Table 4.

Genetic Etiologies of Mitochondrial Hepatopathies Presenting as Chronic Liver Disease or With Later Onset

Mutation/ Syndrome	Defect	Onset/Age at Presentation	Hepatic Presentation	Neurological Features	Other Features	Diagnostic Tests
DGUOK (18)	mtDNA depletion Complex I, III, IV	Late presentation	Progressive cholestasis, may have iron overload, HCC risk	Hypotonia, developmental regression, nystagmus	Lactic acidosis	DGUOK sequence analysis
MPV17/Navajo neurohepatopathy (21)	mtDNA depletion Complex I, III, IV	Chronic/ neonatal to childhood	Progressive liver disease or in multisystem syndrome	Sensorimotor neuropathy, progressive CNS white matter lesions	Acidosis, FTT, corneal anesthesia, abrasions, acral mutilation	MPV 17 sequence analysis
POLG/Alper’s Disease (15, 16)	mtDNA depletion Complex I, III, IV Deficiency	Sub-acute: toddlers, young adults	Later onset liver failure, macro- or micro-vesicular steatosis, cirrhosis	Intractable seizures and developmental regression, blindness, neuropathy, ataxia	Vomiting, GERD	POLG sequence analysis
TWINKLE (C10ORF2) (23)	mtDNA depletion DNA helicase	Chronic	Neonatal liver failure, cirrhosis, elevated liver enzymes	Encephalopathy (athetosis, ataxia, seizures), sensory neuropathy, deafness		C10ORF2 TWINKLE sequence analysis
TRMU (31)	Decreased mito translation (tRNA modifying enzyme)	Chronic	Chronic liver disease/cirrhosis, recurrent acute liver failure			TRMU sequence analysis
SUCLG (22)	mtDNA depletion abnormal succinate synthesis (ATPgen)	Chronic or episodic	Episodes liver failure	Hypotonia/myopath y (progressive), hearing loss	Acidosis	SUCLG1 sequence analysis
ACAD9 (30)	FAO defect Complex I assembly	Episodic	Episodic liver failure			ACAD9 sequencing and deletion analysis
TYMP/MNGIES (40)	Thymidine phosphorylase (TP) deficiency, Complex IV	Chronic	Liver dysfunction, macrovesicular steatosis, cirrhosis	Leuko- encephalopathy, ophthalmoplegia, ptosis, peripheral neuropathy, hearing loss	Pseudo-obstruction, GERD	Plasma thymidine and deoxyuridine levels, TP enzyme activity, TYMP sequencing
Villous atrophy syndrome (50)	Complex III defect	Chronic/early childhood	Hepatomegaly, raised liver enzymes, steatosis	Cerebellar ataxia, sensorineural deafness, seizures	Vomiting, anorexia, chronic diarrhea (resolved later in life), villous atrophy, lactic acidosis, DM
Pearson’s syndrome (24)	mtDNA deletion Complex I, III, VI	Chronic/ infancy	Cirrhosis with hepatomegaly, cholestasis, raised liver enzymes, progressive liver failure, death in early childhood		Refractory sideroblastic anemia, vacuolization of marrow precursors, variable neutropenia and thrombo- cytopenia, lactic acidosis, pancreatic insufficiency	Mt DNA common mutations and deletions screening
HADHA/LCHA D or trifunctional protein deficiency (25)	FAO defect	Chronic, infancy or later	Hepatomegaly, fatty liver, elevated LFTs, cholestasis, liver failure, acute fatty liver of pregnancy	Encephalopathy, peripheral neuropathy	Acidosis, hypoglycemia, pigmentary retinopathy	HADHA sequence analysis
CPT II/ CPT2 deficiency (27)	Carnitine cycle FAO defect	Infantile cardio- hepatopathy, adult myopathy	Liver failure episodes	Seizures	Hypoketotic hypoglycemia, cardiomyopathy, myopathy, rhabdomyolysis	CPT II sequence analysis
MADD (glutaric acidemia II) (28)	FAO defect Complex II, III	Chronic, infancy up to adulthood	Hepatomegaly, steatosis	Neurologic symptoms, myopathy	Hypoglycemia, acidosis	Sequence of ETF A, B, or ETF-DH