Medicine Discovery of a rare muscle disorder

Muscle weakness in the legs, an unsteady gait, permanent risk of stumbling – symptoms such as these are common in people suffering from muscle disorders. However, the patient who came to the university clinic Bergmannsheil with these health conditions didn’t match any known diagnosis. Following thorough examinations, the Bochum-based doctors realised that they were dealing with an entirely new disease.

“We carried out numerous additional diagnostic investigations,” explains Prof Dr Matthias Vorgerd from the Neurological Clinic Bergmannsheil. “But we were not able to isolate the responsible gene or protein at first.” As other members of the patient’s family were likewise affected, the doctors assumed the disease was a hereditary one; together with private lecturer Dr Sabine Hoffjan from the RUB Human Genetics Department, they initiated detailed genetic analysis – and made a discovery. The BICD2 gene was altered in all patients. The cause was subsequently verified after a second affected family had been examined.

Known disease trigger

BICD2 had been known to be a trigger of diseases – but nobody had yet described a BICD2 syndrome that manifested itself in altered skeletal muscles. The problem always originated from the nervous system. Now, doctors observed pathological changes in the lower leg and femoral muscles, whereas no changes were identified in the nervous system. Matthias Vorgerd decided to get to the bottom of this new muscle disorder. “It is important to describe the disease as thoroughly as possible, in order to arrive at statements regarding the heredity process, progression, and therapy options,” explains the neurologist. He additionally consulted the research group headed by Prof Dr Wolfgang Linke from the RUB Institute of Physiology.

The physiologists under the auspices of Dr Andreas Unger performed various lab tests to analyse cells from the biopsies of affected patients. Initially they recorded high-resolution images with the electron microscope. These images showed significant alterations in the normally very orderly arranged muscle structure. Myofibrils, basic components of muscle fibres, were observed with degenerations, other cell organelles were likewise affected. Mitochondria, the energy suppliers of cells, appeared with different shape and the Golgi apparatus, a post office for protein sorting, was larger and more dispersed than normally.

Black hole in physiology

But how does the defect in the BICD2 gene trigger all those changes in the cell? “It is too soon for a definitive answer,” says Andreas Unger. What is clear is that the gene codes for a protein that is essential for vesicular transport processes. “The cargo delivery processes in skeletal muscle cells are a black hole, so to speak; we don’t know much about them yet,” explains Unger.

If a cargo has to be transported for export, it is packed in membrane vesicles and is conveyed by a motor-protein. The BICD2 protein acts as an adapter between the cargo that has to be transported and the motor protein. It is involved in deciding which cargo will be selected and where to be transported, and it influences the speed of the motor protein.

However, many aspects of the BICD2’s physiological function have not yet been fully explored, for example the question which cargo, exactly, it transports. This is why Andreas Unger can only speculate in what way the genetic defect affects the transport processes. “The three-dimensional structure of the BICD2 protein is known to us; it looks like a jack-knife made up of three parts,” he describes. “In order to pick up the cargo, it has to be unfolded. It is conceivable that the protein no longer unfolds properly due to the mutation. But this is merely a hypothesis.”

Impaired regeneration

What is known is: when the pathologically changed BICD2 gene is translated into a protein, one single wrong amino acid is built in due to the defect in the genome. It doesn’t take more than that to strongly impair the function of the protein. The mutation is dominant; individuals whose chromosome in a chromosome pair carries a pathological mutation will develop the disease.

Based on the studies to date, Andreas Unger and his colleagues assume that the diseased BICD2 protein impairs the targeted transport in muscle cells – transport that is crucial for the regeneration of the cell membrane. The membrane contains embedded ion channels and receptors that routinely turn-over; for this purpose, replacement proteins must insert into the cell membrane. “In the widest sense of the word, this is rather like best before dates in our food products,” compares Unger. “Also, membrane proteins require renewal, and that appears to be impaired in BICD2 patients.”

Broad spectrum of disease

New findings suggest that, rather than being a clearly defined syndrome, BICD2 myasthenia describes an entire spectrum of BICD2-triggered disorders. “It is very likely that a severe form of the disease exists that is highly developed at birth and results in death in early infancy,” says Matthias Vorgerd. The team are currently studying a relevant case. That symptomatology is at one end of the clinical spectrum of BICD2 disorders; on the opposite end are conditions with relatively mild symptoms that don’t manifest until late adulthood. The BICD2 spectrum includes disorders whose causes are rooted either in skeletal musculature alone or in the nervous system alone, as well as disorders that are a hybrid of both.

With their first descriptions of the muscular BICD2 disorder, Vorgerd, Unger and their colleagues have raised other clinics’ awareness for the disease spectrum. “If a doctor observes such disease patterns and assumes an underlying hereditary cause, he or she has to examine the patients’ families for BICD2 defects,” explains Matthias Vorgerd. “Clinicians are now to be given a diagnosis code to facilitate the diagnostic process.”

Long-term objective: therapy

Together with other work groups in Germany, the researchers from Bochum plan to gain a better understanding of BICD2 disorder in the upcoming years. In order to achieve this purpose, new insights into the transport processes in healthy muscle cells will likewise be necessary. “At a later stage, that knowledge might help us to come up with therapy options,” hopes Unger. “A conceivable approach would be, for example, to replace the molecule that cannot be properly transported with another one, or to switch to a different cargo system,” considers the researcher. This is only possible if it is understood what the processes are supposed to be like in healthy condition.

It will take years until a therapy is available. Ten at least, according to Matthias Vorgerd’s estimate. Even if a therapy idea did exist, it would have to be tested in a cell culture and subsequently on animals. “Those are lengthy processes, for which there isn’t any money at the moment,” explains the neurologist. BICD2 defects are rare disorders. It is not easy to get funding. The studies so far have been financed by the Heimer Foundation (Heimer-Stiftung). For the industry, this research does not pay off.

“There are maybe 10 to 15 BICD2 patients in Germany,” says Vorgerd. This also means that research material is very much limited. Nevertheless, the team from Bochum have been noticing a positive trend: “Word is getting around in the field that we have specialised in these cases with muscular disease,” explains Andreas Unger. As a result, colleagues from other clinics have been sending tissue samples taken from other patients to Bochum – thus helping promote BICD2 research.