Neurofibromatosis type 1 (NF1) is the most frequent neurocutaneous disorder with 
autosomal dominant inheritance. Phenotype variability is high ranging from 
merely several café-au-lait spots to malignant peripheral nerve sheath tumors or 
severe disfigurement through plexiform neurofibromas. Identification of genetic 
factors that modify the NF1 phenotype would contribute to the understanding of 
NF1 pathophysiology and improve patient counselling. As even monozygotic (MZ) 
twins with NF1 may differ phenotypically, we wondered whether these variations 
might be inherited in a non-Mendelian fashion. Mitochondrial DNA (mtDNA) is 
inherited extrachromosomally through the cytoplasm of the oocyte and often 
harbours heteroplasmic sequence variations. At the time of blastomere 
separation, these variants may be skewedly distributed and effect phenotypic 
differences. Because of their co-localization with the tumor suppressor protein 
neurofibromin, which is mutated in NF1, mitochondria were particular attractive 
candidates for investigation. MtDNA was extracted from nucleated blood cells of 
four pairs of discordant MZ twins with NF1 and from cutaneous neurofibromas of 
one twin pair. We sequenced the entire mitochondrial genome and determined the 
state of heteroplasmy by investigating a microsatellite region of the 
mitochondrial D-loop (D310-tract). The clinical diagnosis was confirmed in all 
patients by detection of pathogenic mutations in the NF1 gene. Monozygosity was 
verified by genotyping. However, we did not detect evidence for mtDNA sequence 
differences or for different degrees of heteroplasmy between individuals of the 
same twin pair. The phenotypic discordance of MZ twins with NF1 cannot be 
explained by skewed distribution of mtDNA mutations or polymorphisms.