Table 3.

Genetic Etiologies of Mitochondrial Hepatopathies Presenting in Neonates or Infants

Mutation/ Syndrome	Defect	Onset/Age at Presentation	Hepatic Presentation	Neurological Features	Other Features	Diagnostic Tests
DGUOK (17-19)	mtDNA depletion Complex I, III, IV	Acute/early neonatal	Neonatal liver failure, progressive, cholestasis, mimic neonatal hemochromatosis, hepatocellular carcinoma risk, can have isolated liver disease	Hypotonia, developmental regression, nystagmus	Lactic acidosis, hypoglycemia	DGUOK sequence analysis
POLG (15, 16)	mtDNA depletion Complex I, III, IV	Acute/neonatal	Neonatal liver failure, micro- or macro-vesicular steatosis, cirrhosis	Encephalopathy, seizures,, myopathy, neuropathy, blindness, developmental regression	Vomiting, GERD	POLG sequence analysis or panel
MPV17/Navajo neuro-hepatopathy (20, 21)	mtDNA depletion Complex I, III, IV	Acute/neonatal	Isolated neonatal/infant liver failure or in multisystem syndrome	Sensorimotor neuropathy, progressive CNS white matter lesions	Acidosis, FTT, corneal anesthesia,/abrasions, acral mutilation	MPV 17 sequence analysis or panel
TWINKLE(PEO1) (C10ORF2) (5, 23)	mtDNA depletion DNA helicase	Acute/neonatal	Neonatal liver failure, cirrhosis, elevated liver enzymes	Encephalopathy (athetosis, ataxia, seizures), sensory neuropathy, deafness		C10ORF2 TWINKLE sequence analysis
TRMU (31, 32)	Decreased mito translation (tRNA modifying enzyme) Complex I, III, IV	Acute/neonatal	Neonatal liver failure, some recover, possibly with cirrhosis			TRMU sequence analysis
TSFM, EFG1, EF- Tu, MRPS16 (37)	Decreased mito translation (elongation)	Acute/neonatal	Liver dysfunction in infancy, hepatomegaly	Hypotonia, dystonia	Hypertrophic cardiomyopathy, tubulopathy	Sequencing individual genes e.g., TSFM or exome sequencing
SUCLG1 (22)	mtDNA depletion abnormal succinate synthesis Complex I, III, IV	Acute/neonatal	Neonatal liver failure, episodic liver failure	Hypotonia/myopathy (progressive), hearing loss	Acidosis, elevated methylmalonic acid	SUCLG1 sequence analysis
BCS1L (35)	Complex III assembly deficiency	Acute/neonatal	Neonatal liver failure, cholestasis, hepatic iron overload		Growth failure, amino- aciduria, lactic acidosis, early death (GRACILE syndrome)	BCS1L sequence analysis
SCO1 (36)	Complex IV deficiency	Acute/neonatal	Neonatal liver failure, hepatomegaly	Hypotonia	Acidosis	SCO1 sequence analysis
FARS2 (41)	Phenylalanyl tRNA synthetase	Acute/neonatal	Neonatal liver failure (Alper’s like)	Intractable seizures, encephalopathy		FARS2 sequence analysis on Nexgen
SLC25A20 (29)	Carnitine acylcarnitine translocase deficiency CACT deficiency (carnitine, FAO)	Acute/neonatal	Neonatal liver failure, steatohepatitis	Myopathy	Hypoglycemia, cardiomyopathy	SLC25A20 sequence analysis
HADHA/ LCHAD or tri-functional protein deficiency (25)	FAO defect	Acute	Hepatomegaly, fatty liver, elevated LFTs, cholestasis, liver failure, AFLP	Encephalopathy, peripheral neuropathy	Acidosis, hypoglycemia, pigmentary retinopathy	HADHA sequence analysis
CPTI deficiency (26)	Carnitine cycle FAO defect	Acute/infancy	Hepatomegaly, liver failure episodes	Reye’s-like episodes of encephalopathy	Hypoketotic hypoglycemia	CPT IA sequence analysis
CPT II deficiency (26, 27)	Carnitine cycle FAO defect	Acute/severe neonatal	Liver failure in infancy	Seizures	Hypoketotic hypoglycemia, cardiomyopathy, myopathy	CPT II sequence analysis