1 2 aim

#apaperaday: Long-term clinical follow-up of a family with Becker muscular dystrophy associated with a large deletion in the DMD gene

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled:  Long-term clinical follow-up of a family with Becker muscular dystrophy associated with a large deletion in the DMD gene

This week we’ll have dystrophinopathy genetic themed picks, for the TREAT-NMD masterclass in Dubai (going today). First pick is from Neuromuscular Disorders by Vogt et al: a follow up of the 1990 England Becker paper DOI: 10.1016/j.nmd.2024.04.004

Dystrophin provides a link between the skeleton of muscle fibers and the connective tissue surrounding fibers, thus providing stability during contraction. Dystrophinopathy can be associated with severe pathology when no functional dystrophin is made (frame-disrupting mutations).

When mutations maintain the reading frame this allows production of a dystrophin that is missing part in the middle while the domains that have the linker functions are present. These dystrophins are partially functional and result in a slower disease progression.

While we know dystrophinopathy involves a spectrum from very severe to milder, generally speaking no dystrophin leads to Duchenne and partially functional dystrophin leads to Becker. In 1990 Kay Davies and S. England published about a Becker patient with a huge deletion.

This patient had a deletion of exon 17-48, which removed hinge 2, repeat 4-18 and part of repeat 19 (see image). Even though this removed 46% of the dystrophin protein, the patient was mildly affected and still ambulant at age 61. This finding inspired the engineering of micro-dystrophins.

Authors provide a long term follow up of this first patient and affected relatives. The index patient was diagnosed when he was 38 years old, with first symptoms of leg muscle weakness appearing at age 35. He was still ambulant at age 61 but died in his 70s wheelchair dependent.

An uncle of the index patient died age 52 due to a cerebral hemorrhage. He was still ambulant with a walking aid at that time but showed no other symptoms. Finally a cousin of the index patient started to have symptoms at age 21 with also hypertrophy of leg muscles.

Creatine kinase blood levels were ~3k. The patient had mainly leg weakness and was a body builder at age 25 with no apparent arm weakness. Later he developed difficulties with stair climbing and used walking aids. At age 59 he uses a wheelchair and also has arm weakness.

This description shows that the deletion of exon 17-48 allows production of a very functional dystrophin, as the disease progression is slow within this family (compared to other Becker mutations). It also shows that within families there is variability in age of onset.

The deletion provided a lot of insight in how different dystrophin domains enabled dystrophin’s linker function and this mini-dystrophin was a starting point for engineering the micro-dystrophins which are now tested in different clinical trials.

One of the micro-dystrophin is approved in USA for 4-5 year olds (@Sarepta Elevidys). Note that this update was funded by Sarepta and that one of the authors is on Sarepta’s SAB (as am I for full disclosure). I do appreciate the follow up and description of family members though.