick disease type C that may fluctuate in a cellular model of the disease are identified using both global and targeted metabolomic analyses by liquid chromatography/tandem mass spectrometry.
  • Evidence snippets:
  • Snippet 1 (score: 0.394) > Background: Niemann-Pick disease type C (NPC) is an inherited disorder characterized by a functional deficiency of cholesterol transport proteins. However, the molecular mechanisms and pathophysiology of the disease remain unknown. Methods: In this study, we identified several metabolite characteristics of NPC that may fluctuate in a cellular model of the disease, using both global and targeted metabolomic analyses by liquid chromatography/tandem mass spectrometry (LC-MS/MS). Three cell lines, HepG2 cells (wild-type[WT]) and two NPC model HepG2 cell lines in which NPC1 was genetically ablated (knockout [KO]1 and KO2), were used for metabolomic analysis. Data were subjected to enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Results: The enrichment analysis of global metabolomics revealed that 8 pathways in KO1 and 16 pathways in KO2 cells were notably altered. In targeted metabolomics for 15 metabolites, 4 metabolites in KO1 and 10 metabolites in KO2 exhibited statistically significant quantitative changes in KO1 or KO2 relative to WT. Most of the altered metabolites were related to creatinine synthesis and cysteine metabolism pathways. Conclusions: In the future, our objective will be to elucidate the relationship between these metabolic alterations and pathophysiology.

[11] Chemotherapy and Mechanisms of Resistance in Breast Cancer

  • Authors: A. Oliveira, R. E. Santos, F. F. O. Rodrigues
  • Year: 2012
  • Venue: Unknown venue
  • URL: https://www.semanticscholar.org/paper/502a86d8bcd7208be6f539fcceba631f82f25a7d
  • DOI: 10.5772/24629
  • Summary: The addition of adjuvant polychemotherapy in advanced breast cancer showed gain by controlling survival of micrometastases in patients with lymph nodes affected by cancer or not.
  • Evidence snippets:
  • Snippet 1 (score: 0.391) > The main reasons responsible for treatment failure in cancer patients are the mechanisms of drug resistance and emergence of disseminated disease (Terek et al, 2003). We identified two types of resistance most relevant to BC: primary resistance, which corresponds to the clinical situation where the patient showed no response to therapy, and secondary or acquired resistance in which, initially, there is an observed response and a subsequent failure of the treatment regimen (Kroger et al, 1999). Several mechanisms may cause the phenotype of multidrug resistance to chemotherapy drugs and are well characterized in in vitro experiments, including alterations in systemic pharmacology (pharmacokinetics and metabolism), extracellular mechanisms (tumor environment, multicellular drug resistance), and cellular mechanisms (cellular pharmacology, activation and inactivation of drugs, modification of specific targets and regulatory pathways of apoptosis) (Leonessa et al, 2003, Riddick et al, 2005. Identification of factors that affect cell metabolism, which are related to drug resistance, will enable the identification of which patients are at particular risk of treatment failure. Among the biochemical and molecular mechanisms of drug resistance, we stress: changes in the activity of topoisomerase II, alterations in the DNA repair mechanism, overexpression of P-glycoprotein; high intracellular concentrations of enzymes purification of cellular metabolism -among them enzymes the family of glutathione S-transferases (GSTs) and changes in the mechanisms of signaling via c-Jun N-terminal kinase 1 (JNK1) -and "apoptosis signal-regulating kinase (ASK1) required for activation of the" mitogenactivated protein (MAP kinases) in apoptosis and cellular restoration. These pathways are also mediated by proteins encoded by genes of GSTs (O'Brien, Tew, 1996;Burg, Mulder, 2002, L'Ecuyer et al, 2004). Different response rates to particular chemotherapy regimens, as observed in patient groups with the same biological characteristics and stage, suggest the existence of different mechanisms of drug resistance, probably induced by genetic alterations (Hayes, Pulford, 1995;O'Brien , Tew, 1996;Pakunlu et al, 2003). Among the mechanisms of purification of cellular metabolism involved in the

[12] Therapeutic potential of adenosine receptor modulators in cancer treatment

  • Authors: Prasenjit Maity, Swastika Ganguly, P. Deb
  • Year: 2025
  • Venue: RSC Advances
  • URL: https://www.semanticscholar.org/paper/3e82b478c427352d279e243b1d513c125ec39a1f
  • DOI: 10.1039/d5ra02235e
  • PMID: 40530308
  • PMCID: 12171953
  • Citations: 10
  • Influential citations: 1
  • Summary: This review primarily focuses on the signaling pathways and the therapeutic potential of various adenosine receptor agonists and antagonists across various cancer types, highlighting their ongoing evaluation in preclinical and clinical trials, and potentially leading to the development of advanced treatments that could aid in tumor suppression.
  • Evidence snippets:
  • Snippet 1 (score: 0.390) > Selective modulators of adenosine receptors provide promising strategies for cancer treatment by directly inhibiting tumour growth or modifying the tumour microenvironment to enhance anti-tumour immune responses. These modulators target specic adenosine receptors: A 1 , A 2A , A 2B , and A 3 , each playing distinct roles in cancer progression (Table 2). Their effects and mechanisms in cancer treatment are actively being explored, and future research will likely continue to rene these pathways for more targeted and effective therapies. Below is an elaboration on the selective modulators for each receptor type, their effects, and mechanisms in cancer treatment. > Many studies have been conducted on the structure-activity relationship (SAR) of adenosine derivatives as agonists of the AR. Adenosine and xanthosine, two purine nucleoside Fig. 6 A 3 adenosine receptors' role in cancer: molecular signaling pathways. ERK1/2 -"Extracellular signal-regulated kinases", ATP -"Adenosine triphosphate", PKA -"protein kinase A", PIP2 -"Phosphatidylinositol 4,5-bisphosphate", FoxP3 -"Forkhead box P3", GSK-3b -"Glycogen synthase kinase-3b", IP3 -"Inositol trisphosphate", cAMP -"Cyclic adenosine monophosphate", JNK -"c-Jun N-terminal kinases", DAG "Diacylglycerol", PKC -"Protein kinase C", PKB -"Protein kinase B", RhoA -"Ras homolog family member A" and NFkB -"Nuclear factor kappalight-chain-enhancer of activated B cells". The figure was created in BioRender. Deb, P. (2025). Review RSC Advances derivatives, constitute the basis for the majority of known AR agonists. Many agonists that target distinct AR subtypes have been developed due to modications to the physiological agonist adenosine.
  • Snippet 2 (score: 0.381) > Adenosine is ubiquitous, released by nearly all cells, and produced in the extracellular environment through the breakdown of ATP by a cascade of ectoenzymes, including apyrase (CD39) and 5 0 -nucleotidase (CD73). 24 When adenosine levels (calcium ion), WBCs (white blood cells), CNS (central nervous system), PI3K (phosphoinositide 3-kinase), ADORA (adenosine receptor A), nM (nanomolar), MAPK (mitogen-activated protein kinase). > become excessive, the body has mechanisms to reduce them. Adenosine kinase can convert adenosine back into adenosine monophosphate (AMP) through phosphorylation, and adenosine deaminase (ADA) can deaminate adenosine into inosine. 16,17 Both processes require sufficient oxygen to function effectively. However, these enzymes may not work efficiently in areas with low oxygen levels, such as in tumours affected by hypoxia. This can lead to the accumulation of adenosine in these regions, which can affect inammation and contribute to tumour growth. Thus, the oxygen-dependent regulation of adenosine metabolism plays a crucial role in the tumour microenvironment. 17 levated levels of CD73 have been noted in multiple cancer types, such as breast, colon, ovarian, melanoma, glioma, glioblastoma, leukemia, and bladder cancer. 18 denosine, in turn, can act on immune cells and other cells in the tumour microenvironment, promoting immunosuppression and supporting tumour growth and metastasis. Therefore, CD73 expression in cancer cells is of interest as a potential target for therapeutic interventions to modulate the immune response against tumours. 19,25,26 denosine is a potent compound that inuences various cells and tissues, including platelets, coronary arteries, smooth muscle, cardiac muscle, and immune cells. 27 As an extracellular messenger, it plays a role in conditions such as neurodegenerative diseases, psychiatric disorders, heart issues, lung injuries, cancers, and eye diseases. 28

[13] Mitochondrial transplantation as a promising therapy for mitochondrial diseases

  • Authors: Tian-Guang Zhang, Chaoyu Miao
  • Year: 2022
  • Venue: Acta Pharmaceutica Sinica. B
  • URL: https://www.semanticscholar.org/paper/72802097939b0bffc319c93d05128d7e3160e0eb
  • DOI: 10.1016/j.apsb.2022.10.008
  • PMID: 36970208
  • PMCID: 10031255
  • Citations: 84
  • Influential citations: 1
  • Summary: Different techniques used in mitochondrial isolation and delivery, mechanisms of mitochondrial internalization and consequences of mitochondrial transplantation, along with challenges for clinical application are presented.
  • Evidence snippets:
  • Snippet 1 (score: 0.389) > Mitochondria, the vital organelles of eukaryotic cells, are integrators of various cellular metabolic pathways, including oxidative phosphorylation, fatty acid oxidation, urea cycle, Krebs cycle, ketogenesis and gluconeogenesis 1 . Mitochondria are also important in many other essential cellular processes such as calcium homeostasis, lipid metabolism, amino acid metabolism, biosynthesis of heme, and thermogenesis 2 . However, they also have important roles in many pathways which can cause both apoptosis and necrosis 3 . Therefore, the importance of the mitochondrion in the maintenance of cellular homeostasis is well established, meanwhile a large amount of evidence shows that mitochondrial dysfunction is deleterious 4 . > Due to the essential function of mitochondria in the human body, mitochondrial dysfunction causes a great variety of mitochondrial diseases, which can affect almost all the organs in the body and present at any age 4,5 . Mitochondrial diseases are a group of metabolic disorders characterized by energy metabolism dysfunction. The pathophysiology is further complicated by the involvement of genetic mutations in nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) which encode mitochondrial proteins. This means that mitochondrial diseases may result from inheritance for nDNA mutations and maternal inheritance for mtDNA mutations. The estimated minimum prevalence of mitochondrial diseases is 1 in 5000, whereas it could be higher 6 . > As advances in molecular and biochemical methodologies led to a better understanding of the mechanisms of mitochondrial disorders for various diseases, mitochondria have become a major target for research institutions and pharma companies. Pharmacological approaches include dietary supplements such as agents increasing respiratory chain function (coenzyme Q10 and riboflavin), agents inducing mitochondrial biogenesis (AICAR and bezafibrate), antioxidants (vitamin C and vitamin E), mitochondrial substrates (L-carnitine) and so on 7,8 . However, these agents fail to significantly alleviate disease symptoms or effectively slow disease progressions, there has therefore been no satisfactory therapeutic strategy available for mitochondrial diseases so far 9 . In addition, all new drugs under clinical trials for treatment of mitochondrial diseases are unable to cure these diseases permanently 9 .

[14] Adenosine A3 Receptor: From Molecular Signaling to Therapeutic Strategies for Heart Diseases

  • Authors: Ratchanee Duangrat, W. Parichatikanond, W. Chanmahasathien, S. Mangmool
  • Year: 2024
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/6ac528ef44867189c2f792b916ab55910821b4ec
  • DOI: 10.3390/ijms25115763
  • PMID: 38891948
  • PMCID: 11171512
  • Citations: 10
  • Summary: Modulating A3ARs serves as a potential therapeutic approach, fueling considerable interest in developing compounds that target A3ARs as potential treatments for heart diseases.
  • Evidence snippets:
  • Snippet 1 (score: 0.388) > Cardiovascular diseases (CVDs), particularly heart failure, are major contributors to early mortality globally. Heart failure poses a significant public health problem, with persistently poor long-term outcomes and an overall unsatisfactory prognosis for patients. Conventionally, treatments for heart failure have focused on lowering blood pressure; however, the development of more potent therapies targeting hemodynamic parameters presents challenges, including tolerability and safety risks, which could potentially restrict their clinical effectiveness. Adenosine has emerged as a key mediator in CVDs, acting as a retaliatory metabolite produced during cellular stress via ATP metabolism, and works as a signaling molecule regulating various physiological processes. Adenosine functions by interacting with different adenosine receptor (AR) subtypes expressed in cardiac cells, including A1AR, A2AAR, A2BAR, and A3AR. In addition to A1AR, A3AR has a multifaceted role in the cardiovascular system, since its activation contributes to reducing the damage to the heart in various pathological states, particularly ischemic heart disease, heart failure, and hypertension, although its role is not as well documented compared to other AR subtypes. Research on A3AR signaling has focused on identifying the intricate molecular mechanisms involved in CVDs through various pathways, including Gi or Gq protein-dependent signaling, ATP-sensitive potassium channels, MAPKs, and G protein-independent signaling. Several A3AR-specific agonists, such as piclidenoson and namodenoson, exert cardioprotective impacts during ischemia in the diverse animal models of heart disease. Thus, modulating A3ARs serves as a potential therapeutic approach, fueling considerable interest in developing compounds that target A3ARs as potential treatments for heart diseases.

[15] Pathological Features in Paediatric Patients with TK2 Deficiency

  • Authors: C. Jou, A. Nascimento, A. Codina, J. Montoya, E. López-Gallardo et al.
  • Year: 2022
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/06d50f7fe5b2be00cf3fcf5dcd84786a3357c0b8
  • DOI: 10.3390/ijms231911002
  • PMID: 36232299
  • PMCID: 9570075
  • Citations: 5
  • Summary: The pathological features in the muscle showed substantial differences in the youngest patients when compared with those that had a later onset of the disease, and additional ultrastructural features are described in the Muscle biopsy, such as sarcomeric de-structuration in the young patients with a more severe phenotype.
  • Evidence snippets:
  • Snippet 1 (score: 0.383) > The mitochondria contains the most intricate metabolic pathways within the cellular metabolism. This complexity is partially explained by the double genetic origin that controls oxidative phosphorylation, where proteins are codified by either nuclear or mitochondrial DNA, and by the fundamental pathways that occur in mitochondria [1,2]. All manners of clinical presentations, ages of disease onset, and inheritance types are possible in mitochondrial diseases, which are a group of rare genetic disorders that impair different mitochondrial biological functions, including ATP biosynthesis [2,3]. Thus, mitochondrial diseases can be caused by mutations in nuclear and mitochondrial genes, and defects in over 300 genes are reported to cause mitochondrial disease [3]. > Mitochondrial thymidine kinase (TK2) is a nuclear DNA-encoded mitochondrial enzyme that catalyses the phosphorylation of thymidine in mitochondria. Its function is essential for thymidine and deoxycytidine triphosphate (dTTP and dCTP) synthesis in noncycling cells to maintain and control mitochondrial DNA (mtDNA) replication. Thus, mutations in the TK2 gene cause mtDNA depletion or multiple mtDNA deletion syndromes [1], which has a deep impact on mitochondrial energy metabolism. Regarding the natural history of the disease, a large series of patients have been previously reported [4][5][6][7][8][9], and the clinical spectrum has been extensively described, with three main phenotypes: (i) infantile-onset myopathy with severe mtDNA depletion, frequent neurological involvement, and a rapid progression to early mortality; (ii) childhood-onset myopathy, with mtDNA depletion and a moderate-to-severe progression of generalized weakness; and (iii) late-onset myopathy, with mild limb weakness at onset and a progression to respiratory insufficiency [6]. Although skeletal muscle seems to be the target organ in TK2 deficiency, it has been suggested that tissues other than muscles may be involved, such as the brain, eyes, heart, and liver [10].

[16] Cellular resistance mechanisms in cancer and the new approaches to overcome resistance mechanisms chemotherapy

  • Authors: Hajir A Al Saihati, A. Rabaan
  • Year: 2023
  • Venue: Saudi Medical Journal
  • URL: https://www.semanticscholar.org/paper/2125940b56a558f93000ed3711007581d1237506
  • DOI: 10.15537/smj.2023.44.4.20220600
  • PMID: 37062547
  • PMCID: 10153614
  • Citations: 7
  • Summary: Finding new medications that can reverse MDR in malignancy cells will augment efficacy of chemotherapeutic agents and allow us to treat cancers that are now incurable.
  • Evidence snippets:
  • Snippet 1 (score: 0.381) > determine the best treatment plan for a specific cancer patient undergoing standard chemotherapy. 1 argeted medications, on the other hand, have benefited from individualized therapy. The advancement of genomic, proteomic, transcriptomic, and screening technologies has led to a better understanding of the molecular pathways that cause specific malignant tumors to originate. Drugs have been developed based on these findings that target a pathway or protein stimulated in the malignant tumor. These have been stimulated kinases, like epidermal growth factor receptor (EGFR) in melanoma, B-Raf proto-oncogene, serine/threonine kinase (BRAF) in pulmonary cancer, and fms-like tyrosine kinase 3 (FLT3) in acute myeloid leukemia (AML) cases. Resistance mechanisms to several chemotherapeutic medicines have been studied widely in mice and cancer cell line models. Bypassing the blocked signaling route, enriched drug efflux via ABC superfamily multi-drug efflux transporters, downregulation of the principal drug target, and chemical changes of medicines into non-effective metabolites are the main processes. Aside from integrating the ultimate understanding of drug resistance mechanisms into clinical practice, only a few of these mechanisms have been proven effective outside of the laboratory context (namely, in patients). In combination with the development of new drug resistance and molecular mechanisms, modern cancer genome sequencing may lead to the validation and identification of clinically relevant resistance mechanisms, allowing for an improved context for using personalized therapeutic regimens in the best treatment decisions for many malignancy cases. 1 We will discuss the most up-to-date information on the cellular resistance mechanisms to chemotherapy, the chemotherapeutics utilized in treatment, and the mechanisms of action of new prospective anti-cancer medicines targeted to overcome these resistance mechanisms. > Drug resistance in cancer chemotherapy. Drug resistance is responsible for more than 90% of cancerrelated deaths. Improved drug efflux, genetic elements (gene amplifications, mutations, and epigenetic alterations), greater deoxyribonucleic acid (DNA) repair capacity, growth factors, and increased xenobiotic metabolism are all possible reasons for MDR of malignant cells during chemotherapy (Figure 1).

[17] Molecular heterogeneity of pyruvate kinase deficiency

  • Authors: P. Bianchi, E. Fermo
  • Year: 2020
  • Venue: Haematologica
  • URL: https://www.semanticscholar.org/paper/37c7c4511f68d4b50ec2fcb00b06ff951dee336f
  • DOI: 10.3324/haematol.2019.241141
  • PMID: 33054047
  • PMCID: 7556514
  • Citations: 10
  • Summary: The extensive molecular heterogeneity of PK deficiency is examined, focusing on the diagnostic impact of genotypes and new acquisitions on pathogenic non-canonical variants and the weakness in understanding the genotype-phenotype correlation.
  • Evidence snippets:
  • Snippet 1 (score: 0.381) > Red cell pyruvate kinase (PK) deficiency is the most common glycolytic defect associated with congenital non-spherocytic hemolytic anemia. The disease, transmitted as an autosomal recessive trait, is caused by mutations in the PKLR gene and is characterized by molecular and clinical heterogeneity; anemia ranges from mild or fully compensated hemolysis to life-threatening forms necessitating neonatal exchange transfusions and/or subsequent regular transfusion support; complications include gallstones, pulmonary hypertension, extramedullary hematopoiesis and iron overload. Since identification of the first pathogenic variants responsible for PK deficiency in 1991, more than 300 different variants have been reported, and the study of molecular mechanisms and the existence of genotype-phenotype correlations have been investigated in-depth. In recent years, during which progress in genetic analysis, next-generation sequencing technologies and personalized medicine have opened up important landscapes for diagnosis and study of molecular mechanisms of congenital hemolytic anemias, genotyping has become a prerequisite for accessing new treatments and for evaluating disease state and progression. This review examines the extensive molecular heterogeneity of PK deficiency, focusing on the diagnostic impact of genotypes and new acquisitions on pathogenic non-canonical variants. The recent progress and the weakness in understanding the genotype-phenotype correlation, and its practical usefulness in light of new therapeutic opportunities for PK deficiency are also discussed.

[18] New Insights into Mitochondria in Health and Diseases

  • Authors: Ya Li, Huhu Zhang, Chunjuan Yu, Xiaolei Dong, Fanghao Yang et al.
  • Year: 2024
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/23002a4ffabfd043f52c664f4d5acab85b8dcac0
  • DOI: 10.3390/ijms25189975
  • PMID: 39337461
  • PMCID: 11432609
  • Citations: 39
  • Summary: This overview outlines the various mechanisms by which mitochondria are involved in numerous illnesses and cellular physiological activities and provides new discoveries regarding the involvement of mitochondria in both disorders and the maintenance of good health.
  • Evidence snippets:
  • Snippet 1 (score: 0.381) > Mitochondria are essential organelles within cells, playing critical roles not only in energy metabolism but also in various cellular activities, such as cell differentiation, signal transduction, and apoptosis. Mitochondrial dysfunction is implicated in a range of diseases, including but not limited to diabetes and its complications, neurodegenerative disorders, myocardial ischemia-reperfusion injury, and heart failure. Therefore, investigating the structure and function of mitochondria as well as the mechanisms underlying mitochondrial dysfunction in disease contexts holds significant scientific and clinical importance. > Basic scientific research: Diseases manifest systemically and exhibit complexity; thus, it is imperative to understand mitochondrial structure at the molecular level along with known pathways while characterizing novel pathways that influence mitochondrial behavior and functionality. For instance, mapping genetic interactions among genes encoding mitochondrial proteins can elucidate interrelations between different aspects of mitochondrial function. The first focused map of mitochondria has been constructed in yeast models, revealing dense and significant connections among localization pathways distributed across various mitochondrial compartments [126]. > Disease diagnosis: A comprehensive understanding of the mechanisms governing mitochondrial dysfunction can facilitate the development of innovative diagnostic tools. By monitoring specific indicators related to mitochondrial function, earlier diagnosis of diseases associated with mitochondrial impairment becomes feasible. Employing nextgeneration sequencing technologies for analyzing the mitochondrial proteome aids in identifying novel proteins and pathways linked to mitochondria while enabling streamlined diagnostics alongside genetic counseling opportunities for patients with mitochondrial diseases [127]. > Drug development: Advancements in our comprehension of how mitochondria contribute to disease processes may promote targeted therapeutic strategies. For example, metformin-a widely used antidiabetic agent-has recently been repurposed as an anticancer drug; its combination with standard epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) significantly improves progression-free survival rates and overall survival outcomes for patients with advanced lung adenocarcinoma [125]. > Personalized medicine: Given that manifestations of mitochondrial dysfunction may vary among individuals, research into mitochondria provides a theoretical foundation for personalized medicine by allowing tailored treatment plans based on individual states of mitochondrial functionality [127].

Notes

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