Cephalalgia, myopathy and familial dementia with CADASIL-like MRI and multiple mtDNA deletions

To describe a patient with cephalalgia, fatiguability,CADASIL-like brain MRI, family history for dementia and no Notch3 mutations, whose muscle biopsy shows signs of mitochondrial dysfunction. Methods: A 67 years old man came to our observation with a several year history of episodic olocranic cephalagia with nausea and vomiting associated, in the last seven years, with easy fatiguability,myalgias and slight hyperckemia (450–500 U/l). EMG was myopathic. A brain MRI showed multiple confluent hyperintense lesions in the subcortical and deep white matter. Neuropsychological examination was normal. EKG showed anterior left hemiblock with mild heart dilatation and 40 % EF at echocardiography. Familiar history was positive for dementia (mother and the 2 maternal aunts). The grand-daughter of one of the two aunts (daughter of a daughter) is affected with schizophrenia. No cognitive problems are reported in the three maternal uncles. The patient underwent skeletal muscle biopsy of left biceps muscle which we studied by histological, histochemical and immunohistochemical (dystrophin, sarcoglycans, caveolin,merosin) methods.Southern blot analysis of the mitochondrial DNA (mtDNA), search for MELAS and MERRF mtDNA point mutations and a genetic test for Notch3 gene (CADASIL) were also performed. Results:Muscle biopsy only showed some fiber size variability and a few COX-negative fibers, half of which ragged red. Southern blot analysis of mtDNA was positive for multiple deletions, which were confirmed by PCR. A3243G, A8344G and A8356G mtDNA point mutations were absent. No Notch3 mutations were found. Conclusions: recent studies have demonstrated that Notch3 gene mutations may also manifest as neuropathy and myopathy and, particularly, cooccur with, and,possibly,predispose to,mtDNA mutations (Finsterer, 2007). A mitochondrial encephalopathy with CADASIL-like MRI, no Notch3 mutations and an 8.3 Kb mtDNA macrodeletion has been described in a patient with typical clinical features of mitochondrial disorder and negative family history (Akhvledani et al, 2007). In our case, we found mtDNA multiple deletions, but no Notch3 mutations in a patient with morphological evidence of mitochondrial dysfunction, but clinical features and family history suggestive of CADASIL. Search for nuclear DNA mutations in genes responsible for mtDNA multiple deletions is underway.