| dc.description.abstracteng | Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant demyelinating disorder characterized by episodic, recurrent peripheral sensory and motor neuropathies, triggered by minor traumas or compression in various locations. A typical clinical manifestation of HNPP is acute, painless, recurrent peripheral nerve palsies. The symptoms are brief and improve generally within days, weeks or months, with full recovery occurring in 50 % of episodes. The affected limbs usually show significant slowing and conduction blocks (CB) in nerve conduction velocity (NCV) studies, distal motor latencies (DML) are increased and sensory nerve conduction velocities are often decreased. In addition, sensory nerve action potential amplitudes are reduced. Only symptomatic treatment is currently available.
The majority of cases of HNPP can be attributed to a heterozygous 1.5 Mb deletion on chromosome 17p11.2 that includes the peripheral myelin protein 22 (PMP22) gene. PMP22 is an intrinsic membrane protein, primarily expressed in myelinating Schwann cells. PMP22 comprises approximately 2-5 % of total myelin protein and is largely confined to compact myelin. Its precise biological functions are still unknown but it has been proposed to serve as a structural component of myelin, required for the flawless development of peripheral nerves, axon maintenance, myelin formation and the determination of myelin thickness and stability.
The histological characteristics of HNPP nerves consist of focal excessive myelin folds (tomacula), characterized by an extremely thickened myelin sheath wrapping around an axon of reduced diameter, and onion bulbs. Tomacula may initially arise from myelin invaginations.
The signaling pathway of progesterone is known to regulate the mRNA expression of myelin genes in the peripheral nervous system. In the present study subcutaneous application of progesterone for a period of two months increased the Pmp22 expression in the HNPP mice (Pmp22+/-) to wild type levels. The expression of Krox-20 and Pmp22 correlated to one another, providing evidence for the role of KROX-20 as an inductor of Pmp22 expression. Surprisingly, the effects of progesterone were not reflected on pathological myelin characteristics, which remained unchanged. This could be due to a possible threshold level that has to be reached for therapeutic effectiveness to occur. Tomacula and myelin invaginations were shown to increase in number as the animals grew older. Decreased NCVs and CMAPs, as well as increased DMLs were detected in electrophysiological studies performed on the HNPP mice. Even CBs were observed in a few mice. This mouse model was, albeit some limitations, shown to largely mimic the pathological features of human patients and can therefore be regarded as a valuable tool for future studies aiming to understand the disease mechanisms and could help lead to the development of new therapies. | de |