Phenotypic and genotypic peculiarities in Chinese patients with Leigh syndrome

Phenotypic and genotypic peculiarities in Chinese patients with Leigh syndrome

Leigh syndrome is a rare, progressive mitochondrial disorder that primarily affects young children, disrupting energy production in cells and damaging the brain, muscles, and other organs. A 2018 study in the Chinese Medical Journal by Yu et al. analyzed 13 pediatric patients with Leigh syndrome from a single Chinese center over 17 years. The team found all patients had mutations in mitochondrial DNA (mtDNA) and concluded that children with eye muscle weakness (ophthalmoplegia), muscle weakness, balance problems (ataxia), or breathing difficulties should undergo mtDNA testing. They also recommended cerebrospinal fluid (CSF) lactate checks and brain imaging for suspected cases.

But as neurologist Josef Finsterer—from the Department of Neurology at Krankenanstalt Rudolfstiftung and the Messerli Institute at the Veterinary University of Vienna—notes in a 2019 comment, while the study offers valuable insights, it leaves key questions unanswered that could deepen our understanding of Leigh syndrome in this population.

First, the study’s retrospective design (relying on past medical records) means not all patients had the same tests. This inconsistency makes it hard to draw reliable conclusions about how often certain symptoms appear—missing data can skew results, so findings may not fully represent Leigh syndrome.

Second, there was no long-term follow-up. Mitochondrial disorders are progressive, so tracking patients as their disease advances is critical to understanding prognosis and treatment needs. Without this, the study only captures a “snapshot” of the disease, not its full trajectory.

Third, first-degree family members (like parents or siblings) weren’t tested. Since ~75% of mtDNA mutations are passed from mothers to children, this information tells us if the mutation was inherited or random (sporadic)—vital for genetic counseling to help families understand their risk.

Another gap is data on stroke-like episodes (SLEs)—sudden neurological events mimicking strokes. These have been reported in some Leigh syndrome patients, and they’re especially relevant here: Patient 1 carried the m.3243A>G mutation in the MT-TK gene, which causes MELAS (a related disorder) in 80% of cases. Around 70% of MELAS patients have at least one SLE, so it’s likely this patient did too—but the study doesn’t confirm it.

One notable finding was Patient 7’s left ventricular hypertrabeculation (LVHT, or noncompaction), a rare heart condition with extra muscle folds that raise risks of arrhythmias, blood clots, heart failure, or sudden death. Few Leigh syndrome patients have been reported with LVHT, so this case is important—but we don’t know if Patient 7 developed complications or received treatment. Since LVHT can run in families, it’s also unclear if relatives were evaluated.

Finsterer also highlighted two unusual absences: none of the patients had nuclear DNA (nDNA) mutations, and none had epilepsy. Most pediatric mitochondrial disorders are caused by nDNA mutations (not mtDNA), so all 13 kids having mtDNA changes is unexpected. Epilepsy is also common in Leigh syndrome—seen in most other cohorts—so why didn’t these patients have it? Could diet, medication (like antioxidants), or other treatments play a role? The study doesn’t say.

Finally, Finsterer pushed back on the idea that elevated CSF lactate or protein are “specific” to Leigh syndrome. These are non-specific findings—they also occur in other mitochondrial disorders like Kearns-Sayre syndrome or MELAS. The true hallmarks of Leigh syndrome are symmetric subcortical brain lesions (on imaging) and symptoms compatible with a mitochondrial disorder.

Overall, the study of 13 Chinese children with Leigh syndrome is a useful addition to research—but it could be more meaningful with a prospective design (following patients forward), family testing, and long-term follow-up. The absence of nDNA mutations and epilepsy also deserves discussion to understand if these are true differences in this population or data gaps.

Yu XL, Yan CZ, Ji KQ, Lin PF, Xu XB, Dai TJ, et al. Clinical, neuroimaging, and pathological analyses of 13 Chinese Leigh syndrome patients with mitochondrial DNA mutations. Chin Med J 2018;131:2705–2712.

Poulton J, Finsterer J, Yu-Wai-Man P. Genetic counselling for maternally inherited mitochondrial disorders. Mol Diagn Ther 2017;21:419–429.

Morin C, Dubé J, Robinson BH, Lacroix J, Michaud J, De Braekeleer M, et al. Stroke-like episodes in autosomal recessive cytochrome oxidase deficiency. Ann Neurol 1999;45:389–392.

Finsterer J, Stöllberger C, Blazek G, Sehnal E. Familal left ventricular hypertrabeculation (noncompaction) is myopathic. Int J Cardiol 2013;164:3. doi: 10.1016/j.ijcard.2011.07.012.

Shemesh A, Margolin E. Kearns Sayre Syndrome. Treasure Island (FL): StatPearls Publishing; 2018 Jan-. Available from http://www.ncbi.nlm.nih.gov/books/NBK482341/12-7.

Finsterer J. Phenotypic and genotypic peculiarities in Chinese patients with Leigh syndrome. Chin Med J. 2019;132:626–627. https://doi.org/10.1097/CM9.0000000000000090

Was this helpful?

YesNo

0 / 0