Leber Hereditary Optical Neuropathy (LHON) and Mitochondrial Encephalomyopathies (MELAS, MERRF and NARP)

BACKGROUND:

These diseases are all caused by mitochondrial DNA mutations, so a maternal family history of neurological disease is an important clue to diagnosis. Leber Hereditary Optic Neuropathy (LHON) results in optic nerve degeneration with painless progressive loss of central vision in early adulthood (median age of onset is 28 years). MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis and Strokelike episodes), MERRF (Myoclonic Epilepsy and Ragged Red Fibers) and NARP (Neuropathy, Ataxia and Retinitis Pigmenosum) exhibit some overlapping disease symptoms including exercise intolerance, weakness, sensorineural hearing loss, seizures, ataxia and short stature. Some combinations of findings are specific for each disorder:

MELAS: stroke like episodes, vomiting, seizures, headache, elevated lactic acid, ragged red fibers seen in muscle biopsy.

MERRF: myoclonic epilepsy, elevated lactic acid, ragged red fibers

NARP: sensory neuropathy, developmental delay, pigmentary retinopathy

Clincial features associated with these syndromes are summarized below:

INDICATIONS FOR TESTING:

• Painless bilateral visual loss is an indication of LHON. The differential diagnosis includes atypical optic neuritis, ischemic optic-neuropathy and amblyopia.

• Any combination of the cardinal symptoms of MELAS, MERRF or NARP.

SAMPLE REQUIREMENTS:

Blood: two 5 ml purple top (EDTA) vacutainers of whole blood inverted several times to mix. Forward within 48 hours at room temperature.

INTERPRETATION:

PCR based assays are used to detect common point mutations in mitochondrial DNA which are diagnostic of each particular syndrome:

LHON11,778, LHON3,460, LHON14,484, LHON15,257 detect 90% of LHON cases
MELAS3,243, MELAS3,271 detect 80%-90% of MELAS cases
MERRF8,344, MERRF8,356 detect 80%-90% of MERRF cases
NARP8,993 detects 90% of NARP cases

COUNSELING ISSUES:

1. All children of a mother with a mitochondrial DNA mutation will inherit the mutation. However, clinical manifestations in the offspring depend on the degree of heteroplasmy (percentage of mutant vs normal mitochondria) present in critical tissues. LHON mutations are homoplasmic whereas MELAS, MERRF and NARP mutations are invariably heteroplasmic.

2. Testing of maternal relatives can confirm the presence of mutations but will not provide specific information regarding a prognosis. Clinical presentation can vary from normal to severe multisystem involvement due to the effects of heteroplasmy, mitotic segregation (random distribution of normal and mutant mitochondria into daughter cells during cell division) and threshold effects (percentage of mutant vs normal mitochondrial DNA necessary to cause disease manifestations).

3. The absence of a discernable mitochondrial DNA mutation does not rule out a disease diagnosis since 10%-20% of mutations are not detectible with current technology.

4. Counseling in LHON is further complicated by a higher frequency of affected males over females (approximately 4:1) suggesting the possibility of an X-linked susceptibility gene in addition to the mitochondrial mutation.

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