25 March 2011
CHARCOT-MARIE-TOOTH TYPE 1A: natural course, pathophysiology and treatment
Camiel Verhamme, 3 december 2010
Charcot-Marie-Tooth type 1A (CMT1A), also known as the Hereditary Motor and Sensory Neuropathy type Ia (HMSN Ia), is the most prevalent hereditary demyelinating neuropathy (1:5000 people). This autosomal dominantly inherited disease is most often caused by duplication in chromosome 17, which includes the
peripheral myelin protein 22 (PMP22)
gene. CMT1A is characterized clinically by distal muscle weakness and wasting, legs more than arms, impaired distal sensation, and reduced to absent reflexes. Foot deformities (pes cavus) and hand deformities (claw hands) are often encountered.
In a large group of CMT1A patients we found that clinical disease severity at the impairment and at the disability level was related to the severity of axonal dysfunction. In a 5-year follow-up study, including patients and controls, it turned out that the slow decline in axonal function and in muscle strength in patients may reflect to a considerable extent a process of normal ageing. We also found a slow increase in physical disability in adult patients, which may well be explained by decreased reserves and compensatory mechanisms together with progression of skeletal deformations due to chronic muscle weakness. We determined the course of the disease in two PMP22-
overexpressing mouse models: an already known severe model (C22) and mild mouse model which we found (C3-PMP); we concluded that these new C3-PMP mice may be more an appropriate model for CMT1A than C22 mice. In this model myelin formation is delayed and normal myelination is never reached during nerve maturation. This dysmyelination may be of major importance in CMT1A and supports that de- and remyelination may not explain all myelin pathology in CMT1A. Another important finding was that also the axons showed impaired maturation. The last study in this thesis was based on the finding that ascorbic acid led to a substantial improvement of myelination in a CMT1A mouse model. In a proof-of-principle study we showed that this was not the case for relatively young CMT1A patients.