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{{Infobox_Disease |
  Name          = {{PAGENAME}} |
  Image          = |
  Caption        = |
  DiseasesDB    = 30792 |
  ICD10          = {{ICD10|G|31|8|g|30}} |
  ICD9          = {{ICD9|330.8}} |
  ICDO          = |
  OMIM          = 256000 |
  MedlinePlus    = |
  eMedicineSubj  = |
  eMedicineTopic = |
  MeshID        = D007888 |
}}
{{SI}}
{{SI}}


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==Overview==
'''Leigh's disease''', a form of '''Leigh syndrome''', also known as '''Subacute Necrotizing Encephalomyelopathy (SNEM)''', is a rare, inherited [[Neurodegenerative disease|neurodegenerative]] disorder that mainly affects the [[Nervous system disease|central nervous system]] and becomes apparent during [[infancy]], often after a [[viral]] [[illness]]. There is  progressive loss of [[mental]] and movement abilities ([[Psychomotor retardation|psychomotor]] [[regression]]) and often leads to death within 2-3 years, usually due to [[Respiratory system|respiratory]] [[failure]].
==Historical Perspective==
Leigh's Syndrome was first described by Archibald Denis Leigh, a British [[neuropsychiatrist]], in 1951. <ref name="pmid14874135">{{cite journal| author=LEIGH D| title=Subacute necrotizing encephalomyelopathy in an infant. | journal=J Neurol Neurosurg Psychiatry | year= 1951 | volume= 14 | issue= 3 | pages= 216-21 | pmid=14874135 | doi=10.1136/jnnp.14.3.216 | pmc=499520 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14874135  }} </ref>


==Overview==
==Pathophysiology==
'''Leigh's disease''', a form of '''Leigh syndrome''', also known as '''Subacute Necrotizing Encephalomyelopathy (SNEM)''', is a rare neurometabolic disorder that affects the [[central nervous system]]. It is named after Denis Archibald Leigh, a British psychiatrist who first described the condition in 1951. <ref> {{cite web|url = http://pb.rcpsych.org/cgi/reprint/22/10/648.pdf|title = Obituaries|journal = Psychiatric Bulletin (1998)|accessdate = 1 Aug 2020}} </ref>
It is thought that manifestation of Leigh's syndrome is caused by [[brain]] [[lesion]] at different parts including [[Brain stem|brainstem]], [[Basal Ganglia|basal]] [[ganglia]], [[cerebellum]], and other regions of the [[brain]]. [[Brain]] lesions may be present in different forms such as [[demyelination]], [[gliosis]], [[spongiosis]], [[necrosis]] and [[capillary]] proliferation. Due to [[demyelination]], [[neurons]] in [[brain]] loses their ability to communicate with other [[neurons]] which hampers basic life functions, [[movements]] and [[Balance disorder|balance]].  [[Lactic acidosis]] may be observed in some patients with [[pyruvate]] buildup, due to defective [[oxidative phosphorylation]]. <ref name="pmid23772060">{{cite journal| author=Baertling F, Rodenburg RJ, Schaper J, Smeitink JA, Koopman WJ, Mayatepek E | display-authors=etal| title=A guide to diagnosis and treatment of Leigh syndrome. | journal=J Neurol Neurosurg Psychiatry | year= 2014 | volume= 85 | issue= 3 | pages= 257-65 | pmid=23772060 | doi=10.1136/jnnp-2012-304426 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23772060  }} </ref>


==Causes==
==Causes==
It is an inherited disorder which usually affects infants, but in rare cases, teenagers and adults, as well. In the case of the disease, mutations in [[mitochondrial DNA]] or in nuclear DNA (gene [[SURF1]]<ref name="pmid17908801">{{cite journal |author=Pronicki M, Matyja E, Piekutowska-Abramczuk D, ''et al.'' |title=Light and electron microscopy characteristics of the muscle of patients with SURF1 gene mutations associated with Leigh disease |journal=J. Clin. Pathol. |volume=61 |issue=4 |pages=460–6 |year=2008 |month=April |pmid=17908801 |doi=10.1136/jcp.2007.051060 |url=http://jcp.bmj.com/cgi/pmidlookup?view=long&pmid=17908801 |pmc=2571978}}</ref> and some COX assembly factors) cause degradation of motor skills and eventually death.
Leigh's syndrome may be caused by [[mutations]] of any of 30 different [[genes]], present in [[nuclear]] [[DNA]]. The most common cause of Leigh's syndrome is mutations in a gene called [[SURF1]] (surfeit1) among [[nuclear DNA]] genes. Around 20 % of the cases are found to be due to mutation in [[mitochondrial DNA]]. Among [[mitochondrial DNA]] genes, [[mutations]] in [[MT-ATP6 gene]], that codes for [[ATP synthase]] is most common cause known to cause the [[disease]]. <ref> 1. Leigh syndrome: MedlinePlus Genetics [Internet]. [cited 2021 Jul 30]. Available from: https://medlineplus.gov/genetics/condition/leigh-syndrome/ </ref>


[[Mitochondria]] are some of the most important [[organelles]] in animal cells as they provide energy for the cell's function.  In humans, their primary function is to convert the potential energy of [[glucose]] and [[fatty acids]] into that of [[adenosine triphosphate]]. The energy in the ATP is then used to carry out virtually all of the cell's metabolic functions. [[Mitochondria]] are also unique in that they carry their own type of [[DNA]], [[mitochondrial DNA]], or mtDNA. The information stored in the mtDNA is used in the creation of new mitochondria.
==Epidemiology and Demographics==
The [[prevalence]] of Leigh's Syndrome is approximately 1 per 40,000 [[live births]] individuals worldwide.<ref> 1. Leigh syndrome: MedlinePlus Genetics [Internet]. [cited 2021 Jul 30]. Available from: https://medlineplus.gov/genetics/condition/leigh-syndrome/ </ref>


When improper mutations of the mtDNA cause the mitochondria to fail to function properly, a person is at risk for number of disorders, including Leigh's disease.  In the case of Leigh's Disease, crucial cells in the brain stem have mutated mtDNA which creates poorly functioning mitochondria.  This causes a chronic lack of energy in the cells, which in turn affects the central nervous system and inhibits an individual's motor skills.
==Risk Factors==
There are no established [[risk factors]] for Leigh's disease.


==Presentation==
==Screening==
The disease is most noted for its degradation in a person’s ability to control their movements. As it progresses rapidly, the earliest signs may be poor sucking ability and loss of head control and motor skills.  Other symptoms include loss of appetite, vomiting, irritability, continuous crying (in infants), and seizures.  A later sign can also be episodes of [[lactic acidosis]], which can lead to impairment of respiratory and kidney function.  Some children can present with loss of development skills or developmental regression and have often had investigations for failure to thrive. As the disease progresses in adults, it may also cause general weakness, [[kidney]] failure and [[heart]] problems.  Life expectancy is usually about a year within the onset of symptoms although both acute fulminating illness of a few days and prolonged survival have been reported.
There is insufficient evidence to recommend routine screening for Leigh's disease.
 
==Natural History, Complications, and Prognosis==
[[Life expectancy]] for [[children]] diagnosed with Leigh's disease usually exceeds no more than two or three years. <ref name="pmid24731534">{{cite journal| author=Sofou K, De Coo IF, Isohanni P, Ostergaard E, Naess K, De Meirleir L | display-authors=etal| title=A multicenter study on Leigh syndrome: disease course and predictors of survival. | journal=Orphanet J Rare Dis | year= 2014 | volume= 9 | issue= | pages= 52 | pmid=24731534 | doi=10.1186/1750-1172-9-52 | pmc=4021638 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24731534  }} </ref>


==Differential diagnosis==
==Differential diagnosis==
Leigh's disease must be differentiated from other diseases that cause neurological manifestations in infants.
Leigh's disease must be differentiated from other [[diseases]] that cause [[Neurological disorders|neurological]] manifestations in [[infants]].
{|
[[Leigh's disease]] must be differentiated from [[birth asphyxia]], [[kernicterus]], [[encephalitis]], [[Thiamine deficiency|thiamine]] deficiency, [[Wilson's disease|Wilson's]] disease, biotin-responsive [[basal ganglia disease]]. [[Perinatal asphyxia|Birth asphyxia]] and [[hyperbilirubinemia]] can cause damage to [[thalamus]] and [[basal ganglia]], which can cause [[Lesion|lesions]] similar to leigh's disease. <ref name="pmid23772060">{{cite journal| author=Baertling F, Rodenburg RJ, Schaper J, Smeitink JA, Koopman WJ, Mayatepek E | display-authors=etal| title=A guide to diagnosis and treatment of Leigh syndrome. | journal=J Neurol Neurosurg Psychiatry | year= 2014 | volume= 85 | issue= 3 | pages= 257-65 | pmid=23772060 | doi=10.1136/jnnp-2012-304426 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23772060  }} </ref>
|- style="background: #4479BA; color: #FFFFFF; text-align: center;"
 
! rowspan="2" |Diseases
==Diagnosis==
! colspan="4" |Type of motor abnormality
The [[diagnosis]] of Leigh's syndrome is suggested based on the [[clinical]] findings, confirmed through [[laboratory]] and [[genetic testing]].
! rowspan="2" |Clinical findings
===Diagnostic study of Choice===
! rowspan="2" |Laboratory findings and diagnostic tests
Magnetic resonance imaging ([[MRI]]) of the brain may reveal abnormal areas in certain parts of the [[brain]] including [[basal ganglia]], [[brain stem]], and [[grey matter]].
! rowspan="2" |Radiographic findings
Finding in MRI suggestive of Leigh's disease includes hyperintense signal abnormalities on T2-weighted magnetic resonance imaging (MRI).<ref name="pmid26739140">{{cite journal| author=Bonfante E, Koenig MK, Adejumo RB, Perinjelil V, Riascos RF| title=The neuroimaging of Leigh syndrome: case series and review of the literature. | journal=Pediatr Radiol | year= 2016 | volume= 46 | issue= 4 | pages= 443-51 | pmid=26739140 | doi=10.1007/s00247-015-3523-5 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26739140  }} </ref>
|- style="background: #4479BA; color: #FFFFFF; text-align: center;"
 
!Spasticity
===History and Symptoms===
!Hypotonia
[[Symptoms]] began to appear from [[infancy]] that begins with [[vomiting]], [[diarrhoea]], and [[Poor growth|poor]] sucking that leads to [[failure to thrive]]. On progressive note, [[muscular system]] involved leading to [[hypotonia]] (decrease [[Tone (linguistics)|tone]]), [[dystonia]] (sustained [[spasm]]) and [[ataxia]] (loss of control over movements). Muscles that controls [[eye movement]] get affected leading to [[ophthalmoparesis]] and [[nystagmus]] ([[Involuntary muscle|involuntary]] eye movement). [[Lungs]] and [[heart]] can be involved leading to [[hypertrophic cardiomyopathy]] and [[respiratory failure]], most common cause of death. [[Peripheral neuropathy]] have been noted in some cases of Leigh's syndrome. [[Hypertrichosis]] can be seen in some patient due SURF1 [[Nuclear DNA|nuclear]] gene [[mutation]].
!Ataxia
<ref name="pmid23772060">{{cite journal| author=Baertling F, Rodenburg RJ, Schaper J, Smeitink JA, Koopman WJ, Mayatepek E | display-authors=etal| title=A guide to diagnosis and treatment of Leigh syndrome. | journal=J Neurol Neurosurg Psychiatry | year= 2014 | volume= 85 | issue= 3 | pages= 257-65 | pmid=23772060 | doi=10.1136/jnnp-2012-304426 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23772060  }} </ref>
!Dystonia
 
|-
===Physical Examinations===
| style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Leigh syndrome]]
Common physical examination findings of Leigh's disease include [[dystonia]], [[nystagmus]], [[autonomic dysfunction]] (due to damage to [[basal ganglia]] and [[brain stem]]).
| style="background: #F5F5F5; padding: 5px;" | -
 
| style="background: #F5F5F5; padding: 5px;" | -
===Laboratory Findings===
| style="background: #F5F5F5; padding: 5px;" |<nowiki>+</nowiki>
Laboratory findings consistent with the [[diagnosis]] of [[Leigh's syndrome]] include high levels of [[acidic]] waste products in the [[blood]] ([[lactic acidosis]]) as well as elevated levels of [[pyruvate]] and [[alanine]].
| style="background: #F5F5F5; padding: 5px;" | +
 
| style="background: #F5F5F5; padding: 5px;" |
===Echocardiogram===
* Progressive [[psychomotor]] regression
There are no [[ECG]] findings associated with Leigh's disease.
* [[Seizures]]
* External [[ophthalmoplegia]]
* [[Lactic acidosis]]
* [[Vomiting]]
| style="background: #F5F5F5; padding: 5px;" |
* Increased [[lactate]] levels in [[blood]] and [[CSF]]
* Genetic testing 
| style="background: #F5F5F5; padding: 5px;" |
* MRI: abnormal [[white matter]] signal in the [[putamen]], [[basal ganglia]], and [[brainstem]] on T2 images
|-
| style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Niemann-Pick]] disease type C
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | +
| style="background: #F5F5F5; padding: 5px;" | +
| style="background: #F5F5F5; padding: 5px;" |
* Progressive [[neurodegeneration]]
* [[Hepatosplenomegaly]]
* Systemic involvement of [[liver]], [[spleen]], or [[lung]] preceedes [[neurologic]] symptoms
| style="background: #F5F5F5; padding: 5px;" |
* Abnormal [[liver]] function tests
* [[Fibroblast]] cell culture with filipin staining
| style="background: #F5F5F5; padding: 5px;" |
* MRI:
**[[Cerebral]] and [[cerebellar]] [[atrophy]]
**Thinning of the [[corpus callosum]]
|-
| style="background: #DCDCDC; padding: 5px; text-align: center;" |Infantile Refsum disease
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | +
| style="background: #F5F5F5; padding: 5px;" | +
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" |
* Abnormalities of the [[optic nerve]] and disc
* [[Retinitis pigmentosa]]
* [[Sensorineural]] hearing loss
* [[Hepatomegaly]] and [[cirrhosis]]
* [[Neurologic]] deterioration is slower than in [[Zellweger syndrome]] or ALD
| style="background: #F5F5F5; padding: 5px;" |Elevated plasma VLCFA levels
| style="background: #F5F5F5; padding: 5px; text-align: center;" |--
|-
| style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Adrenoleukodystrophy]]
| style="background: #F5F5F5; padding: 5px;" | +
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" |
* [[Cognitive]] and behavioral abnormalities
* [[Adrenal insufficiency]]
* [[Hyperpigmented]] skin
* [[Gonadal dysfunction]]
* [[Neurologic]] deterioration progresses at a variable rate
| style="background: #F5F5F5; padding: 5px;" |
* Elevated plasma VLCFA levels
* Molecular [[genetic testing]] for mutations in the ABCD1 gene
| style="background: #F5F5F5; padding: 5px; text-align: center;" |--
|-
| style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Zellweger syndrome]]
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | +
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" |
* [[Craniofacial]] dysmorphism
* [[Hepatomegaly]]
* Neonatal [[seizures]]
* Profound developmental delay
* [[MRI]] findings include [[cortical]] and [[white matter]] abnormalities
* [[Neurologic deterioration]] is rapid and infants rarely survive beyond six months of age
| style="background: #F5F5F5; padding: 5px;" |
* Elevated plasma VLCFA levels
* Elevated levels of [[phytanic acid]], pristanic acid, and pipecolic acid in plasma and [[fibroblasts]]
* Reduced plasmalogen in [[erythrocytes]]
* Molecular [[genetic]] testing for [[mutations]] in the PEX1 or PEX6 genes
| style="background: #F5F5F5; padding: 5px; text-align: center;" |--
|-
| style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Pyruvate dehydrogenase deficiency]]
| style="background: #F5F5F5; padding: 5px;" | +
| style="background: #F5F5F5; padding: 5px;" | +
| style="background: #F5F5F5; padding: 5px;" | +
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" |
* [[Lactic acidosis]]
* [[Seizures]]
* [[Intellectual disability]]
| style="background: #F5F5F5; padding: 5px;" |
* Elevated [[lactate]] and pyruvate levels in [[blood]] and CSF
* Abnormal PDH enzymatic activity in cultured fibroblasts
| style="background: #F5F5F5; padding: 5px; text-align: center;" |--
|-
| style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Arginase deficiency]]
| style="background: #F5F5F5; padding: 5px;" | +
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" |
* [[Hyperammonemia]]
* [[Encephalopathy]]
* [[Respiratory alkalosis]]
| style="background: #F5F5F5; padding: 5px;" |
* Elevated [[ammonia]] level
* Elevated [[arginine]] level
| style="background: #F5F5F5; padding: 5px; text-align: center;" |--
|-
| style="background: #DCDCDC; padding: 5px; text-align: center;" |Holocarboxylase synthetase deficiency
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | +
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" |
* [[Ketoacidosis]]
* [[Dermatitis]]
* [[Alopecia]]
* [[Seizures]]
* [[Developmental delay]]
| style="background: #F5F5F5; padding: 5px;" |Elevated levels of:
* Beta-hydroxyisovalerate
* Beta-methylcrotonylglycine
* Beta-hydroxypropionate
* Methylcitrate
* Tiglylglycine
| style="background: #F5F5F5; padding: 5px; text-align: center;" |--
|-
| style="background: #DCDCDC; padding: 5px; text-align: center;" |Glutaric aciduria type 1
| style="background: #F5F5F5; padding: 5px;" |<nowiki>-</nowiki>
| style="background: #F5F5F5; padding: 5px;" |<nowiki>-</nowiki>
| style="background: #F5F5F5; padding: 5px;" |<nowiki>-</nowiki>
| style="background: #F5F5F5; padding: 5px;" |<nowiki>+</nowiki>
| style="background: #F5F5F5; padding: 5px;" |
* Episodes of [[metabolic decompensation]] and [[encephalopathy]] often precipitated by [[infection]] and [[fever]]
* Rarely presents in the newborn period
* Microencephalic [[macrocephaly]]
* [[Seizures]] (approximately 20 percent)
* [[Cognitive function]] is preserved
| style="background: #F5F5F5; padding: 5px;" |Elevated levels of:
* [[glutaric acid]]
* 3-hydroxyglutaric acid
| style="background: #F5F5F5; padding: 5px;" |
* MRI:
**[[Frontal]] and [[temporal]] [[atrophy]]
|-
| style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Ataxia telangiectasia]]
| style="background: #F5F5F5; padding: 5px;" |<nowiki>-</nowiki>
| style="background: #F5F5F5; padding: 5px;" |<nowiki>-</nowiki>
| style="background: #F5F5F5; padding: 5px;" |<nowiki>+</nowiki>
| style="background: #F5F5F5; padding: 5px;" |<nowiki>-</nowiki>
| style="background: #F5F5F5; padding: 5px;" |
* Progressive [[cerebellar]] [[ataxia]]
* Abnormal eye movements
* [[Oculocutaneous]] [[telangiectasias]]
* Immune deficiency
* Increased risk of [[malignancy]]
| style="background: #F5F5F5; padding: 5px;" |
* Elevated serum alpha-fetoprotein level
* Low [[IgA]] and [[IgG]] levels
* [[Lymphopenia]]
* Genetic testing for [[mutation]] in the ATM gene
| style="background: #F5F5F5; padding: 5px; text-align: center;" |--
|-
| style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Pontocerebellar]] [[hypoplasias]]
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | +
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" |
* Progressive muscle [[atrophy]]
* [[Microcephaly]]
* [[Developmental delay]]
| style="background: #F5F5F5; padding: 5px;" |[[Genetic]] testing for PCH gene mutations
| style="background: #F5F5F5; padding: 5px;" |
* MRI :
**Small [[cerebellum]] and [[brainstem]] including the [[pons]]
|-
| style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Metachromatic leukodystrophy]]
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | +
| style="background: #F5F5F5; padding: 5px;" | +
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" |
* Regression of motor skills
* [[Seizures]]
* [[Optic atrophy]]
* Reduced or absent [[deep tendon reflexes]]
* [[Intellectual disability]]
| style="background: #F5F5F5; padding: 5px;" |
* Deficient arylsulfatase A enzyme activity in [[leukocytes]] or cultured skin fibroblasts
| style="background: #F5F5F5; padding: 5px; text-align: center;" |--
|-
| style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Pelizaeus-Merzbacher]]
| style="background: #F5F5F5; padding: 5px;" | +
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | +
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" |
* [[Nystagmus]]
* [[Cognitive impairment]]
* Onset in infancy
* Slowly progressive
* Language development may be normal
| style="background: #F5F5F5; padding: 5px;" |
* [[Genetic]] testing for [[mutations]] in PLP1 gene
| style="background: #F5F5F5; padding: 5px;" |
*MRI:
**[[White matter]] abnormalities
|-
| style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Angelman syndrome]]
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | +
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" |
* Profound [[intellectual disability]]
* Postnatal [[microcephaly]]
* Typical abnormal behaviors (paroxysmal laughter, easily excitable)
| style="background: #F5F5F5; padding: 5px;" |
* Methylation studies and [[chromosome]] microarray to detect chromosome 15 anomalies and UBE3A mutations
| style="background: #F5F5F5; padding: 5px; text-align: center;" |--
|-
| style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Rett syndrome]]
| style="background: #F5F5F5; padding: 5px;" | +
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | -
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| style="background: #F5F5F5; padding: 5px;" |
* Occurs almost exclusively in females
* Normal development during first six months followed by regression and loss of milestones
* Loss of speech capability
* Stereotypic hand movements
* [[Seizures]]
* [[Autistic]] features
| style="background: #F5F5F5; padding: 5px;" |
* Clinical diagnosis
* [[Genetic]] testing for MECP2 mutations
| style="background: #F5F5F5; padding: 5px; text-align: center;" |--
|-
| style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Lesch-Nyhan syndrome]]
| style="background: #F5F5F5; padding: 5px;" | +
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | +
| style="background: #F5F5F5; padding: 5px;" |
* [[Self-mutilating]] behavior
* [[Urinary]] stones due to [[hyperuricemia]]
| style="background: #F5F5F5; padding: 5px;" |
* Elevated [[uric acid]] level
* Abnormal enzymatic activity of HPRT in cultured fibroblasts
* [[Genetic]] testing for HPRT gene [[mutations]]
| style="background: #F5F5F5; padding: 5px; text-align: center;" |--
|-
| style="background: #DCDCDC; padding: 5px; text-align: center;" |Miller-Dieker lissencephaly
| style="background: #F5F5F5; padding: 5px;" | +
| style="background: #F5F5F5; padding: 5px;" | +
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| style="background: #F5F5F5; padding: 5px;" |
* [[Lissencephaly]]
* [[Microcephaly]]
* [[Dysmorphic]] features
* [[Seizures]]
* Failure to thrive
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* Cytogenetic testing for 17p13.3 microdeletion
| style="background: #F5F5F5; padding: 5px; text-align: center;" |--
|-
| style="background: #DCDCDC; padding: 5px; text-align: center;" |Dopa-responsive [[dystonia]]
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| style="background: #F5F5F5; padding: 5px;" |
* Onset in early childhood
* Symptoms worsen with [[fatigue]] and exercise
| style="background: #F5F5F5; padding: 5px;" |
* Positive response to a trial of [[levodopa]]
| style="background: #F5F5F5; padding: 5px; text-align: center;" |--
|}


===X-ray===
There are no [[X-rays|x-ray]] findings associated with Leigh's disease.
===Echocardiography or Ultrasound===
[[Echocardiography]] may be helpful in the diagnosis of Leigh's disease. Findings on an echocardiography suggestive of Leigh's disease includes [[cardiomyopathy]] and [[Pericardial effusion.|pericardial effusion. <ref name="pmid20502985">{{cite journal| author=Hadzsiev K, Maasz A, Kisfali P, Kalman E, Gomori E, Pal E | display-authors=etal| title=Mitochondrial DNA 11777C>A mutation associated Leigh syndrome: case report with a review of the previously described pedigrees. | journal=Neuromolecular Med | year= 2010 | volume= 12 | issue= 3 | pages= 277-84 | pmid=20502985 | doi=10.1007/s12017-010-8115-9 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20502985  }} </ref>]]
===CT Scan===
A [[Head]] [[Computed tomography|CT]] scan may be helpful in the diagnosis of Leigh's disease. Findings on CT scan suggestive of Leigh's disease include bilateral symmetric subcortical hypodensities. <ref name="pmid26739140">{{cite journal| author=Bonfante E, Koenig MK, Adejumo RB, Perinjelil V, Riascos RF| title=The neuroimaging of Leigh syndrome: case series and review of the literature. | journal=Pediatr Radiol | year= 2016 | volume= 46 | issue= 4 | pages= 443-51 | pmid=26739140 | doi=10.1007/s00247-015-3523-5 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26739140  }} </ref>


==Treatment==
==Treatment==
It is a very rare disorder which affects only a small portion of the population, and as of yet, there is no cure for Leigh's disease.  It usually affects infants under 2 years of age, but, in rarer cases, teenagers and adults as well.  A high-fat, low-carbohydrate diet may be recommended. Adults may have puffiness and/or swelling of the eye area and the hands.  It is currently treated with [[Vitamin B1]], or [[thiamin]], but even with treatment, infants rarely live longer than two or three years after the onset of the disease. In cases of older people, the disease takes longer, but is still almost always fatal.
There is no treatment for [[Leigh's disease]]; the mainstay of therapy is supportive care. [[Anticonvulsant|Anti-epileptic drugs]] can be used to manage patient who present with [[epilepsy]]. In addition, [[coenzyme Q10]], [[thiamine]] and [[biotin]] can be used to [[Supplements|supplement]] [[deficiencies]]. <ref name="pmid22513923">{{cite journal| author=Pfeffer G, Majamaa K, Turnbull DM, Thorburn D, Chinnery PF| title=Treatment for mitochondrial disorders. | journal=Cochrane Database Syst Rev | year= 2012 | volume=  | issue= 4 | pages= CD004426 | pmid=22513923 | doi=10.1002/14651858.CD004426.pub3 | pmc=7201312 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22513923  }} </ref>
 
==X-linked Leigh's disease==
There is another form of this disease called the X-linked Leigh's disease which is not a [[mutation]] in the [[oxidative phosphorylation]] [[enzymes]] (which are both on the mtDNA and the [[nuclear DNA]]). The X-linked Leigh's disease is a mutation of a gene encoding [[Pyruvate dehydrogenase (lipoamide) alpha 1|PDHA1]], part of the [[pyruvate dehydrogenase complex]], located on the [[X chromosome]].<ref>{{OMIM|308930|LEIGH SYNDROME, X-LINKED}}</ref>


==References==
==References==
{{reflist|2}}
{{reflist|2}}


 
[[Category:Needs content]]
{{Diseases of the nervous system}}
{{Diseases of the nervous system}}
{{Mitochondrial diseases}}
{{Mitochondrial diseases}}

Latest revision as of 11:31, 18 August 2021

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]


Overview

Leigh's disease, a form of Leigh syndrome, also known as Subacute Necrotizing Encephalomyelopathy (SNEM), is a rare, inherited neurodegenerative disorder that mainly affects the central nervous system and becomes apparent during infancy, often after a viral illness. There is progressive loss of mental and movement abilities (psychomotor regression) and often leads to death within 2-3 years, usually due to respiratory failure.

Historical Perspective

Leigh's Syndrome was first described by Archibald Denis Leigh, a British neuropsychiatrist, in 1951. [1]

Pathophysiology

It is thought that manifestation of Leigh's syndrome is caused by brain lesion at different parts including brainstem, basal ganglia, cerebellum, and other regions of the brain. Brain lesions may be present in different forms such as demyelination, gliosis, spongiosis, necrosis and capillary proliferation. Due to demyelination, neurons in brain loses their ability to communicate with other neurons which hampers basic life functions, movements and balance. Lactic acidosis may be observed in some patients with pyruvate buildup, due to defective oxidative phosphorylation. [2]

Causes

Leigh's syndrome may be caused by mutations of any of 30 different genes, present in nuclear DNA. The most common cause of Leigh's syndrome is mutations in a gene called SURF1 (surfeit1) among nuclear DNA genes. Around 20 % of the cases are found to be due to mutation in mitochondrial DNA. Among mitochondrial DNA genes, mutations in MT-ATP6 gene, that codes for ATP synthase is most common cause known to cause the disease. [3]

Epidemiology and Demographics

The prevalence of Leigh's Syndrome is approximately 1 per 40,000 live births individuals worldwide.[4]

Risk Factors

There are no established risk factors for Leigh's disease.

Screening

There is insufficient evidence to recommend routine screening for Leigh's disease.

Natural History, Complications, and Prognosis

Life expectancy for children diagnosed with Leigh's disease usually exceeds no more than two or three years. [5]

Differential diagnosis

Leigh's disease must be differentiated from other diseases that cause neurological manifestations in infants. Leigh's disease must be differentiated from birth asphyxia, kernicterus, encephalitis, thiamine deficiency, Wilson's disease, biotin-responsive basal ganglia disease. Birth asphyxia and hyperbilirubinemia can cause damage to thalamus and basal ganglia, which can cause lesions similar to leigh's disease. [2]

Diagnosis

The diagnosis of Leigh's syndrome is suggested based on the clinical findings, confirmed through laboratory and genetic testing.

Diagnostic study of Choice

Magnetic resonance imaging (MRI) of the brain may reveal abnormal areas in certain parts of the brain including basal ganglia, brain stem, and grey matter. Finding in MRI suggestive of Leigh's disease includes hyperintense signal abnormalities on T2-weighted magnetic resonance imaging (MRI).[6]

History and Symptoms

Symptoms began to appear from infancy that begins with vomiting, diarrhoea, and poor sucking that leads to failure to thrive. On progressive note, muscular system involved leading to hypotonia (decrease tone), dystonia (sustained spasm) and ataxia (loss of control over movements). Muscles that controls eye movement get affected leading to ophthalmoparesis and nystagmus (involuntary eye movement). Lungs and heart can be involved leading to hypertrophic cardiomyopathy and respiratory failure, most common cause of death. Peripheral neuropathy have been noted in some cases of Leigh's syndrome. Hypertrichosis can be seen in some patient due SURF1 nuclear gene mutation. [2]

Physical Examinations

Common physical examination findings of Leigh's disease include dystonia, nystagmus, autonomic dysfunction (due to damage to basal ganglia and brain stem).

Laboratory Findings

Laboratory findings consistent with the diagnosis of Leigh's syndrome include high levels of acidic waste products in the blood (lactic acidosis) as well as elevated levels of pyruvate and alanine.

Echocardiogram

There are no ECG findings associated with Leigh's disease.

X-ray

There are no x-ray findings associated with Leigh's disease.

Echocardiography or Ultrasound

Echocardiography may be helpful in the diagnosis of Leigh's disease. Findings on an echocardiography suggestive of Leigh's disease includes cardiomyopathy and pericardial effusion. [7]

CT Scan

A Head CT scan may be helpful in the diagnosis of Leigh's disease. Findings on CT scan suggestive of Leigh's disease include bilateral symmetric subcortical hypodensities. [6]

Treatment

There is no treatment for Leigh's disease; the mainstay of therapy is supportive care. Anti-epileptic drugs can be used to manage patient who present with epilepsy. In addition, coenzyme Q10, thiamine and biotin can be used to supplement deficiencies. [8]

References

  1. ↑ LEIGH D (1951). "Subacute necrotizing encephalomyelopathy in an infant". J Neurol Neurosurg Psychiatry. 14 (3): 216–21. doi:10.1136/jnnp.14.3.216. PMC 499520. PMID 14874135.
  2. ↑ 2.0 2.1 2.2 Baertling F, Rodenburg RJ, Schaper J, Smeitink JA, Koopman WJ, Mayatepek E; et al. (2014). "A guide to diagnosis and treatment of Leigh syndrome". J Neurol Neurosurg Psychiatry. 85 (3): 257–65. doi:10.1136/jnnp-2012-304426. PMID 23772060.
  3. ↑ 1. Leigh syndrome: MedlinePlus Genetics [Internet]. [cited 2021 Jul 30]. Available from: https://medlineplus.gov/genetics/condition/leigh-syndrome/
  4. ↑ 1. Leigh syndrome: MedlinePlus Genetics [Internet]. [cited 2021 Jul 30]. Available from: https://medlineplus.gov/genetics/condition/leigh-syndrome/
  5. ↑ Sofou K, De Coo IF, Isohanni P, Ostergaard E, Naess K, De Meirleir L; et al. (2014). "A multicenter study on Leigh syndrome: disease course and predictors of survival". Orphanet J Rare Dis. 9: 52. doi:10.1186/1750-1172-9-52. PMC 4021638. PMID 24731534.
  6. ↑ 6.0 6.1 Bonfante E, Koenig MK, Adejumo RB, Perinjelil V, Riascos RF (2016). "The neuroimaging of Leigh syndrome: case series and review of the literature". Pediatr Radiol. 46 (4): 443–51. doi:10.1007/s00247-015-3523-5. PMID 26739140.
  7. ↑ Hadzsiev K, Maasz A, Kisfali P, Kalman E, Gomori E, Pal E; et al. (2010). "Mitochondrial DNA 11777C>A mutation associated Leigh syndrome: case report with a review of the previously described pedigrees". Neuromolecular Med. 12 (3): 277–84. doi:10.1007/s12017-010-8115-9. PMID 20502985.
  8. ↑ Pfeffer G, Majamaa K, Turnbull DM, Thorburn D, Chinnery PF (2012). "Treatment for mitochondrial disorders". Cochrane Database Syst Rev (4): CD004426. doi:10.1002/14651858.CD004426.pub3. PMC 7201312 Check |pmc= value (help). PMID 22513923.

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