Mitochondrial DNA-associated Leigh syndrome

Alternate names

MILS; Leigh disease, maternally inherited; Subacute necrotizing encephalomyelopathy maternally inherited; Maternally inherited Leigh syndrome

Definition

Mitochondrial DNA-associated Leigh syndrome is a progressive brain disorder that usually appears in infancy or early childhood.

Epidemiology

Leigh syndrome in general is rare and is estimated to affect about 1 in 30,000 to 1 in 40,000 people at birth. Mitochondrial DNA-associated Leigh syndrome, which is more rare than nuclear gene-encoded Leigh syndrome, is likely to occur in about 1 in 100,000 to 1 in 140,000 births. Leigh syndrome is much more common in certain populations. For example, it occurs in approximately 1 in 2,000 newborns in the Saguenay Lac-Saint-Jean region of Quebec, Canada and in approximately 1 in 1,700 on the Faroe Islands (between Norway and Iceland).

Cause

• Mitochondrial DNA-associated Leigh syndrome is a subtype of Leigh syndrome and is caused by changes in mitochondrial DNA.
• Mutations in at least 11 mitochondrial genes have been found to cause mtDNA-associated Leigh syndrome.

Inheritance

Unaffected mother and affected father leads to all unaffected children, affected mother and unaffected father leads to all affected children

Mitochondrial inheritance patterns

This condition has an inheritance pattern known as maternal or mitochondrial inheritance. Because mitochondria can be passed from one generation to the next only through egg cells (not through sperm cells), only females pass mitochondrial DNA-associated Leigh syndrome to their children.

Signs and symptoms

• Affected children may experience vomiting, seizures, delayed development, muscle weakness, and problems with movement.
• Heart disease, kidney problems, and difficulty breathing can also occur in people with this disorder.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Abnormality of Krebs cycle metabolism
• Increased CSF lactate

30%-79% of people have these symptoms

• Bilateral tonic-clonic seizure(Grand mal seizures)
• Chorea
• Dyskinesia(Disorder of involuntary muscle movements)
• Dystonia
• Episodic vomiting
• Failure to thrive(Faltering weight)
• Focal T2 hyperintense basal ganglia lesion
• Gait ataxia(Inability to coordinate movements when walking)
• Generalized myoclonic seizure
• Increased serum lactate
• Infantile muscular hypotonia(Decreased muscle tone in infant)
• Lacticaciduria(High urine lactic acid levels)
• Muscle weakness(Muscular weakness)
• Ophthalmoparesis(Weakness of muscles controlling eye movement)
• Pigmentary retinopathy
• Sensorimotor neuropathy(Nerve damage causing decreased feeling and movement)
• Severe global developmental delay
• Spasticity(Involuntary muscle stiffness, contraction, or spasm)

5%-29% of people have these symptoms

• Abnormal renal tubule morphology
• Abnormal speech prosody
• Apnea
• Bulbar signs
• Cardiac conduction abnormality
• Demyelinating peripheral neuropathy
• Developmental regression(Loss of developmental milestones)
• Dilated cardiomyopathy(Stretched and thinned heart muscle)
• Dysphagia(Poor swallowing)
• Episodic respiratory distress(Episodic difficulty breathing)
• Fever
• Hepatic failure(Liver failure)
• Hepatomegaly(Enlarged liver)
• Hyperalaninemia(Increased blood alanine)
• Hyperreflexia(Increased reflexes)
• Hypertrophic cardiomyopathy(Enlarged and thickened heart muscle)
• Hyperventilation(Rapid breathing)
• Hyporeflexia(Decreased reflex response)
• Hypothermia(Abnormally low body temperature)
• Infantile spasms
• Mitochondrial myopathy
• Multiple glomerular cysts
• Nystagmus(Involuntary, rapid, rhythmic eye movements)
• Optic atrophy
• Rod-cone dystrophy
• Segmental peripheral demyelination/remyelination
• Sensorineural hearing impairment

1%-4% of people have these symptoms

• Low plasma citrulline
• Ragged-red muscle fibers

Diagnosis

The diagnosis of mtDNA-associated Leigh syndrome is established clinically in a proband with progressive neurologic disease with motor and intellectual developmental delay, signs and symptoms of brain stem and/or basal ganglia disease, raised lactate concentration in blood and/or cerebrospinal fluid, and any one of the following:

• Characteristic features on brain imaging
• Typical neuropathologic changes
• Typical neuropathology in a similarly affected sib
• Identification of a pathogenic variant in one of the 14 mitochondrial genes known to be involved in mtDNA-associated Leigh syndrome confirms the diagnosis.

Treatment

• Supportive treatment includes use of sodium bicarbonate or sodium citrate for acute exacerbations of acidosis and antiepileptic drugs for seizures.
• Dystonia is treated with benzhexol, baclofen, tetrabenazine, and gabapentin alone or in combination, or by injections of botulinum toxin.
• Anticongestive therapy may be required for cardiomyopathy.
• Regular nutritional assessment of daily caloric intake and adequacy of diet and psychological support for the affected individual and family are essential.

NIH genetic and rare disease info

• NIH info on Mitochondrial DNA-associated Leigh syndrome

Mitochondrial DNA-associated Leigh syndrome is a rare disease.