GENE DEFECTS FOUND IN LIMB-GIRDLE DYSTROPHY

The gene for an enzyme called calpain 3, on chromosome 15, probably plays a role in some cases of limb-girdle muscular dystrophy (LGMD). Researchers at Indiana University and Henry Ford Hospital in Detroit, as well as in France and Brazil, found that some cases of recessive LGMD are associated with flaws in the calpain 3 gene.

Meanwhile, Kevin Campbell, MDA grantee at the University of Iowa, Iowa City, was among those who found that flaws in the gene for adhalin, a structural muscle protein, cause other cases of recessive LGMD. The adhalin gene is on chromosome 17.

LGMD can also be caused by defects on chromosome 5 (dominant form) and chromosomes 2 and 13.

NEUROTROPHIC FACTOR SHOWS PROMISE

Glial-cell-derived neurotrophic factor, or GDNF, has potential as a future treatment for amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). MDA-funded researcher Lucien Houenou at Wake Forest University's Bowman Gray School of Medicine in Winston-Salem, N.C., was among those who did laboratory tests and found GDNF was effective in saving motor neurons from cell destruction. Motor neurons, nerve cells that control voluntary muscles, are destroyed in ALS and SMA. Neurotrophic factors are natural substances that promote nerve growth during development and after injury.

RILUZOLE HAS MODEST EFFECT IN ALS

The experimental drug riluzole has been tested in a recent clinical trial involving over 950 people with amyotrophic lateral sclerosis (ALS) in the United States and Europe. MDA ALS centers were involved in the American part of the trial. People with ALS who took riluzole, which partially blocks the central nervous system chemical glutamate, showed an average three-month increase in survival time over those who got a placebo. However, there was no significant effect on muscle function. Information about riluzole is available through its manufacturer, Rhone-Poulenc Rorer, at 1-800-798-7425.

SODIUM CHANNELS EYED IN MYOTONIC DYSTROPHY

MDA-supported myotonic dystrophy (MMD) researchers Allen Roses and John Gilbert at Duke University in Durham, N.C., and J. Randall Moorman at the University of Virginia in Charlottesville have been studying how an expanded stretch of DNA on chromosome 19 leads to this complex disease. The researchers say muscle sodium channels may be involved in some of the symptoms. Sodium channels are microscopic pores that open under certain circumstances and allow sodium to enter cells. A protein called myotonin protein kinase, which is affected by the expanded DNA on chromosome 19, normally plays a role in closing sodium channels, the researchers found. They say too little myotonin protein kinase might keep sodium channels from closing properly, causing myotonia, or inability to relax muscles after contracting them.

VITAMIN E HELPS SOME WITH ATAXIA

MDA grantee Faycal Hentati at the Institut National de Neurologie in Tunis, Tunisia, was part of an international team that found that a form of genetic ataxia (abnormal coordination of movement) linked to chromosome 8 is caused by a flaw in a gene for alpha tocopherol transfer protein. Alpha tocopherol is another name for vitamin E. Large doses of vitamin E relieved the symptoms of people with this form of ataxia. The researchers caution that the chromosome 8 form of ataxia, called ataxia with vitamin E deficiency, is not the same as Friedreich's or other ataxias. However, since the symptoms are very similar to those of Friedreich's ataxia, the two disorders can be confused, and vitamin E levels should be checked in all patients where any question exists.

ATAXIN MAY BE ABNORMAL IN SCA1

MDA grantee Huda Zoghbi at Baylor College of Medicine in Houston has been studying a different form of ataxia, spinocerebellar ataxia type 1 (SCA1). In 1993, Zoghbi and others found that an expanded gene on chromosome 6 causes the disease. The protein coded for by this gene was recently identified and called ataxin 1. Zoghbi now reports that people with SCA1 make a normal amount of ataxin 1 and that it's in the right place in cells. Therefore, the researchers say, the expanded gene probably changes ataxin 1's chemical makeup so that it has a toxic effect. Continuing studies may shed further light on the biochemical problems caused by the abnormal ataxin and what might be done about them.

MYOBLAST TRANSFER UPDATE

Myoblast transfer, an experimental muscle-cell transplant procedure developed a few years ago to treat muscular dystrophy, has been a disappointment in clinical trials. MDA-sponsored trials in the early 1990s found no improvement in muscle function in boys with Duchenne dystrophy who underwent myoblast transfer procedures. Biopsy samples showed few of the transplanted cells survived and little of the needed protein, dystrophin, was produced.

One clinical trial remains in progress. At California Pacific Medical Center in San Francisco, MDA is supporting Robert Miller's trial of five boys with Duchenne who are 2 to 5 years old, younger than boys in previous trials. Miller is trying the procedure in younger boys in hopes that their muscles may more readily accept the transplanted cells.

Meanwhile, MDA is funding several animal studies aimed at improving the techniques of myoblast transfer and understanding the biology of muscle repair. Investigators are probing the problem of possible immune-system rejection of transplanted cells and are exploring ways to produce millions of myoblasts without "wearing out" the cells before they're transplanted. Researchers are also trying to devise better methods of delivering myoblasts to major muscle groups without using multiple intramuscular injections.

GENE THERAPY UPDATE

MDA grantee Jeffrey Chamberlain at the University of Michigan recently attended a gene therapy conference where scientists compared notes on their progress. Chamberlain reports that most gene therapy investigators working on muscular dystrophy are trying to improve the ability of viruses to deliver genes safely and effectively. Special attention is being given to making the gene-carrying viruses less likely to trigger an attack by the immune system. In many early experiments, scientists saw evidence that these attacks probably killed most of the muscle cells that contained viruses.

Because viruses are a problem, some researchers are exploring nonviral delivery vehicles for gene therapy, but these approaches are still in their infancy.