Citation, DOI & article data
Leigh syndrome, also known as subacute necrotizing encephalomyelopathy (SNEM), is a mitochondrial disorder with progressive neurodegeneration that invariably leads to death, usually in childhood.
Leigh syndrome is encountered in approximately 1 in 40,000 births, although some populations have much higher incidence (e.g. in Quebec, Canada) 9. There is no known gender or racial predilection 9.
Typically, symptoms become evident before the age of 2 years, with a presentation in later childhood (juvenile form) or adulthood (adult form) being uncommon. Symptoms include 6,9:
- psychomotor delay/regression
- superimposed signs of basal ganglia and brainstem dysfunction
- respiratory rhythm disturbance
- cranial nerve palsies
Leigh disease is one of many mitochondrial disorders, due to a broad range of genetic mutations in either nuclear DNA (nDNA) or mitochondrial DNA (mtDNA) 8,9. Nuclear DNA mutations are more common (~75%) and are inherited in a Mendelian fashion with both autosomal recessive and X-linked inheritance encountered 9. Cases due to mitochondrial DNA are less common (25%) and only inherited from the mother 9. Some mutations (e.g. SURF1) are particularly devastating 1.
Chronic energy deprivation leads to histological features such as 3:
These findings are similar to those seen in infarction 4.
The inheritance pattern may be either autosomal recessive or X-linked.
CSF lactate may be elevated.
CT demonstrates regions of low-density matching areas of the abnormal T2 signal on MRI (see below) 5. Occasionally some of these areas can show contrast enhancement 5.
MRI abnormalities are heterogeneous and differ depending on the underlying genetic abnormality 8. Generally, the distribution tends to be symmetrical.
T2: characterized by high signal typically in 3:
- periaqueductal grey matter
- putamen: characteristic but not always present 6
- other sites of T2 signal change include:
- T1: usually demonstrates reduced signal in T2 abnormal areas, although some areas of hyperintensity can be seen, as can some enhancement
- DWI: in the acute setting some restricted diffusion may be evident
- elevated choline
- occasionally elevated lactate
- reduced NAA
Treatment and prognosis
Prognosis is poor, with death usually occurring in childhood. The later the onset, the slower the deterioration. Death is most frequently due to respiratory failure 6.
The factors associated with a worse outcome are 10:
- disease onset before 6 months of age
- admission to an intensive care
- brainstem lesions
- MRS lactate peak
History and etymology
It is named after Archibald Denis Leigh (1915-1998), a British neuropathologist, who first described the condition in 1951 2,9.
Wernicke encephalopathy (WE)
- similar appearance but different demographics
- mammillary bodies not involved in Leigh disease
- enhancement more common in WE
- hemorrhagic change more common in WE 4
- other mitochondrial disorders
- brainstem and basal ganglia involvement less pronounced
acute necrotizing encephalitis of childhood
- lactate levels are usually normal
- biotin-thiamine-responsive basal ganglia disease
- 1. Medina L, Chi TL, DeVivo DC et-al. MR findings in patients with subacute necrotizing encephalomyelopathy (Leigh syndrome): correlation with biochemical defect. AJR Am J Roentgenol. 1990;154 (6): 1269-74. doi:10.2214/ajr.154.6.2159689 - Pubmed citation
- 2. Leigh D. Subacute necrotizing encephalomyelopathy in an infant. J. Neurol. Neurosurg. Psychiatr. 1951;14 (3): 216-21. doi:10.1136/jnnp.14.3.216 - Free text at pubmed - Pubmed citation
- 3. Warmuth-metz M, Hofmann E, Büsse M et-al. Uncommon morphologic characteristics in Leigh's disease. AJNR Am J Neuroradiol. 20 (6): 1158-60. AJNR Am J Neuroradiol (full text) - Pubmed citation
- 4. Cavanagh JB, Harding BN. Pathogenic factors underlying the lesions in Leigh's disease. Tissue responses to cellular energy deprivation and their clinico-pathological consequences. Brain. 1994;117 ( Pt 6) (6): 1357-76. doi:10.1093/brain/117.6.1357 - Pubmed citation
- 5. Paltiel HJ, O'gorman AM, Meagher-villemure K et-al. Subacute necrotizing encephalomyelopathy (Leigh disease): CT study. Radiology. 1987;162 (1): 115-8. Radiology (abstract) - Pubmed citation
- 6. Arii J, Tanabe Y. Leigh syndrome: serial MR imaging and clinical follow-up. AJNR Am J Neuroradiol. 2000;21 (8): 1502-9. AJNR Am J Neuroradiol (full text) - Pubmed citation
- 7. Manzi SV, Hager KH, Murtagh FR et-al. MR imaging in a patient with Leigh's disease (subacute necrotizing encephalomyelopathy). Pediatr Radiol. 1991;21 (1): 62-3. Pediatric Radiol (full text) - Pubmed citation
- 8. Saneto RP, Friedman SD, Shaw DW. Neuroimaging of mitochondrial disease. Mitochondrion. 8 (5-6): 396-413. doi:10.1016/j.mito.2008.05.003 - Pubmed
- 9. Ruhoy IS, Saneto RP. The genetics of Leigh syndrome and its implications for clinical practice and risk management. The application of clinical genetics. 7: 221-34. doi:10.2147/TACG.S46176 - Pubmed
- 10. Chang X, Wu Y, Zhou J, Meng H, Zhang W, Guo J. A meta-analysis and systematic review of Leigh syndrome: clinical manifestations, respiratory chain enzyme complex deficiency, and gene mutations. Medicine 2020;99:5(e18634) doi:10.1097/MD.0000000000018634