Table 3.

Autosomal Recessive Leigh-Like Syndromes

Disease NameGeneDistinguishing Clinical FeaturesLaboratory FindingsReference
Mitochondrial DNA depletion syndrome (hepatocerebral) POLG Roving eye movements, prominent seizuresHepatocerebral diseaseMultiple RCE deficiencies 1, isolated complex IV defic (rare) Taanman et al [2009]
Mitochondrial DNA depletion syndrome (encephalopathic)SUCLA2 2Hypotonia, muscle atrophy, hyperkinesia, severe SNHLGrowth restrictionMMA, multiple RCE deficElpeleg et al [2005], Ostergaard et al [2007]
SUCLG1 Severe myopathyRecurrent hepatic failureMMA, multiple RCE defic Van Hove et al [2010]
FBXL4 SeizuresFacial dysmorphism, skeletal abnormalities, poor growth, gastrointestinal dysmotility, renal tubular acidosisMultiple RCE defic Shamseldin et al [2012]
Defect of mt tRNA modification TRMU LS reported in 1 personUsually → benign reversible liver failure w/o neurologic symptoms Taylor et al [2014]
GTPBP3 LLS in 4 unrelated personsHypertrophic cardiomyopathy Kopajtich et al [2014]
Mitochondrial translation (formylation) defect MTFMT Cystic leukoencephalopathy in someMay be slowly progressive in some, w/survival into 20sTucker et al [2011], Haack et al [2014]
Mitochondrial translation (mitoribosome) defect MRPS34 LS in 4 unrelated persons, LLS in 2 affected sibsMay 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 othersIsolated 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 MRIImprovement can occur, liver failure in some personsMultiple 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 neuropathyCataracts, growth hormone defic, skeletal dysplasia in 3 adultsEnzymology not performed Schwartzentruber et al [2014]
Asparaginyl aminoacyl tRNA synthetase deficiency (mt translation defect) NARS2 Seizures, myoclonus, & SNHL in 2 sibsMultiple RCE defic Simon et al [2015]
Mitochondrial translation (elongation) defect GFM1 Axial hypotonia, spasticity, refractory seizuresProgressive hepato-encephalopathy in someMultiple RCE defic Valente et al [2007]
TSFM Juvenile-onset, ataxia, neuropathy, optic atrophyGrowth restriction, HCM Ahola et al [2014]
GFM2 LL encephalopathy in 2 sibsScoliosis, bradycardiaLow CIII+IV activity Fukumura et al [2015]
Mitochondrial translation defectMTRFR (C12orf65)Ophthalmoplegia, optic atrophy, axonal neuropathyRelatively slow disease progressionMultiple RCE defic (fbs) Antonicka et al [2010]
Polyribonucleotide nucleotidyltransferase deficiencyPNPT1 3Choreoathetosis & dyskinesia; also isolated SNHLSevere hypotoniaComplex III+IV defic in liver in 1 person (nml activ in mb & fbs) Vedrenne et al [2012]
Primary coenzyme Q10 deficiency PDSS2 Refractory seizuresNephrotic syndrome 4Complexes I+III, II+III & coenzyme Q10 defic (mb) López et al [2006]
COQ9 Hypotonia, seizuresComplexes II+III & coenzyme Q10 defic Danhauser et al [2016]
Primary pyruvate dehydrogenase (PDH) complex deficiency PDHB CC agenesis / hypoplasiaPDH 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 encephalopathyHypoglycemia, ketoacidosis, liver failurePDH defic (fbs), ↑ plasma branched-chain amino acidsGrafakou et al [2003], Quinonez et al [2013]
Lipoic acid synthesis defect LIAS Seizures w/burst suppression (EEG)Mild HCMCombined 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/FILALiver 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 activSoreze et al [2013], Tort et al [2014]
MEGDEL syndrome (See SERAC1 Deficiency.) SERAC1 SNHLMay have liver involvement in infancy; later normalizes3-methylglutaconic aciduria Wortmann et al [2012]
Defects of mitochondrial dynamics DNM1L Hypotonia, seizuresMultiple RCE defic Zaha et al [2016]
MFF Seizures, microcephaly Koch et al [2016]
OPA1 Hypotonia, peripheral neuropathy, cerebellar ataxiaOphthalmoplegiaComplex IV defic Rubegni et al [2017]
SLC25A46 Spastic diplegia Janer et al [2016]
Mitochondrial chaperone deficiency CLPB Developmental regression, seizuresCataracts3-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 & contracturesEnzymology not performed Spiegel et al [2009]
Thiamine metabolism dysfunction syndrome 5 (episodic encephalopathy type) TPK1 Episodic encephalopathy, ataxia, dystonia, spasticity2-ketoglutaric aciduria Mayr et al [2011]
Biotinidase deficiency BTD Deafness, optic atrophy, seizures, ataxia 4Alopecia, eczemaCharacteristic organic aciduria Mitchell et al [1986]
Biotin-thiamine-responsive basal ganglia disease (thiamine transporter-2 deficiency) SLC19A3 See footnote 4.Nml RCE activityFassone et al [2013], Gerards et al [2013]
Ethylmalonic encephalopathy ETHE1 Neurodevelopmental delay & regression, pyramidal & extrapyramidal signsAcrocyanosis, petechiae & diarrhea in infancyEthylmalonic 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 deficiencyECHS1 3Psychomotor delay, SNHL, nystagmus, hypotonia, spasticity, athetoid mvmtsHCM in 1 person↑ urinary excretion of S-(2-carboxypropyl) cysteine; nml RCE activ in 1 person, mult RCE defic in 1 otherPeters 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]

α-KGDH = alpha-ketoglutarate dehydrogenase; BCKDH = branched chain ketoacid dehydrogenase; CC = corpus callosum; EEG = electroencephalogram; fbs = cultured skin fibroblasts; FILA = fatal infantile lactic acidosis; HCM = hypertrophic cardiomyopathy; LLS = Leigh-like syndrome; LS = Leigh syndrome; mb = muscle biopsy; MMA = methylmalonic aciduria; mt = mitochondrial; PDH = pyruvate dehydrogenase; RCE = respiratory chain enzyme; SNHL = sensorineural hearing loss


RCE activity measured on muscle biopsy except in one individual noted


Founder variant in Faroe Islands


One family reported


Allelic with Amish lethal microcephaly, mitochondrial thiamine pyrophosphate carrier deficiency

From: Mitochondrial DNA-Associated Leigh Syndrome and NARP

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