Table 3.

Mitochondrial DNA Depletion Syndromes

Phenotype 1GeneDisorder/PhenotypeAdditional Common Manifestations 2
Hepatocerebral (Encephalohepatopathic) DGUOK DGUOK deficiencyDD, hypotonia, nystagmus, lactic acidosis
POLG Alpers-Huttenlocher syndrome DD, psychomotor regression, epilepsy, hearing impairment
MPV17 MPV17 deficiency DD, hypotonia, poor weight gain, hearing impairment, lactic acidosis
TWNK Encephalohepatopathy (OMIM 271245)DD, hypotonia, lactic acidosis
TFAM Encephalohepatopathy (OMIM 617156)IUGR, hypoglycemia
Encephalomyopathic FBXL4 FBXL4 deficiency DD, hypotonia, epilepsy, hearing impairment, lactic acidosis
SUCLG1 SUCLG1 deficiency DD, hypotonia, hearing impairment, ↑ MMA
RRM2B RRM2B encephalomyopathic MDMD DD, hypotonia, GI dysmotility, renal tubulopathy
OPA1 Encephalomyopathy (OMIM 616896)DD, HCM, optic atrophy
ABAT Encephalomyopathy w/↑ GABA (OMIM 613163)DD, hypotonia, epilepsy, ↑ GABA in plasma, urine, & CSF
RNASEH1 Encephalomyopathy (OMIM 616479)Ophthalmoplegia, ptosis, ataxia
Neurogastrointestinal encephalopathic TYMP MNGIE type 1 GI dysmotility, cachexia, peripheral neuropathy, ophthalmoplegia, muscle weakness, leukoencephalopathy 3
Myopathic TK2 TK2 deficiency Hypotonia, loss of acquired motor skills
AGK Sengers syndrome (OMIM 212350)Hypotonia, HCM, cataracts
MGME1 Myopathy (OMIM 615084)Ptosis, ophthalmoplegia
SLC25A4 Cardiomyopathy (OMIM 617184)Hypotonia, HCM
(Mitochondrial DNA depletion phenotype is assoc w/autosomal dominant inheritance.)
Encephaloneuropathic TWNK Infantile-onset spinocerebellar ataxia Hypotonia, hearing impairment

CSF = cerebrospinal fluid; DD = developmental delay; GABA = gamma-aminobutyric acid; GI = gastrointestinal; HCM = hypertrophic cardiomyopathy; IUGR = intrauterine growth restriction; MDMD = mitochondrial DNA maintenance defect; MMA = methylmalonic acid; MNGIE = mitochondrial neurogastrointestinal encephalopathy


Within each phenotypic category, mitochondrial DNA depletion syndromes are ordered by relative prevalence.


Common manifestations seen in addition to the primary phenotype (i.e., in addition to encephalohepatopathy, encephalomyopathy, etc.)


Leukoencephalopathy is not present in POLG-related neurogastrointestinal encephalopathy.

From: SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria

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