Abstracts from the Fourth International Symposium on Neuroacanthocytosis
July 1-2, 2008
London and Oxford
Chairs: Prof. Kailash Bhatia, MD, FRCP, Institute of Neurology, University College London; Prof. Anthony P. Monaco, MD, PhD, Wellcome Trust Centre for Human Genetics, University of Oxford
Organizers: Antonio Velayos-Baeza, PhD; Susanne Schneider, MD; Glenn Irvine
1-5 McLeod syndrome: brain and neuromuscular pathology
H. H. Jung
Dept. of Neurology, University Hospital Zurich, Zurich, Switzerland
The McLeod neuroacanthocytosis syndrome (MLS) is an X-linked multisystem disorder with haematological, neuromuscular, and central nervous system (CNS) involvement. MLS is caused by mutations in the XK gene that encodes the XK protein, a putative membrane transport protein which is covalently linked to the Kell glycoprotein. The function of the XK/Kell-complex is not yet clarified. The Kell protein is an endothelin-3 converting enzyme generating the bioactive endothelin-3. The XK protein shares important homologies with the ced-8 protein of the nematode C. elegans, in which it acts as a cell death effector downstream of the caspase ced-3.
CNS manifestations of the MLS comprise chorea, neuropsychiatric and cognitive abnormalities, and generalized seizures. Imaging studies in MLS patients revealed caudate nucleus and putamen atrophy as well as decreased glucose uptake in positron emission tomography studies without clear evidence for extrastriatal pathology. Neuropathological examination demonstrated unspecific neuronal loss and astrocytic gliosis in the caudate nucleus, putamen and, less pronounced, in the globus pallidum. Extended work-up did not demonstrate specific features of the pathological alterations. The severity of the striatal pathology varied considerably between the patients, also in those carrying an identical mutation. In contrast to choreoacanthocytosis (ChAc), there was no involvement of the substantia nigra and thalamus and only minor cortical gliosis was present in some patients.
Virtually all MLS patients had elevated serum creatine kinase levels, and about 50% develop weakness and muscular atrophy. In a series of 10 muscle biopsies of MLS patients, clear but unspecific myopathic changes were present only in four patients. All patients, however, had neurogenic changes of variable degree. Motor and sensory nerve examinations demonstrated axonal sensory-motor neuropathy. Cardiac manifestations of MLS developed in more than half of the patients and include congestive cardiomyopathy, dilated cardiomyopathy, atrial fibrillation and tachyarrhythmia. Cardiac histopathology is not specific and reveals focal myocyte hypertrophy, slight variation of myofiber size and interstitial fibrosis.