Spinal muscular atrophy (SMA), is a disease in which muscle-controlling nerve cells in the spinal cord malfunction or fail to develop properly. Research in recent years has suggested that these cells, known as motor neurons, may fail to mature, but the precise reason for their malfunction has remained obscure.

The disorder is recessive, meaning a person with SMA inherits a flawed gene from each parent. One of the genes will reside on each of a pair of chromosomes.

SMA comes in three, somewhat arbitrarily divided, categories: type 1, the most severe, type 2, of intermediate severity, and type 3, the least severe. All involve muscle weakness as a result of lack of stimulation of muscles by nerves. In type 1, children usually die by age 2 because of respiratory complications. People with types 2 and 3 may lead relatively normal lives, although they have severe weakness and generally need a wheelchair by adulthood.

FIRST CLUES

In 1990, MDA-supported researchers T. Conrad Gilliam at New York's Columbia University and Kay Davies at England's University of Oxford were among those who mapped the genetic defect for SMA to a small area of chromosome 5.

Then, early in 1995, two teams, one international (with MDA support) and the other French, each announced that they thought they had found "the SMA gene" on chromosome 5.

The international team, which included MDA grantee Dr. Alex MacKenzie at Children's Hospital of Eastern Ontario (Canada), called their gene NAIP, for "neuronal apoptosis inhibitory protein." They suggested the protein made from this gene might be one that stops apoptosis, a type of cell death.

The French called theirs SMN, for "survival motor neuron," suggesting the gene's protein somehow allows motor neurons to evade death.

CURIOUSER AND CURIOUSER

This year, MDA-funded researchers Arthur Burghes and Thomas Prior at Ohio State University in Columbus, and Davies at Oxford, have been among the many investigators who have come close to unlocking some of the secrets of chromosome 5 and, they hope, SMA itself.

Separate research teams on both sides of the Atlantic have found that the SMA region of chromosome 5 contains sets of genes that are nearly duplicates of each other (making research and genetic testing very confusing). The SMA region of chromosome 5 (see illustration on page 25) contains two nearly identical SMN genes. The researchers decided to call one SMN-T and the other SMN-C. ("T" stands for telomeric, toward the end of the chromosome. "C" stands for centromeric, near the centromere, where the two "arms" of the chromosome join.)

The NAIP gene also has two copies, one of which lies between SMN-C and SMN-T, and the other lying on the other side of the SMN-T gene, farther away from the centromere. The two NAIP genes differ by only a few chemical sequences, known as exon 5. The NAIP gene nearest the centromere looks like a gene but doesn't act like one and has been called an NAIP "pseudogene."

GENE CONVERSIONS RESULT IN MILDER DISEASE

When research teams that included Davies, Burghes and Prior took a close look at the genetic situation in patients with different types of SMA, they noted some important differences between chromosome samples from children with type 1 SMA and those from people with types 2 and 3, in addition to differences in samples from those with SMA and those from people without SMA.

Virtually all those with SMA were missing either all or part of the SMN-T gene on both chromosome 5s, whereas almost all people without SMA have this gene. But, those with the less severe forms of the disease had something different; they had more than one copy of the SMN-C gene. (Most people without SMA have only one copy of the SMN-C gene. Some have more than one.)

Researchers now believe that, in the less severe forms of SMA, the SMN-T gene is not actually missing; instead, it's been converted to SMN-C, which seems to mitigate the severity of the disease. Since the conversion makes an extra "copy" of SMN-C, these patients end up with more than the average amount of SMN-C DNA.

And what of NAIP? The NAIP gene, it's now believed, may serve only as a marker of the extent of the deletion of SMN-T. The absence of SMN-T is now thought of as the primary cause of SMA, but the loss of the NAIP-5 gene usually indicates that the whole SMN-T is gone. Loss of NAIP-5 is more common in type 1 SMA.

Researchers haven't ruled out a possible role for the NAIP-5 gene in motor neuron preservation, however. (This has yet to be determined and would likely make genetic testing and predictions even more complex!)

THE SMN PROTEIN

The next step for researchers is to find out what exactly the SMN protein does, how it does it and whether its function can in any way be compensated for by any kind of therapy.

What it does is hard to say, but it's found in newly discovered structures known as gems, which are inside the nucleus (command center) in many kinds of cells. The gems, scientists believe, help process RNA, the chemical step that comes between DNA -- the genes themselves -- and proteins made from the genes.

Loss of this RNA-processing step could affect the function of a cell in many ways -- a problem, in that it makes the situation complicated, but also a possible advantage, because there may be several biochemical pathways that lend themselves to therapeutic intervention (by drugs, for example).

Just why motor neurons in the spinal cord are particularly hard hit in SMA is hard to say, since gems and SMN are normally present in the brain, kidney, liver, cardiac and skeletal muscle, as well as in skin and white blood cells, and these tissues function normally in people with SMA.

If SMN is lacking or reduced in quantity because of a genetic defect, logic dictates it won't be present in normal amounts in any tissue of the body. Therefore, scientists speculate, there must be something about the motor neurons that makes them especially sensitive to SMN deficiencies. What causes that sensitivity remains to be discovered.

CAN BOOSTING SMN-C HELP?

There must be a difference between SMN-T and SMN-C, since extra SMN-C helps in SMA, but doesn't completely fix the problem. To make matters more confounding, not all SMN-C genes are alike, Burghes emphasizes. "In general, it is true that the SMN-C copy number is increased in milder patients," he said. "There are some SMN-C alleles [genes] that can compensate the phenotype [symptoms] and others that do not. We don't have the molecular difference between these."

Analyses of the genes and their proteins show that 90 percent of the protein molecules produced from the SMN-T gene are long proteins, what the researchers call "full length." About 10 percent are shorter versions of the SMN protein, with some parts removed compared to the full-length form. (Many genes produce multiple versions of a protein; these are known as protein "isoforms.")

The proteins produced from the SMN-C gene are mostly shorter forms of the protein. Only about 20 percent to 30 percent are the full-length form.

Does it matter? It seems it probably does, Burghes and Davies say. The full-length protein seems necessary for motor neuron survival. But an SMN-C gene, which produces some full-length protein, probably "can compensate partially," Davies said.

Could SMN-C protein production be boosted? An intriguing possibility, researchers say, not unlike the proposal to boost production of the muscle protein utrophin to compensate for the loss of the dystrophin protein in Duchenne dystrophy -- something Davies has been studying intensely (see "Utrophin Researcher" in Quest, vol. 4, no. 4, 1997).

"This is a question that has been raised by many of us working in SMA," Burghes said. "The question [of increasing SMN-C production] is how -- and what will it do? We are trying to get at this now."

GENETIC TESTING for SMA

Genetic testing for the absence of the SMN-T gene on both chromosomes is commercially available. Ask your MDA clinic doctor or genetic counselor, or call MDA at (800) 572-1717. More specialized SMA testing that can detect carriers (who have only one SMN-T deletion) is available by calling MDA's 800 number. MDA staff will forward your name to the Ohio State University research group.