Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview

Shamima Rahman; David R Thorburn; Megan Ball

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Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview

Shamima Rahman, FRCP, FRCPCH, PhD, David R Thorburn, PhD, and Megan Ball, MD.

Author Information and Affiliations

Initial Posting: October 1, 2015; Last Update: May 1, 2025.

Estimated reading time: 1 hour

Summary

The purpose of this overview is to:

1.: Briefly describe the clinical characteristics of nuclear gene-encoded Leigh syndrome spectrum (LSS);
2.: Review the genetic causes of nuclear gene-encoded LSS;
3.: Review the differential diagnosis of nuclear gene-encoded LSS with a focus on genetic conditions;
4.: Provide an evaluation strategy to identify the genetic cause of nuclear gene-encoded LSS in a proband (when possible);
5.: Review management of nuclear gene-encoded LSS with a focus on disorders with targeted therapies;
6.: Inform genetic counseling of family members of an individual with nuclear gene-encoded LSS.

1. Clinical Characteristics of Nuclear Gene-Encoded Leigh Syndrome Spectrum

Nuclear gene-encoded Leigh syndrome spectrum (LSS) is a continuum of progressive neurodegenerative disorders caused by abnormalities of mitochondrial energy generation.

Onset of nuclear gene-encoded LSS is typically in infancy or early childhood with sudden neurodevelopmental regression. This decompensation is often associated with elevated lactate concentration in the blood and/or cerebrospinal fluid (CSF) following an intercurrent illness or metabolic challenge (e.g., surgery, anesthesia, prolonged fasting). Although the clinical manifestations of LSS can vary, there is significant overlap between the clinical features (see Table 1) and biochemical features of both nuclear-encoded LSS and mitochondrial DNA (mtDNA)-encoded LSS.

Initial clinical features may be nonspecific and may vary with the age of onset. Approximately 75% of individuals present in the first 24 months of life, with some manifesting features in utero.

Prenatally, intrauterine growth restriction, cardiomegaly, microcephaly, and oligohydramnios have been reported.
Early-onset LSS (age <2 years) may present with nonspecific features such as poor weight gain, feeding difficulties, persistent vomiting, hypotonia, and developmental delay.
Later-onset LSS (age >2 years) may present in childhood, adolescence, or even adulthood with predominant muscle weakness, movement disorders (ataxia and/or dystonia), peripheral neuropathy, and neurobehavioral/psychiatric manifestations.

Other neurologic manifestations include developmental delay/regression, hypotonia, spasticity, seizures, movement disorders (including chorea), cerebellar ataxia, and peripheral neuropathy. Brain stem lesions may cause respiratory issues (apnea, central hypo- or hyperventilation, or irregular respiration), bulbar problems (e.g., abnormal swallowing and speech), and abnormalities of thermoregulation.

Sensorineural hearing loss is present in approximately 15% of individuals.

Ophthalmologic manifestations may include ophthalmoplegia, ptosis, optic atrophy, and retinopathy.

Extraneurologic manifestations can include hypertrophic cardiomyopathy, gastrointestinal dysmotility, hepatopathy, renal tubulopathy, anemia, and hypertrichosis.

It should be noted that several disorders, e.g., SURF1-related LSS and PDHA1-related LSS, have been associated with a continuous spectrum of disease ranging from LSS to isolated features including peripheral neuropathy (Charcot-Marie-Tooth disease) and episodic dystonia.

Typical neuroradiologic findings are bilateral, typically symmetric hyperintensities on T₂-weighted magnetic resonance imaging (MRI) or hypodensities on computed tomography (CT) in the brain stem and/or basal ganglia, with or without the same findings in the thalamus, cerebellum, subcortical white matter, and/or spinal cord that may fluctuate with time [McCormick et al 2023] (full text). Corresponding restricted diffusion may be evident on diffusion-weighted imaging. Additional findings may include cerebral or cerebellar atrophy.

Magnetic resonance spectroscopy (MRS) exhibiting a lactate peak (in the absence of acute seizures) is suggestive of a mitochondrial disorder (including nuclear gene-encoded LSS).

Prognosis. The prognosis is generally poor. Most affected individuals experience episodic deterioration interspersed with plateaus of stabilization; typically, eventual progressive neurologic decline occurs in stepwise decrements. Up to 50% of individuals die by age three years, most often as a result of respiratory or cardiac failure or neurologic deterioration. However, disease progression can vary and survival into adulthood may occasionally occur.

Poor prognosis has been associated with early-onset disease and brain stem involvement (e.g., apneas) [Sofou et al 2014, Ogawa et al 2020, Ardissone et al 2021].

Conflicting reports regarding the prognosis of specific genetic causes of LSS can make it difficult to provide adequate counseling for families. Ogawa et al [2020] reported better outcomes for individuals with ECHS1-, NDUFAF6-, or SURF1-related LSS. While Wedatilake et al [2013] also reported better outcomes in SURF1-related LSS, Stenton et al [2022b] and Lim et al [2022] reported poorer prognoses in SURF1-related LSS.

Survival into adulthood has been reported for individuals with some disorders, including MECR- and MTFMT-related LSS [Hayhurst et al 2019, Heimer et al 2016].

Table 1.

Nuclear-Encoded Leigh Syndrome Spectrum: Frequency of Select Clinical Features

Feature		% of Persons w/Feature	Comment
Neurologic features	Developmental delay	>70%
	Hypotonia	~60%
	Developmental regression	~50%
	Spasticity	~40%
	Dystonia	~35%
	Ataxia	~30%
	Muscle weakness	~30%
	Epilepsy	~30%
	Respiratory abnormalities	~30%	Apnea, hypoventilation, hyperventilation, or irregular respiration
	Dysphagia	~25%
	Sensorineural hearing loss	~15%
	Peripheral neuropathy	~10%
Ophthalmologic features	Ophthalmoplegia	~25%
	Optic atrophy	~15%
	Retinopathy	~10%
Other	Poor weight gain	~40%
	Gastrointestinal manifestations	~25%	Vomiting, gastroparesis, intestinal dysmotility, constipation
	Cardiac manifestations	~15%	Hypertrophic or dilated cardiomyopathy; rarely, conduction defects
	Hepatic manifestations	<10%	Elevated liver transaminases, hepatomegaly, or liver failure
	Renal manifestations	<5%	Tubulopathy
	Endocrine manifestations	<5%	Diabetes, adrenal insufficiency

1.: Estimated percentages are based on several cohorts of individuals with nuclear gene-encoded LSS and mtDNA-encoded LSS (~1,000 individuals); however, each clinical feature was not reported for every individual [Rahman et al 1996, Sofou et al 2014, Ogawa et al 2017, Sofou et al 2018, Alves et al 2020, Hong et al 2020, Lee et al 2020, Ardissone et al 2021, Lim et al 2022, Stenton et al 2022b, Tinker et al 2022, Zilber et al 2023].

Nomenclature

The term "Leigh syndrome spectrum" comprises both Leigh syndrome and Leigh-like syndrome. "Leigh-like syndrome" has been used historically when clinical and other features strongly suggest Leigh syndrome but do not fulfil the stringent diagnostic criteria for Leigh syndrome because of atypical or normal neuroimaging, lack of evidence of abnormal energy metabolism, atypical neuropathology (variation in the distribution or character of lesions or with the presence of additional unusual features such as extensive cortical destruction), and/or incomplete evaluation. The authors recommend that the term "Leigh-like" no longer be used, as it is now incorporated within the umbrella term LSS.

2. Causes of Nuclear Gene-Encoded Leigh Syndrome Spectrum

The pathogenic variants in more than 120 nuclear genes associated with autosomal recessive, autosomal dominant, and X-linked nuclear gene-encoded Leigh syndrome spectrum (LSS) are summarized below [Rahman et al 2017, McCormick et al 2023] (see Table 2 in McCormick et al [2023]).

McCormick et al [2023] (full text) determined that the diagnosis of nuclear gene-encoded LSS is established in a proband fulfilling clinical criteria for LSS who has one or two pathogenic (or likely pathogenic) variants in a specific nuclear gene listed in Tables 2a, 2b, 3, 4a, and 4b consistent with the expected mode of inheritance.

Clinical Criteria

Clinical criteria for nuclear gene-encoded LSS are adapted from Table 2 McCormick et al 2023] (full text).

Typical neuroradiologic findings. Bilateral, typically symmetric hyperintensities on T₂-weighted magnetic resonance imaging (MRI) or hypodensities on CT in the brain stem and/or basal ganglia with or without bilateral, T₂-weighted hyperintensities on MRI or hypodensities on computed tomography (CT) in the thalamus, cerebellum, subcortical white matter, and/or spinal cord.

AND ≥1 of the following characteristic neurologic clinical features:

Developmental regression
Developmental delay
Neurobehavioral/psychiatric features

AND ≥1 of the following biochemical and/or mitochondrial abnormalities:

Elevated concentration of lactate in blood and/or cerebrospinal fluid (CSF)
Elevated glycine concentrations (if the responsible gene is required for biosynthesis of lipoic acid)
Magnetic resonance spectroscopy (MRS) lactate peak (in the absence of acute seizures)
Respiratory chain enzyme activity deficiency (<30% enzyme activity) in affected tissues (muscle, liver, fibroblasts)
Pyruvate dehydrogenase complex deficiency (in fibroblasts, >2 standard deviations below mean)
Mitochondrial fission/fusion defect (detected by electron microscopy of muscle or immunofluorescence studies of cultured skin fibroblasts)
Diminished respiratory activity measured by microscale oxygraphy (e.g., Oroboros or Seahorse assays)

Neuropathologic features of Leigh syndrome. Leigh syndrome was originally defined in 1951 by characteristic neuropathologic features, including multiple focal symmetric necrotic lesions in the basal ganglia, thalamus, brain stem, dentate nuclei, and optic nerves. Histologically, these lesions have a spongiform appearance and are characterized by demyelination, gliosis, and vascular proliferation. Although neuronal loss can occur, typically the neurons are relatively spared.

The advent of widespread use of MRI made it possible to establish a diagnosis of LSS by neuroimaging, and thus postmortem examination is now rarely performed outside of a research context.

Autosomal Recessive Leigh Syndrome Spectrum

Autosomal recessive nuclear gene-encoded LSS (Table 2a and 2b) includes:

Pathogenic (or likely pathogenic) variants in genes encoding proteins needed for:
- Oxidative phosphorylation (OXPHOS) enzyme activity and assembly;
- Mitochondrial DNA (mtDNA) maintenance (see Mitochondrial DNA Maintenance Defects Overview) and gene expression;
- Cofactor biosynthesis (lipoic acid and coenzyme Q₁₀ [see Primary Coenzyme Q₁₀ Deficiency Overview]);
- Mitochondrial membrane lipid remodeling, quality control, and dynamics;
- Pyruvate dehydrogenase (see Primary Pyruvate Dehydrogenase Complex Deficiency Overview), biotinidase, and B vitamin transport and metabolism.
Organic acidemias with accumulation of metabolites leading to secondary OXPHOS dysfunction.

Table 2a.

Autosomal Recessive Leigh Syndrome Spectrum with Targeted Therapy: Associated Genes

Gene	Proportion of Nuclear-Encoded LSS	Distinguishing Clinical & Laboratory Features			Pathogenic Mechanism	References
Gene	Proportion of Nuclear-Encoded LSS	Neurologic ¹	Other	Laboratory findings	Pathogenic Mechanism	References
BTD	<1%	Deafness; optic atrophy; seizures; ataxia	Alopecia; eczema	Characteristic organic aciduria; ketolactic acidosis	Defect of B vitamin transport/metabolism	Biotinidase Deficiency
COQ4	<1%	Seizures; dystonia; cerebellar atrophy	Poor growth	↓ coenzyme Q₁₀ (fb), CII + III deficiency (fb)	Defect of mt cofactor biosynthesis (coenzyme Q₁₀)	Primary Coenzyme Q₁₀ Deficiency Overview, Lu et al [2019], Ogawa et al [2020]
COQ7	<1%	SNHL; cerebral atrophy	Oligohydramnios; IUGR; renal dysplasia; HCM	↓ coenzyme Q₁₀ (fb), CII + III deficiency (fb)	Defect of mt cofactor biosynthesis (coenzyme Q₁₀)	Primary Coenzyme Q₁₀ Deficiency Overview, Kwong et al [2019]
COQ9	1 person	Refractory seizures	Prenatal onset; IUGR; HCM	Complexes I + III, II + III, & coenzyme Q₁₀ deficiency (m)	Defect of mt cofactor biosynthesis (coenzyme Q₁₀)	Primary Coenzyme Q₁₀ Deficiency Overview, Smith et al [2018]
DLAT	<1%	Episodic dystonia; globus pallidus lesions		PDH deficiency (fb)	Defect of pyruvate metabolism	Primary Pyruvate Dehydrogenase Complex Deficiency Overview, Head et al [2005]
PDHB	<5%	CC agenesis/hypoplasia; microcephaly		PDH deficiency (fb)	Defect of pyruvate metabolism	Primary Pyruvate Dehydrogenase Complex Deficiency Overview, Quintana et al [2009]
PDHX	<1%	Thin CC / CC agenesis; neonatal lactic acidosis; status epilepticus late in disease (teens/20s)		PDH deficiency (fb)	Defect of pyruvate metabolism	Primary Pyruvate Dehydrogenase Complex Deficiency Overview, Schiff et al [2006]
PDSS2	<1%	Refractory seizures; SNHL	Nephrotic syndrome; HCM	Complexes I + III, II + III, & coenzyme Q₁₀ deficiency (m)	Defect of mt cofactor biosynthesis (coenzyme Q₁₀)	Primary Coenzyme Q₁₀ Deficiency Overview
SLC19A3	<5%	Spasticity; dystonia; seizures; central hypoventilation		RCE activity normal	Defect of B vitamin transport/metabolism	Biotin-Thiamine-Responsive Basal Ganglia Disease
SLC25A19	<1%	Bilateral striatal necrosis; episodic encephalopathy w/fever; seizures; chronic progressive polyneuropathy → distal weakness & contractures		Enzymology not performed	Defect of B vitamin transport/metabolism	SLC25A19-Related Thiamine Metabolism Dysfunction
TPK1	<5%	Episodic encephalopathy; ataxia; dystonia; seizures; spasticity	Early onset	2-ketoglutaric aciduria	Defect of B vitamin transport/metabolism	Mayr et al [2011], Zhao et al [2023]

: AR = autosomal recessive; CC = corpus callosum; fb = cultured skin fibroblasts; HCM = hypertrophic cardiomyopathy; IUGR = intrauterine growth restriction; LSS = Leigh syndrome spectrum; m = muscle biopsy; MRS = magnetic resonance spectroscopy; MT = mitochondrial; PDH = pyruvate dehydrogenase; RCE = respiratory chain enzyme; SNHL = sensorineural hearing loss
1.: Other than those of classic Leigh syndrome

Table 2b.

Autosomal Recessive Leigh Syndrome Spectrum: Other Associated Genes

Gene	Proportion of Nuclear-Encoded LSS	Distinguishing Clinical & Laboratory Features			Pathogenic Mechanism	References
Gene	Proportion of Nuclear-Encoded LSS	Neurologic ¹	Other	Laboratory findings	Pathogenic Mechanism	References
ATP5MK (ATP5MD)	<1%	Movement disorder; ophthalmoplegia	HCM	↓ ATP synthesis (fb)	Complex V deficiency	Barca et al [2018]
ATP5PO	<1%	Infantile onset; progressive epileptic encephalopathy; progressive cerebral atrophy	HCM	Complex V deficiency (fb)	Complex V deficiency	Ganapathi et al [2022]
BCS1L	<1%	SNHL	Proximal renal tubulopathy; hepatic involvement; pili torti	Complex III deficiency (m)	Complex III deficiency	de Lonlay et al [2001]
CLPB	<1%	Progressive cerebral & cerebellar atrophy	Cataract; neutropenia; HCM	3-methylglutaconic aciduria; multiple RCE deficiencies	Defect of mt protein quality control	CLPB Deficiency
COA6	1 person		HCM	Complex IV deficiency	Complex IV deficiency	Stenton et al [2022b]
COX10	<1%	SNHL	HCM; anemia (due to defect of mt heme A biosynthesis)	Complex IV deficiency (m)	Complex IV deficiency	Antonicka et al [2003]
COX15	<1%	Seizures, retinopathy	HCM, hepatic steatosis	Complex IV deficiency (m)	Complex IV deficiency	Oquendo et al [2004]
COX4I1	1 person	Microcephaly; seizures; cerebral atrophy	Short stature	Multiple RCE deficiencies (m)	Complex IV deficiency	Pillai et al [2019]
COX8A	1 person	Seizures; hypotonia; spasticity; leukodystrophy		Complex IV deficiency (m)	Complex IV deficiency	Hallmann et al [2016]
DLD	<5%	Episodic encephalopathy	Hypoglycemia; ketoacidosis; liver failure	↑ plasma BCAAs, ↑ urine alpha-ketoglutarate, PDH deficiency (fb)	Defect of pyruvate metabolism	Dihydrolipoamide Dehydrogenase Deficiency
DNAJC30	<1%	Ataxia; dystonia; ophthalmoparesis; optic atrophy		Complex I deficiency (m)	Complex I deficiency	Stenton et al [2022a]
DNM1L ²	1 person	Hypotonia	Neonatal onset	Impaired mt fission (fb)	Defect of mt dynamics	Hogarth et al [2018]
EARS2	<5%	Leukoencephalopathy w/thalamus & brain stem involvement & ↑ lactate (MRI); MRI changes may improve w/time.	Improvement can occur; liver failure in some individuals.	Multiple RCE deficiencies	Defect of mt gene expression	Martinelli et al [2012]
ECHS1	~5%	Psychomotor delay; SNHL; nystagmus; hypotonia; spasticity; athetoid movements; optic atrophy	HCM	↑ urinary excretion of S-(2-carboxypropyl) cysteine; typically normal RCE w/variable RCE deficiencies in some individuals (m)	mt toxicity	Mitochondrial Short-Chain Enoyl-CoA Hydratase 1 Deficiency
ETHE1	<1%	Neurodevelopmental delay & regression; pyramidal & extrapyramidal signs; seizures	Acrocyanosis; petechiae; frequent vomiting & diarrhea in infancy	Ethylmalonic aciduria	mt toxicity	Ethylmalonic Encephalopathy
FARS2	<1%	Severe epilepsy & myoclonus; Alpers syndrome neuropathology in some individuals		Variable RCE deficiencies	Defect of mt gene expression	FARS2 Deficiency
FASTKD2	1 person	Seizures; spastic tetraparesis; optic atrophy			Defect of mt gene expression	Gouiza et al [2024]
FBXL4	<5%	Seizures	Facial dysmorphism; skeletal abnormalities; poor growth; GI dysmotility; renal tubular acidosis	Multiple RCE deficiencies	Dysregulation of mitophagy	FBXL4-Related Encephalomyopathic mtDNA Depletion Syndrome, Nguyen-Dien et al [2023]
FOXRED1	<5%	Seizures; myoclonus	Slowly progressive; survival possible into 20s in some	Complex I deficiency (m)	Complex I deficiency	Calvo et al [2010], Fassone et al [2010]
GFM1	<1%	Axial hypotonia; spasticity; refractory seizures	Progressive hepatoencephalopathy in some	Multiple RCE deficiencies	Defect of mt gene expression	Valente et al [2007]
GFM2	<1%			Multiple RCE deficiencies	Defect of mt gene expression	Fukumura et al [2015]
GTPBP3	<1%		Typically early onset; HCM	Multiple RCE deficiencies	Defect of mt gene expression	Kopajtich et al [2014]
HIBCH	<5%	Developmental regression; seizures; ataxia		↑ plasma 4-hydroxybutyrylcarnitine levels; ↑ urine 2-methyl-2,3-dihydroxybutyrate; variable deficiency of RCEs & PDH	mt toxicity	Ferdinandusse et al [2013]
HPDL	<1%	Seizures; spastic paraplegia; microcephaly; visual disturbance	Early onset	Variable RCE deficiencies	Defect of mt cofactor biosynthesis (coenzyme Q₁₀)	Husain et al [2020], Ma et al [2025]
HTRA2	1 person	Nystagmus; hypotonia	Poor growth	CI deficiency (m), no elevation of 3-methylglutaconic acid in this individual	Defect of mt protein quality control	Gurusamy et al [2024]
IARS2	<5%	Infantile spasms w/hypsarrhythmia; diffuse cerebral atrophy; SNHL; peripheral sensory neuropathy	Cataracts; sideroblastic anemia; growth hormone deficiency; skeletal dysplasia	↓ respiratory activity (Oroboros)	Defect of mt gene expression	Schwartzentruber et al [2014]
KGD4 (MRPS36)	2 sibs	Spastic tetraparesis; hyperkinetic movement disorder; seizures; diffuse cerebral atrophy	Early onset; HCM	↑ plasma glutamine & glutamate; low 2-oxoglutarate dehydrogenase complex activity (fb)	2-oxoglutarate dehydrogenase deficiency	Galosi et al [2024]
L2HGDH	1 person			↑ L-2-hydroxyglutaric acid in urine	mt toxicity	Stenton et al [2022b]
LIAS	<1%	Seizures w/burst suppression (EEG)	Mild HCM	Combined deficiency of PDH + glycine cleavage enzyme; ↑ urine & plasma glycine; deficient lipoylated proteins (western blot)	Defect of mt cofactor biosynthesis (lipoic acid)	Baker et al [2014]
LIPT1	<1%	Spastic tetraparesis; dystonia	Liver dysfunction	↑ glutamine & proline; ↓ levels of lysine & BCAAs; normal glycine (unlike other lipoic acid synthesis defects); severe ↓ of PDH & α-KGDH activity; strong ↓ of BCKDH activity (fb); normal RCE activity	Defect of mt cofactor biosynthesis (lipoic acid)	Soreze et al [2013]
LONP1	1 person		Neonatal onset	mtDNA depletion (m)	Defect of mt protein quality control	Peter et al [2018]
LRPPRC	<5%	Metabolic (acidosis & ketosis) & neurologic (stroke-like) crises; seizures	Survival 5 days to 30 yrs; median age at death 1.6 yrs	Complex IV deficiency (m)	Complex IV deficiency	Mootha et al [2003], Debray et al [2011]
MECR	<1%	Dystonia; chorea; optic atrophy	Survival to adulthood	Reduced protein lipoylation; ↓ respiratory activity (fb)	Defect of mt cofactor biosynthesis (lipoic acid)	MECR-Related Neurologic Disorder, Heimer et al [2016]
MFF	<1%	Seizures; optic atrophy; peripheral neuropathy; microcephaly; cerebellar atrophy		Multiple RCE deficiencies; elongated mitochondria & peroxisomes (EM)	Defect of mt dynamics	Koch et al [2016]
MFN2	1 person	Seizures; psychiatric disturbance; optic atrophy; dystonia; chorea; sensorimotor neuropathy	Hypothyroidism	Multiple mtDNA deletions (m)	Defect of mt dynamics	Souza et al [2019]
MPC1	1 person	Microcephaly; seizures	Poor growth		Defect of pyruvate metabolism	Jiang et al [2022]
MPV17	<1%	Peripheral neuropathy; ataxia; SNHL	Episodic hypoglycemia & metabolic acidosis; prolonged jaundice	CI & CIII deficient activity; mtDNA depletion (m)	mtDNA maintenance defect	MPV17-Related mtDNA Maintenance Defect, Souza et al [2019]
MRPL3	<1%	SNHL	Early onset; cataracts; liver dysfunction; HCM	Multiple RCE deficiencies (m)	Defect of mt gene expression	Alsharhan et al [2021]
MRPL39	2 persons	Seizures	Early onset; HCM		Defect of mt gene expression	Amarasekera et al [2023]
MRPS34	<1%	Microcephaly	Typically early onset, but survival to adulthood has been reported	Multiple RCE deficiencies	Defect of mt gene expression	Lake et al [2017]
MTFMT	<5%	Cystic leukoencephalopathy in some; typically shows a milder clinical course	May be slowly progressive in some, w/survival into 20s	Multiple RCE deficiencies	Defect of mt gene expression	Tucker et al [2011], Hayhurst et al [2019]
MTRFR (C12orf65)	<1%	Ophthalmoplegia; optic atrophy; axonal neuropathy	Relatively slow disease progression	Multiple RCE deficiencies (fb)	Defect of mt gene expression	Antonicka et al [2010]
MTO1	<1%		HCM		Defect of mt gene expression	Stenton et al [2022b]
NARS2 ³	<1%	SNHL		Multiple RCE deficiencies	Defect of mt gene expression	Simon et al [2015]
NAXE	<1%	Encephalopathy assoc w/febrile illness; cerebellar atrophy	Erythematous rash (1 person); nephrotic syndrome (1 person)	Normal RCE in 1 person (m)	mt toxicity	Kremer et al [2016]
NDUFA10	<1%		HCM	Complex I deficiency (m)	Complex I deficiency	Hoefs et al [2011]
NDUFA12	<1%	Severe dystonia	Hypertrichosis	Complex I deficiency (m)	Complex I deficiency	Ostergaard et al [2011]
NDUFA13	<1%			Complex I deficiency (m)	Complex I deficiency	Angebault et al [2015]
NDUFA2	<1%	Cystic Leukoencephalopathy	HCM	Complex I deficiency (m)	Complex I deficiency	Hoefs et al [2008]
NDUFA4	<1%	Epilepsy; sensory axonal peripheral neuropathy; leukoencephalopathy	Slowly progressive; survival into 20s/30s	Complex IV deficiency (m)	Complex IV deficiency	Pitceathly et al [2013]
NDUFA9	<1%			Complex I deficiency (m)	Complex I deficiency	van den Bosch et al [2012]
NDUFAF2	<1%	MRI: symmetric lesions in mamillothalamic tracts, substantia nigra / medial lemniscus, medial longitudinal fasciculus, & spinothalamic tracts		Complex I deficiency (m)	Complex I deficiency	Barghuti et al [2008]
NDUFAF3	<1%	Cavitating leukoencephalopathy (1 person); optic atrophy (1 person)	Frequent vomiting	Complex I deficiency (fb, m)	Complex I deficiency	Baertling et al [2017]
NDUFAF4	1 person	Seizures		Complex I deficiency (fb)	Complex I deficiency	Baertling et al [2017]
NDUFAF5 (C20orf7)	<5%		FILA; later onset w/survival into early adulthood in some persons	Complex I deficiency (m)	Complex I deficiency	Sugiana et al [2008], Gerards et al [2010]
NDUFAF6 (C8orf38)	<5%	Dystonia; movement disorders	Later onset in some persons w/survival to early adulthood	Complex I deficiency (m)	Complex I deficiency	Pagliarini et al [2008]
NDUFAF8 (C17ORF89)	<1%	Infantile spasms; hypsarrhythmia; periventricular cystic encephalomalacia; corpus callosum dysgenesis		Complex I deficiency (m, fb)	Complex I deficiency	Floyd et al [2016], Alston et al [2020]
NDUFB8	<1%		HCM	Complex I deficiency (m, fb)	Complex I deficiency	Piekutowska-Abramczuk et al [2018]
NDUFC2	<1%	Seizures		Complex I deficiency (fb)	Complex I deficiency	Alahmad et al [2020]
NDUFS1	<5%	Cystic leukoencephalopathy	HCM	Complex I deficiency (m)	Complex I deficiency	Bénit et al [2001]
NDUFS2	<1%	Optic atrophy	HCM	Complex I deficiency (m)	Complex I deficiency	Loeffen et al [2001]
NDUFS3	<1%			Complex I deficiency (m)	Complex I deficiency	Bénit et al [2004]
NDUFS4	<5%		Early onset; HCM	Complex I deficiency (m)	Complex I deficiency	Budde et al [2000]
NDUFS6	<1%	Episodic deterioration w/hypoventilation	Early onset	Multiple RCE deficiencies (m); BN-PAGE assembly defect of complex I (fb)	Complex I deficiency	Rouzier et al [2019]
NDUFS7	<1%			Complex I deficiency (m)	Complex I deficiency	Triepels et al [1999]
NDUFS8	<1%	Leukodystrophy	HCM	Complex I deficiency (m)	Complex I deficiency	Loeffen et al [1998]
NDUFV1	~5%	Cystic leukoencephalopathy; dystonia		Complex I deficiency (m)	Complex I deficiency	Bénit et al [2001]
NDUFV2	<1%	Spasticity	Optic atrophy; HCM	Complex I deficiency (m)	Complex I deficiency	Cameron et al [2015]
NUBPL	<1%	Characteristic MRI changes: predominant abnormalities of cerebellar cortex, deep cerebral white matter, & corpus callosum		Complex I deficiency (m)	Complex I deficiency	Calvo et al [2010]
OPA1 ⁴	<1%	Ataxia; seizures; peripheral neuropathy; spasticity; optic atrophy; cerebellar atrophy		Variable RCE results (m)	Defect of mt dynamics	Mitochondrial DNA Maintenance Defects Overview, Nasca et al [2017]
PET100	<5%	Prominent myoclonus & seizures; spastic tetraparesis	Survival to 20s (50%)	Complex IV deficiency (m)	Complex IV deficiency	Lim et al [2014]
PET117	1 family			Complex IV deficiency (m)	Complex IV deficiency	Renkema et al [2017]
PMPCA	<1%	Spastic paraplegia; ataxia; cerebellar atrophy		Fragmented mitochondria (fb) in 1 person	Defect in mt protein quality control	Rubegni et al [2019]
PMPCB	<1%	Ataxia; seizures; cerebellar atrophy		Multiple RCE deficiencies; ↓ aconitase activity (m) in 1 person	Defect in mt protein quality control	Vögtle et al [2018], Matthews et al [2024]
PNPT1	<1%	Choreoathetosis & dyskinesia; also isolated SNHL	Severe hypotonia	Complex III + IV deficiency in liver in 1 person (normal activity in m & fb)	Defect of mt gene expression	Vedrenne et al [2012]
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)	mtDNA maintenance defect	POLG-Related Disorders, Taanman et al [2009]
PTCD3	<1%	Seizures; optic atrophy; SNHL		Multiple RCE deficiencies	Defect of mt gene expression	Borna et al [2019]
RNASEH1	1 person	Cerebellar ataxia; psychosis; ophthalmoplegia; polyneuropathy	Late onset	Multiple mtDNA deletions, complex I deficiency (m)	mtDNA maintenance defect	Mitochondrial DNA Maintenance Defects Overview, Souza et al [2019]
RRM2B	<1%	Ophthalmoplegia; ataxia; SNHL; demyelinating polyneuropathy	HCM	mtDNA depletion (m)	mtDNA maintenance defect	RRM2B Mitochondrial DNA Maintenance Defects, Souza et al [2019]
SCO2	<5%	Early onset; severe muscle weakness	HCM; febrile syndrome not assoc w/infections	Complex IV deficiency (m)	Complex IV deficiency	Joost et al [2010], Kistol et al [2023]
SDHA	<1%		Course may be indolent w/survival into adulthood in some; HCM	Complex II deficiency (m); succinate peak (brain MRS)	Complex II deficiency	Bourgeron et al [1995], Pagnamenta et al [2006]
SDHAF1	<5%	Leukoencephalopathy on MRI (1 person w/neuropathologic LS)		Complex II deficiency (m); succinate peak (brain MRS)	Complex II deficiency	Ohlenbusch et al [2012]
SDHB	<1%	Optic atrophy (1 person)			Complex II deficiency	Kaur et al [2020]
SERAC1	<5%	SNHL; distinct brain MRI pattern	MEG(H)DEL syndrome; may have liver involvement in infancy that later normalizes	3-methylglutaconic aciduria; variable RCE deficiencies	Defect of mt membrane lipids	SERAC1 Deficiency
SLC25A46	2 persons	Seizures; spastic diplegia; optic atrophy; pontocerebellar hypoplasia		↑ mt connectivity	Defect of mt dynamics	Abrams et al [2015], Janer et al [2016]
SPG7	1 person	Spastic paraparesis; ophthalmoplegia; optic atrophy; psychosis; abnormal movements; global cerebral atrophy		Multiple mtDNA deletions (m)	Defect of mt protein quality control	Souza et al [2019]
SQOR	2 families	Episodic encephalopathy following infections	Liver failure in 1 person	Complex IV deficiency in 1 person (m & liver); RCE activity in fb normal in 1 person	mt toxicity	Friederich et al [2020]
SUCLA2	<5%	Hypotonia; muscle atrophy; hyperkinesia; severe SNHL	Poor growth	↑ urine & plasma MMA; multiple RCE deficiencies	mt DNA maintenance defect	SUCLA2-Related mtDNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria
SUCLG1	<1%	Severe myopathy; SNHL; dystonia	Recurrent hepatic failure; poor growth; HCM	↑ urine & plasma MMA; multiple RCE deficiencies	mt DNA maintenance defect	SUCLG1-Related mtDNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria
SURF1	~50% of complex IV-deficient LS (~30% of nuclear-encoded LS)	Developmental regression (71%); nystagmus + ophthalmoplegia (52%); movement disorder (52%); peripheral neuropathy	Typically early onset; hypertrichosis (48%); median survival 5.4 yrs	Complex IV deficiency (more severe fb than m)	Complex IV deficiency	Wedatilake et al [2013]
TACO1	<5%	Cognitive dysfunction; dystonia; visual impairment; periventricular white matter lesions	Late onset (age 4-16 yrs); slowly progressive	Complex IV deficiency (m)	Complex IV deficiency	Weraarpachai et al [2009], Oktay et al [2020]
TARS2	<5%	Microcephaly; seizure; cerebellar atrophy; CC dysplasia	Early onset	Multiple RCE deficiencies	Defect of mt gene expression	Diodato et al [2014]
TIMMDC1	1 person	Cerebellar syndrome; basal ganglia abnormalities (CT); subsequent MRI unremarkable		Complex I deficiency (m)	Complex I deficiency	Kremer et al [2017]
TMEM126B	1 person	Gait disturbance	Liver dysfunction		Complex I deficiency	Zhou et al [2023]
TOMM7	1 person	Early onset; hypotonia; dystonia; optic atrophy			Defect of mt membranes	Yeole et al [2025]
TRMU	<1%		Usually causes benign reversible liver failure w/o neurologic symptoms	Multiple RCE deficiencies	Defect of mt gene expression	TRMU Deficiency
TSFM	<1%	Juvenile onset; ataxia; hyperkinetic movement disorder; neuropathy; optic atrophy	Poor growth; HCM	Multiple RCE deficiencies	Defect of mt gene expression	Ahola et al [2014]
TTC19	<5%	Ataxia; severe olivopontocerebellar atrophy	Slowly progressive; survival into 20s/30s	Complex III deficiency (m)	Complex III deficiency	Ghezzi et al [2011]
TWNK	1 person	Ptosis; ophthalmoplegia; optic atrophy; SNHL; sensory axonal neuropathy	Cataracts	mtDNA depletion, multiple mtDNA deletions (m)	mtDNA maintenance defect	Mitochondrial DNA Maintenance Defects Overview, Souza et al [2019]
UQCRC2	<1%		Reye syndrome w/metabolic acidosis & hypoglycemia	Complex III deficiency (fb)	Complex III deficiency	Burska et al [2021], Bansept et al [2023]
UQCRQ	1 family	Dystonia; ataxia	Slowly progressive; survival into 30s	Complex III deficiency (m)	Complex III deficiency	Barel et al [2008]
VPS13D	<1%	Ataxia; seizures			Dysregulation of mitophagy	Gauthier et al [2018]

: α-KGDH = alpha-ketoglutarate dehydrogenase; BCAA = branched-chain amino acid; BCKDH = branched-chain ketoacid dehydrogenase; BN-PAGE = blue native polyacrylamide gel electrophoresis; CC = corpus callosum; CT = computed tomography; EEG = electroencephalogram; EM = electron microscopy; fb = cultured skin fibroblasts; FILA = fatal infantile lactic acidosis; GI = gastrointestinal; HCM = hypertrophic cardiomyopathy; IUGR = intrauterine growth restriction; LS = Leigh syndrome; LSS = Leigh syndrome spectrum; m = muscle biopsy; MEGD(H)EL syndrome = 3-methylglutaconic aciduria with deafness-dystonia, (hepatopathy), encephalopathy, 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.: Other than those of classic Leigh syndrome
2.: Autosomal dominant DNM1L-related LSS has also been reported (see Table 3).
3.: Isolated SNHL without Leigh syndrome in some individuals; Alpers syndrome in others
4.: Autosomal dominant OPA1-related LSS has also been reported (see Table 3).

Autosomal Dominant Leigh Syndrome Spectrum

Causes of autosomal dominant nuclear gene-encoded LSS are summarized in Table 3. Two genes, DNM1L and OPA1, have been associated with both autosomal dominant LSS and autosomal recessive LSS and, thus, have been included in both Table 2b and Table 3. No targeted treatments are available for autosomal dominant nuclear gene-encoded LSS.

Table 3.

Autosomal Dominant Leigh Syndrome Spectrum: Associated Genes

Gene	Proportion of Nuclear-Encoded LSS	Distinguishing Clinical & Laboratory Features			Pathologic Mechanism	References
Gene	Proportion of Nuclear-Encoded LSS	Neurologic ¹	Other	Laboratory findings	Pathologic Mechanism	References
DNM1L ²	<1%	Infantile spasms w/burst suppression		Multiple RCE deficiencies; elongated mitochondria & peroxisomes on electron microscopy (m)	Defect of mt dynamics	Zaha et al [2016]
OPA1 ²	2 persons	Seizures; optic atrophy; peripheral neuropathy; cerebellar atrophy		mtDNA depletion (fb)	Defect of mt dynamics	Mitochondrial DNA Maintenance Defects Overview, Di Nottia et al [2024]
SLC25A4	1 person	Hypotonia	Neonatal onset; HCM; cataracts	mtDNA depletion, multiple RCE deficiencies (m)	mtDNA maintenance defect	Mitochondrial DNA Maintenance Defects Overview, Souza et al [2019]
SSBP1	1 person	Overlapping LSS, Pearson, & Kearns-Sayre phenotype; ptosis; ophthalmoplegia	HCM; cataract; neutropenia	mtDNA depletion	mtDNA maintenance defect	Gustafson et al [2019]

: fb = cultured skin fibroblasts; HCM = hypertrophic cardiomyopathy; fb = fibroblasts; LSS = Leigh syndrome spectrum; m = muscle biopsy; mt = mitochondrial; mtDNA = mitochondrial DNA; RCE = respiratory chain enzyme
1.: Other than those of classic Leigh syndrome
2.: Autosomal recessive LSS has also been reported in association with biallelic pathogenic variants in this gene (see Table 2b).

X-Linked Leigh Syndrome Spectrum

Causes of X-linked nuclear gene-encoded LSS are summarized in Tables 4a and 4b.

Table 4a.

X-Linked Leigh Syndrome Spectrum with Targeted Therapy: Associated Genes

Gene	Proportion of Nuclear-Encoded LSS	Distinguishing Clinical & Laboratory Features			Pathologic Mechanism	Reference
Gene	Proportion of Nuclear-Encoded LSS	Neurologic ¹	Other	Laboratory findings	Pathologic Mechanism	Reference
PDHA1	~10%	Developmental delay; hypotonia; seizures; choreoathetosis; dystonia; episodic ataxia in some; microcephaly; cerebral atrophy; cystic lesions in basal ganglia, brain stem, & cerebral hemispheres; agenesis of CC	Facial dysmorphism	↓/↓-normal lactate-to-pyruvate ratio in blood & CSF; PDH deficiency (fb)	Defect of pyruvate metabolism	Primary Pyruvate Dehydrogenase Complex Deficiency Overview

: CC = corpus callosum; CSF = cerebrospinal fluid; fb = cultured skin fibroblasts; LSS = Leigh syndrome spectrum; PDH = pyruvate dehydrogenase
1.: Other than those of classic Leigh syndrome

Table 4b.

X-Linked Leigh Syndrome Spectrum: Other Genes

Gene	Proportion of Nuclear-Encoded LSS	Distinguishing Clinical & Laboratory Features		Pathologic Mechanism	Reference
Gene	Proportion of Nuclear-Encoded LSS	Neurologic ¹	Laboratory findings	Pathologic Mechanism	Reference
AIFM1	<1%	Encephalomyopathy w/bilateral striatal lesions	Multiple RCE deficiencies (m)	Dysregulation of mitophagy	Ghezzi et al [2010]
HSD17B10	<1%	Seizures; ataxia; microcephaly; visual impairment; movement disorders; diffuse cerebral atrophy	↑ urine 2-methyl-3-hydroxybutyrate & tiglylglycine	Defect of mitochondrial gene expression	Upadia et al [2021]
NDUFA1	<1%	DD; axial hypotonia; nystagmus; choreoathetosis; myoclonic epilepsy; survival to 30s in 2 persons; spinal cord lesions in 1 person	Complex I deficiency (m)	Complex I deficiency	Fernandez-Moreira et al [2007]

: DD = developmental delay; LSS = Leigh syndrome spectrum; m = muscle biopsy; RCE = respiratory chain enzyme
1.: Other than those of classic Leigh syndrome

Pathologic Mechanism of Genes in Nuclear-Encoded Leigh Syndrome Spectrum

Table 5.

Pathologic Mechanism of Genes in Nuclear-Encoded LSS

Pathologic Mechanism	Genes
Complex I deficiency	DNAJC30, FOXRED1, NDUFA1, NDUFA2, NDUFA9, NDUFA10, NDUFA12, NDUFA13, NDUFAF2, NDUFAF3, NDUFAF4, NDUFAF5, NDUFAF6, NDUFAF8, NDUFB8, NDUFC2, NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS6, NDUFS7, NDUFS8, NDUFV1, NDUFV2, NUBPL, TIMMDC1, TMEM126B
Complex II deficiency	SDHA, SDHAF1, SDHB
Complex III deficiency	BCS1L, TTC19, UQCRC2, UQCRQ
Complex IV deficiency	COA6, COX4I1, COX8A, COX10, COX15, LRPPRC, NDUFA4, PET100, PET117, SCO2, SURF1, TACO1
Complex V deficiency	ATP5PO, ATP5MK (ATP5MD)
Defect of pyruvate metabolism	DLAT, DLD, MPC1, PDHA1, PDHB, PDHX
Defect of B vitamin transport/metabolism	BTD, SLC19A3, SLC25A19, TPK1
Defect of cofactor biosynthesis (coenzyme Q₁₀)	COQ4, COQ7, COQ9, HPDL, PDSS2
Defect of cofactor biosynthesis (lipoic acid)	LIAS, LIPT1, MECR
Defect of mtDNA maintenance	MPV17, POLG, RNASEH1, RRM2B, SLC25A4, SSBP1, SUCLA2, SUCLG, TWNK
Defect of mitochondrial gene expression	EARS2, FARS2, FASTKD2, GFM1, GFM2, GTPBP3, HSD17B10, IARS2, MRPL3, MRPL39, MRPS34, MTFMT, MTO1, MTRFR (C12ORF65), NARS2, PNPT1, PTCD3, TARS2, TRMU, TSFM
Defect of mitochondrial protein quality control	CLPB, HRTA2, LONP1, PMPCA, PMPCB, SPG7
Defect of mitochondrial membranes	SERAC1, TOMM7
Defect of mitochondrial dynamics	DNM1L, MFF, MFN2, OPA1, SLC25A46
Dysregulation of mitophagy	AIFM1, FBXL4, VPS13D
Mitochondrial toxicity	ECHS1, ETHE1, HIBCH, L2HGDH, NAXE, SQOR
Other	KGD4 (MRPS36)

: mtDNA = mitochondrial DNA

3. Differential Diagnosis of Nuclear Gene-Encoded Leigh Syndrome Spectrum

The differential diagnosis of genetic causes of nuclear gene-encoded Leigh syndrome spectrum (LSS) include mitochondrial DNA-associated Leigh syndrome (see Mitochondrial DNA-Associated Leigh Syndrome Spectrum and Primary Mitochondrial Disorders Overview).

Other non-mitochondrial monogenic disorders that cause or resemble LSS are listed in Table 6.

Table 6.

Non-Mitochondrial Monogenic Disorders That Cause or Resemble Leigh Syndrome Spectrum

Key Feature	Gene(s)	Disorder	MOI
Infantile bilateral striatal necrosis	ADAR	ADAR-related Aicardi-Goutières syndrome	AR AD ¹
Infantile bilateral striatal necrosis	NUP62	NUP62-related infantile bilateral striatal necrosis (OMIM 605815)	AR
Infection-induced acute encephalopathy	RANBP2	RANBP2-related susceptibility to infection-induced acute encephalopathy 3 (OMIM 608033)	AD
Neurodegenerative &/or neurodevelopmental disorders with similar changes on neuroimaging	ALDH5A1	Succinic semialdehyde dehydrogenase deficiency	AR
	ATP7B	Wilson disease	AR
	FTL	Neuroferritinopathy	AD
	GAMT	GAMT deficiency (See Creatine Deficiency Disorders.)	AR
	GCDH	Glutaric acidemia type 1	AR
	MCEE MMAA MMAB MMADHC MMUT	Isolated methylmalonic acidemia	AR
	MOCS1 MOCS2 MOCS3 GPHN	Molybdenum cofactor deficiency	AR
	MORC2	Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy (OMIM 619090)	AD
	PANK2	Pantothenate kinase-associated neurodegeneration	AR
	PCCA PCCB	Propionic acidemia	AR
	RNF213	Moyamoya disease 2, susceptibility to (OMIM 607151)	AD AR
	SLC39A8	SLC39A8-CDG	AR
	SUOX	Isolated sulfite oxidase deficiency	AR

: AD = autosomal dominant; AR = autosomal recessive; CDG = congenital disorder of glycosylation; MOI = mode of inheritance
1.: ADAR-related Aicardi-Goutières syndrome can be inherited in an autosomal recessive or autosomal dominant manner depending on the specific pathogenic variant.

Acquired non-genetic conditions in the differential diagnosis of LSS include viral encephalopathy, hypoxic-ischemic encephalopathy, Wernicke encephalopathy secondary to thiamine deficiency, and acute necrotizing encephalopathy (which may be triggered by viral infection).

4. Evaluation Strategies to Identify the Genetic Cause of Nuclear Gene-Encoded Leigh Syndrome Spectrum in a Proband

Establishing a specific genetic cause of nuclear gene-encoded LSS:

Can aid in discussions of prognosis (which are beyond the scope of this GeneReview) and genetic counseling;
Usually involves a medical history, physical examination, imaging studies such as brain MRI, biochemical testing, family history, and genomic/genetic testing.

While some clinical features are associated with some specific nuclear-encoded LSS genes (see Tables 2a, 2b, 3, 4a, and 4b), the significant overlap in the clinical and/or biochemical features alone among the causative genes makes it difficult to narrow down the likely molecular diagnosis based on these findings. Additionally, there is significant clinical overlap between nuclear-encoded LSS and mtDNA-encoded LSS. Hence, it would be unusual for specific clinical and/or imaging findings to guide testing of a subset of genes.

Medical history. A detailed history should be taken, particularly in respect to neurologic features. Exacerbation of manifestations or periods of regression during times of metabolic stress (e.g., viral illness, surgery, and/or fasting) should be explored, as this is highly suggestive of nuclear-encoded LSS. See Tables 2a, 2b, 3, 4a, and 4b for further gene-specific information.

Physical examination. There are no pathognomonic clinical signs of nuclear-encoded LSS. A standard physical examination as well as detailed neurologic and ophthalmologic examinations should be completed in all individuals.

Some examples of specific clinical features that may increase suspicion for a particular gene include hypertrichosis (suggestive of SURF1-related LSS). See Tables 2a, 2b, 3, 4a, and 4b for additional gene-specific information.

Imaging. Characteristic patterns of brain lesions on imaging described for some specific nuclear-encoded LSS genes include the following:

NDUFAF2 deficiency is associated with brain stem lesions seen within the mamillothalamic tracts, substantia nigra, medial lemniscus, medial longitudinal fasciculus, and spinothalamic tracts on T₂-weighted MRI [Fassone & Rahman 2012].
SERAC1 deficiency is associated with a distinctive brain MRI pattern affecting the basal ganglia, especially the putamen. Initially there are T₂-weighted signal changes of the pallidum, and later swelling of the putamen and caudate nucleus with an "eye" representing early sparing of the dorsal putamen, followed by progressive involvement of the putamina.
Brain malformations are typically seen in males with a hemizygous PDHA1 pathogenic variant and some females with a heterozygous PDHA1 pathogenic variant [Patel et al 2012].

Family history. A three-generation family history should be taken with attention to relatives with manifestations of nuclear gene-encoded LSS, or other clinical features compatible with a mitochondrial disorder. Relevant findings can be identified from direct examination of the individual or review of medical records, including results of molecular genetic testing, neuroimaging studies, and/or autopsy examinations.

Biochemical and Genomic/Genetic Testing

Testing for treatable disorders. Disorders with targeted therapy (see Tables 2a and 4a) should be rapidly tested biochemically or genetically as indicated; if this is not possible, trials of the relevant vitamins/cofactors should be instituted as soon as the diagnosis is considered. Ideally, therapy should continue until these disorders have been excluded by biochemical and/or genetic testing, and continued for life if the diagnosis is confirmed.

Biochemical Testing

Elevated blood and/or cerebrospinal fluid (CSF) lactate concentrations may strongly support the diagnosis of nuclear-encoded LSS.

Note: A normal blood and/or CSF lactate concentration does not exclude nuclear-encoded LSS.
A normal to low lactate-to-pyruvate ratio may indicate a disorder associated with pyruvate dehydrogenase complex deficiency.

Plasma amino acids may show:

Increased alanine concentration, reflecting persistent hyperlactatemia;
Elevated glycine concentrations that may indicate a defect in lipoic acid biosynthesis (except LIPT1 deficiency).

Acylcarnitine profile may be abnormal, with characteristic patterns associated with the following disorders:

Elevated hydroxy-C4-carnitine may be associated with HIBCH deficiency;
Elevated C3-carnitine may be associated with SUCLG1 and SUCLA2 deficiencies.

Abnormalities in urine organic acids may be nonspecific and may show lactic aciduria, increased Krebs cycle intermediates, and increased dicarboxylic acids. However, some gene defects are associated with a specific urine metabolite profile, including the following:

SERAC1, CLPB, and HTRA2 deficiencies are associated with 3-methylglutaconic aciduria.
SUCLG1 and SUCLA2 deficiencies are associated with methylmalonic aciduria.
ETHE1 deficiency is associated with ethylmalonic aciduria.
ECHS1 and HIBCH deficiencies are associated with marked elevation of urine 2-methyl-2,3-dihydroxybutyrate and S-(2-carboxypropyl) cysteine.

See Tables 2a, 2b, 3, 4a, and 4b for further gene-specific information.

Measurement of enzyme activity. Traditionally tissue biopsy was the first-line diagnostic test in the investigation of LSS and other mitochondrial disorders. However, it is an invasive procedure that often requires general anesthesia, which increases the risk of a metabolic decompensation. Although the widespread use of genomic testing has obviated the need for muscle biopsy in many instances, in a small minority of individuals, enzymatic testing of a muscle or skin biopsy may be necessary to confirm the pathogenicity of variants of uncertain significance identified by genomic testing.

Activity of enzymes, such as pyruvate dehydrogenase (PDH), are typically measured in cultured skin fibroblasts (fb), and respiratory chain enzymes are typically measured in a skeletal muscle biopsy (m); see Tables 2a, 2b, 3, 4a, and 4b for further gene-specific information.
Respiratory chain enzymology can identify deficient enzyme activity (<30% of control mean values) of one or more of the respiratory chain enzyme complexes. Complex I and Complex IV deficiencies are the most common enzyme abnormalities observed in individuals with nuclear-encoded LSS.
Although identifying deficiency of an enzyme can help prioritize molecular genetic testing, this approach still leaves a large number of genes to be tested (e.g., respiratory chain complex I-deficient LSS has been shown to be caused by pathogenic variants in at least 28 nuclear genes and six mtDNA genes).

Molecular Genetic Testing

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Choice of approach may depend on clinical suspicion and availability of testing. Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1); however, this approach in the diagnosis of nuclear gene-encoded LSS may be difficult given the significant clinical overlap between different genes. Comprehensive genomic testing does not require a phenotype-driven hypothesis (see Option 2).

Option 1

A mitochondrial disorders multigene panel that includes, at a minimum, genes associated with disorders that have targeted therapy (see Tables 2a and 4a) as well as some or all of the genes included in Section 2 and other genes of interest (see Section 3) is most likely to identify the genetic cause of the condition while limiting identification of pathogenic variants and variants of uncertain significance in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

Comprehensive genomic testing does not require the clinician to determine which gene is likely involved and may provide or suggest a diagnosis not previously considered (e.g., variant in a different gene[s] that results in a similar clinical phenotype). Exome sequencing is most commonly used; genome sequencing is also possible.

Genome sequencing is preferred (if available), as it allows analysis of the mitochondrial and nuclear genome, and typically has the highest diagnostic rate. About 30% of children with suspected LSS have mtDNA-encoded LSS (see Section 3).
When testing children, family trio genome sequencing should be considered to assist in the identification of either biallelic pathogenic variants that cause rare autosomal recessive disorders or de novo pathogenic variants.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

5. Management of Nuclear Gene-Encoded Leigh Syndrome

Treatment of Manifestations

Targeted Therapies

In GeneReviews, a targeted therapy is one that addresses the specific underlying mechanism of disease causation (regardless of whether the therapy is significantly efficacious for one or more manifestation of the genetic condition); would otherwise not be considered without knowledge of the underlying genetic cause of the condition; or could lead to a cure. —ED

Targeted therapies are available for some specific nuclear gene-encoded Leigh syndrome spectrum (LSS) disorders, listed in Table 7.

Table 7.

Leigh Syndrome Spectrum Disorders with Targeted Therapies

Disorder	Treatment	Comments
Biotin-thiamine-responsive basal ganglia disease (thiamine transporter-2 deficiency)	Biotin & thiamine supplementation	Manifestations typically resolve within days.
Biotinidase deficiency	Biotin supplementation	All persons w/profound biotinidase deficiency (<10% mean normal serum enzyme activity) & those w/partial biotinidase deficiency (10%-30% of mean normal serum enzyme activity) should be treated w/oral biotin in the free form as opposed to the protein-bound form. Persons w/biotinidase deficiency who are diagnosed before they have developed manifestations (e.g., by newborn screening) & who are treated w/biotin have normal development.
Primary coenzyme Q₁₀ deficiency	Coenzyme Q₁₀ supplementation	Treatment should be instituted as early as possible because it can limit disease progression & reverse some manifestations; however, established severe neurologic &/or kidney damage cannot be reversed. Response is highly variable, & depends on both the specific genetic defect & disease severity, but also other unknown factors.
Primary pyruvate dehydrogenase complex deficiency	Ketogenic diet	Response to ketogenic diet has been shown to be most beneficial in persons w/milder disease.
Primary pyruvate dehydrogenase complex deficiency	Thiamine	Thiamine has been used w/limited success. Response is variable & depends on the specific genetic defect.
SLC25A19-related thiamine metabolism dysfunction	Thiamine	Thiamine treatment is lifelong. Thiamine dose must be ↑ during febrile illness, surgery, or acute decompensation (by 25%).
TPK1-related LSS	Thiamine	Variable response to thiamine among affected persons, w/response reported in approximately 50% of individuals [Zhao et al 2023]. More effective with early diagnosis

Supportive Treatment

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 8).

Table 8.

Nuclear Gene-Encoded Leigh Syndrome Spectrum: Treatment of Manifestations

Manifestation/Concern	Treatment	Considerations/Other
Acute acidosis	Sodium bicarbonate or sodium citrate for significant acidosis Consider THAM if hypernatremia occurs.	Avoidance of lactate-containing solutions (e.g., Ringer's lactate)
Epilepsy	Treatment w/ASM by experienced neurologist	Sodium valproate should be avoided because of its inhibitory effects on the mitochondrial respiratory chain. ¹ Education of parents/caregivers ²
Dystonia	Benzhexol, baclofen, tetrabenazine, & gabapentin may be useful, alone or in various combinations.	Initial dose should be low & gradually ↑ until manifestations are controlled, or intolerable side effects occur.
Dystonia	Botulinum toxin injection has been used in persons w/LSS & severe intractable dystonia	Should be used w/caution given potential side effects of exacerbating muscle weakness. Should not be used in head & neck because of risk of adverse events (e.g., impaired swallow).
Pulmonology	Referral to pulmonologist as needed Ventilatory support for persons w/LSS & respiratory compromise
Feeding/Nutrition	Caloric & nutritional supplementation as needed (incl micronutrients) Feeding therapy as needed; gastrostomy tube placement may improve nutritional intake for those w/persistent feeding issues, choking, or aspiration risk due to dysphagia	Low threshold for clinical feeding eval &/or radiographic swallowing study when showing clinical signs or symptoms of dysphagia While ketogenic diet may be indicated for persons w/PDH deficiency or drug-resistant epilepsy, there is no evidence for efficacy of ketogenic diet in other forms of LSS.
Development/Cognition	See Developmental Delay / Intellectual Disability Management Issues.
Myopathy &/or ataxia	PT & OT	Equipment to prevent falling, maintain independent mobility as appropriate
Eyes	Standard treatments for eye movement disorders as advised by ophthalmologist
Cardiomyopathy	Anticongestive therapy or antiarrhythmic therapy may be required & treatment should be managed by a cardiologist.
Gastrointestinal	Stool softeners, laxatives for constipation as needed
Liver	Treatments for liver failure as advised by hepatologist
Renal	Electrolyte monitoring & replacement for renal tubular losses as advised by nephrologist
Hearing	Hearing aids or cochlear implants for SNHL Referral to speech-language therapist Referral to hearing support services	Counsel to avoid excessive noise exposure, which can exacerbate hearing loss.
Endocrine	Treatment for diabetes mellitus or adrenal insufficiency managed by endocrinologist
Neurobehavioral/ Psychiatric	Standard treatments for anxiety &/or depression	Psychological support for affected person & family is essential.
Family/Community	Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.	Ongoing assessment of need for palliative care involvement &/or home nursing

: ASM = anti-seizure medication; LSS = Leigh syndrome spectrum; OT = occupational therapy; PDH = pyruvate dehydrogenase; PT = physical therapy; SNHL = sensorineural hearing loss; THAM = tris-hydroxymethyl aminomethane
1.: De Vries et al [2020]
2.: Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Epilepsy Foundation Toolbox.

Surveillance

Affected individuals should be followed at regular intervals (typically every 6-12 months) to monitor progression of known manifestations and the appearance of new manifestations. Neurologic, ophthalmologic, audiologic, and cardiologic evaluations are recommended (see Table 9). Surveillance may be directed by knowledge of phenotypes known to be associated with specific gene defects [Rahman et al 2017].

Table 9.

Nuclear Gene-Encoded Leigh Syndrome Spectrum: Recommended Surveillance

System/Concern	Evaluation	Frequency
Neurologic	Neurology assessment for ataxia/movement disorders, neuropathy, & seizures	At each visit
Pulmonary	Monitor for evidence of aspiration, nocturnal hypoventilation, or sleep-disordered breathing.
Feeding/Nutrition	Measurement of growth parameters Eval of nutritional status (incl micronutrients) & safety of oral intake
Gastroenterology	Assess for nausea, constipation, or dysmotility.
Development/ Cognition	Monitor developmental progress, educational needs, & cognitive issues.	At least annually
Musculoskeletal	Physical medicine, OT/PT assessment of mobility, self-help skills	At least annually
Ophthalmology	Ophthalmology eval	Every 6-12 months or as advised by ophthalmologist
Cardiac	Blood pressure Electrocardiogram Echocardiogram	Annually or as advised by cardiologist
Liver	Liver function tests incl transaminases, albumin, bilirubin, & coagulation studies	Annually
Renal	Urinalysis, urine albumin-to-creatinine ratio, urine amino acids Serum electrolytes, BUN, creatinine
Hearing	Audiology eval
Hematology	Complete blood count
Endocrine	Fasting glucose Consider hemoglobin A1c or OGTT if clinical features consistent w/diabetes mellitus. Consider early morning cortisol & ACTH stimulation test if concerns about adrenal insufficiency.	Annually
Family/Community	Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources), care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning).	At each visit

: ACTH = adrenocorticotropic hormone; BUN = blood urea nitrogen; OGTT = oral glucose tolerance test; OT = occupational therapy; PT = physical therapy

Agents/Circumstances to Avoid

A Delphi review has examined drug safety in mitochondrial disorders [De Vries et al 2020]. However, it is important to tailor medication recommendations to each individual.

Sodium valproate should be avoided if possible, because of its inhibitory effect on respiratory chain enzymes. Absolute contraindication in all individuals with POLG-related disease [De Vries et al 2020].
Anesthesia can potentially aggravate respiratory manifestations and precipitate respiratory failure; thus, careful consideration should be given to its use and to monitoring the individual prior to, during, and after its use [Shear & Tobias 2004, Niezgoda & Morgan 2013].
Prolonged propofol use during maintenance anesthesia may increase the risk of lactic acidosis.
Catabolism should be prevented by minimizing preoperative fasting and considering intravenous glucose perioperatively during prolonged anesthesia (unless the individual is on a ketogenic diet).
Neuromuscular blocking drugs should be avoided in individuals with muscle disease, or if necessary, used under strict monitoring.
Avoid lactate-containing agents (e.g., Ringer's lactate) in those at risk of lactic acidosis [Parikh et al 2017, De Vries et al 2020].

6. Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Nuclear gene-encoded Leigh syndrome spectrum (LSS) can be inherited in an autosomal recessive, X-linked, or autosomal dominant manner.

Of the more than 115 nuclear gene-encoded LSS-related genes identified to date, pathogenic variants in all but six genes are associated with autosomal recessive inheritance.
LSS caused by a heterozygous or hemizygous pathogenic variant in AIFM1, NDUFA1, HSD17B10, or PDHA1 is inherited in an X-linked manner. Note: Almost equal numbers of males and females affected with PDHA1-related LSS have been reported [Lissens et al 2000, Imbard et al 2011]. Although relatively few affected individuals with NDUFA1-, HSD17B10-, and AIFM1-related LSS have been reported, it is expected that the same sex ratio would be seen in all four X-linked disorders.
SLC25A4- and SSBP1-related LSS are autosomal dominant disorders. To date, SSBP1- and SLC25A4-related LSS have each been reported in a single individual and in both instances have occurred as the result of a de novo pathogenic variant.
Two genes, DNM1L and OPA1, have been associated with both autosomal dominant and autosomal recessive LSS.

Genetic counseling regarding risk to family members depends on accurate diagnosis, determination of the mode of inheritance in each family, and results of molecular genetic testing.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

The parents of an affected child are presumed to be heterozygous for an LSS-related pathogenic variant.
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an LSS-related pathogenic variant and to allow reliable recurrence risk assessment.
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
- A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
- Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

If both parents are known to be heterozygous for an LSS-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. Individuals with autosomal recessive LSS are not known to reproduce.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an LSS-related pathogenic variant.

Carrier detection. Carrier testing for at-risk relatives requires prior identification of the LSS-related pathogenic variants in the family.

X-Linked Inheritance – Risk to Family Members

Parents of a male proband

The father of an affected male will not have X-linked LSS nor will he be hemizygous for an AIFM1, HSD17B10, NDUFA1, or PDHA1 pathogenic variant; therefore, he does not require further evaluation/testing.
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the familial pathogenic variant cannot be detected in her leukocyte DNA, she most likely has gonadal mosaicism.
If a male is the only affected family member (i.e., a simplex case):
- The mother may be heterozygous for the X-linked LSS-related pathogenic variant or have somatic/gonadal mosaicism; or
- The affected male may have a de novo pathogenic variant (in which case the mother is not a heterozygote). (About 60%-63% of males with PDHA1-related primary pyruvate dehydrogenase complex deficiency [PDCD] have the disorder as the result of a de novo pathogenic variant [see Primary Pyruvate Dehydrogenase Complex Deficiency Overview]).
Molecular genetic testing of the mother is recommended to evaluate her genetic status and inform recurrence risk assessment. Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.

Parents of a female proband

A female proband may have X-linked LSS as the result of a de novo pathogenic variant or she may have the disorder as the result of a pathogenic variant inherited from her mother or, possibly, her father. (About 85%-95% of females with PDHA1-related primary PDCD have the disorder as the result of a de novo pathogenic variant.)
Detailed evaluation of the parents and review of the extended family history may help to distinguish probands with a de novo pathogenic variant from those with an inherited pathogenic variant. Molecular genetic testing of the mother (and possibly the father either concurrently or subsequently if the mother's testing is unrevealing) can help to determine if the pathogenic variant was inherited.

Sibs of a proband

The risk to sibs of a male proband of inheriting an X-linked LSS-related pathogenic variant depends on the genetic status of the mother: if the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%.
The risk to sibs of a female proband of inheriting a pathogenic variant depends on the genetic status of the mother and the father: if the mother of the proband has an X-linked LSS-related pathogenic variant, the chance of transmitting it in each pregnancy is 50%; if the father of the proband has a pathogenic variant, he will transmit it to all his daughters and none of his sons.
The risk that a sib who inherits an X-linked LSS-related pathogenic variant will have manifestations of the disorder cannot be fully predicted. The risk of manifestations is influenced by the sex of the sib and – in the case of PDHA1-related primary PDCD – the sex of the proband, and, to an extent, the type of pathogenic variant segregating in the family (i.e., an insertion/deletion pathogenic variant or a missense pathogenic variant).
- Males who inherit an X-linked LSS-related pathogenic variant will be affected; females who inherit a pathogenic variant will be heterozygotes and their clinical manifestations may range from asymptomatic to as severely affected as hemizygous males.
- As a result of the difference in PDHA1 pathogenic variants typically identified in male and female probands, it is difficult to fully predict what clinical manifestations may occur in a heterozygous or hemizygous sib who is a different sex from the proband. Theoretically, the female sibs of a male proband with a missense pathogenic variant may be asymptomatic or have milder manifestations than the proband, whereas an insertion/deletion pathogenic variant in a female proband may not be compatible with life in a hemizygous male fetus. Conclusive data regarding these possibilities are not available, as there are few known families in which both male and female relatives are known to have a PDHA1 pathogenic variant (with the exception of male probands born to asymptomatic heterozygous mothers).
If the proband represents a simplex case and the pathogenic variant cannot be detected in the leukocyte DNA of the mother (or, if the proband is female and the pathogenic variant cannot be detected in the leukocyte DNA of the mother or the father), the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of parental gonadal mosaicism.

Offspring of a proband

Males with X-linked LSS have not been known to reproduce.
Each child of a female with X-linked LSS has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has an X-linked LSS-related pathogenic variant, the parent's family members may be at risk.

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

All probands reported to date with DNM1L-, OPA1-, SLC25A4-, or SSBP1-related autosomal dominant LSS whose parents have undergone molecular genetic testing have the disorder as the result of a de novo pathogenic variant.
Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
- The proband has a de novo pathogenic variant.
- The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

If a parent of the proband has the autosomal dominant LSS-related pathogenic variant, the risk to the sibs of inheriting the variant is 50%.
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [Rahbari et al 2016].

Offspring of a proband. Individuals with DNM1L-, OPA1-, SLC25A4-, or SSBP1-related autosomal dominant LSS have not been known to reproduce.

Other family members. Given that all probands with autosomal dominant LSS reported to date have the disorder as a result of a de novo pathogenic variant, the risk to other family members is presumed to be low.

Related Genetic Counseling Issues

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the LSS-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

United Mitochondrial Disease Foundation
Phone: 888-317-UMDF (8633)
Email: info@umdf.org
umdf.org
Association Contre Les Maladies Mitochondriales
France
Phone: 33 6 30 84 58 27
Email: assoammi@gmail.com
association-ammi.org
Deutsche Gesellschaft für Muskelkranke e.V.
Germany
Email: info@dgm.org
dgm.org
International Mito Patients
mitopatients.org
Mito Foundation
Australia
Phone: 61-1-300-977-180
Email: info@mito.org.au
mito.org.au
MitoAction
Phone: 888-648-6228
Email: support@mitoaction.org
mitoaction.org
MitoCanada
Canada
Phone: 289-807-2929
Email: info@mitocanada.org
mitocanada.org
Mitocon – Insieme per lo studio e la cura delle malattie mitocondriali Onlus
Mitocon is the reference association in Italy for patients suffering from mitochondrial diseases and their families and is the main link between patients and the scientific community.
Italy
Phone: 06 66991333/4
Email: info@mitocon.it
mitocon.it
People Against Leigh Syndrome (PALS)
peopleagainstleighs.org
The Freya Foundation
The aim of The Freya Foundation is to raise awareness for the condition called PDH, or pyruvate dehydrogenase deficiency complex.
United Kingdom
Email: thefreyafoundation@gmail.com
thefreyafoundation.co.uk
The Lily Foundation
United Kingdom
Email: liz@thelilyfoundation.org.uk
thelilyfoundation.org.uk
RDCRN Patient Contact Registry: North American Mitochondrial Disease Consortium
Patient Contact Registry

Chapter Notes

Author Notes

Prof Rahman, Prof Thorburn, and Dr Ball are actively involved in clinical research regarding individuals with nuclear gene-encoded Leigh syndrome spectrum (LSS). They would be happy to communicate with persons who have any questions regarding diagnosis of nuclear gene-encoded LSS or other considerations.

Professor Rahman's web page

Professor Thorburn's web page

Professor Rahman's research interests include identification of novel nuclear genes causing mitochondrial disease using a combination of approaches including homozygosity mapping and exome and genome next-generation sequencing. Her group has identified a number of nuclear genes causing childhood-onset mitochondrial disorders, including genes involved in mitochondrial DNA maintenance and expression, complex I and complex IV function, and biosynthesis of coenzyme Q₁₀. Other research interests aim to identify biomarkers and novel therapies for childhood mitochondrial disorders.

Professor Thorburn's research focuses on improving diagnosis, prevention, and treatment of mitochondrial energy generation disorders. This has included translating knowledge of mitochondrial DNA genetics into reproductive options for families, defining diagnostic criteria and epidemiology, and discovery of new "disease" genes through genomic, multi-omic, and targeted functional testing. His group also uses pluripotent and other cellular models to understand pathogenic mechanisms and trial new treatment approaches.

Acknowledgments

The authors would like to acknowledge the support of clinicians, researchers, and patient advocacy groups for nuclear gene-encoded LSS. They would also like to acknowledge all the patients and families who have generously given their time and shared their experiences to advance the understanding of nuclear gene-encoded LSS.

Revision History

1 May 2025 (bp) Comprehensive update posted live
16 July 2020 (bp) Comprehensive update posted live
1 October 2015 (me) Review posted live
17 February 2015 (sr) Original submission

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Rahman S, Thorburn DR, Ball M. Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview. 2015 Oct 1 [Updated 2025 May 1]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025.
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Summary
Clinical Characteristics of Nuclear Gene-Encoded Leigh Syndrome Spectrum
Causes of Nuclear Gene-Encoded Leigh Syndrome Spectrum
Differential Diagnosis of Nuclear Gene-Encoded Leigh Syndrome Spectrum
Evaluation Strategies to Identify the Genetic Cause of Nuclear Gene-Encoded Leigh Syndrome Spectrum in a Proband
Management of Nuclear Gene-Encoded Leigh Syndrome
Genetic Counseling
Resources
Chapter Notes
References

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Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview

Summary

1. Clinical Characteristics of Nuclear Gene-Encoded Leigh Syndrome Spectrum

Table 1.

Nomenclature

2. Causes of Nuclear Gene-Encoded Leigh Syndrome Spectrum

Clinical Criteria

Autosomal Recessive Leigh Syndrome Spectrum

Table 2a.

Table 2b.

Autosomal Dominant Leigh Syndrome Spectrum

Table 3.

X-Linked Leigh Syndrome Spectrum

Table 4a.

Table 4b.

Pathologic Mechanism of Genes in Nuclear-Encoded Leigh Syndrome Spectrum

Table 5.

3. Differential Diagnosis of Nuclear Gene-Encoded Leigh Syndrome Spectrum

Table 6.

4. Evaluation Strategies to Identify the Genetic Cause of Nuclear Gene-Encoded Leigh Syndrome Spectrum in a Proband

Biochemical and Genomic/Genetic Testing

Biochemical Testing

Molecular Genetic Testing

Option 1

Option 2

5. Management of Nuclear Gene-Encoded Leigh Syndrome

Treatment of Manifestations

Targeted Therapies

Table 7.

Supportive Treatment

Table 8.

Surveillance

Table 9.

Agents/Circumstances to Avoid

6. Genetic Counseling

Mode of Inheritance

Autosomal Recessive Inheritance – Risk to Family Members

X-Linked Inheritance – Risk to Family Members

Autosomal Dominant Inheritance – Risk to Family Members

Related Genetic Counseling Issues

Prenatal Testing and Preimplantation Genetic Testing

Resources

Chapter Notes

Author Notes

Acknowledgments

Revision History

References

Literature Cited

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Tests in GTR by Gene

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