Table 2.

Autosomal Recessive Leigh Syndrome

GeneProportion of AR LS Caused by Mutation of GeneDistinguishing Clinical FeaturesReference
HCMNeurologic 1Other
Complex I-deficient Leigh syndrome 2
NDUFS1 <5%Cystic leukoencephalopathy Bénit et al [2001]
NDUFS2 <5%+ Loeffen et al [2001]
NDUFS3 <5% Bénit et al [2004]
NDUFS4 ~5%+ Budde et al [2000]
NDUFS7 <5% Triepels et al [1999]
NDUFS8 <5%+Leukodystrophy Loeffen et al [1998]
NDUFV1 <5%Cystic leukoencephalopathy Bénit et al [2001]
NDUFV2 1 person+SpasticityOptic atrophy Cameron et al [2015]
NDUFA2 1 family+ Hoefs et al [2008]
NDUFA9 1 family van den Bosch et al [2012]
NDUFA10 1 family+ Hoefs et al [2011]
NDUFA12 1 familySevere dystoniaHypertrichosis 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]
NDUFAF3 1 family Baertling et al [2017a]
NDUFAF4 1 family Baertling et al [2017b]
<5%FILA (1 person); survival into 20s in 1 familySugiana et al [2008], Gerards et al [2010]
1 family Pagliarini et al [2008]
FOXRED1 <5%Seizures & myoclonusSlowly progressive; survival possible into 20sCalvo et al [2010], Fassone et al [2010]
NUBPL Calvo et al [2010]
NDUFAF8 (C17ORF89)1 person Floyd et al [2016]
Complex II-deficient Leigh syndrome 3
SDHA <5%+ (may occur)Course may be indolent w/survival into adulthood.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 4
UQCRQ 1 familySlowly progressive; survival into 30s Barel et al [2008]
TTC19 <5%Severe olivopontocerebellar atrophySlowly progressive; survival into 20s/30s Ghezzi et al [2011]
BCS1L <5%SNHLProximal renal tubulopathy, hepatic involvement, pili torti de Lonlay et al [2001]
Complex IV-deficient Leigh syndrome 5
NDUFA4 1 familyEpilepsy, sensory axonal peripheral neuropathySlowly progressive; survival into 20s/30s Pitceathly et al [2013]
COX8A 1 personSeizures, 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 yrsPéquignot et al [2001], Wedatilake et al [2013]
COX10 <5%+SNHLAnemia (due to defect of mitochondrial heme A biosynthesis) Antonicka et al [2003]
COX15 <5%+Seizures Oquendo et al [2004]
SCO2 <5%+ Joost et al [2010]
LRPPRC 6<5%Metabolic & neurologic (stroke-like) crisesSurvival 5 days – >30 yrs; median age at death 1.6 yrsMootha et al [2003], Debray et al [2011]
TACO1 1 familyCognitive dysfunction, dystonia, visual impairmentLate onset (4-16 yrs), slowly progressive Weraarpachai et al [2009]
PET100 7<5%Prominent seizuresSurvival to 20s (50%) Lim et al [2014]

FILA = fatal infantile lactic acidosis; HCM = hypertrophic cardiomyopathy; LS = Leigh syndrome; SNHL = sensorineural hearing loss


Neurologic findings other than those of classic Leigh syndrome


Defining feature: complex I deficiency (identified on muscle biopsy)


Complex II deficiency on muscle biopsy; also succinate peak on brain magnetic resonance spectroscopy (MRS)


Complex III deficiency on muscle biopsy


Complex IV deficiency on muscle biopsy. Note: In SURF1-related LS, complex IV deficiency is more severe in cultured skin fibroblasts than in muscle.


Founder pathogenic variant in French-Canadian population from Saguenay-Lac St Jean


Founder pathogenic variant in Lebanese population

From: Mitochondrial DNA-Associated Leigh Syndrome and NARP

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