Recommended panel testing at Breda Genetics for this condition:
Leigh syndrome is an early-onset progressive neurodegenerative disorder with characterized by focal, bilateral lesions in one or more areas of the central nervous system, including the brainstem, thalamus, basal ganglia, cerebellum, and spinal cord. The lesions are consistening of areas of demyelination, gliosis, necrosis, spongiosis, or capillary proliferation. Clinical symptoms depend on which areas of the central nervous system are involved.
Leigh syndrome is caused by a defect in aerobic energy production, ranging from the pyruvate dehydrogenase complex to the oxidative phosphorylation pathway. As such, Leigh syndrome may be caused by mutation in one of several different genes affecting the functioning of any of the mitochondrial respiratory chain complexes (complex I, II, III, IV, and V).
MT-ATP6: the most frequently mutated mitochondrial gene
Between 10% and 30% of individuals with Leigh syndrome carry mitochondrial DNA mutations, the most common of which are the 8993T>G or 8993T>C mutations in the MT-ATP6 gene. These individuals are often referred to as having maternally inherited Leigh syndrome. These patients harbor very high proportions (above 95%) of the mitochondrial DNA mutation. Lower proportions of this mutation are associated with a milder phenotype such as the NARP syndrome (Neurogenic Ataxia and Retinitis Pigmentosa). Other mitochondrial genes mutated in Leigh syndrome may be MT-CO3, MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND5, MT-ND6, MT-TK, MT-TV, MT-TW.
SURF1: the most frequently mutated nuclear gene
However, most patients with Leigh syndrome carry mutations in a nuclear gene: mutations have been identified in genes encoding either one of the subunits of the pyruvate dehydrogenase (PDH) complex, one of the subunits of respiratory complexes I or II, or a protein involved in the assembly of respiratory complex IV. Disruption of complex IV, also called cytochrome c oxidase or COX, is the most common cause of Leigh syndrome. The most frequently mutated nuclear gene is SURF1. Missense, nonsense, frame-shifting and exonic deletions have been reportefd in SURF1. SURF1-related Leigh syndrome is autosomal recessively inherited.
Other nuclear genes mutated in Leigh syndrome are: ADAR1, BCS1L, C12orf65, C20ORF7, C8ORF38, COX10, COX15, DLD, EARS2, ETHE1, FARS2, FOXRED1, GFM1, HIBCH, LIAS, LIPT1, MTFMT, NDUFA1, NDUFA10, NDUFA11, NDUFA12, NDUFA2, NDUFA9, NDUFAF2, NDUFAF5, NDUFAF6, NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS7, NDUFS8, NDUFV1, NUP62, PDHB, PDHX, PDSS2, PET100, POLG, RANBP2, SCO2, SDHA, SERAC1, SLC19A3, SLC25A19, SUCLA2, SUCLG1, TACO1, TTC19, and UQCRQ.
There is also a form of Leigh syndrome which is inherited in an X-linked manner and which is caused by mutation in the PDHA1 gene)
The French-Canadian (or Saguenay-Lac Saint Jean) type of Leigh syndrome with COX deficiency is caused by mutation in the LRPPRC gene.
In rare instances, Leigh syndrome may be caused by large deletions of the mitochondrial DNA, which may be tested by MLPA or algorithmic CNV testing based on NGS data from exome sequencing.
It is very important to highlight that the genetic cause of Leigh syndrome remains unknown in some cases (even when the syndrome is biochemically confirmed).
Other known genetic disorders that cause or resemble Leigh syndrome include:
- Defective lipoic acid biosynthesis caused by mutation in the LIAS or LIPT1 gene.
- Thiamine transporter-2 deficiency caused by mutation in the SLC19A3 gene.
- Biotinidase deficiency, caused by mutation in the BTD gene and a similar disorder caused by mutation in the HLCS gene (early-onset multiple carboxylase deficiency).
- Organic acidurias such as ethylmalonic encephalopathy caused by mutation of ETHE1 and 3-hydroxy-isobutyryl-CoA hydrolase deficiency caused by mutation of HIBCH.
- Autosomal recessive infantile bilateral striatal necrosis, which is caused by mutation in the SLC25A19, NUP62, or ADAR1 gene.
- Infection-triggered familial acute necrotizing encephalopathy caused by mutation in the RANBP2 gene.
- Neurodegeneration with brain iron accumulation 1 (caused by PANK2 mutations) and neurodegeneration with brain iron accumulation 3 (also known as neuroferrinopathy, caused by mutation in the FTL gene).
- Methylmalonic acidemia (MUT, MMAA, MMAB, MCEE, or MMADHC mutations).
- Propionic acidemias (PCCA or PCCB).
Recommended panel testing at Breda Genetics for this condition:
References
Leigh syndrome: One disorder, more than 75 monogenic causes. Lake NJ, Compton AG, Rahman S, Thorburn DR. Ann Neurol. 2016 Feb;79(2):190-203. PMID: 26506407
Leigh syndrome: neuropathology and pathogenesis. Lake NJ, Bird MJ, Isohanni P, Paetau A. J Neuropathol Exp Neurol. 2015 Jun;74(6):482-92. PMID: 25978847
Mitochondrial DNA-Associated Leigh Syndrome and NARP. Thorburn DR, Rahman J, Rahman S. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. SourceGeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 2003 Oct 30 [updated 2017 Sep 28]. PMID: 20301352
Leigh syndrome: Resolving the clinical and genetic heterogeneity paves the way for treatment options. Gerards M, Sallevelt SC, Smeets HJ. Mol Genet Metab. 2016 Mar;117(3):300-12. PMID: 26725255
The genetics of Leigh syndrome and its implications for clinical practice and risk management. Ruhoy IS, Saneto RP. Appl Clin Genet. 2014 Nov 13;7:221-34. Appl Clin Genet. 2014 Nov 13;7:221-34. PMID: 25419155
Mitochondrial DNA Deletion Syndromes. Goldstein A1, Falk MJ1.
In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. Source: GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.
2003 Dec 17 [updated 2019 Jan 31]. (PMID: 20301382).
OMIM: 256000
