Leigh's disease

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.

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 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	-	-	+	+	Progressive psychomotor regression Seizures External ophthalmoplegia Lactic acidosis Vomiting	Increased lactate levels in blood and CSF Genetic testing	MRI: abnormal white matter signal in the putamen, basal ganglia, and brainstem on T2 images
Niemann-Pick disease type C	-	-	+	+	Progressive neurodegeneration Hepatosplenomegaly Systemic involvement of liver, spleen, or lung preceedes neurologic symptoms	Abnormal liver function tests Fibroblast cell culture with filipin staining	MRI: Cerebral and cerebellar atrophy Thinning of the corpus callosum
Infantile Refsum disease	-	+	+	-	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	Elevated plasma VLCFA levels	--
Adrenoleukodystrophy	+	-	-	-	Cognitive and behavioral abnormalities Adrenal insufficiency Hyperpigmented skin Gonadal dysfunction Neurologic deterioration progresses at a variable rate	Elevated plasma VLCFA levels Molecular genetic testing for mutations in the ABCD1 gene	--
Zellweger syndrome	-	+	-	-	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	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	--
Pyruvate dehydrogenase deficiency	+	+	+	-	Lactic acidosis Seizures Intellectual disability	Elevated lactate and pyruvate levels in blood and CSF Abnormal PDH enzymatic activity in cultured fibroblasts	--
Arginase deficiency	+	-	-	-	Hyperammonemia Encephalopathy Respiratory alkalosis	Elevated ammonia level Elevated arginine level	--
Holocarboxylase synthetase deficiency	-	+	-	-	Ketoacidosis Dermatitis Alopecia Seizures Developmental delay	Elevated levels of: Beta-hydroxyisovalerate Beta-methylcrotonylglycine Beta-hydroxypropionate Methylcitrate Tiglylglycine	--
Glutaric aciduria type 1	-	-	-	+	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	Elevated levels of: glutaric acid 3-hydroxyglutaric acid	MRI: Frontal and temporal atrophy
Ataxia telangiectasia	-	-	+	-	Progressive cerebellar ataxia Abnormal eye movements Oculocutaneous telangiectasias Immune deficiency Increased risk of malignancy	Elevated serum alpha-fetoprotein level Low IgA and IgG levels Lymphopenia Genetic testing for mutation in the ATM gene	--
Pontocerebellar hypoplasias	-	+	-	-	Progressive muscle atrophy Microcephaly Developmental delay	Genetic testing for PCH gene mutations	MRI : Small cerebellum and brainstem including the pons
Metachromatic leukodystrophy	-	+	+	-	Regression of motor skills Seizures Optic atrophy Reduced or absent deep tendon reflexes Intellectual disability	Deficient arylsulfatase A enzyme activity in leukocytes or cultured skin fibroblasts	--
Pelizaeus-Merzbacher	+	-	+	-	Nystagmus Cognitive impairment Onset in infancy Slowly progressive Language development may be normal	Genetic testing for mutations in PLP1 gene	MRI: White matter abnormalities
Angelman syndrome	-	-	+	-	Profound intellectual disability Postnatal microcephaly Typical abnormal behaviors (paroxysmal laughter, easily excitable)	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	+	-	-	+	Self-mutilating behavior Urinary stones due to hyperuricemia	Elevated uric acid level Abnormal enzymatic activity of HPRT in cultured fibroblasts Genetic testing for HPRT gene mutations	--
Miller-Dieker lissencephaly	+	+	-	-	Lissencephaly Microcephaly Dysmorphic features Seizures Failure to thrive	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.

References

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