Goal 1.

Describe the clinical characteristics of nuclear gene-encoded LSS.

Goal 2.

Review the genetic causes of nuclear gene-encoded LSS.

Goal 3.

Provide an evaluation strategy to identify the genetic cause of nuclear gene-encoded LSS in a proband (when possible).

Goal 4.

Review management of nuclear gene-encoded LSS, especially treatable disorders.

Goal 5.

Inform genetic counseling of family members of an individual with nuclear gene-encoded LSS.

Autosomal Recessive Leigh Syndrome Spectrum

Autosomal recessive nuclear gene-encoded LSS (Table 1) includes:

• Pathogenic variants in genes encoding proteins needed for:
  • OXPHOS enzyme activity and assembly;
  • Mitochondrial DNA maintenance (see Mitochondrial DNA Maintenance Defects Overview) and gene expression;
  • Cofactor biosynthesis (lipoic acid and coenzyme Q₁₀);
  • 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.

Autosomal Dominant Leigh Syndrome Spectrum

DNM1L. To date, DNM1L is the only gene known to be associated with autosomal dominant LSS [Zaha et al 2016]; heterozygous de novo variants in this gene account for <1% of LSS. DNM1L-LSS is associated with infantile spasms with burst suppression on EEG; laboratory findings include multiple respiratory chain enzyme deficiencies and elongated mitochondria and peroxisomes on electron microscopy. Autosomal recessive DNM1L-related disease has been reported but – to date – not in association with LSS.

X-Linked Leigh Syndrome Spectrum

Causes of X-linked nuclear gene-encoded LSS are summarized in Table 2.

Clinical Findings

Clinical manifestations of LSS are described in Tables 1 and 2.

Retrospective review of the currently known genetic causes of nuclear gene-encoded Leigh syndrome (see Tables 1 and 2) suggests some differences in phenotype, but clinical findings in individuals with variants in different genes typically overlap [Rahman et al 2017]. Hence, it would now be unusual for specific clinical and/or imaging findings to guide testing of a subset of genes, but these differences may be useful in guiding variant curation. For example:

• More than 40 individuals with pathogenic variants in SURF1 or LRPPRC have been reported [Debray et al 2011, Wedatilake et al 2013] (see Table 1). 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 males with a hemizygous variant in PDHA1 and some females with a heterozygous variant [Patel et al 2012] (see Table 2). 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 manifestations, or other clinical features compatible with a mitochondrial disorder. Documentation of relevant findings in relatives can be accomplished either through direct examination of those individuals or by review of their medical records including the results of molecular genetic testing, neuroimaging studies, and autopsy examinations.

Specific findings such as a family history in which affected individuals are related to each other through females (i.e., no male-to-male transmission) may prompt initial investigation of X-linked genes, or consanguinity may prompt initial investigation of autosomal recessive genes. Of course, such features are sometimes a chance occurrence and the possibility of an underlying mitochondrial DNA (mtDNA) variant should be followed up with more comprehensive testing if no pathogenic variants are identified in nuclear genes [Alston et al 2011].

Biochemical Testing

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

• Suggest LSS as opposed to 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. Activity of enzymes, such as PDH, are typically measured in cultured skin fibroblasts (fbs; see Tables 1 and 2), and respiratory chain enzymes are typically measured in a skeletal muscle biopsy (mb; see Tables 1 and 2).

• 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 (see Table 1), one X-linked gene (see Table 2), and six genes encoded by mtDNA.
• Moreover, although muscle biopsy was traditionally used as a first-line diagnostic test in the investigation of Leigh syndrome and other mitochondrial disorders, the widespread availability of multigene panels and comprehensive genomic testing has obviated the need for muscle biopsy in many instances. However, in a small minority of individuals enzymatic testing of a muscle or skin biopsy may be necessary to confirm pathogenicity of variants of uncertain significance identified by multigene panel, exome or genome sequencing.

Molecular Genetic Testing

Testing approaches can include use of a multigene panel, or more comprehensive genomic testing of an exome or genome.

A mitochondrial disorders multigene panel that includes some or all of the genes listed in Tables 1 and 2 is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants 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. Of note, given the rarity of some of the genes associated with nuclear gene-encoded LSS, some panels may not include all the genes mentioned in this overview. (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. (5) While the vast majority of individuals with classic Leigh syndrome have nuclear or mtDNA defects related to mitochondrial energy generation, this may not be true for individuals with Leigh-like syndrome; thus, use of a multigene panel with a more extensive gene list may be considered.

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

Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.

If exome or genome sequencing is not diagnostic, analysis for copy number variants, typically by algorithmic analysis for read depth and other parameters, (often called exome array) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.

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

Testing for Treatable Disorders

Treatable disorders should be rapidly tested for 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.

Treatable causes of nuclear gene-encoded LSS (see Treatment of Manifestations):

• Biotin-thiamine-responsive basal ganglia disease, also known as thiamine transporter-2 deficiency (caused by mutation of SLC19A3)
• Biotinidase deficiency (BTD)
• Coenzyme Q₁₀ biosynthesis defect (PDSS2, COQ9)

Treatment of Manifestations

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

• Biotin-thiamine-responsive basal ganglia disease (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, COQ9). 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 LSS includes the following:

• Acidosis. Sodium bicarbonate or sodium citrate is appropriate for acute exacerbations of acidosis.
• Seizures. Appropriate anti-seizure medications 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. While the ketogenic diet may be indicated for individuals with pyruvate dehydrogenase (PDH) deficiency or drug-resistant epilepsy, there is no evidence for efficacy of the ketogenic diet in other forms of LSS.
• Psychological support for the affected individual and family is essential.

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. Surveillance may be directed by knowledge of phenotypes known to be associated with specific gene defects [Rahman et al 2017].

Agents/Circumstances to Avoid

A recent Delphi review has examined drug safety in mitochondrial disorders [De Vries et al 2020].

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 80 nuclear gene-encoded LSS-related genes identified to date, pathogenic variants in all but four genes are associated with autosomal recessive inheritance.
• LSS caused by a heterozygous or hemizygous pathogenic variant in AIFM1, NDUFA1, or PDHA1 is inherited in an X-linked manner. Note: Almost equal numbers of males and females affected with PDHA1-LSS have been reported [Lissens et al 2000, Imbard et al 2011]. Although relatively few affected individuals with NDUFA1-LSS and AIFM1-LSS have been reported, it is expected that the same sex ratio would be seen in all three X-linked disorders.
• LSS caused by a heterozygous pathogenic variant in DNM1L is an autosomal dominant disorder; to date, all individuals with DNM1L-LSS have had the disorder as the result of a de novo pathogenic variant.

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 LSS – Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one LSS-causing pathogenic variant based on family history).
• If the causative pathogenic variants have been identified in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are carriers and to allow reliable recurrence risk assessment. (De novo variants are known to occur at a low but appreciable rate in autosomal recessive disorders [Jónsson et al 2017].)
• 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-causing 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 a pathogenic variant.

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

X-Linked LSS – 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, 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: 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.
• If a woman has more than one affected child and no other affected relatives and if the pathogenic variant identified in the proband cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. (Note: If the mother has both somatic and germline mosaicism for the variant, she may be mildly/minimally affected.)
• If a male is the only affected family member (i.e., a simplex case):
  • The mother may be a heterozygote (approximately 25% of mothers of children with PDHA1 pathogenic variants were found to be heterozygous for the pathogenic variant [Lissens et al 2000, Imbard et al 2011]); or
  • The proband may have a de novo pathogenic variant, in which case the mother is not a heterozygote. 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 the de novo variant presumably occurring in early or mid-embryogenesis [Imbard et al 2011].

Parents of a female proband. A female proband may have inherited the AIFM1, NDUFA1, or PDHA1 pathogenic variant from either her mother or (theoretically) her father (if he has germline mosaicism for the pathogenic variant), or the pathogenic variant may be de novo.

Sibs of a male proband. The risk to sibs of a male proband depends on the genetic status of the mother:

• If the mother of the proband has an AIFM1, NDUFA1, or PDHA1 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 with manifestations ranging from mild learning difficulty to LSS depending on the X-chromosome inactivation ratio.
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is greater than that of the general population because of the possibility of maternal germline mosaicism.

Sibs of a female proband. The risk to sibs of a female proband depends on the genetic status of the mother (see above) and the father. Theoretically, the father of an affected female may have germline mosaicism for a pathogenic variant, in which case all of his daughters (and none of his sons) would be at risk of inheriting a pathogenic variant.

Offspring of a male proband. Males with X-linked LSS are not known to reproduce.

Offspring of a female proband. Each child of a female with X-linked LSS has a 50% chance of inheriting the pathogenic variant; males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant are likely to be affected with manifestations ranging from mild learning difficulty to LSS depending on the X-chromosome inactivation ratio.

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

Autosomal Dominant LSS – Risk to Family Members

Parents of a proband

• All probands reported to date with DNM1L-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 confirm their genetic status and to allow reliable recurrence risk counseling.
• If the DNM1L pathogenic variant found in the proband cannot be detected in parental DNA, the pathogenic variant most likely occurred de novo in the proband. Another possible explanation is that the proband inherited a pathogenic variant from a parent with germline mosaicism. Although theoretically possible, no instances of parental germline mosaicism have been reported to date.

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 DNM1L pathogenic variant, the risk to the sibs of inheriting the variant is 50%.
• If the DNM1L 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 theoretic possibility of parental germline mosaicism [Rahbari et al 2016].

Offspring of a proband. Individuals with DNM1L-LSS are not known to reproduce.

Other family members. Given that all probands with autosomal dominant DNM1L-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.

Prenatal Testing and Preimplantation Genetic Testing

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

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

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

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

• 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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