Genetics and its relation to neuromuscular diseases By: Isam Adam, Jason Fong, Cody Boehner, Ella Dehestani, and Anissa Santiago

Rationale and objectives From the personal experience of one of our group members, our attention is drawn to the topic of neuromuscular diseases, primarily spinal muscular atrophy, and the relation between such diseases and genetics We wish to identify the genetic causes of various neuromuscular diseases and draw connections between the genome and the disease We expect to see mutated exons in the presence of neuromuscular diseases, such that the affected gene is altered in some way that it is unable to properly encode for the normal protein, failing to sustain regular cell processes

Findings In our presentation, we will be exploring three different types of neuromuscular diseases and their genetics: Duchenne Muscular Dystrophy Spinal Muscular Atrophy Myotonic Muscular Dystrophy

Duchenne Muscular dystrophy Duchenne Muscular Dystrophy, also known as DMD is classified as an X-linked disorder The mutation in the DMD gene causes Duchenne muscular dystrophy The DMD gene encodes for the production of dystrophin, a protein located primarily in skeletal and cardiac muscle and helps stabilize and protect muscle fibers

Duchenne Muscular dystrophy The female counterpart is a carrier in this disease, and it is rare for the female to show symptoms of the disease If the female counterpart is a carrier, this means the disease can be given to a male offspring if they received the X chromosome mutation If the mother has a daughter, she too can become a carrier if she receives the X chromosome mutation.

Duchenne Muscular dystrophy Symptoms · Frequent falls · Muscle weakness · Trouble walking · Trouble running · Waddling gait · Big calves · Difficulty swallowing · Fatigue · Possibility of scholiosis

Spinal muscular atrophy Spinal Muscular Atrophy, also known as SMA is classified as an autosomal recessive disorder This is caused by mutations on chromosome 5 in a gene called SMN1 This means, there is a deficiency of a motor neuron called “SMN” OR “survival of motor neuron.” In this type of situation, both the mother and father are carriers of this disease

Spinal muscular atrophy There are 4 major types of SMA: Type I Type II Type III Type IV

Spinal muscular atrophy Type I Usually diagnosed during an infant’s first six months. Babies with SMA type I face many physical challenges, including muscle weakness and trouble breathing, coughing, and swallowing They may need breathing assistance or a feeding tube Often fatal early on in life 60% of all SMA cases are Type I Also known as Werdnig-Hoffmann disease.

Spinal muscular atrophy Type II Usually diagnosed after six month of age, but before two years of age. The first sign is often a delay in meeting motor milestones, or failing to meet milestones entirely Individuals affected by SMA type II can typically sit up without help, though they may need assistance getting into a seated position, but they are unable to walk and will require a wheelchair

Spinal muscular atrophy Type III Usually diagnosed after 18 months of age, but before three years of age However, SMA type III can be diagnosed as late as the teenage years Individuals affected by SMA type III are initially able to walk, but have increasingly limited mobility as they grow and eventually, many need to use a wheelchair Also called Kugelberg-Welander disease or juvenile SMA

Spinal muscular atrophy Type IV SMA type IV is very rare It usually surfaces in adulthood, and it leads to mild motor impairment While symptoms can begin as early as age 18, they usually begin after age 35

Spinal muscular atrophy Most people have two copies of the SMN1 gene Individuals who have one faulty copy and one functioning copy are called carriers Carriers do not have SMA, but they may pass the faulty gene on to their children SMA is an autosomal recessive genetic disorder This means that, generally, both parents must pass on the mutation for the child to have SMA When two carriers have a child, there is a 25% chance that the child will be unaffected, a 50 % chance that the child will also be a carrier, and a 25% chance that the child will have SMA.

Myotonic muscular dystrophy Myotonic Muscular Dystrophy, also known as MMD, is classified as an autosomal dominant disorder carried on chromosome 19 or 3 Myotonic dystrophy type 1 is caused by mutations in the DMPK gene, while type 2 is caused by mutation in the CNBP gene

Myotonic muscular dystrophy These genes' functions are not yet clear, but the protein that is produced from the DMPK gene affect in type 1 may play a role in intercellular communications The mutated gene produces an expanded form of mRNA which forms clumps inside the cell and interferes with the production of other proteins, thus leading to the symptoms of myotonic muscular dystrophy

Myotonic muscular dystrophy Symptoms Difficulty releasing one’s grip Weakness of muscles in the hands and feet Difficulty swallowing Abnormal heart rhythms

conclusion For each type of neuromuscular disease, there is some type of mutation that causes a change in the production of some type of protein, directly or indirectly The short term treatment involves the injection of the missing, necessary proteins for muscular functions However, in order to cure the disease, the DNA of the individual's cells must be altered in some way in order to correct the mutation, or to function in a way that would compensate for the mutation As science and technology continues to progress, it may be possible to change an individual's DNA without risk factors and completely cure the disease, however presently, there are other treatments of the diseases that involve minor DNA translations, corrections, addition of proteins, etc.

Follow up questions Can the inherited mutation be repaired after the individual is diagnosed? Why are parents not tested for the mutation in order to predict or prevent the spread of disease?

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