Complex I-deficient Leigh syndrome spectrum 2 |
NDUFS1 | <5% | Cystic leukoencephalopathy | HCM | Complex I deficiency (mb) | Bénit et al [2001] |
NDUFS2 | <5% | | HCM | Loeffen et al [2001] |
NDUFS3 | <5% | | | Bénit et al [2004] |
NDUFS4 | ~5% | | HCM | Budde et al [2000] |
NDUFS7 | <5% | | | Triepels et al [1999] |
NDUFS8 | <5% | Leukodystrophy | HCM | Loeffen et al [1998] |
NDUFV1 | <5% | Cystic leukoencephalopathy | | Bénit et al [2001] |
NDUFV2 | 1 person | Spasticity | Optic atrophy; HCM | Cameron et al [2015] |
NDUFA2 | 1 family | | HCM | Hoefs et al [2008] |
NDUFA9 | 1 family | | | van den Bosch et al [2012] |
NDUFA10 | 1 family | | HCM | Hoefs et al [2011] |
NDUFA12 | 1 family | Severe dystonia | Hypertrichosis | Ostergaard et al [2011] |
NDUFAF2 | <5% | MRI: symmetric lesions in mamillothalamic tracts, substantia nigra / medial lemniscus, medial longitudinal fasciculus, & spinothalamic tracts | | Barghuti et al [2008] |
NDUFAF4 | 1 person | Seizures | | Complex I deficiency (fbs) | Baertling et al [2017] |
NDUFAF5 (C20orf7) | <5% | | FILA (1 person); survival into 20s in 1 family | Complex I deficiency (mb) | Sugiana et al [2008], Gerards et al [2010] |
NDUFAF6 (C8orf38) | 1 family | | | Pagliarini et al [2008] |
FOXRED1 | <5% | Seizures & myoclonus | Slowly progressive; survival possible into 20s | Calvo et al [2010], Fassone et al [2010] |
NUBPL | <1% | Characteristic MRI changes: predominant abnormalities of cerebellar cortex, deep cerebral white matter, & corpus callosum | | Calvo et al [2010] |
NDUFAF8 (C17ORF89) | 3 persons | Infantile spasms; hypsarrhythmia; periventricular cystic encephalomalacia | | Floyd et al [2016], Alston et al [2020] |
TIMMDC1 | 1 person | Cerebellar syndrome; basal ganglia abnormalities (CT); subsequent MRI unremarkable | | Kremer et al [2017] |
Complex II-deficient Leigh syndrome spectrum 2 |
SDHA | <5% | | Course may be indolent w/survival into adulthood; ±HCM. | Complex II deficiency (mb); succinate peak (brain MRS) | Bourgeron et al [1995], Pagnamenta et al [2006] |
SDHAF1 | <5% | Leukoencephalopathy on MRI (1 person w/neuropathologic LS) | | Ohlenbusch et al [2012] |
Complex III-deficient Leigh syndrome spectrum 2 |
UQCRQ | 1 family | | Slowly progressive; survival into 30s | Complex III deficiency (mb) | Barel et al [2008] |
TTC19 | <5% | Severe olivopontocerebellar atrophy | Slowly progressive; survival into 20s/30s | Ghezzi et al [2011] |
BCS1L | <5% | SNHL | Proximal renal tubulopathy, hepatic involvement, pili torti | de Lonlay et al [2001] |
Complex IV-deficient Leigh syndrome spectrum 2 |
NDUFA4 | 1 family | Epilepsy; sensory axonal peripheral neuropathy | Slowly progressive; survival into 20s/30s | Complex IV deficiency (mb) | Pitceathly et al [2013] |
COX8A | 1 person | Seizures; hypotonia; spasticity | | Hallmann et al [2016] |
SURF1 | ~50% of complex IV-deficient LS (~10% of all LS) | Developmental regression (71%); nystagmus + ophthalmoplegia (52%); movement disorder (52%) | Hypertrichosis (48%); median survival 5.4 yrs | Complex IV deficiency (more severe fbs than mb) | Wedatilake et al [2013] |
COX10 | <5% | SNHL | HCM; anemia (due to defect of mt heme A biosynthesis) | Complex IV deficiency (mb) | Antonicka et al [2003] |
COX15 | <5% | Seizures | HCM | Oquendo et al [2004] |
SCO2 | <5% | | HCM | Joost et al [2010] |
LRPPRC 3 | <5% | Metabolic & neurologic (stroke-like) crises | Survival 5 days - 30 yrs; median age at death 1.6 yrs | Mootha et al [2003], Debray et al [2011] |
TACO1 | <5% | Cognitive dysfunction; dystonia; visual impairment; periventricular white matter lesions | Late onset (4-16 yrs); slowly progressive | Weraarpachai et al [2009], Oktay et al [2020] |
PET100 4 | <5% | Prominent seizures | Survival to 20s (50%) | Lim et al [2014] |
PET117 | 1 family | | | Renkema et al [2017] |
Complex V-deficient Leigh syndrome 2 |
ATP5MD 5 | <1% | | | ↓ ATP synthesis (fbs) | Barca et al [2018] |
Leigh syndrome assoc w/defects of mitochondrial DNA maintenance |
POLG | <1% | Roving eye movements; prominent seizures; more often presents as Alpers or other epilepsy syndromes than LSS | Hepatocerebral disease | Multiple RCE deficiencies; isolated complex IV deficiency (rare) | Taanman et al [2009] |
SUCLA 6 | <5% | Hypotonia; muscle atrophy; hyperkinesia; severe SNHL | Growth retardation | MMA; multiple RCE deficiencies | Elpeleg et al [2005], Ostergaard et al [2007] |
SUCLG1 | <1% | Severe myopathy | Recurrent hepatic failure | Van Hove et al [2010] |
FBXL4 | <5% | Seizures | Facial dysmorphism, skeletal abnormalities, poor growth, GI dysmotility, renal tubular acidosis | Multiple RCE deficiencies | Shamseldin et al [2012] |
Leigh syndrome assoc w/defects of mitochondrial gene expression |
TRMU | 1 person | LS reported in 1 person | Usually causes benign reversible liver failure w/o neurologic symptoms | Multiple RCE deficiencies | Taylor et al [2014] |
GTPBP3 | <1% | | HCM | Kopajtich et al [2014] |
MTFMT | <5% | Cystic leukoencephalopathy in some & typically shows a milder clinical course | May be slowly progressive in some, w/survival into 20s | Tucker et al [2011], Hayhurst et al [2019] |
EARS2 | <5% | Leukoencephalopathy w/thalamus & brain stem involvement & ↑ lactate (MRI); MRI changes may improve w/time. | Improvement can occur; liver failure in some cases. | Martinelli et al [2012] |
FARS2 | <1% | Severe epilepsy; Alpers neuropathology in some cases | | Isolated complex IV defic in 1 person; enzymology not performed in any others | Shamseldin et al [2012] |
IARS2 | 1 person | LS → death at 18 mos in 1 child; SNHL; peripheral sensory neuropathy | Cataracts, growth hormone defic, & skeletal dysplasia in 3 adults | Enzymology not performed | Schwartzentruber et al [2014] |
NARS2 7 | <1% | SNHL | | Multiple RCE deficiencies | Simon et al [2015] |
PTCD3 | 1 person | | | Borna et al [2019] |
MRPS34 | <1% | | Microcephaly | Lake et al [2017] |
GFM1 | <1% | Axial hypotonia; spasticity; refractory seizures | Progressive hepato-encephalopathy in some cases | Valente et al [2007] |
GFM2 | <1% | | | Fukumura et al [2015] |
TSFM | <1% | Juvenile onset; ataxia; neuropathy; optic atrophy | Growth retardation; HCM | Ahola et al [2014] |
MTRFR (C12orf65) | <1% | Ophthalmoplegia; optic atrophy; axonal neuropathy | Relatively slow disease progression | Multiple RCE deficiencies (fbs) | Antonicka et al [2010] |
PNPT1 | <1% | 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] |
Leigh syndrome assoc w/defects of mitochondrial cofactor biosynthesis |
PDSS2 8 | <1% | Refractory seizures | Nephrotic syndrome | Complexes I+III, II+III, & coenzyme Q10 defic (mb) | López et al [2006] |
COQ9 8 | <1% | Refractory seizures | Antenatal onset; IUGR; HCM | Smith et al [2018] |
LIAS | <1% | Seizures w/burst suppression (EEG) | Mild HCM | Combined defic of PDH + glycine cleavage enzyme, ↑ urine & plasma glycine, deficient lipoylated proteins (western blot) | Baker et al [2014] |
LIPT1 | 1 person | 1 person w/LS; 2 w/FILA | Liver dysfunction | ↑ glutamine & proline, ↓ levels of lysine & BCAAs & normal glycine (unlike 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] |
Leigh syndrome assoc w/defects of mitochondrial membrane lipids, dynamics, & quality control |
SERAC1 | <5% | SNHL | MEG(H)DEL syndrome; may have liver involvement in infancy that later normalizes | 3-methylglutaconic aciduria, variable RCE deficiencies | Wortmann et al [2012], Maas et al [2017] |
MFF | <1% | Seizures; optic atrophy; peripheral neuropathy | | Multiple RCE deficiencies; elongated mitochondria & peroxisomes (EM) | Koch et al [2016] |
SLC25A46 | 2 persons | Seizures; spastic diplegia; optic atrophy | | ↑ mt connectivity | Abrams et al [2015], Janer et al [2016] |
CLPB | <1% | | Cataract, neutropenia, HCM | 3-methylglutaconic aciduria, multiple RCE deficiencies | Saunders et al [2015] |
Leigh syndrome assoc w/pyruvate dehydrogenase complex deficiency |
PDHB 8 | <1% | CC agenesis/hypoplasia | | PDH deficiency (fbs) | Quintana et al [2009] |
DLAT 8 | <1% | Episodic dystonia | | Head et al [2005] |
DLD 8 | <1% | Episodic encephalopathy | Hypoglycemia, ketoacidosis, liver failure | ↑ plasma BCAAs, PDH deficiency (fbs) | Grafakou et al [2003], Quinonez et al [2013] |
PDHX 8 | <1% | Thin CC/CC agenesis; status epilepticus late in disease (teens/20s) | | PDH deficiency (fbs) | Schiff et al [2006] |
Leigh syndrome assoc w/defects of B vitamin transport & metabolism |
SLC25A19 9 | <1% | Bilateral striatal necrosis; episodic encephalopathy; chronic progressive polyneuropathy → distal weakness & contractures | | Enzymology not performed | Spiegel et al [2009] |
TPK1 | <1% | Episodic encephalopathy; ataxia; dystonia; spasticity | | 2-ketoglutaric aciduria | Mayr et al [2011] |
BTD 8 | <1% | Deafness; optic atrophy; seizures; ataxia 8 | Alopecia, eczema | Characteristic organic aciduria | Mitchell et al [1986] |
SLC19A3 8 | <5% | See footnote 8. | | RCE activity nml | Fassone et al [2013], Gerards et al [2013] |
Leigh syndrome assoc w/mitochondrial toxicity |
HIBCH | <5% | Developmental regression; seizures; ataxia | | ↑ plasma 4-hydroxybutyrylcarnitine levels; variable deficiency of RCEs & PDH | Ferdinandusse et al [2013] |
ECHS1 | <5% | Psychomotor delay; SNHL; nystagmus; hypotonia; spasticity; athetoid movements | HCM | ↑ urinary excretion of S-(2-carboxypropyl) cysteine; normal RCE activ in 1 person, multiple RCE deficiency in 1 other | Peters et al [2014], Sakai et al [2015] |
ETHE1 | <1% | Neurodevelopmental delay & regression; pyramidal & extrapyramidal signs | Acrocyanosis, petechiae, & diarrhea in infancy | Ethylmalonic aciduria | Mineri et al [2008] |
SQOR | 2 families | Episodic encephalopathy following infections | Liver failure in 1 person | Complex IV deficiency in 1 person (mb & liver); RCE activ in fb nml in 1 person | Friederich et al [2020] |
SLC39A8 | 1 family | Dystonia; seizures; hypotonia; cerebellar atrophy | Strabismus; short stature; recurrent infections | ↓ blood & urine manganese, type II glycosylation defect | Riley et al [2017] |