Leigh syndrome
Leigh syndrome | |
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Other names | Juvenile subacute necrotizing encephalomyelopathy, Leigh disease, infantile subacute necrotizing encephalomyelopathy, subacute necrotizing encephalomyelopathy (SNEM)[1] |
Detection of numerous ragged red fibers in a muscle biopsy | |
Specialty | Neurology |
Leigh syndrome (also called Leigh disease and subacute necrotizing encephalomyelopathy) is an inherited neurometabolic disorder that affects the
Signs and symptoms
The symptoms of Leigh syndrome were classically described as beginning in infancy and leading to death within a span of several years;[1] however, as more cases are recognized, it is apparent that symptoms can emerge at any age—including adolescence or adulthood—and patients can survive for many years following diagnosis.[6] Symptoms are often first seen after a triggering event that taxes the body's energy production, such as an infection or surgery. The general course of Leigh syndrome is one of episodic developmental regression during times of metabolic stress. Some patients have long periods without disease progression while others develop progressive decline.[7]
Infants with the syndrome have symptoms that include diarrhea, vomiting, and dysphagia (trouble swallowing or sucking), leading to a failure to thrive.[1] Children with early Leigh disease also may appear irritable and cry much more than healthy babies. Seizures are often seen, with reported prevalence of seizures in Leigh syndrome that ranges from 40% to 79%.[8] Excess lactate may be seen in the urine, cerebrospinal fluid, and blood of a person with Leigh syndrome.[6]
As the disease progresses, the
However, respiratory failure is the most common cause of death in people with Leigh syndrome. Other neurological symptoms include peripheral neuropathy, loss of sensation in extremities caused by damage to the peripheral nervous system.[1]
Hypertrichosis is seen in Leigh syndrome caused by mutations in the nuclear gene SURF1.[7]
Genomics
Mutations in mitochondrial DNA (mtDNA) and over 30 genes in nuclear DNA (gene SURF1[10] and some COX assembly factors) have been implicated in Leigh disease.[1]
Disorders of
Mitochondrial DNA mutations
Between 20 and 25 percent of Leigh syndrome cases are caused by mutations in mitochondrial DNA. The most common of these mutations is found in 10 to 20 percent of Leigh syndrome and occurs in
Mitochondrial DNA is passed down matrilineally in a pattern called
Nuclear DNA mutations
75 to 80 percent of Leigh syndrome is caused by mutations in nuclear DNA; mutations affecting the function or assembly of the fourth complex involved in oxidative phosphorylation, cytochrome c oxidase (COX), cause most cases of Leigh disease. Mutations in a gene called SURF1 (surfeit1) are the most common cause of this subtype of Leigh syndrome. The protein that SURF1 codes for is terminated early and therefore cannot perform its function, shepherding the subunits of COX together into a functional protein complex. This results in a deficit of COX protein, reducing the amount of energy produced by mitochondria.[1] SURF1 is located on the long arm of chromosome 9.[13] Some types of SURF1 mutations cause a subtype of Leigh syndrome that has a particularly late onset but similarly variable clinical course.[7] Another nuclear DNA mutation that causes Leigh syndrome, gene DLD, affects another protein complex in the mitochondria, the pyruvate dehydrogenase complex.[1][9]
Other nuclear genes associated with Leigh syndrome are located on chromosome 2 (BCS1L and NDUFA10); chromosome 5 (SDHA, NDUFS4, NDUFAF2, and NDUFA2); chromosome 8 (NDUFAF6), chromosome 10 (COX15); chromosome 11 (NDUFS3, NDUFS8, and FOXRED1); chromosome 12 (NDUFA9 and NDUFA12); and chromosome 19 (NDUFS7). Many of these genes affect the first oxidative phosphorylation complex.[9]
X-linked Leigh syndrome
Leigh syndrome can also be caused by deficiency of the pyruvate dehydrogenase complex (PDHC), the x-linked gene being PDHA1.[9] In general, there are two major presentations of PDH deficiency, metabolic and neurologic, which occur at equal frequency.[14] The metabolic form presents as severe lactic acidosis in the newborn period, and many die as newborns.[14] Patients with the neurologic presentation are hypotonic (low muscle tone), feed poorly, lethargic, and develop seizures, mental retardation, microcephaly, blindness and spasticity secondary to contractures.[14] "Between these two extremes, there is a continuous spectrum of intermediate forms...A number of patients with primarily neurological symptoms fit into the category of Leigh's syndrome."[14]
French Canadian Leigh syndrome
The type of Leigh syndrome found at a much higher rate in the
French Canadian Leigh syndrome has similar symptoms to other types of Leigh syndrome. The age of onset is, on average, 5 months and the median age of death is 1 year and 7 months. Children with the disease are
Estimates of the rate of
Pathophysiology
The characteristic symptoms of Leigh syndrome are at least partially caused by bilateral, focal
The lactic acidosis sometimes associated with Leigh syndrome is caused by the buildup of
Diagnosis
Leigh syndrome is suggested by clinical findings and confirmed with laboratory and genetic testing.[7]
Clinical findings
Dystonia,
Differential diagnosis
Other diseases can have a similar clinical presentation to Leigh syndrome; excluding other causes of similar clinical symptoms is often a first step to diagnosing Leigh syndrome. Conditions that can appear similar to Leigh disease include
Treatment
Clinical trials of the drug EPI-743 for Leigh syndrome are ongoing.[18]
In 2016,
Prognosis
Different genetic causes and types of Leigh syndrome have different prognoses, though all are poor. The most severe forms of the disease, caused by a full deficiency in one of the affected proteins, cause death at a few years of age. If the deficiency is not complete, the prognosis is somewhat better and an affected child is expected to survive 6–7 years, and in rare cases, to their teenage years.[6]
Epidemiology
Leigh syndrome occurs in at least 1 of 40,000 live births, though certain populations have much higher rates. In the Saguenay–Lac-Saint-Jean region of central Quebec, Leigh syndrome occurs at a rate of 1 in 2000 newborns.[1]
History
Leigh syndrome was first described by
See also
References
- ^ a b c d e f g h i j k l m n o p q "Leigh syndrome". Genetics Home Reference. National Institute of Health. 23 September 2013. Retrieved 16 October 2013.
- .
- .
- PMID 1206418.
- PMID 26725255.
- ^ a b c d "NINDS Leigh's Disease Information Page". National Institute of Neurological Diseases and Stroke. NIH. 16 December 2011. Archived from the original on 3 December 2013. Retrieved 25 November 2013.
- ^ S2CID 45323262.
- PMID 24731534.
- ^ a b c d e f g h i "Leigh Syndrome". Online Mendelian Inheritance in Man. McKusick–Nathans Institute of Genetic Medicine. 13 March 2013. Retrieved 25 November 2013.
- PMID 17908801.
- ^ "MT-ATP6". Genetics Home Reference. NIH. 19 November 2013. Retrieved 25 November 2013.
- S2CID 73445211.
- ^ "SURF1". Genetics Home Reference. NIH. 19 November 2013. Retrieved 25 November 2013.
- ^ PMID 7853374.
- ^ a b c d "Leigh Syndrome, French Canadian type". Online Mendelian Inheritance in Man. Johns Hopkins University. 1 December 2011. Retrieved 25 December 2013.
- PMID 27502960.
- PMID 15206559.
- ^ "EPI743 | Mitochondrial Disease Action Committee - MitoAction". Archived from the original on 2013-08-19. Retrieved 2013-07-24.
- ^ Roberts, Michelle (2016-09-27). "First 'three person baby' born using new method". BBC News. Retrieved 2016-09-28.
- PMID 14874135.
Further reading
- GeneReviews/NCBI/NIH/UW entry on Mitochondrial DNA-Associated Leigh Syndrome and NARP
- OMIM entries on Mitochondrial DNA-Associated Leigh Syndrome and NARP
- Leigh syndrome at NIH's Office of Rare Diseases