Neuromuscular disorders: genes, genetic counseling and therapeutic trials

Abstract

Neuromuscular disorders (NMD) are a heterogeneous group of genetic conditions, with autosomal dominant, recessive, or X-linked inheritance. They are characterized by progressive muscle degeneration and weakness. Here, we are presenting our major contributions to the field during the past 30 years. We have mapped and identified several novel genes responsible for NMD. Genotype-phenotype correlations studies enhanced our comprehension on the effect of gene mutations on related proteins and their impact on clinical findings. The search for modifier factors allowed the identification of a novel "protective"; variant which may have important implication on therapeutic developments. Molecular diagnosis was introduced in the 1980s and new technologies have been incorporated since then. Next generation sequencing greatly improved our capacity to identify disease-causing mutations with important benefits for research and prevention through genetic counseling of patients' families. Stem cells researches, from and for patients, have been used as tools to study human genetic diseases mechanisms and for therapies development. The clinical effect of preclinical trials in mice and canine models for muscular dystrophies are under investigation. Finally, the integration of our researches and genetic services with our post-graduation program resulted in a significant output of new geneticists, spreading out this expertise to our large country.

Is it the right time for an infant screening for Duchenne muscular dystrophy?

“…In that event, we have to consider that some of them are treatable such as Pompe disease, but others are untreatable, with early or even later clinical onset. In such cases, genetic counselling, psychological support and follow-up will be offered [ 36 ]. On the other hand, we are also conscious that subjects with DMD gene mutation-related cardiomyopathy have normal or near normal CK, so that they cannot be identified by this programme.…”

Origin and age of the causative mutations in KLC2, IMPA1, MED25 and WNT7A unravelled through Brazilian admixed populations

“…A cluster of 19 individuals with this disease was identified in Lagoa community, which is near to the KLC2 cluster and three other families here investigated 33 . Historically, other neurodegenerative disorders were found in Brazilian families, including SPG8 and X-linked SPG, among others highly spread in Brazil 34 ; there are also documented affected individuals living in the Iberian region 35 , a population that represents our ancient colonizers.…”

A well‐tolerated core needle muscle biopsy process suitable for children and adults

“…Since the discovery of the genetic basis of DMD and highly accurate and robust genetic testing from blood, there has been a dramatic reduction in the need for diagnostic muscle biopsies 2‐4 . Even in the context of more rare forms of muscular dystrophy, broad‐based genetic testing is often an efficient means of diagnosis 5 …”