UMDF Letteratura - Leigh Syndrome: Clinical Features and Biochemical and DNA Abnormalities (article review)

Review of S. Rahman, et. al.; Leigh Syndrome: Clinical Features and Biochemical and DNA Abnormalities; Ann Neurol 1996; 39:343-351:

Dr. Rahman and her colleagues studied 67 Australian cases of confirmed or suspected Leigh?s Syndrome (LS) and report some interesting results.

Symptoms: The symptoms found in the confirmed LS patients which were part of this study (with the percentage of patients with the symptom):

Developmental Delay, 100%

Lactate raised, 91%

Hypotonia, 86%

CT/MRI typical (for Leigh?s), 83%

Respiratory disturbance, 71%

Reflexes increased, 66%

Weakness, 57%

Spasticity, 54%

Bulbar problems, 49%

Failure to thrive, 49%

Nystagmus, 46%

Poor feeding, 46%

Seizures, 40%

Ataxia, 37%

Ophthalmoplegia/squint, 34%

Optic atrophy, 34%

Unexplained vomiting, 34%

Involuntary movements, 29%

Dystonia, 20%

Reflexes decreased, 17%

Ptosis, 17%

CT/MRI normal, 12%

Cranial nerve palsies, 9%

Peripheral neuropathy, 6%

Cardiac problems, 6%

Lactate normal, 3%

Causes: LS was confirmed in 35 patients and specific biochemical or DNA defects were identified in 80% of these patients. LS was suspected in the remaining 32 patients and specific biochemical or DNA defects were identified in 41% of them.

Specific point mutations in the mitochondrial DNA were found in 11 of the cases at positions 8993 (T to G [NARP] and T to C) and 8344 (A to G). One case had a large mitochondrial DNA deletion (4-kb). Enzyme defects were found in 29 of the patients: 13 in complex I of the respiratory chain; 9 in complex IV (COX) of the respiratory chain; and 7 in the pyruvate dehydrogenase complex.

Inheritance: Less than half of the patients were thought to have an autosomal type of inheritance. Mitochondrial DNA point mutations (11 cases) and deletions (1 case) are maternally inherited or occur randomly. X-linked inheritance was found in 6 of the cases (PDHC E1alpha). The enzyme defects were thought to be divided among maternal and autosomal recessive.

Gender specificity: They found male patients outnumbered females, three to two. (This has also been observed in other studies.) They attribute part of this difference to the X-linked nature of some cases, but note that this is also true for non-X-linked cases.

Prognosis: The article includes a chart with survival plotted against age (through 21 years). For Leigh?s patients, it shows a 50% survival rate to 3 years of age, decreasing to less than 20% by mid-teens. The survival rate for Leigh?s-like patients never falls below 60%.

Other Observations: The researchers were surprised at the high numbers of complex I related cases (more than one third of those with enzyme defects). They attribute this to improved techniques used to analyze this complex. They recommend testing for complex defects I and mitochondrial DNA mutations in cases older than 3 years.

They found that the intensity of symptoms appears more dependent upon the area of brain involvement than a specific genetic mutation.

In comparing their patients? defects and symptoms with other published studies they found some differences, but they didn?t feel their study included enough cases to warrant any conclusions based on this.

Reviewer: Mark Fleming 12/5/96