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