Table 1. [Autosomal Recessive Leigh Syndrome Spectrum]. - GeneReviews®

Table 1.

Autosomal Recessive Leigh Syndrome Spectrum

Gene	Proportion of AR LSS Caused by Biallelic Variants in Gene	Distinguishing Clinical & Laboratory Features			Reference
Gene	Proportion of AR LSS Caused by Biallelic Variants in Gene	Neurologic ¹	Other	Laboratory Findings	Reference
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)		Complex II deficiency (mb); succinate peak (brain MRS)	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		Complex IV deficiency (mb)	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]
SUCLA2 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	MMA; multiple RCE deficiencies	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	Complexes I+III, II+III, & coenzyme Q₁₀ defic (mb)	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/ primary pyruvate dehydrogenase complex deficiency
PDHB ⁸	<1%	CC agenesis/hypoplasia		PDH deficiency (fbs)	Quintana et al [2009]
DLAT ⁸	<1%	Episodic dystonia		PDH deficiency (fbs)	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]

: α-KGDH = alpha-ketoglutarate dehydrogenase; AR = autosomal recessive; BCAA = branched-chain amino acid; BCKDH = branched-chain ketoacid dehydrogenase; CC = corpus callosum; EEG = electroencephalogram; EM = electron microscopy; fbs = cultured skin fibroblasts; FILA = fatal infantile lactic acidosis; GI = gastrointestinal; HCM = hypertrophic cardiomyopathy; IUGR = intrauterine growth restriction; LS = Leigh syndrome; LSS = Leigh syndrome spectrum; mb = muscle biopsy; MEGD(H)EL syndrome = 3-methylglutaconic aciduria with deafness-dystonia, encephalopathy, (hepatopathy) and Leigh-like syndrome; MMA = methylmalonic aciduria; MRS = magnetic resonance spectroscopy; mt = mitochondrial; PDH = pyruvate dehydrogenase; RCE = respiratory chain enzyme; SNHL = sensorineural hearing loss
1.: Neurologic findings other than those of classic Leigh syndrome
2.: Genes encoding subunits are listed first, followed by genes encoding assembly factors.
3.: Founder pathogenic allelic variant in French-Canadian population from Saguenay-Lac St Jean
4.: Founder pathogenic variant in Lebanese population
5.: Ashkenazi Jewish founder variant
6.: Founder variant in Faroe Islands
7.: Isolated SNHL without Leigh syndrome in some individuals; Alpers syndrome in others
8.: Potentially treatable; see Management.
9.: Allelic with Amish lethal microcephaly, mitochondrial thiamine pyrophosphate carrier deficiency

From: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview

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