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IEMbase 0411: POLG-related mitochondrial DNA polymerase gamma deficiency 4A

Scope

Field Value
IEMbase ID 411
Nosology 9.2.01.01
Gene POLG
External IDs OMIM:203700; ORPHA:726
Generated mapping CANDIDATE; Mitochondrial_Neurogastrointestinal_Encephalomyopathy.yaml
Candidate DisMech targets No exact local target
Review date 2026-07-07

IEMbase phenotype signal

IEMbase represents POLG-related mitochondrial DNA polymerase gamma catalytic subunit deficiency 4A, with aliases mitochondrial depletion syndrome 4A, Alpers-Huttenlocher syndrome, and MTDPS4A. It records autosomal dominant and autosomal recessive inheritance. Biochemical rows include liver mtDNA depletion, urinary 3-methylglutaconic acid, and increased plasma lactate. Clinical rows include ataxia, developmental delay, hypotonia, intellectual disability, perinatal death, impaired vision, vomiting, intractable epilepsy, progressive liver failure, psychomotor retardation, and valproate-induced fatal liver toxicity.

DisMech phenotype coverage

The generated MNGIE candidate is not an exact match. Local Mitochondrial_Neurogastrointestinal_Encephalomyopathy.yaml includes a rare POLG-related MNGIE-like subtype, but the defining syndrome there is gastrointestinal dysmotility/cachexia, ptosis/ophthalmoplegia, neuropathy, and leukoencephalopathy, not the Alpers-Huttenlocher/hepatocerebral epilepsy-liver-failure phenotype.

Local Sensory_Ataxic_Neuropathy_Dysarthria_Ophthalmoparesis.yaml is useful POLG context and includes mtDNA instability and a valproate avoidance warning, but it is a SANDO/ataxia-neuropathy target. Local Mitochondrial_DNA_Depletion_Syndrome_7.yaml has Alpers-like hepatocerebral features but is TWNK-related, not POLG MTDPS4A.

Concordance and completeness

Judgement: true POLG Alpers-Huttenlocher/MTDPS4A local gap; reject MNGIE as an exact mapping.

The available local POLG entries cover adjacent POLG-spectrum disease, but none represents the IEMbase combination of POLG, infantile/childhood mtDNA depletion, intractable epilepsy, progressive liver failure, psychomotor regression, and valproate-triggered fatal hepatotoxicity as the primary disease identity.

Curation actions

  • Keep this record unmapped until a POLG Alpers-Huttenlocher syndrome or MTDPS4A target exists.
  • Do not map to Mitochondrial_Neurogastrointestinal_Encephalomyopathy.yaml.
  • Use local SANDO/POLG material only as general POLG-spectrum context.
  • If curated, include POLG, liver mtDNA depletion, lactate, 3-methylglutaconic acid, intractable epilepsy, progressive liver failure, psychomotor regression, and explicit valproate contraindication.