Leigh syndrome: the genetic heterogeneity story continues

This scientific commentary refers to ‘ECHS1 mutations in Leigh disease: a new inborn error of metabolism affecting valine metabolism’ by Peters et al. (doi:10.1093/awu216).

Mitochondrial disorders are the most common inherited metabolic abnormalities of energy production. Patients can present with a wide variety of clinical phenotypes depending on the tissue affected. In general, tissues with the highest energy demands, such as brain, muscle, heart and liver, are the most severely affected. Several neurological syndromes are caused by defective mitochondrial energy production, of which Leigh syndrome is one of the best known. Leigh syndrome is an often fatal, progressive neurodegenerative disorder, first described in 1951 by the British psychiatrist and neuropathologist Denis Leigh (1951). Typically, patients with Leigh syndrome present with focal, bilateral lesions commonly found in the basal ganglia, thalamus, cerebellum, brainstem or spinal cord. Clinical symptoms depend on the affected area of the CNS and include among others hypotonia, psychomotor delay, dystonia, seizures, ataxia, dysphagia and failure to thrive.

The first cases of Leigh syndrome were suggested to result from a deficiency of thiamine metabolism on the basis of their similarity with Wernicke’s encephalopathy. Remarkably, a direct link between Leigh syndrome and defective thiamine metabolism was only proven 60 years later by the identification of pathogenic mutations in hTHTR2 (now known as SLC19A3), a thiamine transporter, in patients with Leigh syndrome (Gerards et al., 2013). To date, mutations in over 35 genes have been associated with the disorder and this number is increasing annually. In this issue of Brain, Peters and colleagues add to the total by identifying pathogenic mutations in ECHS1 as a cause of Leigh syndrome (Peters et al., 2014). Semi-quantitative metabolite screening in patients revealed an increase in metabolites similar to that seen with 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency, previously associated with Leigh-like disease. However, no pathogenic mutations in HIBCH were detected. Instead, further metabolic analysis pointed towards a possible defect in short-chain enoyl-CoA hydratase (ECHS1). Sequence analysis of the gene encoding this enzyme revealed that the patients were indeed compound heterozygous for two mutations, for which pathogenicity was confirmed by complementation assays, thereby adding mutations in ECHS1 to the ever growing list of causes of Leigh syndrome.

Genetics of Leigh syndrome

Mutations causing Leigh syndrome may be found in the mitochondrial DNA (mtDNA) and nuclear DNA and often affect subunits or assembly factors of the oxidative phosphorylation system (OXPHOS), the most important process for cellular energy production. However, mutations have also been described in genes involved in mtDNA transcription, translation or replication, as well as in other mitochondrial processes such as coenzyme Q10 biosynthesis and pyruvate metabolism (Finsterer, 2008). Furthermore, mutations have been identified in genes that indirectly affect OXPHOS or mitochondrial functioning. For example mutations in SLC19A3, the gene encoding the thiamine transporter SLC19A3, result in decreased import of thiamine into the cell. This indirectly affects mitochondrial function as the active form of thiamine, thiamine pyrophosphate (TPP), is an important cofactor for several mitochondrial processes (Gerards et al., 2013). Peters and colleagues now add yet another process to the list of causes of Leigh syndrome, namely defective β-oxidation of short and medium-chain fatty acids. Besides the direct effect of ECHS1 mutations on β-oxidation, the accumulation of toxic intermediates may cause secondary protein damage, contributing to the presentation of the clinical symptoms (Peters et al., 2014).

Diagnosis of Leigh syndrome

Over the years, the term ‘Leigh syndrome’ has been used more broadly to describe patients with neurological symptoms, even when no clear mitochondrial defects were present and Leigh syndrome-specific CNS lesions were not detectable. In some cases the term ‘Leigh-like’ syndrome has been used to characterize patients with symptoms resembling Leigh syndrome to a certain degree. As proposed by Baertling et al. (2014), the term ‘Leigh syndrome’ should be used in cases where the three most characteristic features of the disease are present, these being: (i) a neurodegenerative phenotype; (ii) mitochondrial dysfunction; and (iii) bilateral CNS lesions. In cases where these criteria are only partially fulfilled, but other symptoms indicative of Leigh syndrome are present as well, the term ‘Leigh-like’ syndrome should be considered.

Owing to the clinical and genetic heterogeneity, the identification of the genetic cause in patients with Leigh syndrome has previously been rather challenging. The development of next generation sequencing has largely overcome this problem and has changed genetic diagnostics by enabling sequence analysis of all candidate genes or even the whole exome/genome in a relatively short period of time. Still, detailed characterization of clinical symptoms and biochemical or metabolic data remains valuable for determining the pathology and treatment options, and can in some cases point directly towards a specific mitochondrial process or even a specific gene. Leigh syndrome accompanied by decreased activity of one of the OXPHOS complexes in muscle may be caused by mutations in one of the subunits or assembly factors of that complex. For example, mutations in the complex IV assembly factor SURF1 account for 25–75% of patients with Leigh syndrome in combination with complex IV deficiency (Pequignot et al., 2001). However, it should be noted that normal activity of the OXPHOS complexes in muscle does not exclude genes involved in that process, as the deficiency can be expressed in tissues other than muscle, e.g. in the heart, brain or liver. The importance of biochemical and/or metabolic data to establish clinical diagnosis is also illustrated by Peters et al. who identified ECHS1 as a disease gene based on clinical symptoms and metabolic profiling. A recent review by Baertling et al. (2014) provides a detailed guide for clinical and genetic diagnosis of Leigh syndrome, including typical clinical phenotypes, laboratory parameters and specific MRI findings, which may assist in selecting treatment options. With the current sequencing strategies available, exome sequencing combined with metabolic and biochemical profiling is probably the most successful approach for the identification of mutations causing Leigh syndrome. The metabolic, biochemical and clinical data can be used for candidate gene selection if too many candidate genes remain after filtering of exome data. Furthermore, they can provide insights into pathophysiological mechanisms and reveal possible therapeutic targets.

Treatment of Leigh syndrome

Although a growing number of patients survive until adulthood, the general outcome for patients with Leigh syndrome is very poor and most die in early childhood (Finsterer, 2008). The lack of extensive clinical studies due to the low life expectancy, as well as the many different pathways involved in Leigh syndrome, has hampered research into therapeutics, and no general causative treatment is available to date. However, over the last few years several case reports have appeared, outlining specific treatment options based on the underlying genetic defect. Some patients with primary coenzyme Q deficiency responded to Q10 treatment (Van Maldergem et al., 2002) and treatment with biotin and thiamine has been suggested for patients with a thiamine transport deficiency due to mutations in SLC19A3 (Gerards et al., 2013). Furthermore, high doses of L-carnitine and a ketogenic diet have been reported to improve certain, but not all, clinical symptoms in specific cases (Finsterer, 2008). Some of these interventions have few or no adverse effects and should be considered on a case-by-case basis as a preemptive treatment; in some patients, this could even be life-saving. In a recent study, administration of rapamycin, a specific inhibitor of the mTOR pathway, enhanced survival and attenuated disease progression in a mouse model of Leigh syndrome due to NDUFS4 deficiency (Johnson et al., 2013). Even though the exact mechanism of rescue needs to be elucidated and rapamycin has several adverse effects, this study implies that inhibition of the mTOR pathway might be beneficial for comparable patients with Leigh syndrome. Further studies are warranted to fully understand the molecular spectrum of Leigh syndrome and to determine how, and under what circumstances, particular compounds will be beneficial. The identification of novel genes associated with Leigh syndrome is crucial and will contribute to the ultimate goal, namely the development of personalized therapeutic strategies to alleviate or treat the symptoms associated with Leigh syndrome.

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