Grandmother: Dr. Abdul Hafeez Yahya Khoja
Last week, the US Food and Drug Administration approved Evrysdi (risdiplam) to treat patients two months old or older with Spinal Muscular Atrophy (SMA), an often fatal, inherited disease that affects On muscle strength and movement. It is the second drug to treat this disease and the first that can be taken orally, and it provides an important treatment option for these patients. The approval for the first treatment for this devastating disease (by injection) came less than four years ago, from the Office of Neuroscience at the FDA’s Center for Drug Evaluation and Research.
The efficacy of the new drug Evrysdi in treating patients with early childhood or late onset of disease was evaluated in two clinical studies. The first study, which began in children, involved 21 patients, who had an average age of 6.7 months when the study began. The effectiveness is based on being able to sit without support for at least five seconds and to survive without “permanent ventilation.” After 12 months of treatment, 41 percent of patients were able to sit independently for more than five seconds, which is an important difference from the normal development of the disease because nearly all untreated children with childhood SMA could not sit independently. After 23 months or more of treatment, 81 percent of patients were alive without permanent ventilation, which is a significant improvement over typical disease progression without treatment.
Patients with SMA later in life were evaluated in the second, randomized placebo-controlled study. The study included 180 patients with spinal muscular atrophy, between the ages of 2-25. The primary endpoint was the change from baseline in the overall score (motor function test) at a one-year mark. Patients under treatment with Evrysdi experienced an average score increase of 1.36 over one year, compared to a decrease of 0.19 in patients taking placebo (the ineffective treatment).
The most common side effects of the new drug Evrysdi include fever, diarrhea, rashes, mouth ulcers, joint pain, and urinary tract infections, in addition to other side effects that appear in those with early infection, such as upper respiratory infection, pneumonia, constipation and vomiting.
Spinal muscular atrophy
> What is spinal muscular atrophy? The term spinal muscular atrophy refers to a group of genetic diseases that destroy and kill specialized nerve cells in the brain and spinal cord (called motor neurons). Motor neurons control basic skeletal muscle activity such as speaking, walking, breathing, and swallowing, and the movement of the arms, legs, face, chest, throat, and tongue. When there are disturbances in the signals between the motor neurons and the muscles, the muscles gradually weaken, begin to emaciate and develop tremors (called fasciculations).
The causes of spinal muscular atrophy. The most common form of SMA is caused by an abnormal or missing gene known as the motor neuron 1 gene (SMN1) that is responsible for the production of an essential protein for motor neurons.
The most common form of SMA results from defects in both copies of the motor neuron 1 (SMN1) gene on chromosome 5q that produce the motor neuron (SMN) protein and maintain the health and function of these cells. Individuals with SMN have insufficient levels of the SMN protein, which leads to loss of motor neurons in the spinal cord and thus to weakness and wasting of skeletal muscles. This weakness is often more severe in the trunk, leg and arm muscles than in the muscles in the hands and feet. There are many types of SMA that are caused by mutations in other genes, and these types differ in the age at which they appear and the severity of muscle weakness. However, there is overlap between all types.
> The role of heredity and how is the disease inherited? Except in rare cases, SMA is inherited in an autosomal recessive fashion, meaning that the affected individual has two mutated genes, and often inherits one from each parent. Those who carry a single mutated gene are carriers of the disease without developing any symptoms. Recessive chromosomal diseases may affect more than one person of the same generation (siblings or cousins).
Types of conditions
There is a wide range of weakness in SMA that is caused by defects in the SMN1 gene. From prenatal infection with breathing difficulties at birth to mild weakness in adults. Accordingly, this most common form of SMA can be classified into four types, which are:
Type 1: It is called Werdnig-Hoffmann disease. It usually appears in children before 6 months of age. Severe cases are accompanied by a decrease in movements even in the womb and are born with cramps and breathing difficulties, and death occurs in the first year of life without treatment. Symptoms include decreased muscle tone, decreased movement of the extremities, decreased tendon response, straining, swallowing and feeding difficulties, and impaired breathing. These children also develop scoliosis (curvature of the spine) or other structural abnormalities as they age. Without any treatment, affected children never sit or stand, and the vast majority usually die from respiratory failure before the age of two years. Today, with more proactive clinical care and newly available disease modification treatment, these children have been able to live longer and reach higher movement milestones such as sitting and even walking.
> Type II: It is the moderate form, its first symptoms appear between 6 and 18 months of age, and some people may appear early. Affected people are able to sit without support but are unable to stand or walk without assistance, and some may lose the ability to remain seated independently over time without treatment. They may experience breathing difficulties including hypoventilation during sleep. Disease progression is variable without treatment. Life expectancy drops but most people live to their teens or young adults. With disease-modifying treatment and preemptive clinical care, type 2 patients improved greatly.
> Type III: Symptoms appear after 18 months of age, with difficulty walking and running, climbing stairs, or getting up from a chair, then the injured can walk independently. Proximal leg muscles are often affected first, with tremors appearing in the hands. Complications include scoliosis and joint cramps – chronic shortening of the muscles or tendons around the joints – due to abnormal muscle tension and weakness, which prevents the joints from moving freely, and they are susceptible to a respiratory infection. With care, care and disease-modifying treatment, most of them enjoy good results and a normal life.
Type IV: symptoms appear after the age of 21 years, with mild to moderate weakness in nearby muscles and other symptoms.
Diagnosis and treatment
Diagnosis. A blood test is available to look for missing or mutations in the SMN1 gene. This test identifies at least 95 percent of the types of disease (I, II, and III) and may also reveal whether a person carries a defective gene that can be transmitted to children. If the SMN1 gene is not found, electromyography (which records the electrical activity of the muscles during contraction and at rest), nerve conduction velocity study (to measure a nerve’s ability to send an electrical signal), muscle biopsy (to diagnose many neuromuscular disorders), and tests Other blood.
Are there treatments for this disease? Until recently, there was no complete cure for SMA that was available to control symptoms and prevent complications.
Pharmacological treatments. In December 2016. The US Food and Drug Administration approved nusinersen (Spinraza ™) as the first drug approved for treating children and adults with spinal muscular atrophy. The drug is given by injection into the fluid surrounding the spinal cord and is designed to increase the production of the full-length SMN protein, which is critical for the maintenance of motor neurons. The benefit is best documented in infants and children, especially when started early. Several other treatments are in late stages of development and may become available for affected individuals in the near future.
In May 2019. The US Food and Drug Administration approved the abeparovec-xioi (Zolgensma ™) gene therapy for children younger than 2 years of age with childhood SMA. The safe virus delivers a fully functional human gene to the target motor neurons, which in turn improves muscle movement and function and improves survival.
On August 7, 2020, the US Food and Drug Administration approved the new drug Evrysdi (risdiplam), which led to significant improvement after 23 months or more of treatment, during which 81 percent of patients were able to survive without permanent ventilation.
Physical therapy, occupational therapy and rehabilitation may help improve posture, prevent joint rigidity, and slow muscle weakness and atrophy. Stretching and strengthening exercises may help reduce contractures, increase range of motion, and maintain circulation. Some people require additional treatment for speech and swallowing difficulties. Assistive devices such as braces or braces, orthoses, speech syntheses and wheelchairs may be helpful in improving functional independence.
> Proper nutrition and calories are essential for maintaining weight and strength while avoiding fasting for long periods. People who are unable to chew or swallow may need to have a feeding tube inserted. Non-invasive ventilation at night can improve breathing during sleep, and some individuals may also need daytime breathing assistance due to weak neck, throat and chest muscles.