Leigh's disease

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Leigh's disease
ICD-10 G31.8
ICD-9 330.8
OMIM 256000
DiseasesDB 30792
MeSH D007888

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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 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. [1]

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[2] and some COX assembly factors) cause degradation of motor skills and eventually death.

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.

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.

Presentation

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.

Differential diagnosis

Leigh's disease must be differentiated from other diseases that cause neurological manifestations in infants.

Diseases Type of motor abnormality Clinical findings Laboratory findings and diagnostic tests Radiographic findings
Spasticity Hypotonia Ataxia Dystonia
Leigh syndrome - - + +
Niemann-Pick disease type C - - + +
  • Abnormal liver function tests
  • Fibroblast cell culture with filipin staining
Infantile Refsum disease - + + - Elevated plasma VLCFA levels --
Adrenoleukodystrophy + - - -
  • Elevated plasma VLCFA levels
  • Molecular genetic testing for mutations in the ABCD1 gene
--
Zellweger syndrome - + - - --
Pyruvate dehydrogenase deficiency + + + -
  • Elevated lactate and pyruvate levels in blood and CSF
  • Abnormal PDH enzymatic activity in cultured fibroblasts
--
Arginase deficiency + - - - --
Holocarboxylase synthetase deficiency - + - - Elevated levels of:
  • Beta-hydroxyisovalerate
  • Beta-methylcrotonylglycine
  • Beta-hydroxypropionate
  • Methylcitrate
  • Tiglylglycine
--
Glutaric aciduria type 1 - - - + Elevated levels of:
Ataxia telangiectasia - - + - --
Pontocerebellar hypoplasias - + - - Genetic testing for PCH gene mutations
Metachromatic leukodystrophy - + + -
  • Deficient arylsulfatase A enzyme activity in leukocytes or cultured skin fibroblasts
--
Pelizaeus-Merzbacher + - + -
Angelman syndrome - - + -
  • Methylation studies and chromosome microarray to detect chromosome 15 anomalies and UBE3A mutations
--
Rett syndrome + - - +
  • 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
  • Clinical diagnosis
  • Genetic testing for MECP2 mutations
--
Lesch-Nyhan syndrome + - - + --
Miller-Dieker lissencephaly + + - -
  • Cytogenetic testing for 17p13.3 microdeletion
--
Dopa-responsive dystonia + - - +
  • Onset in early childhood
  • Symptoms worsen with fatigue and exercise
  • Positive response to a trial of levodopa
--


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.

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 PDHA1, part of the pyruvate dehydrogenase complex, located on the X chromosome.[3]

References

  1. "Obituaries" (PDF). Psychiatric Bulletin (1998). Retrieved 1 Aug 2020. Check date values in: |accessdate= (help)
  2. Pronicki M, Matyja E, Piekutowska-Abramczuk D; et al. (2008). "Light and electron microscopy characteristics of the muscle of patients with SURF1 gene mutations associated with Leigh disease". J. Clin. Pathol. 61 (4): 460–6. doi:10.1136/jcp.2007.051060. PMC 2571978. PMID 17908801. Unknown parameter |month= ignored (help)
  3. Online Mendelian Inheritance in Man (OMIM) LEIGH SYNDROME, X-LINKED -308930


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