A guide to diagnosis and treatment of Leigh syndrome

Abstract

Leigh syndrome is a devastating neurodegenerative disease, typically manifesting in infancy or early childhood. However, also late-onset cases have been reported. Since its first description by Denis Archibald Leigh in 1951, it has evolved from a postmortem diagnosis, strictly defined by histopathological observations, to a clinical entity with indicative laboratory and radiological findings. Hallmarks of the disease are symmetrical lesions in the basal ganglia or brain stem on MRI, and a clinical course with rapid deterioration of cognitive and motor functions. Examinations of fresh muscle tissue or cultured fibroblasts are important tools to establish a biochemical and genetic diagnosis. Numerous causative mutations in mitochondrial and nuclear genes, encoding components of the oxidative phosphorylation system have been described in the past years. Moreover, dysfunctions in pyruvate dehydrogenase complex or coenzyme Q10 metabolism may be associated with Leigh syndrome. To date, there is no cure for affected patients, and treatment options are mostly unsatisfactory. Here, we review the most important clinical aspects of Leigh syndrome, and discuss diagnostic steps as well as treatment options.

Leigh-Like Syndrome Due to Homoplasmic m.8993T>G Variant with Hypocitrullinemia and Unusual Biochemical Features Suggestive of Multiple Carboxylase Deficiency (MCD)

“…More recently, Baertling et al (2014) refined the diagnostic criteria to include the three most commonly described features: (1) neurodegenerative disease with variable symptoms; (2) bilateral neuroimaging or CNS lesions and (3) a variety of nuclear or mitochondrially encoded genetic causes of deficient mitochondrial energy metabolism. The term "Leigh-like syndrome" was proposed when these diagnostic criteria are only partially met but highly suggestive for LS (Rahman et al 1996;Baertling et al 2014).…”

Leigh syndrome: One disorder, more than 75 monogenic causes

“…The similarity of the neuropathology to Wernicke encephalopathy, a condition of thiamine deficiency, and findings of elevated blood lactate and pyruvate suggested that a metabolic abnormality was the underlying disease etiology. 19,20 Before the first genetic mutation was identified in 1991, 5 40 years of clinical and biochemical investigation provided evidence that deficiency of the PDHc, and of nicotinamide adenine dinucleotide (NADH):ubiquinone oxidoreductase (complex I) and cytochrome c oxidase (complex IV) within the OXPHOS pathway, could cause LS. [21][22][23] Together with the finding of abnormal mitochondrial morphology in skeletal muscle tissue from patients, these abnormalities suggested a common theme of defective mitochondrial energy metabolism.…”

Widening the Heterogeneity of Leigh Syndrome: Clinical, Biochemical, and Neuroradiologic Features in a Patient Harboring a NDUFA10 Mutation

“…Indeed, despite its typical features, MRI imaging alone may lack specificity in LS detection, as other mitochondrial conditions and nonmitochondrial diseases can show similar basal ganglia alterations on MRI. Therefore, LS diagnosis is currently based on a combined set of clinical, biochemical, and neuroimaging findings (Rahman et al 1996;Baertling et al 2014). …”