PHENOTYPIC VARIABILITY IN NARP (NEUROGENIC MUSCLE WEAKNESS ATAXIA RETINITIS PIGMENTOSA): CORRELATION WITH LEVELS OF MUTANT MITOCHONDRIAL DNA IN BLOOD

Objectives: To describe the clinical presentations of five patients with the NARP 8993 mutation and to assess correlation between levels of mutant mitochondrial DNA in lymphocytes and severity of disease.

Methods: Patients were assessed neurologically and mitochondrial point mutation testing done via standard PCR methods. Gel densitometry was used to determine percentage mutation in lymphocyte mitochondrial DNA.

Results: The proband presented at 11 months with hypotonia. By 6 years she had developed marked cerebellar signs. Her sister presented at 17 years with a distal axonal neuropathy. A younger sister had severe hypoxic encephalopathy but could walk and talk by 2 years. The girls were of different paternity. Their mother, at 39 years, developed intermittent ataxia. An unrelated male patient presented at 16 months with ataxia, dystonia and global delay. Serum and CSF lactate were elevated in the proband at 4.9 and 3.7 mmol/l (0.7–1.8) respectively. Muscle biopsy showed no specific features. Magnetic Resonance Imaging showed prominence of the cerebellar folia. Motor nerve conduction studies were suggestive of axonal neuropathy. The proband was positive for the T8993G NARP mutation with 92% heteroplasmy. Her older sister had 84%, mother, 59% and the youngest sibling, 1% mutation in blood. The unrelated male had a T8993C mutation with 94% heteroplasmy.

Conclusion: Early presentation with heteroplasmy over 90% of the NARP T8993G and T8993C mutations in blood was not associated with early onset Leigh Syndrome. Dystonia, cerebellar signs and global delay were prominent. Levels of heteroplasmy correlated with age of onset and disease severity.