Table 3. [Autosomal Recessive Leigh-Like Syndromes]. - GeneReviews®

Disease Name	Gene	Distinguishing Clinical Features	Laboratory Findings	Reference
Mitochondrial DNA depletion syndrome (hepatocerebral)	POLG	Roving eye movements, prominent seizures	Hepatocerebral disease	Multiple RCE deficiencies ¹, isolated complex IV defic (rare)	Taanman et al [2009]
Mitochondrial DNA depletion syndrome (encephalopathic)	SUCLA2 ²	Hypotonia, muscle atrophy, hyperkinesia, severe SNHL	Growth restriction	MMA, multiple RCE defic	Elpeleg et al [2005], Ostergaard et al [2007]
SUCLG1	Severe myopathy	Recurrent hepatic failure	MMA, multiple RCE defic	Van Hove et al [2010]
FBXL4	Seizures	Facial dysmorphism, skeletal abnormalities, poor growth, gastrointestinal dysmotility, renal tubular acidosis	Multiple RCE defic	Shamseldin et al [2012]
Defect of mt tRNA modification	TRMU	LS reported in 1 person	Usually → benign reversible liver failure w/o neurologic symptoms	Taylor et al [2014]
GTPBP3	LLS in 4 unrelated persons	Hypertrophic cardiomyopathy	Kopajtich et al [2014]
Mitochondrial translation (formylation) defect	MTFMT	Cystic leukoencephalopathy in some	May be slowly progressive in some, w/survival into 20s	Tucker et al [2011], Haack et al [2014]
Mitochondrial translation (mitoribosome) defect	MRPS34	LS in 4 unrelated persons, LLS in 2 affected sibs	May be slowly progressive in some, w/survival into late teens	Lake et al [2017]
Phenylalanyl aminoacyl tRNA synthetase deficiency (mt translation defect) (See FARS2 Deficiency.)	FARS2	Severe epilepsy; Alpers neuropathology in others		Isolated complex IV defic in 1 person; enzymology not performed in any others	Shamseldin et al [2012]
Glutamyl aminoacyl tRNA synthetase deficiency (mt translation defect)	EARS2	Leukoencephalopathy w/thalamus & brain stem involvement & ↑ lactate on MRI	Improvement can occur, liver failure in some persons	Multiple RCE defic	Martinelli et al [2012]
Isoleucyl aminoacyl tRNA synthetase deficiency (mt translation defect)	IARS2	LS causing death at 18 mo in 1 child; SNHL, peripheral sensory neuropathy	Cataracts, growth hormone defic, skeletal dysplasia in 3 adults	Enzymology not performed	Schwartzentruber et al [2014]
Asparaginyl aminoacyl tRNA synthetase deficiency (mt translation defect)	NARS2	Seizures, myoclonus, & SNHL in 2 sibs		Multiple RCE defic	Simon et al [2015]
Mitochondrial translation (elongation) defect	GFM1	Axial hypotonia, spasticity, refractory seizures	Progressive hepato-encephalopathy in some	Multiple RCE defic	Valente et al [2007]
TSFM	Juvenile-onset, ataxia, neuropathy, optic atrophy	Growth restriction, HCM	Ahola et al [2014]
GFM2	LL encephalopathy in 2 sibs	Scoliosis, bradycardia	Low CIII+IV activity	Fukumura et al [2015]
Mitochondrial translation defect	MTRFR (C12orf65)	Ophthalmoplegia, optic atrophy, axonal neuropathy	Relatively slow disease progression	Multiple RCE defic (fbs)	Antonicka et al [2010]
Polyribonucleotide nucleotidyltransferase deficiency	PNPT1 ³	Choreoathetosis & dyskinesia; also isolated SNHL	Severe hypotonia	Complex III+IV defic in liver in 1 person (nml activ in mb & fbs)	Vedrenne et al [2012]
Primary coenzyme Q₁₀ deficiency	PDSS2	Refractory seizures	Nephrotic syndrome ⁴	Complexes I+III, II+III & coenzyme Q₁₀ defic (mb)	López et al [2006]
COQ9	Hypotonia, seizures		Complexes II+III & coenzyme Q₁₀ defic	Danhauser et al [2016]
Primary pyruvate dehydrogenase (PDH) complex deficiency	PDHB	CC agenesis / hypoplasia		PDH defic (fbs)	Quintana et al [2009]
PDHX	Thin CC / CC agenesis; status epilepticus late in disease (teens/20s)		Schiff et al [2006]
DLAT	Hypotonia, seizures, ataxia		Head et al [2005]
DLD	Episodic encephalopathy	Hypoglycemia, ketoacidosis, liver failure	PDH defic (fbs), ↑ plasma branched-chain amino acids	Grafakou et al [2003], Quinonez et al [2013]
Lipoic acid synthesis defect	LIAS	Seizures w/burst suppression (EEG)	Mild HCM	Combined defic of PDH + glycine cleavage enzyme, ↑ urine & plasma glycine, defic lipoylated proteins on western blot	Baker et al [2014]
LIPT1	1 person w/LS; 2 w/FILA	Liver dysfunction	↑ glutamine & proline, ↓ levels of lysine & branched-chain amino acids & nml glycine (vs other lipoic acid synthesis defects); severe ↓ of PDH & α-KGDH activ & strongly ↓ BCKDH activ (fbs); nml RCE activ	Soreze et al [2013], Tort et al [2014]
MEGDEL syndrome (See SERAC1 Deficiency.)	SERAC1	SNHL	May have liver involvement in infancy; later normalizes	3-methylglutaconic aciduria	Wortmann et al [2012]
Defects of mitochondrial dynamics	DNM1L	Hypotonia, seizures		Multiple RCE defic	Zaha et al [2016]
MFF	Seizures, microcephaly			Koch et al [2016]
OPA1	Hypotonia, peripheral neuropathy, cerebellar ataxia	Ophthalmoplegia	Complex IV defic	Rubegni et al [2017]
SLC25A46	Spastic diplegia		Janer et al [2016]
Mitochondrial chaperone deficiency	CLPB	Developmental regression, seizures	Cataracts	3-methylglutaconic aciduria	Saunders et al [2015]
Thiamine metabolism dysfunction syndrome 4 (bilateral striatal degeneration & progressive polyneuropathy type) ⁵	SLC25A19	Bilateral striatal necrosis; episodic encephalopathy; chronic progressive polyneuropathy → distal weakness & contractures		Enzymology not performed	Spiegel et al [2009]
Thiamine metabolism dysfunction syndrome 5 (episodic encephalopathy type)	TPK1	Episodic encephalopathy, ataxia, dystonia, spasticity		2-ketoglutaric aciduria	Mayr et al [2011]
Biotinidase deficiency	BTD	Deafness, optic atrophy, seizures, ataxia ⁴	Alopecia, eczema	Characteristic organic aciduria	Mitchell et al [1986]
Biotin-thiamine-responsive basal ganglia disease (thiamine transporter-2 deficiency)	SLC19A3	See footnote 4.		Nml RCE activity	Fassone et al [2013], Gerards et al [2013]
Ethylmalonic encephalopathy	ETHE1	Neurodevelopmental delay & regression, pyramidal & extrapyramidal signs	Acrocyanosis, petechiae & diarrhea in infancy	Ethylmalonic aciduria	Mineri et al [2008]
3-hydroxyisobutyryl-CoA hydrolase deficiency	HIBCH	Developmental regression, seizures, ataxia		↑ plasma 4-hydroxybutyrylcarnitine levels; variable defic of RCEs & PDH	Ferdinandusse et al [2013]
Short-chain enoyl-CoA hydratase deficiency	ECHS1 ³	Psychomotor delay, SNHL, nystagmus, hypotonia, spasticity, athetoid mvmts	HCM in 1 person	↑ urinary excretion of S-(2-carboxypropyl) cysteine; nml RCE activ in 1 person, mult RCE defic in 1 other	Peters et al [2014], Sakai et al [2015]
Manganese-dependent β-galactosyltransferase deficiency (See SLC39A8-CDG.)	SLC39A8	Psychomotor delay, dystonia, seizures		↓ manganese levels, complex IV defic (muscle)	Riley et al [2017]

Disease Name

Gene

Distinguishing Clinical Features

Laboratory Findings

Reference

Neurologic

Other

Mitochondrial DNA depletion syndrome (hepatocerebral)

POLG

Roving eye movements, prominent seizures

Hepatocerebral disease

Multiple RCE deficiencies ¹, isolated complex IV defic (rare)

Taanman et al [2009]

Mitochondrial DNA depletion syndrome (encephalopathic)

SUCLA2 ²

Hypotonia, muscle atrophy, hyperkinesia, severe SNHL

Growth restriction

MMA, multiple RCE defic

Elpeleg et al [2005], Ostergaard et al [2007]

SUCLG1

Severe myopathy

Recurrent hepatic failure

MMA, multiple RCE defic

Van Hove et al [2010]

FBXL4

Seizures

Facial dysmorphism, skeletal abnormalities, poor growth, gastrointestinal dysmotility, renal tubular acidosis

Multiple RCE defic

Shamseldin et al [2012]

Defect of mt tRNA modification

TRMU

LS reported in 1 person

Usually → benign reversible liver failure w/o neurologic symptoms

Taylor et al [2014]

GTPBP3

LLS in 4 unrelated persons

Hypertrophic cardiomyopathy

Kopajtich et al [2014]

Mitochondrial translation (formylation) defect

MTFMT

Cystic leukoencephalopathy in some

May be slowly progressive in some, w/survival into 20s

Tucker et al [2011], Haack et al [2014]

Mitochondrial translation (mitoribosome) defect

MRPS34

LS in 4 unrelated persons, LLS in 2 affected sibs

May be slowly progressive in some, w/survival into late teens

Lake et al [2017]

Phenylalanyl aminoacyl tRNA synthetase deficiency (mt translation defect) (See FARS2 Deficiency.)

FARS2

Severe epilepsy; Alpers neuropathology in others

Isolated complex IV defic in 1 person; enzymology not performed in any others

Shamseldin et al [2012]

Glutamyl aminoacyl tRNA synthetase deficiency (mt translation defect)

EARS2

Leukoencephalopathy w/thalamus & brain stem involvement & ↑ lactate on MRI

Improvement can occur, liver failure in some persons

Multiple RCE defic

Martinelli et al [2012]

Isoleucyl aminoacyl tRNA synthetase deficiency (mt translation defect)

IARS2

LS causing death at 18 mo in 1 child; SNHL, peripheral sensory neuropathy

Cataracts, growth hormone defic, skeletal dysplasia in 3 adults

Enzymology not performed

Schwartzentruber et al [2014]

Asparaginyl aminoacyl tRNA synthetase deficiency (mt translation defect)

NARS2

Seizures, myoclonus, & SNHL in 2 sibs

Multiple RCE defic

Simon et al [2015]

Mitochondrial translation (elongation) defect

GFM1

Axial hypotonia, spasticity, refractory seizures

Progressive hepato-encephalopathy in some

Multiple RCE defic

Valente et al [2007]

TSFM

Juvenile-onset, ataxia, neuropathy, optic atrophy

Growth restriction, HCM

Ahola et al [2014]

GFM2

LL encephalopathy in 2 sibs

Scoliosis, bradycardia

Low CIII+IV activity

Fukumura et al [2015]

Mitochondrial translation defect

MTRFR (C12orf65)

Ophthalmoplegia, optic atrophy, axonal neuropathy

Relatively slow disease progression

Multiple RCE defic (fbs)

Antonicka et al [2010]

Polyribonucleotide nucleotidyltransferase deficiency

PNPT1 ³

Choreoathetosis & dyskinesia; also isolated SNHL

Severe hypotonia

Complex III+IV defic in liver in 1 person (nml activ in mb & fbs)

Vedrenne et al [2012]

Primary coenzyme Q₁₀ deficiency

PDSS2

Refractory seizures

Nephrotic syndrome ⁴

Complexes I+III, II+III & coenzyme Q₁₀ defic (mb)

López et al [2006]

COQ9

Hypotonia, seizures

Complexes II+III & coenzyme Q₁₀ defic

Danhauser et al [2016]

Primary pyruvate dehydrogenase (PDH) complex deficiency

PDHB

CC agenesis / hypoplasia

PDH defic (fbs)

Quintana et al [2009]

PDHX

Thin CC / CC agenesis; status epilepticus late in disease (teens/20s)

Schiff et al [2006]

DLAT

Hypotonia, seizures, ataxia

Head et al [2005]

DLD

Episodic encephalopathy

Hypoglycemia, ketoacidosis, liver failure

PDH defic (fbs), ↑ plasma branched-chain amino acids

Grafakou et al [2003], Quinonez et al [2013]

Lipoic acid synthesis defect

LIAS

Seizures w/burst suppression (EEG)

Mild HCM

Combined defic of PDH + glycine cleavage enzyme, ↑ urine & plasma glycine, defic lipoylated proteins on western blot

Baker et al [2014]

LIPT1

1 person w/LS; 2 w/FILA

Liver dysfunction

↑ glutamine & proline, ↓ levels of lysine & branched-chain amino acids & nml glycine (vs other lipoic acid synthesis defects); severe ↓ of PDH & α-KGDH activ & strongly ↓ BCKDH activ (fbs); nml RCE activ

Soreze et al [2013], Tort et al [2014]

MEGDEL syndrome (See SERAC1 Deficiency.)

SERAC1

SNHL

May have liver involvement in infancy; later normalizes

3-methylglutaconic aciduria

Wortmann et al [2012]

Defects of mitochondrial dynamics

DNM1L

Hypotonia, seizures

Multiple RCE defic

Zaha et al [2016]

MFF

Seizures, microcephaly

Koch et al [2016]

OPA1

Hypotonia, peripheral neuropathy, cerebellar ataxia

Ophthalmoplegia

Complex IV defic

Rubegni et al [2017]

SLC25A46

Spastic diplegia

Janer et al [2016]

Mitochondrial chaperone deficiency

CLPB

Developmental regression, seizures

Cataracts

3-methylglutaconic aciduria

Saunders et al [2015]

Thiamine metabolism dysfunction syndrome 4 (bilateral striatal degeneration & progressive polyneuropathy type) ⁵

SLC25A19

Bilateral striatal necrosis; episodic encephalopathy; chronic progressive polyneuropathy → distal weakness & contractures

Enzymology not performed

Spiegel et al [2009]

Thiamine metabolism dysfunction syndrome 5 (episodic encephalopathy type)

TPK1

Episodic encephalopathy, ataxia, dystonia, spasticity

2-ketoglutaric aciduria

Mayr et al [2011]

Biotinidase deficiency

BTD

Deafness, optic atrophy, seizures, ataxia ⁴

Alopecia, eczema

Characteristic organic aciduria

Mitchell et al [1986]

Biotin-thiamine-responsive basal ganglia disease (thiamine transporter-2 deficiency)

SLC19A3

See footnote 4.

Nml RCE activity

Fassone et al [2013], Gerards et al [2013]

Ethylmalonic encephalopathy

ETHE1

Neurodevelopmental delay & regression, pyramidal & extrapyramidal signs

Acrocyanosis, petechiae & diarrhea in infancy

Ethylmalonic aciduria

Mineri et al [2008]

3-hydroxyisobutyryl-CoA hydrolase deficiency

HIBCH

Developmental regression, seizures, ataxia

↑ plasma 4-hydroxybutyrylcarnitine levels; variable defic of RCEs & PDH

Ferdinandusse et al [2013]

Short-chain enoyl-CoA hydratase deficiency

ECHS1 ³

Psychomotor delay, SNHL, nystagmus, hypotonia, spasticity, athetoid mvmts

HCM in 1 person

↑ urinary excretion of S-(2-carboxypropyl) cysteine; nml RCE activ in 1 person, mult RCE defic in 1 other

Peters et al [2014], Sakai et al [2015]

Manganese-dependent β-galactosyltransferase deficiency (See SLC39A8-CDG.)

SLC39A8

Psychomotor delay, dystonia, seizures

↓ manganese levels, complex IV defic (muscle)

Riley et al [2017]

From: Mitochondrial DNA-Associated Leigh Syndrome and NARP

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Adam MP, Feldman J, Mirzaa GM, et al., editors.

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