Genetic Mutation May Cause Peripheral Neuropathy

Chicago, December 28, 2007: In a report submitted to the Journal of Neuroscience this week, researchers at the University of Chicago have identified an inherited genetic mutation that may cause a human nerve disorder called peripheral neuropathy (PN). PN affects about 3% of individuals over the age of 60, and includes symptoms such as pain in the limbs, hands, and feet, as well as increasing weakness and numbness in the extremities. Symptoms become progressively worse over time, due to increased damage to nerves located outside the central nervous system (brain and spinal cord). Currently, there is no known treatment.

Brian Popko and his colleagues recently discovered that mice carrying mutations in only one copy of a gene coding for part of the dynein protein ended up having severe problems with proprioception, which is the ability to perceive the spatial orientation of body parts. Dynein is essential for the proper function of sensory nerve cells. Found throughout the body, the protein plays an important role in axon to cell body signaling. Axons are the elongated tendrils of nerve cells that relay chemical messages, and which are the main means of nervous communication.

Mice with the dynein protein mutation also had hind leg movement problems, something that is commonly evidenced in many human neuropathies as well, especially Charcot-Marie-Tooth (CMT) Disease and hereditary sensory neuropathy. CMT Disease affects about 1 in 2,500 individuals and results in progressive loss of muscle tissue as well as loss of sensation in limbs. Damage to both sensory and motor nerves is highly characteristic of this disease. Hereditary sensory neuropathy results in damage to the sensory nerves only, resulting in loss of limb sensation and reflex.

The importance of dynein cannot be understated: mice containing mutations in both copies of the dynein gene die before birth. Furthermore, mutations in different parts of the dynein gene produced different variations of neuropathy.

The Chicago researchers now plan to look for human patients that have similar dynein mutations, in order to assess how different genetic mutations affect the human form of PN.

One potential clue as to why and how the dynein protein is involved in PN may come from earlier studies on the effect of statin drugs on the disease. Various researchers reported that individuals taking statin drugs were 14 times more likely to develop PN than individuals not taking the drugs. Statins are widely prescribed for treatment of high cholesterol because they lower the levels of low-density lipoprotein (LDL) cholesterol. This is accomplished when the drug blocks production of a liver enzyme (called HMG-CoA reductase) used to manufacture cholesterol.

References:Mutation May Cause Inherited Neuropathy ScienceDaily. Retrieved December 28, 2007, from http://www.sciencedaily.com­ /releases/2007/12/071226003821.htm

Statin Drugs May Increase Risk Of Peripheral Neuropathy. ScienceDaily. Retrieved December 28, 2007, from http://www.sciencedaily.com­ /releases/2002/05/020514075710.htm

Proprioceptive Sensory Neuropathy in Mice with a Mutation in the Cytoplasmic Dynein Heavy Chain 1 Gene. Xiang-Jun Chen, Eleni N. Levedakou, Kathleen J. Millen, Robert L. Wollmann, Betty Soliven, and Brian Popko. The Journal of Neuroscience, December 26, 2007, 27(52):14515-14524.

Statin therapy and small fibre neuropathy: a serial electrophysiological study. Lo YL, Leoh TH, Loh LM, Tan CE. J. Neurol. Sci. 2003 Apr 15;208(1-2):105-8.

Peripheral neuropathy and lipid-lowering therapy. Ziajka PE, Wehmeier T. South Med J. 1998 Jul;91(7):667-8.