Dr Monika Hofer: Identifying and treating nemaline myopathy

Allyson Taylor was a secondary school teacher who was enjoying retirement until, out of the blue, the muscles controlling her arms and legs became progressively weaker over 18 months. Allyson was understandably desperate to find out what was wrong with her. Primary muscle diseases are generally rare and, occasionally, the pathway to diagnosis can take years. The answers came from Dr Monika Hofer, consultant neuropathologist.

Dr Hofer’s perspective

Allyson was under the care of Dr David Hilton-Jones, consultant neurologist and a muscle specialist with more than 40 years’ experience. He requested removal of a small piece of muscle tissue (a biopsy) from Allyson’s left shoulder, which can be done under local anesthetic. As a muscle pathologist, I perform my own biopsies, and so I met Allyson for the first time in June 2017 when she came to the hospital theatre. This gave me the opportunity to get to know her and learn about her illness. Allyson’s history was striking as much for its sentiments as its specifics; for example, she was upset by not being able to cycle with her grandchildren. She was so anxious for an explanation that she had contacted former pupils who had gone on to medical school, via Facebook, seeking their ideas.

On examining the biopsy sample under the microscope, it showed only some muscle fibre degeneration. This finding corresponded to the clinical evidence of loss of muscle bulk, but it didn’t explain why Allyson was experiencing such weakness. Dr Hilton-Jones and Allyson agreed to repeat the biopsy from another muscle – knowing from experience that some disease processes are patchy and may not be seen in a single biopsy sample.

On examining the new biopsy sample, I saw something that led directly to the diagnosis. Many fibres contained aggregates of nemaline rods (tiny little sand-like structures). Alone, these are non-specific, but they can be a characteristic feature of some childhood genetic myopathies, in which the muscle fibres do not function properly. I also knew that nemaline rods had been reported in late-onset acquired (non-genetic) myopathies and a little delving led me to the original paper from 1966, which described the disease called sporadic late-onset nemaline myopathy (SLONM) – a very rare disease, with a limited amount of information in the scientific literature. The disease is progressive and causes muscle weakness that affects the ability to swallow, makes breathing difficult and can affect the heart, making it harder for blood to be pumped around the body.

I immediately contacted Dr Hilton-Jones, who confirmed that the clinical context would fit. Allyson was also known to have an abnormal protein in her blood called a monoclonal gammopathy of uncertain significance (MGUS). MGUS is fairly common in older patients and usually doesn’t cause harm, but it is known to be associated with SLONM. The use of electron microscopy, which provided very high resolution images, confirmed that the structures in the muscle biopsy were indeed rods. We then liaised with a team in Paris (led by Professor Olivier Benveniste) who had a few months earlier published a research paper on SLONM, and they agreed with our findings. The exact underlying pathophysiology of this disease is not clearly understood, but it is thought to entail a malfunction of the immune system. It is not clear what leads to the formation of the nemaline rods.

The recommended treatment for SLONM with MGUS involves transplantation of blood stem cells from the patient’s own bone marrow, following suppression of the immune system with high doses of melphalan, a chemotherapy drug. Allyson was referred for this treatment as soon as we were sure of the diagnosis, and received a stem cell transplant under the care of Dr Karthik Ramasamy, consultant haematologist at the Churchill Hospital, Oxford. She is now receiving follow-up monitoring by the haematology team, since there is a small risk that her MGUS may develop into myeloma, a type of bone marrow cancer

One of our Oxford medical students, Casmir Turnquist, with Allyson’s consent, has already presented a poster raising awareness of this rare disease at the annual British Neuropathological Society meeting in London earlier this year.

At her worst, Allyson’s swallowing was badly affected and she needed to have a feeding tube implanted… She was so weak that she could only walk a few steps. Now, a year on, she’s walking long distances, but still gets tired. Her feeding tube has been removed and she only has minor swallowing problems.

Allyson’s experience

In spring 2015 I was fit and healthy; my hobby was golf and I played at competition level. During that summer I became progressively weaker and experienced back pain and fatigue. Gradually, I became less and less mobile and had to give up my golf.

Having tried all manner of treatments I was referred to a range of specialists and tried Alexander technique, Pilates, aqua aerobics and physiotherapy. I saw an osteopath and even tried acupuncture! I saw a haematologist, who diagnosed the MGUS, a rheumatologist, neurologist, back surgeon, cardiologist and then eventually, in May 2017, it was suggested that I be referred to Dr Hilton-Jones. He had the advantage of considerable experience and also the benefit of the team working with him. He sent me for the electrical tests and then the biopsies as described by Dr Hofer.

In September 2017 I was overjoyed to receive a diagnosis at last. Unfortunately, the previous two and a half years had resulted in considerable weakness and, before I started treatment, my condition deteriorated even more sharply. By Christmas 2017, my diet was soups and milkshakes; I had great difficulty with stairs and slopes and could walk only a very short distance. My family were extremely worried.

Following my stay in hospital my mobility deteriorated further, but after the initial three months’ recovery time I was able to walk again. I gradually built up the distance I could walk and now I can walk several kilometres, so long as the route is flat. Stairs are still very difficult but I am back to the gym and enjoy aqua aerobics. When I’m in water my body feels free. I enjoy yoga stretch, although my teacher does have to help me up off the floor afterwards.

I know that I will never play golf again, nor undertake our previous holiday activities of climbing hills and bike rides but, in the words of my five-year-old granddaughter, I don’t have to go to heaven so soon because now I have curly hair!