Research Review No. 90.
A series of interesting studies.
The Studies:
In the latest issue of the Journal, Neuromuscular Disorders, there are four
articles (2,3,4,5), which deal with various aspects of Duchenne Muscular
Dystrophy (DMD) and one (1), which comments on these. Therefore, I have
decided to combine these five articles into one research review.
The first study (2) from U.S.A. and Brazil examined a family of Labrador
Retrievers, which lack the ability to produce dystrophin. The dogs were studied
over three generations of male animals with clear sym[toms of DMD they did not
find any detectable deletions or duplications in the dystrophin gene. These male
dogs had markedly increased serum creatine kinase activity, absence of
membrane dystrophin, but no clinical signs of muscle weakness were detectable.
They conclude that in such exceptional situations with muscle totally lacking in
dystrophin, but which may be functional. They conclude that: “Unlocking the
secrets that protect these dogs from a severe clinical myopathy is a great
challenge which may have important implications for future treatment of human
muscular dystrophies.”
In the second of these studies (3), members of the Brazilian team
summarize the clinical history of Ringo, one of the dystrophic dogs above.
Despite the absence of dystrophin from his muscles he only had a mild form of
the condition. He died of cardiac arrest at the age of 12, demonstrating a normal
life span. One of his descendants displayed a similar condition. The authors also
note that the levels of utrophin in these dogs did not differ from that of severely
affected dogs. They conclude with the words: “But most importantly, the
demonstration that it is possible to have a functional muscle, in a medium-large
animal even in the absence of dystrophin, brings new hope for Duchenne
patients.”
In the third of these papers (4), we move from dogs to humans. In this
study from China, the authors assessed the progression and variation of fatty
infiltration of the thigh muscles of DMD patients, aged around the mean of 6
years. In all 171 boys were examined using muscle magnetic resonance imaging.
They note that fatty infiltration of all the thigh muscles developed rapidly after
seven years of age. However within these observations the results were very
variable, and they consider that these should be taken into consideration when
planning clinical trials.
The last (5) of this clutch of papers comes from Belgium and examines
renal function in children and adolescents with DMD. The study included 20 DMD
patients ranging in age from 5 to 22 years. Full medical histories were taken.
They consider that their study demonstrates a high prevalence of hyperfiltration
and hypertension. It could not be determined whether the hypertension was due
to the steroid treatment undergone by the majority of these patients. The also
note that urine creatinine measurements were of no value to evaluate renal
function in DMD.
In their commentary (1), the authors draw attention to a study from 2006
(6), which documents “a four-and-a-half year old boy with a diagnosis of
Duchenne dystrophy on the basis of a grossly elevated CK, an out-of-frame
duplication of exons 18–30, and a dystrophic muscle biopsy, with complete
absence of dystrophin, but no clinical evidence of any deficit and able to run, to
hop on one leg and to go up and down steps without difficulty. This inspired a
new section in this Journal (Neuromuscular Disorders), Clinical Casebook, to
document such cases with a conflict between clinical and laboratory
observations, and to promote further documentation and discussion. They
comment on other similar human cases and raise the questions: “How do these
cases have good muscle function in the absence of dystrophin and
correspondingly how good is dystrophin as a marker of muscle function?”
Among the concluding remarks to their commentary they state: ”Taken
together, these cases are a clarion call that nature provides us with opportunities
to study and value the exception of the individual patient. Furthermore, these
studies suggest that DMD is in fact a very complex and multifaceted disease.”
We should take these comments very seriously.
References
1)
Dubowitz, V. & Cohn, R.D. (2015) Dystrophin and Duchenne dystrophy.
Neuromuscular Disorders. 25(5):361-362.
2)
Vieira, N.M., Guo, L.T., Estrela, E., Kunkel, L.M., Zatz, M. & Shelton, G.D.
(2015) Muscular dystrophy in a family of Labrador Retrievers with no muscle
dystrophin and a mild phenotype. Neuromuscular Disorders. 25(5):363-370.
3)
Zatz, M., Vieira, N.M., Zucconi, E., Pelatti, M., Gomes, J., Vainzof, M.,
Martins-Bach, A.B., Otadu, M.C.G., Bento dos Santos, G., Amaro Jr., E, Landini,
V. & Andrade, T. (2015) A normal life without muscle dystrophin. Neuromuscular
Disorders. 25(5):371-374.
4)
Li, W., Zheng, Y., Zhang, W., Wang, Z., Xiao. J. & Yuan, Y. (2015)
Progression and variation of fatty infiltration of the thigh muscles in Duchenne
muscular dystrophy, a muscle magnetic resonance imaging study.
Neuromuscular Disorders. 25(5):375-380.
5)
Braat, E., Liesbeth Hoste, L., De Waele, L., Olivier Gheysens, O., Pieter
Vermeersch, P., Goffin, K., Pottel, H., Nathalie Goemans, N. & Levtchenko, E.
(2015) Renal function in children and adolescents with Duchenne muscular
dystrophy. Neuromuscular Disorders. 25(5):381-387.
6)
Dubowitz V. (2006) Enigmatic conflict of clinical and molecular diagnosis
in Duchenne/Becker muscular dystrophy. Neuromuscular Disorders. 16:865–6.
Karl A. Bettelheim
26.5.2015