CMT 2C: Gene Links Rare CMT, SMA Forms

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Gene Links Rare CMT, SMA Forms

http://quest.mda.org/news/gene-links-rare-cmt-sma-forms

Three teams of researchers in the United States and Europe have identified

specific mutations in a chromosome-12 gene for the TRPV4 protein that tie

together the origins of type 2C Charcot-Marie-Tooth disease (CMT2C) and two rare

forms of spinal muscular atrophy (SMA).

The results are surprising, as SMA and CMT typically arise from very different

causes. SMA is considered a disease of the motor neurons in the spinal cord,

while CMT is a disease of the peripheral nerve fibers. SMA usually is caused by

mutations in the SMN gene on chromosome 5. CMT can be caused by mutations in any

of more than 20 different genes.

Increased understanding of additional mechanisms involved in CMT and SMA may

point the way toward new therapeutic targets and will almost certainly lead to

improvements in diagnosis.

About the new findings

The new findings, detailed in three papers published online Dec. 27, 2009, in

the journal Nature Genetics, identify two mutations in the TRPV4 protein that

can cause CMT2C, one that causes scapuloperoneal SMA, and one that causes

congenital distal SMA. (See below for more on these three diseases.)

The TRVP4 protein is a cellular channel (tunnel) present in a variety of

tissues, including nerve fibers, that opens and closes to allow calcium and

other positively charged particles to move into and out of cells.

The newly identified mutations result in malfunctions of TRPV4. These

malfunctions appear to cause abnormalities of calcium concentration (too high or

too low, depending on the mutation) in the nerve fibers.

The findings, which are somewhat unexpected, unify the underlying mechanisms of

CMT2C and both the targeted rare forms of SMA, showing that they all arise from

abnormalities in the nerve fibers. Traditionally, SMA has been thought of as

primarily resulting from problems in the cell bodies that reside in the spinal

cord, not the fibers (axons) in the periphery; while CMT, on the other hand, is

traditionally thought of as a peripheral nerve disease.

About CMT2C

CMT, also known as hereditary motor and sensory neuropathy (HMSN), is caused by

malfunctions of the peripheral nerves, bundles of nerve fibers (axons) that run

between the spinal cord and the periphery of the body, controlling movement and

sensation.

Most forms of CMT predominantly affect movement and sensation in the lower legs,

feet, forearms and hands.

CMT2C, by contrast, involves not only weakness of the hands and feet but

weakness of the respiratory muscles and larynx, causing shortness of breath and

hoarseness; nearly normal sensory function with the exception of hearing loss;

and urinary urgency or incontinence. Skeletal abnormalities of the feet and

spine also are characteristics of CMT2C.

About scapuloperoneal SMA

SMA usually is caused by a mutation in the SMN gene on chromosome 5, leading to

a loss in the spinal cord of muscle-controlling nerve cells called motor

neurons. The result is varying degrees of weakness and atrophy.

By contrast, scapuloperoneal SMA, which is not caused by an SMN mutation,

involves weakness concentrated in the area of the shoulder blades, lower legs

and larynx, with normal numbers of motor neurons in the spinal cord.

About congenital distal SMA

Like scapuloperoneal SMA, congenital distal SMA is not caused by mutations in

the SMN gene. It is characterized by weakness of the legs, as well as

contractures (frozen joints), particularly in the knees and ankles.

MDA's role

Study team member Henry Houlden, a neurologist at University College London in

the United Kingdom holds a current MDA grant for studies in type 1A CMT.

A number of former MDA grantees also contributed to the work, including

Fischbeck of the National Institute of Neurological Disorders and Stroke (NINDS)

in Bethesda, Md., who now serves as an adviser to MDA's translational research

program; neurologist Teepu Siddique of Northwestern University Feinberg School

of Medicine in Chicago, also a former MDA clinic director at that institution;

neurologist Dyck at the Mayo Clinic in Rochester, Minn.; and neurologist

Padberg at Radboud University Nijmegen Medical Center, Nijmegen, the

Netherlands.

Meaning for patients

There is no immediate potential for treatment from the new findings. However,

the more that is known about the underlying mechanisms of any disease, the more

possibility there is for development of therapeutics. There are near-term

implications for improved DNA testing to diagnose these rare diseases.