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Nuclear Gene-Encoded Leigh Syndrome Overview

, FRCP, FRCPCH, PhD and , PhD.

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Summary

Clinical characteristics.

Leigh syndrome (or subacute necrotizing encephalomyelopathy) is characterized by decompensation (often with elevated lactate levels in blood and/or CSF) during an intercurrent illness. It is typically associated with psychomotor retardation or regression, often followed by transient or prolonged stabilization or even improvement, but inevitably resulting in eventual progressive neurologic decline, typically occurring in stepwise decrements. Neurologic manifestations include hypotonia, spasticity, movement disorders (including chorea), cerebellar ataxia, and peripheral neuropathy.

Extraneurologic manifestations may include hypertrophic cardiomyopathy, hypertrichosis, anemia, renal tubulopathy, liver involvement, ptosis, and muscle weakness. Onset is typically between ages three and 12 months; about 50% of affected individuals die by age three years, most often as a result of respiratory or cardiac failure. Later onset (including in adulthood) and long-term survival may occasionally occur.

Diagnosis/testing.

The diagnosis of nuclear gene-encoded Leigh syndrome is established in individuals with a characteristic clinical presentation, bilateral symmetric T2-weighted hyperintensities in the basal ganglia and/or brain stem on brain MRI, elevated lactate in blood and/or cerebrospinal fluid (CSF), and either identification of pathogenic variants in a specific nuclear gene or exclusion of mutation of mtDNA.

Note: The term "Leigh-like syndrome" is often used when clinical and other features strongly suggest Leigh syndrome but do not fulfill the stringent diagnostic criteria because of atypical or normal neuroimaging, normal blood and CSF lactate levels, atypical neuropathology, and/or incomplete evaluation.

Genetic counseling.

Nuclear gene-encoded Leigh syndrome and Leigh-like syndrome are inherited in either an autosomal recessive or X-linked manner.

Management.

Treatment of manifestations: Specific treatment is possible for the three nuclear gene-encoded Leigh-like syndromes: biotin-thiamine-responsive basal ganglia disease (BTBGD), biotinidase deficiency, and coenzyme Q10 deficiency caused by mutation of PDSS2. Supportive care for any of the causes of nuclear gene-encoded Leigh syndrome includes treatment of acidosis, seizures, dystonia, and cardiomyopathy with attention to nutritional status and psychological support for caregivers.

Prevention of primary manifestations: Prevention of manifestations is possible for biotin-thiamine-responsive basal ganglia disease (BTBGD), biotinidase deficiency, and coenzyme Q10 deficiency caused by mutation of PDSS2. See Treatment of manifestations.

Prevention of secondary complications: Because anesthesia can potentially aggravate respiratory symptoms and precipitate respiratory failure, careful consideration should be given to its use and close monitoring prior to, during, and after its use.

Surveillance: Affected individuals should be followed at regular intervals (typically every 6-12 months) to monitor progression and the appearance of new manifestations. Neurologic, ophthalmologic, audiologic and cardiologic evaluations are recommended.

Agents/circumstances to avoid: Sodium valproate, barbiturates, and dichloroacetate.

Definition

Clinical Manifestations of Nuclear Gene-Encoded Leigh Syndrome

Leigh syndrome (or subacute necrotizing encephalomyelopathy) is characterized by decompensation (often with elevated lactate levels in blood and/or CSF) during an intercurrent illness. It is typically associated with psychomotor retardation or regression, often followed by transient or prolonged stabilization or even improvement, but inevitably resulting in eventual progressive neurologic decline, typically occurring in stepwise decrements.

Neurologic manifestations include hypotonia, spasticity, movement disorders (including chorea), cerebellar ataxia, and peripheral neuropathy.

Extraneurologic manifestations may include hypertrophic cardiomyopathy, hypertrichosis, anemia, renal tubulopathy, liver involvement, ptosis, and muscle weakness.

Onset is typically between ages three and 12 months, frequently following a viral infection. About 50% of affected individuals die by age three years, most often as a result of respiratory or cardiac failure.

Later onset (including in adulthood) and long-term survival may occasionally occur.

Life expectancy and extraneurologic manifestations appear to be related, at least in part, to the underlying genetic defect [Wedatilake et al 2013].

Establishing the Diagnosis of Nuclear Gene-Encoded Leigh Syndrome

Establishing the diagnosis of nuclear gene-encoded Leigh syndrome requires the following [Rahman et al 1996, Lake et al 2015]:

  • Characteristic clinical presentation (see Definition)
  • Bilateral symmetric T2-weighted hyperintensities in the basal ganglia and/or brain stem on brain MRI
  • Elevated lactate in blood and/or cerebrospinal fluid (CSF)
  • Either identification of pathogenic variants in a specific nuclear gene or exclusion of mutation of mtDNA.
    Note: If post mortem examination is performed, characteristic neuropathologic changes include: multiple focal symmetric necrotic lesions in the basal ganglia, thalamus, brain stem, dentate nuclei, and optic nerves. Histologically, 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.

Leigh-like syndrome. The term "Leigh-like syndrome" is often used when clinical and other features strongly suggest Leigh syndrome but do not fulfil the stringent diagnostic criteria because of atypical or normal neuroimaging, normal blood and CSF lactate levels, atypical neuropathology (variation in the distribution or character of lesions or with the additional presence of unusual features such as extensive cortical destruction), and/or incomplete evaluation.

Prevalence of Nuclear Gene-Encoded Leigh syndrome

Prevalence of nuclear gene-encoded Leigh syndrome is approximately 1:40,000 [Rahman et al 1996].

Causes

Nuclear gene-encoded Leigh syndrome can be subdivided by mode of inheritance and gene: autosomal recessive inheritance (see Table 1 and Table 2) and X-linked inheritance (see Table 3). While pathogenic variants in more than 50 nuclear genes can cause nuclear gene-encoded Leigh syndrome, all but a few of these gene defects are associated with a very limited number of cases.

Autosomal Recessive Leigh Syndrome and Leigh-Like Syndromes

Causes of autosomal recessive nuclear gene-encoded Leigh syndrome (Table 1) include mutation of genes encoding OXPHOS enzymes and their assembly factors; defects of mitochondrial DNA maintenance, gene expression, and protein synthesis; cofactor biosynthesis (lipoic acid and coenzyme Q10); mitochondrial membrane lipid remodeling; pyruvate dehydrogenase; biotinidase; vitamin transporters; and organic acidemias with accumulation of metabolites leading to secondary OXPHOS dysfunction.

Although mutation of a given gene may lead to either ‘classic’ Leigh syndrome or a Leigh-like syndrome, mutation of certain genes typically results in classic Leigh syndrome (Table 1) and mutation of other genes typically causes Leigh-like syndromes or other clinical presentations and are only rarely associated with classic Leigh syndrome (Table 2).

Table 1.

Autosomal Recessive Leigh Syndrome

GeneProportion of AR LS caused by Mutation of This GeneDistinguishing Clinical FeaturesReference
HCMNeurologic 1Other
Complex I-deficient Leigh syndrome 2
NDUFS1<5%Cystic leukoencephalopathyBénit 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%+LeukodystrophyLoeffen et al [1998]
NDUFV1<5%Cystic leukoencephalopathyBénit et al [2001]
NDUFA21 family+Hoefs et al [2008]
NDUFA91 familyVan den Bosch et al [2012]
NDUFA101 family+Hoefs et al [2011]
NDUFA121 familySevere dystoniaHypertrichosisOstergaard et al [2011]
NDUFAF2<5%MRI: symmetric lesions in mamillo-thalamic tracts, substantia nigra/medial lemniscus, medial longitudinal fasciculus, & spinothalamic tractsBarghuti et al [2008]
NDUFAF5
(C20orf7)
<5%FILA (1 patient); survival into 20s in 1 familySugiana et al [2008]
Gerards et al [2010]
NDUFAF6
(C8orf38)
1 familyPagliarini et al [2008]
FOXRED1<5%Seizures & myoclonusSlowly progressive; survival possible into 20sCalvo et al [2010]
Fassone et al [2010]
Complex II-deficient Leigh syndrome 3
SDHA<5%+ (may occur)Course may be indolent w/survival into adulthoodBourgeron et al [1995]
Pagnamenta et al [2006]
SDHAF1<5%Leukoencephalopathy on MRI (1 case neuropathologic LS)Ohlenbusch et al [2012]
Complex III-deficient Leigh syndrome 4
UQCRQ1 familySlowly progressive; survival into 30sBarel et al [2008]
TTC19<5%Severe olivo-ponto-cerebellar atrophySlowly progressive; survival into 20s/30sGhezzi et al [2011]
BCS1L<5%SNHLProximal renal tubulopathy, hepatic involvement, pili tortide Lonlay et al [2001]
Complex IV-deficient Leigh syndrome 5
NDUFA41 familyEpilepsy, sensory axonal peripheral neuropathySlowly progressive; survival into 20s/30sPitceathly et al [2013]
SURF1~50% of complex IV deficient LS (~10% of all LS)Developmental regression (71%), nystagmus + ophthalmoplegia (52%), movement disorder (52%)Hypertrichosis (48%); median survival 5.4yWedatilake et al [2013]
COX10<5%+SNHLAnemia (due to defect of mitochondrial heme A biosynthesis)Antonicka et al [2003]
COX15<5%+SeizuresOquendo et al [2004]
SCO2<5%+Joost et al [2010]
LRPPRC 6<5%Metabolic & neurologic (stroke-like) crisesSurvival 5 days –>30y; Median age at death 1.6yDebray et al [2011]
TACO11 familyCognitive dysfunction, dystonia, visual impairmentLate onset (4-16y), slowly progressiveWeraarpachai 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

1.

Neurologic findings other than those of classic Leigh syndrome

2.

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

3.

Complex II deficiency on muscle biopsy; also succinate peak on brain MRS

4.

Complex III deficiency on muscle biopsy

5.

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

6.

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

7.

Founder pathogenic variant in Lebanese population

Table 2.

Autosomal Recessive Leigh-Like Syndromes

Disease NameGeneDistinguishing Clinical FeaturesLaboratory FindingsReference
NeurologicOther
Mitochondrial DNA depletion syndrome (hepatocerebral)POLGRoving eye movements, prominent seizuresHepatocerebral diseaseMultiple RCE deficiencies 1, isolated complex IV defic (rare)Taanman et al [2009]
Mitochondrial DNA depletion syndrome (encephalopathic)SUCLA2 2Hypotonia, muscle atrophy, hyperkinesia, severe SNHLGrowth retardationMMA, multiple RCE deficienciesElpeleg et al [2005], Ostergaard et al [2007]
SUCLG1Severe myopathyRecurrent hepatic failureMMA, multiple RCE deficienciesVan Hove et al [2010]
FBXL4SeizuresFacial dysmorphism, skeletal abnormalities, poor growth, gastrointestinal dysmotility, renal tubular acidosisMultiple RCE deficienciesShamseldin et al [2012]
Defect of mt tRNA modificationTRMULS reported in 1 personUsually causes benign reversible liver failure w/out neurologic symptomsTaylor et al [2014]
Mitochondrial translation (formylation) defectMTFMTCystic leukoencephalopathy in someMay be slowly progressive in some, w/survival into 20sTucker et al [2011], Haack et al [2014]
Phenylalanyl aminoacyl tRNA synthetase deficiency (mt translation defect)FARS2Severe epilepsy; Alpers neuropathology in othersIsolated complex IV deficiency in 1 person; enzymology not performed in any othersShamseldin et al [2012]
Glutamyl aminoacyl tRNA synthetase deficiency (mt translation defect)EARS2Leukoencephalopathy w/thalamus & brain stem involvement & high lactate (MRI)Improvement can occur, liver failure in some casesMultiple RCE deficienciesMartinelli et al [2012]
Isoleucyl aminoacyl tRNA synthetase deficiency (mt translation defect)IARS2LS causing death at 18m in 1 child; SNHL, peripheral sensory neuropathyCataracts, growth hormone deficiency, skeletal dysplasia in 3 adultsEnzymology not performedSchwartzentruber et al [2014]
Mitochondrial translation (elongation) defectGFM1Axial hypotonia, spasticity, refractory seizuresProgressive hepato-encephalopathy in someMultiple RCE deficienciesValente et al [2007]
TSFMJuvenile-onset, ataxia, neuropathy, optic atrophyGrowth retardation, HCMAhola et al [2014]
Mitochondrial translation defectC12orf65Ophthalmoplegia, optic atrophy, axonal neuropathyRelatively slow disease progressionMultiple RCE deficiencies (fbs)Antonicka et al [2010]
Polyribonucleotide nucleotidyltransferase deficiencyPNPT1 3Choreoathetosis & dyskinesia; also isolated SNHLSevere hypotoniaComplex III+IV deficiency in liver in 1 person (nml activ in mb & fbs)Vedrenne et al [2012]
Coenzyme Q10 deficiency (decaprenyl-diphosphate synthase subunit 2 deficiency)PDSS2Refractory seizuresNephrotic syndrome 4Complexes I+III, II+III & coenzyme Q10 deficiency (mb)López et al [2006]
Lipoic acid synthesis defectLIASSeizures w/burst suppression (EEG)Mild HCMCombined deficiency of PDH + glycine cleavage enzyme, elevated urine & plasma glycine, defic lipoylated proteins (western blot)Baker et al [2014]
LIPT11 person w/LS; 2 w/FILALiver dysfunctionIncreased glutamine & proline, low levels of lysine & branched-chain amino acids & nml glycine (unlike other lipoic acid synthesis defects); severe decrease of PDH & α-KGDH activ & strongly reduced BCKDH activ (fbs); nml RCE activSoreze et al [2013], Tort et al [2014]
MEGDEL syndromeSERAC1SNHLMay have liver involvement in infancy; later normalizes3-methylglutaconic aciduriaWortmann et al [2012]
PDH B defiencyPDHBCC agenesis/hypoplasiaPDH deficiency (fbs)Quintana et al [2009]
Dihydrolipoamide dehydrogenase deficDLDEpisodic encephalopathyHypoglycemia, ketoacidosis, liver failureElevated plasma branched-chain amino acids, PDH deficiency (fbs)Grafakou et al [2003], Quinonez et al [2013]
PDH E3 binding protein deficiencyPDHXThin CC/CC agenesis; status epilepticus late in disease (teens/20s)PDH deficiency (fbs)Schiff et al [2006]
Thiamine metabolism dysfunction syndrome 4 (bilateral striatal degeneration & progressive polyneuropathy type) 5SLC25A19Bilateral striatal necrosis; episodic encephalopathy; chronic progressive polyneuropathy resulting in distal weakness & contracturesEnzymology not performedSpiegel et al [2009]
Thiamine metabolism dysfunction syndrome 5 (episodic encephalopathy type)TPK1Episodic encephalopathy, ataxia, dystonia, spasticity2-ketoglutaric aciduriaMayr et al [2011]
Biotinidase deficiencyBTDDeafness, optic atrophy, seizures, ataxia 4Alopecia, eczemaCharacteristic organic aciduriaMitchell et al [1986]
Biotin-thiamine-responsive basal ganglia disease (thiamine transporter-2 deficiency)SLC19A3See footnote 4Nml RCE activityGerards et al [2013], Fassone et al [2013]
Ethylmalonic encephalopathyETHE1Neurodevelopmental delay & regression, pyramidal & extrapyramidal signsAcrocyanosis, petechiae & diarrhea in infancyEthylmalonic aciduriaMineri et al [2008]
3-hydroxyisobutyrylCoA hydrolase deficiencyHIBCHDevelopmental regression, seizures, ataxiaElevated plasma 4-hydroxybutyrylcarnitine levels; variable defic of RCEs & PDHFerdinandusse et al [2013]
Short-chain enoyl-CoA hydratase deficiencyECHS1 3Psychomotor delay, SNHL, nystagmus, hypotonia, spasticity, athetoid mvmtsHCM in 1 personIncreased urinary excretion of S-(2-carboxypropyl) cysteine; nml RCE activ in 1 person, mult RCE defic in 1 otherPeters et al [2014], Sakai et al [2015]

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

1.

RCE activity measured on muscle biopsy except in one case noted

2.

Founder variant in Faroe Islands

3.

Single family reported

4.

Treatable; see Management.

5.

Allelic with Amish lethal microcephaly, mitochondrial thiamine pyrophosphate carrier deficiency

X-Linked Leigh Syndrome and Leigh-Like Syndromes

Nuclear gene-encoded Leigh syndrome and Leigh-like syndrome inherited in an X-linked manner are summarized in Table 3.

Table 3.

X-Linked Leigh Syndrome and Leigh-like Syndrome

Disease NameGeneDistinguishing FeaturesLaboratory FindingsReference
PDH deficiencyPDHA1Psychomotor retardation; seizures; choreoathetosis; dystonia; episodic ataxia in some; microcephaly; cerebral atrophy; cystic lesions in basal ganglia, brain stem, & cerebral hemispheres; agenesis of corpus callosum; facial dysmorphismLow/low-normal lactate/pyruvate ratio in blood and CSF; PDH deficiency (fbs)Rahman et al [1996]
Complex I-deficient LSNDUFA1Developmental delay; axial hypotonia; nystagmus; choreoathetosis; myoclonic epilepsy; survival to 30s in 2 casesComplex I deficiency (mb)Fernandez-Moreira et al [2007]
X-linked mt encephalomyopathyAIFM1Encephalomyopathy w/bilateral striatal lesionsMultiple RCE deficiencies (mb)Ghezzi et al [2010]

LS = Leigh syndrome; PDH = pyruvate dehydrogenase; RCE = respiratory chain enzyme

Differential Diagnosis of Nuclear Gene-Encoded Leigh Syndrome

Differential diagnosis of nuclear gene-encoded Leigh syndrome includes mitochondrial DNA-associated Leigh syndrome, non-mitochondrial genetic causes of bilateral striatal necrosis (e.g., mutation of ADAR1, NUP62, or RANBP2), and acquired non-genetic causes such as viral encephalopathy.

Mitochondrial DNA-associated Leigh syndrome (also known as maternally inherited Leigh syndrome, MILS) is summarized in Table 4. See also Mitochondrial DNA-Associated Leigh Syndrome and NARP and Mitochondrial Disorders Overview.

Table 4.

Mitochondrial DNA-Associated Leigh syndrome

GeneMuscle Biopsy FindingsReference
MT-ND1Complex I deficiencyKirby et al [2004]
MT-ND2Ugalde et al [2007]
MT-ND3Lebon et al [2003]
MT-ND4Komaki et al [2003]
MT-ND5Santorelli et al [1997a]
MT-ND6Kirby et al [2000]
MT-CO3Complex IV deficiencyTiranti et al [2000]
MT-ATP6Complex V deficiencyHarding et al [1992]
MT-TIMultiple RCE deficienciesCox et al [2012]
MT-TKRahman et al [1996]
MT-TL1Rahman et al [1996]
MT-TVMcFarland et al [2002]
MT-TWSantorelli et al [1997b]
Large-scale mtDNA deletionRahman et al [1996]

RCE = respiratory chain enzyme

Evaluation Strategy

Once Leigh syndrome or a Leigh-like syndrome (Table 1, Table 2, and Table 3) is considered in an individual, determining the specific cause aids in discussions of prognosis and treatment (see Testing, Treatable disorders) and in genetic counseling. The following information can be used to establish the specific cause of Leigh syndrome for a given individual: clinical findings, family history, specialized testing, and molecular genetic/genomic testing.

Clinical findings. Clinical manifestations of Leigh syndrome and Leigh-like syndrome are described in Table 1, Table 2, and Table 3.

Although retrospective review of the more common genetic causes of Leigh syndrome (Table 1 and Table 3) suggests some differences in phenotype, clinical findings in individuals with mutation of different genes typically overlap; thus, in only a few situations can specific clinical and/or imaging findings guide testing of a subset of genes. For example:

  • More than 40 individuals with pathogenic variants in SURF1 or LRPPRC have been reported [Debray et al 2011, Wedatilake et al 2013]. Mean survival is longer in those with SURF1 deficiency (5.4 years) than in those with LRPPRC deficiency (1.8 years), apparently due to the occurrence of more frequent and severe metabolic crises in the latter. SURF1 deficiency also appears to have a high incidence of hypertrichosis and peripheral neuropathy [Wedatilake et al 2013].
  • Brain malformations are typically seen in those with mutation of PDHA1 [Patel et al 2012]. Specific brain tracts may be involved in some subgroups of complex I deficiency; for example, brain stem lesions are seen within the mamillothalamic tracts, substantia nigra, medial lemniscus, medial longitudinal fasciculus, and spinothalamic tracts on T2-weighted MRI in individuals with mutation of NDUFAF2 [Fassone & Rahman 2012].

Family history. A three-generation family history should be obtained with attention to other relatives with neurologic signs and symptoms, or other clinical features compatible with mitochondrial disease. Documentation of relevant findings in relatives can be accomplished either through direct examination of those individuals or review of their medical records including the results of molecular genetic testing, neuroimaging studies, and autopsy examinations.

Specific findings such as a maternal family history of disease may prompt initial investigation of mitochondrial DNA, or consanguinity may prompt initial investigation of autosomal recessive genes. Of course, such features are sometimes a chance occurrence and should be followed up with more comprehensive testing if no pathogenic variants are identified [Alston et al 2011].

Testing

Elevated lactate levels in blood and/or cerebrospinal fluid can:

  • Suggest Leigh syndrome versus other disorders with similar clinical findings;
  • Implicate mutation of one of the genes causing PDH deficiency when the ratio of lactate to pyruvate is normal to low [Debray et al 2007].

Measurement of enzyme activity. Enzymes, such as PDH, are typically measured in cultured skin fibroblasts (fbs in Table 1, Table 2, and Table 3), and respiratory chain enzymes are typically measured in skeletal muscle (mb in Table 1, Table 2, and Table 3). Although identifying an enzyme defect can help prioritize molecular genetic testing, this approach can still leave a large number of genes to be tested (e.g., respiratory chain complex I-deficient Leigh syndrome has to date been shown to be caused by pathogenic variants in at least 15 autosomal genes (Table 1), one X-linked gene (Table 3), and six genes encoded by mtDNA (Table 4).

Molecular genetic testing approaches can include serial single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

  • Serial single-gene testing can be considered if (1) mutation of a particular gene accounts for a large proportion of the disease or (2) clinical findings, laboratory findings, and/or ancestry (Table 1, Table 2, and Table 3) indicate that mutation of a particular gene is most likely. Typically sequence analysis of the gene of interest is performed first, followed by gene-targeted deletion/duplication analysis if only one pathogenic variant for autosomal recessive disorders or no pathogenic variant for either autosomal recessive or X-linked disorders is found.
  • A multigene panel that includes many or all of these genes and other genes of interest (see Differential Diagnosis) may also be considered. 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; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (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.
  • More comprehensive genomic testing (when available) including exome sequencing, genome sequencing, and mitochondrial sequencing may be considered if serial single-gene testing (and/or use of a multigene panel) fails to confirm a diagnosis in an individual with features of nuclear gene-encoded Leigh syndrome. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Treatable disorders. The causes of nuclear gene-encoded Leigh-like syndrome which are treatable (see Treatment of Manifestations) include:

These disorders should be rapidly tested biochemically or genetically as indicated or, 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, 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. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Nuclear gene-encoded Leigh syndrome and Leigh-like syndrome are inherited in either an autosomal recessive or X-linked manner.

Risk to Family Members – Autosomal Recessive Leigh Syndrome

Parents of a proband

  • The parents of an affected individual are obligate heterozygotes (i.e., carriers of one pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • At conception, each sib of an affected individual has 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. No affected individual has reproduced.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier of a pathogenic variant.

Carrier (heterozygote) detection. Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family.

Risk to Family Members – X-Linked Leigh Syndrome

Nuclear gene-encoded Leigh syndrome caused by mutation of PDHA1, NDUFA1, and AIFM1 is inherited in an X-linked manner.

Almost equal numbers of males and females affected with PDHA1-associated Leigh syndrome have been reported [Lissens et al 2000, Imbard et al 2011]. Although relatively few affected individuals with NDUFA1-associated LS and AIFM1-associated LS have been reported, it is expected that the same gender ratio would be seen in all three disorders.

Parents of a proband

Sibs of a proband

  • The risk to sibs depends on the genetic status of the mother.
  • If the mother of the proband has a PDHA1, NDUFA1, or AIFM1 pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant are likely to be affected unless they have a favorably skewed X-chromosome inactivation ratio.
  • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the PDHA1, NDUFA1, or AIFM1 pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is low but greater than that of the general population because of the possibility of maternal germline mosaicism.

Offspring of a proband. No affected individual has reproduced.

Other family members. The proband's maternal aunts may be at risk of being heterozygous and the aunts' sons may be at risk of inheriting a pathogenic variant and being affected.

Heterozygote (Carrier) Detection

Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the pathogenic variant has been identified in the proband.

Females who are heterozygous for a PDHA1, NDUFA1, or AIFM1 pathogenic variant are likely to be affected unless they have a favorably skewed X-chromosome inactivation ratio. The pattern of X-chromosome inactivation, particularly in the brain, is expected to largely determine clinical status.

Note: The 11 heterozygous mothers reported by Imbard et al [2011] were said to be asymptomatic. In the authors’ experience, however, some learning difficulties or other features are often present.

Related Genetic Counseling Issues

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for nuclear gene-encoded Leigh syndrome are possible.

Note: For families with X-linked Leigh syndrome, molecular genetic prenatal test results cannot be used to predict the risk of an affected outcome for a female conceptus carrying the familial pathogenic variant.

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.

  • National Library of Medicine Genetics Home Reference
  • Australian Mitochondrial Disease Foundation (AMDF)
    Suite 4, Level 6, 9-13 Young Street
    Sydney
    Australia
    Phone: 1-300-977-180
    Fax: 02-9999-3474
    Email: info@amdf.org.au
  • Metabolic Support UK
    United Kingdom
    Phone: 0845 241 2173
  • Muscular Dystrophy Association - USA (MDA)
    222 South Riverside Plaza
    Suite 1500
    Chicago IL 60606
    Phone: 800-572-1717
    Email: mda@mdausa.org
  • The Lily Foundation
    31 Warren Park
    Surrey CR6 9LD
    United Kingdom
    Phone: 07947 257247
    Fax: 01883 623799
    Email: liz@thelilyfoundation.org.uk
  • United Mitochondrial Disease Foundation (UMDF)
    8085 Saltsburg Road
    Suite 201
    Pittsburg PA 15239
    Phone: 888-317-8633 (toll-free); 412-793-8077
    Fax: 412-793-6477
    Email: info@umdf.org
  • Mitochondrial Disease Registry and Tissue Bank
    Massachusetts General Hospital
    185 Cambridge Street
    Simches Research Building 5-238
    Boston MA 02114
    Phone: 617-726-5718
    Fax: 617-724-9620
    Email: nslate@partners.org
  • RDCRN Patient Contact Registry: North American Mitochondrial Disease Consortium

Management

Treatment of Manifestations

Specific treatment is possible for the following three nuclear gene-encoded Leigh-like syndromes:

  • Biotin-thiamine-responsive basal ganglia disease (BTBGD) (also known as thiamine transporter-2 deficiency) (mutation of SLC19A3). Biotin (5-10 mg/kg/day) and thiamine (in doses ranging from 300-900 mg) should be given orally as early in the disease course as possible and continued lifelong. Symptoms typically resolve within days.
  • Biotinidase deficiency (BTD). All symptomatic children with profound biotinidase deficiency improve when treated with 5-10 mg of oral biotin per day. Biotin treatment should be continued lifelong in all individuals with profound biotinidase deficiency.
  • Coenzyme Q10 biosynthesis deficiency (PDSS2). Supplementation with oral coenzyme Q10 (10-30 mg/kg/day in children and 1200-3000 mg/day in adults) should be commenced as early in the disease course as possible and continued lifelong [Rahman et al 2012]

Supportive management for any of the causes of nuclear gene-encoded Leigh syndrome includes the following:

  • Acidosis. Sodium bicarbonate or sodium citrate is appropriate for acute exacerbations of acidosis.
  • Seizures. Appropriate antiepileptic drugs tailored to the type of seizure should be administered under the supervision of a neurologist. Sodium valproate and barbiturates should be avoided because of their inhibitory effects on the mitochondrial respiratory chain [Melegh & Trombitas 1997, Anderson et al 2002].
  • Dystonia
    • Benzhexol, baclofen, tetrabenezine, and gabapentin may be useful, alone or in various combinations; an initial low dose should be started and gradually increased until symptom control is achieved or intolerable side effects occur.
    • Botulinum toxin injection has also been used in individuals with Leigh syndrome and severe intractable dystonia.
  • Cardiomyopathy. Medical therapy may be required and should be supervised by a cardiologist.
  • Nutrition. Regular assessment of daily caloric intake and adequacy of dietary structure including micronutrients and feeding management is indicated.
  • Psychological support for the affected individual and family is essential.

Prevention of Primary Manifestations

For treatment of the following disorders, see Treatment of Manifestations.

  • Thiamine transporter deficiency (mutation of SLC19A3)
  • Biotinidase deficiency (BTD)
  • Coenzyme Q10 biosynthesis defect (PDSS2)

Prevention of Secondary Complications

Anesthesia can potentially aggravate respiratory symptoms 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].

Surveillance

Affected individuals should be followed at regular intervals (typically every 6-12 months) to monitor progression and the appearance of new manifestations. Neurologic, ophthalmologic, audiologic, and cardiologic evaluations are recommended.

Agents/Circumstances to Avoid

Sodium valproate and barbiturates should be avoided because of their inhibitory effect on the mitochondrial respiratory chain [Melegh & Trombitas 1997, Anderson et al 2002].

Dichloroacetate (DCA) reduces blood lactate by activating the PDH complex.

  • A double-blind, placebo-controlled trial of DCA in a different mitochondrial disease, MELAS, found no benefit and in fact documented a toxic effect of DCA on peripheral nerves [Kaufmann et al 2006].
  • A subsequent report described the results of long-term administration of DCA to 36 children with congenital lactic acidosis (randomized control trial followed by an open label extension) [Stacpoole et al 2008]. This study concluded that oral DCA is well tolerated in young children with congenital lactic acidosis and that it was not possible to determine whether the peripheral neuropathy associated with long-term DCA administration is attributable to the drug or to the underlying disease process. It therefore appears prudent for individuals with nuclear gene-encoded Leigh syndrome to avoid DCA, in view of the underlying risk for peripheral neuropathy caused by the disease itself in these conditions.

References

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Chapter Notes

Author Notes

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.

David 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 Next Generation DNA sequencing. His group also uses cellular and mouse models to understand pathogenic mechanisms and trial new treatment approaches.

Revision History

  • 1 October 2015 (me) Review posted live
  • 17 February 2015 (sr) Original submission
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