2012 AAN Meeting: Limb-Girdle MD, Distal MD Briefs

Findings about ANO5 mutations, DNAJB6 mutations and dysferlin gene transfer were presented

Article Highlights:

Presentations at the 2012 American Academy of Neurology meeting included the following findings:

  • Dysferlin gene transfer benefited dysferlin-deficient mice, setting the stage for human trials.
  • Mutations in the anoctamin 5 (ANO5) gene have been found to cause type 2L limb-girdle MD and type 3 Miyoshi myopathy (a distal MD) in Dutch and Danish studies, increasing the number of people known to have these mutations.
  • Those with muscle weakness due to ANO5 mutations may be at increased risk of heart problems, according to Danish researchers.
  • Mutations in the DNAJB6 gene have been identified as a cause of type 1 LGMD (LGMD1).
by Margaret Wahl on May 9, 2012 - 12:15pm

The 2012 annual meeting of the American Academy of Neurology (AAN), held in New Orleans April 21-28, included findings related to limb-girdle muscular dystrophy (LGMD) and distal muscular dystrophy.

LGMD is characterized by weakness of the proximal muscles (those close to the center of the body), while distal muscular dystrophy is characterized by weakness of the distal muscles (those far from the center of the body).

Gene transfer effective in dysferlin-deficient mice

William Grose from Nationwide Children's Hospital in Columbus, Ohio, presented encouraging results from experiments with dysferlin gene transfer (gene therapy) in dysferlin-deficient mice. Mutations in the dysferlin gene interfere with repair of muscle-fiber membranes and cause LGMD2B and a distal muscular dystrophy known as type 1 Miyoshi myopathy.

The investigators injected dysferlin genes, encased in viral delivery vehicles known as AAV2/5 vectors, directly into the diaphragm muscle, and into lower leg muscles via the bloodstream in the mice.

Among the findings:

  • Robust dysferlin protein production followed intramuscular and vascular (bloodstream) injections.
  • The muscles receiving the dysferlin gene transfer were resistant to laser-induced injury.
  • Force generation and resistance to fatigue were restored in the diaphragm.

The investigators say the stage has been set for testing dysferlin gene transfer in clinical trials.

To learn more, see the following:

  • DD/LGMD  Bloch, a description of a current MDA research grant to Robert Bloch at the University of Maryland, who is studying dysferlin as a prerequisite for designing gene or drug therapy involving this protein
  • LDMD/DD — Levy, a description of a current MDA research grant to Jennifer Levy at the University of Iowa, who is studying muscle damage in dysferlin deficiency

More people found to have ANO5 mutations

Two presentations, one from a Dutch research group and the other from a Danish group, expanded on the 2010 identification of mutations in a gene called anoctamin 5 (ANO5) as the cause of type 2L limb-girdle muscular dystrophy (LGMD2L) and type 3 Miyoshi myopathy, a form of distal muscular dystrophy.

The ANO5 protein made from the ANO5 gene is thought to be a chloride channel, regulating the flow of chloride ions in cells. It may play a role in the repair of muscle-fiber membranes, and a deficiency of, or defect in, this protein may hinder this type of membrane repair.

The Dutch group performed physical examinations and DNA analyses on 32 people with apparent LGMD for which no genetic mutation had been identified, and on 12 people with apparent Miyoshi-type muscular dystrophy for which no genetic mutation had been identified.

Among the Dutch group’s findings:

  • ANO5 mutations were identified in 13 people (41 percent of the 32 examined) with apparent LGMD and eight (67 percent of the 12 examined) with apparent Miyoshi myopathy.
  • Three of the identified LGMD2L patients had heart abnormalities, but none of the identified type 3 Miyoshi myopathy patients did.
  • The Danish group performed genetic testing on 26 people with unclassified but apparent LGMD, five with apparent but unclassified distal muscle abnormalities, and 15 with unexplained elevations in serum creatine kinase levels, an indicator of muscle damage.

Among the Danish group’s findings:

  • ANO5 mutations were identified in 10 people (38 percent of the 26 tested) with apparent LGMD, four (80 percent of the five tested) with distal muscle abnormalities, and two (13 percent of the 15 tested) with unexplained elevated creatine kinase levels.
  • Because all participants in the Danish study with ANO5 mutations eventually developed proximal weakness, even if they started out with distal weakness, these investigators decided to classify everyone with weakness and ANO5 mutations as having LGMD2L. They also classified the two people with ANO5 mutations and unexplained creatine kinase elevations as having LGMD2L.
  • ANO5 mutations increased the incidence of a type of cardiac abnormalitity called premature ventricular contractions, prompting the investigators to suggest that people with these mutations undergo regular cardiac examinations.
  • LGMD2L may be the third most common type of LGMD2 in Denmark.

The association of mutations in the ANO5 gene with some forms of LGMD and distal MD is similar to findings several years ago regarding the dysferlin gene. In 1998, scientists found that mutations in the gene for the dysferlin protein could cause a form of LGMD now known as LGMD2B or a form of distal muscular dystrophy now known as type 1 Miyoshi myopathy. And in 2003, it was found that dysferlin appears to play an essential role in repairing damaged muscle fibers. That's now a suspected role for ANO5 as well.

At least 12 other genes can, when mutated, cause various forms of type 2 LGMD (LGMD2), which is inherited in a recessive pattern. Recessive disorders require two genetic mutations, usually one from each parent, to cause symptoms. Miyoshi myopathy is also inherited in a recessive pattern.

To learn more about the ANO5 findings, see the following articles:

DNAJB6 mutations can cause LGMD1

Neurologist Matthew Harms from Washington University School of Medicine in St. Louis gave a presentation at the AAN meeting about the recent identification of mutations in the DNAJB6 gene as a cause of type 1 LGMD (LGMD1), which refers to LGMD inherited in an autosomal dominant pattern.

Autosomal dominant disorders require only one genetic mutation, either inherited from one parent or occurring for the first time in the child, to cause symptoms. At least seven other genes can, when flawed, cause LGMD1. The newly identified form of the disease has been dubbed LGMD1D.

The DNAJB6 protein that's made from the DNAJB6 gene is a member of the heat shock protein family, which assists in the folding and unfolding of other proteins and helps protect cells from various stresses. Abnormalities in the DNAJB6 protein appear to lead to abnormal aggregation (clumping) of cellular proteins, including DNAJB6 itself.

The investigators first identified a DNAJB6 mutation in three members of one LGMD-affected family and then found a second LGMD-causing mutation in the same gene in other families.

MDA supported neurologist and molecular geneticist Robert Baloh for this work. Baloh, who left Washington University in January 2012, now heads the Neuromuscular Division at Cedars-Sinai Medical Center in Los Angeles.

To learn more, see the following articles:

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