Leigh syndrome (also known as subacute necrotizing encephalomyelopathy, juvenile subacute necrotizing encephalopathy, Leigh disease, and infantile necrotizing encephalopathy) typically presents in infancy, however, later onset of diseases has been reported in older children and adults. Leigh syndrome has been linked to 85 different mutations involving either nuclear or mitochondrial genes that affect mitochondrial function in the cell leading to impaired energy metabolism. The presenting symptoms and signs include developmental delay, psychomotor regression, dystonia, ataxia, external ophthalmoplegia, vomiting, weakness, lactic acidosis and seizure.
Leigh syndrome was first described as subacute necrotizing encephalomyelopathy in a case report by neuropsychiatrist Archibald Denis Leigh in 1951.
In a study conducted looking at the registers from regional and local pediatric hospitals and National Swedish Board of Health and Welfare register of causes of death from Swedish health care region, with a total population of 1,759,457 the prevalence of Leigh syndrome in preschool children was 1 in every 32,000.
Many patients with Leigh syndrome develop movement disorder issues including ophthalmoparesis (weakness in extraocular muscles) or nystagmus (involuntary eye movement). In addition, patients may develop optic atrophy.
Non-ocular systemic manifestations
Patients often present with failure to thrive with psychomotor retardation and regression, and progressive neurological abnormalities such as hypotonia. Some patients also have multisystemic manifestation including cardiomyopathy, hepatic, renal tubulopathy or hematological. Patients with Leigh syndrome often have elevated lactic acid in their blood, urine and cerebrospinal fluid (CSF) and have multi-organ and central nervous system (CNS) damage, including the brain spongiform changes in cerebellum, basal ganglia, and brainstem.
Leigh syndrome may present with gastrointestinal manifestations such as vomiting, diarrhea, and dysphagia. It has been attributed to damage in the swallowing center located in brainstem. These difficulties lead to decrease nutrition intake, which can exacerbate subsequent malnutrition or failure to thrive. In addition, Leigh syndrome is also associated with muscle and movement issues. Patient often have hypotonia (weak muscle tone), dystonia (involuntary muscle contractions) and ataxia (trouble with balance). In addition, sensory deficits such as peripheral neuropathy can occur.
Patients with Leigh Syndrome can have many causes leading to defective mitochondrial function. Researchers showed that patients diagnosed with Leigh syndrome may have mitochondrial DNA point mutations or heteroplasmic deletion where both wild type and mutated mitochondrial DNA coexist in the cytoplasm. In addition, patients could present with enzymatic defect in respiratory chain. Common enzymes involved include complex I, complex IV and pyruvate dehydrogenase complex. In addition, dysfunction in coenzyme Q10 metabolism has been associated with Leigh syndrome.
Due to the inheritance nature of the disease, consanguinity is a known risk factor. Gender or race are not known risk factors.
Disruption in mitochondrial metabolism occur through nuclear or mitochondrial DNA mutations on different parts of the electron transport chain. These include abnormalities of the pyruvate dehydrogenase complex and respiratory chain. 85 different genes have been associated with Leigh syndrome.
The classic pathological finding of Leigh syndrome includes bilateral necrotizing lesions with microcytes and spongiform in the thalamus, basal ganglia, brainstem and spinal cord.
History/Physical examination/Signs and Symptoms
Detailed family history of at least three generations with a focus on early childhood deaths or histories of multisystem diseases in the family.
- Brain: seizure, ataxia, developmental delay or regression, dystonia
- Eye: ophthalmoparesis, optic atrophy, nystagmus
- Skeletal Muscle: weakness, hypotonia, ptosis
- Short stature
- Heart: cardiomyopathy
- Kidney: glomerulopathy
- Gastrointestinal: nausea, vomiting, change in motility
- Metabolic acidosis
Clinical diagnosis/Diagnostic Procedures/Laboratory Tests
Laboratory studies to order: CBC, serum creatine kinase, serum lactate and pyruvate If lumbar puncture was performed, CSF could be analyzed for pyruvate, amino acids, lactate, 5-methyltetrahydrofolate.
If a patient presents with positive family history, failure to thrive and regression of developmental movement, magnetic resonance imaging (MRI) of the brain can be used to look for lesions located in the thalamus, basal ganglia, brainstem and spinal cord. Brain MRI with T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequence images can show abnormal white matter signal in the putamen, basal ganglia and brainstem.
Researchers has developed a computational diagnostic tool for Leigh disease built on Molecular Interaction NetwoRKs (MINERVA) platform that is freely available at vmh.uni.lu/#leighmap. This tool links phenotypes and genotype via systematic literature mining and was blindly validated by two investigators to correctly identify gene in 80% of the cases.
Due to the early age of onset, the differential diagnosis to Leigh syndrome include other congenital syndromes manifesting as mitochondrial myopathies with multisystem involvement.
|Barth Syndrome||Dilated cardiomyopathy, skeletal myopathy,
neutropenia and short stature
|GRACILE||Growth retardation, amino aciduria, cholestasis,
iron overload, lactic acidosis, and early death
|Leber hereditary optic neuropathy (LHON)||severe and permanent visual loss in young man.
No myopathy generally but some patients can present with cardiac conduction defects and movement disorder.
|Severe encephalomyopathy of infancy or childhood||symptoms and signs of encephalopathy, seizures, hypotonia, respiratory failure, feeding difficulties, and/or ophthalmopathy, can include hepato-intestinal, nephropathy manifestations or cardiomyopathy|
|Maternally inherited deafness and diabetes (MIDD)||defect in insulin secretion, sensorineural hearing loss, macular retinal dystrophy, myopathy, cardiac disorders and focal segmental glomerulosclerosis, age of onset between 30-40 years old|
|Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS)||MELAS and Leigh syndrome have the highest prevalence. Mitochondrial encephalomyopathy with lactic acidosis, migraine-like headaches, vomiting, short stature, muscle weakness and stroke-like episodes results in hemiparesis, hemianopia, cortical blindness.|
|Mitochondrial neurogastrointestinal encephalopathy (MNGIE)||progressive severe gastrointestinal dysmotility, cachexia, ophthalmoplegia, ptosis, symmetric polyneuropathy and asymptomatic leukoencephalopathy|
|Myoclonic epilepsy with ragged red fibers (MERRF)||myoclonus associated with generalized epilepsy, ataxia and myopathy, spasticity, dementia, optic atrophy, bilateral deafness, peripheral neuropathy, lipomatosis and cardiomyopathy with Wolff-Parkinson-White Syndrome|
|Neuropathy, ataxia, and retinitis pigmentosa (NARP)||developmental delay, sensory polyneuropathy, pigment retinopathy, ataxia, muscle weakness, epilepsy and dementia. Onset is later than Leigh Syndrome usually in older childhood and adulthood|
|Pearson Syndrome||failure to thrive, muscle and neurological impairment, sideroblastic anemia and pancreatic dysfunction (insulin-dependent diabetes, and exocrine pancreatic insufficiency)|
Most mutations associated with Leigh Syndrome does not have a cure; thus, most patients are treated with symptomatic management. For patients with specific mutations, they can respond to specific vitamin supplementation.
Anticonvulsant drugs are often used to manage patient who present with epilepsy. In addition, coenzyme Q10, thiamine and biotin are used to supplement deficiencies.
Leigh Syndrome has poor prognosis with high childhood mortality, death occurs often within 2 years of disease onset. A retrospective study showed that the median survival is 90 days for neonatal mitochondrial cytopathies including Leigh syndrome.
- Genetics Home Reference (GHR) maintained by U.S. national library of medicine and has detailed explanation of Leigh Syndrome
- Leigh syndrome maintained by the national center for advancing translational sciences include additional resources
- American College of Medical Genetics and Genomics and the National Society of Genetic Counselors provide online directories of genetic specialist to search for healthcare providers.
- Ask the Mito Doc has a form to submit a question for mitochondrial disease specialists.
- There are national support groups including MitoAction, People Against Leigh Syndrome (PALS), and United Mitochondrial Disease Foundation.
- Facebook has a Leigh's Syndrome Parent Network, allowing parents of patients with Leigh syndrome to connect with each other.
- ↑ 1.0 1.1 1.2 Rahman J, Noronha A, Thiele I, Rahman S. Leigh map: A novel computational diagnostic resource for mitochondrial disease. Ann Neurol. 2017;81(1):9-16. doi:10.1002/ana.24835
- ↑ 2.0 2.1 2.2 Lake NJ, Compton AG, Rahman S, Thorburn DR. Leigh syndrome: One disorder, more than 75 monogenic causes. Ann Neurol. 2016;79(2):190-203. doi:10.1002/ana.24551
- ↑ Noble P. Denis Archibald Leigh. Psychiatr Bull. 1998;22(10):648-649. doi:10.1192/pb.22.10.648
- ↑ Darin N, Oldfors A, Moslemi AR, Holme E, Tulinius M. The incidence of mitochondrial encephalomyopathies in childhood: Clinical features and morphological, biochemical, and DNA abnormalities. Ann Neurol. 2001;49(3):377-383. doi:10.1002/ana.75
- ↑ 5.0 5.1 5.2 Finsterer J. Leigh and Leigh-Like Syndrome in Children and Adults. Pediatr Neurol. 2008;39(4):223-235. doi:10.1016/j.pediatrneurol.2008.07.013
- ↑ 6.0 6.1 Rahman S, Blok $ R B, Dahl H-HM, et al. Leigh Syndrome: Clinical Features and Bi&he&al and DNA Abnormahties.
- ↑ 7.0 7.1 7.2 Baertling F, Rodenburg RJ, Schaper J, et al. A guide to diagnosis and treatment of Leigh syndrome. J Neurol Neurosurg Psychiatry. 2014;85(3):257-265. doi:10.1136/jnnp-2012-304426
- ↑ Ruhoy IS, Saneto RP. The genetics of leigh syndrome and its implications for clinical practice and risk management. Appl Clin Genet. 2014;7:221-234. doi:10.2147/TACG.S46176
- ↑ Sweeney MG, Hammans SR, Duchen LW, et al. Mitochondrial DNA mutation underlying Leigh’s syndrome: Clinical, pathological, biochemical, and genetic studies of a patient presenting with progressive myoclonic epilepsy. J Neurol Sci. 1994;121(1):57-65. doi:10.1016/0022-510X(94)90157-0
- ↑ 10.0 10.1 Lee HF, Tsai CR, Chi CS, Lee HJ, Chen CCC. Leigh Syndrome: Clinical and Neuroimaging Follow-Up. Pediatr Neurol. 2009;40(2):88-93. doi:10.1016/j.pediatrneurol.2008.09.020
- ↑ Barth PG, Valianpour F, Bowen VM, et al. X-linked cardioskeletal myopathy and neutropenia (Barth syndrome): An update. Am J Med Genet. 2004;126A(4):349-354. doi:10.1002/ajmg.a.20660
- ↑ Visapää I, Fellman V, Vesa J, et al. GRACILE Syndrome, a Lethal Metabolic Disorder with Iron Overload, Is Caused by a Point Mutation in BCS1L. Am J Hum Genet. 2002;71(4):863-876. doi:10.1086/342773
- ↑ Newman NJ, Lott MT, Wallace DC. The clinical characteristics of pedigrees of Leber’s hereditary optic neuropathy with the 11778 mutation. Am J Ophthalmol. 1991;111(6):750-762. http://www.ncbi.nlm.nih.gov/pubmed/2039048.
- ↑ Gibson K, Halliday JL, Kirby DM, Yaplito-Lee J, Thorburn DR, Boneh A. Mitochondrial oxidative phosphorylation disorders presenting in neonates: clinical manifestations and enzymatic and molecular diagnoses. Pediatrics. 2008;122(5):1003-1008. doi:10.1542/peds.2007-3502
- ↑ Donovan LE, Severin NE. Maternally inherited diabetes and deafness in a North American kindred: tips for making the diagnosis and review of unique management issues. J Clin Endocrinol Metab. 2006;91(12):4737-4742. doi:10.1210/jc.2006-1498
- ↑ Chinnery PF, Johnson MA, Wardell TM, et al. The epidemiology of pathogenic mitochondrial DNA mutations. Ann Neurol. 2000;48(2):188-193. doi:10.1002/1531-8249(200008)48:2<188::AID-ANA8>3.0.CO;2-P
- ↑ Lee HN, Eom S, Kim SH, et al. Epilepsy Characteristics and Clinical Outcome in Patients With Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS). Pediatr Neurol. 2016;64:59-65. doi:10.1016/j.pediatrneurol.2016.08.016
- ↑ Pacitti D, Levene M, Garone C, Nirmalananthan N, Bax BE. Mitochondrial Neurogastrointestinal Encephalomyopathy: Into the Fourth Decade, What We Have Learned So Far. Front Genet. 2018;9:669. doi:10.3389/fgene.2018.00669
- ↑ DiMauro S, Hirano M. MERRF.; 1993. http://www.ncbi.nlm.nih.gov/pubmed/20301693.
- ↑ Holt IJ, Harding AE, Petty RK, Morgan-Hughes JA. A new mitochondrial disease associated with mitochondrial DNA heteroplasmy. Am J Hum Genet. 1990;46(3):428-433. http://www.ncbi.nlm.nih.gov/pubmed/2137962.
- ↑ Pearson HA, Lobel JS, Kocoshis SA, et al. A new syndrome of refractory sideroblastic anemia with vacuolization of marrow precursors and exocrine pancreatic dysfunction. J Pediatr. 1979;95(6):976-984. http://www.ncbi.nlm.nih.gov/pubmed/501502.
- ↑ LEIGH D. Subacute necrotizing encephalomyelopathy in an infant. J Neurol Neurosurg Psychiatry. 1951;14(3):216-221. http://www.ncbi.nlm.nih.gov/pubmed/14874135.
- ↑ Garcia-Cazorla A. Long-term Follow-up of Neonatal Mitochondrial Cytopathies: A Study of 57 Patients. Pediatrics. 2005;116(5):1170-1177. doi:10.1542/peds.2004-2407
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