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.

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].

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).

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.

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.

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:

• Biotin-thiamine-responsive basal ganglia disease (BTBGD) (also known as thiamine transporter-2 deficiency) (mutation of SLC19A3)
• Biotinidase deficiency (BTD)
• Coenzyme Q₁₀ biosynthesis defect (PDSS2)

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.

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

• The father of an affected child will not have X-linked Leigh syndrome nor will he be hemizygous for the PDHA1, NDUFA1, or AIFM1 pathogenic variant; therefore, he does not require further evaluation/testing.
• The mother of an affected child may be heterozygous for a pathogenic variant; see Heterozygote (Carrier) Detection. Approximately 25% of mothers of children with PDHA1 pathogenic variants were found to be heterozygous for a PDHA1 variant [Lissens et al 2000, Imbard et al 2011].
• If only one family member is affected (i.e., a simplex case), the mother may be a heterozygote or the affected child may have a de novo or somatic PDHA1, NDUFA1, or AIFM1 pathogenic variant (in which case the mother is not heterozygous).
  • Data reported by Lissens et al [2000] and Imbard et al [2011] suggest that up to 75% of affected individuals have a de novo pathogenic variant.
  • In at least seven affected individuals, somatic mosaicism has been demonstrated with mutation presumably occurring in early or mid-embryogenesis [Imbard et al 2011].
• In a family with more than one affected individual, the mother of an affected child is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the pathogenic variant cannot be detected in her leukocyte DNA, she has germline mosaicism.
• Note: If the mother is the individual in whom the pathogenic variant first occurred, she may have somatic and germline mosaicism for the variant and may be mildly/minimally affected.

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.

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.

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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