Spinal muscular atrophy: what is it, treatment, medications, prognosis

What is spinal muscular atrophy?

Spinal muscular atrophy (SMA) is a group of inherited diseases characterized by the loss of certain nerve cells in the spinal cord called motor neurons or anterior horn cells. Motor neurons (i.e. motor neurons) receive nerve impulses transmitted from the brain to spinal cord (brain stem), and, in turn, transmit impulses to the muscle through peripheral nerves. Loss of motor neurons leads to progressive muscle weakness and wasting (atrophy) of the muscles closest to the trunk (proximal muscles), such as the shoulders, hips, and back. These muscles are essential for crawling, walking, sitting, and head control. More severe types of SMA can affect the muscles involved in swallowing and breathing. SMA is subdivided into subtypes based on the age of onset and the maximum attained. SMA types 0, 1, 2, 3, and 4 are inherited as autosomal recessive genetic disorders and are associated with abnormalities (mutations) in genes 

SMN1 and SMA2which are located on chromosome 5.

Signs and symptoms

SMA type 0 - the most severe form of the disease, characterized by decreased fetal mobility, joint abnormalities, difficulty swallowing and respiratory failure.

​SMA type 1 - the most common type of spinal muscular atrophy, as well as a severe form of the disease. Infants with SMA type 1 experience severe weakness before 6 months of age and never sit up on their own. Muscle weakness, lack of motor development, and poor muscle tone are the main clinical manifestations of type 1 SMA. Infants with the most severe prognosis have problems sucking or swallowing. Some people experience diaphragmatic (abdominal) breathing in the first few months of life. Muscle weakness occurs on both sides of the body; eye muscles are not affected. Twitching of the tongue is common. Intelligence is normal. Most sick children die before the age of two, but survival may depend on the degree of respiratory function.

Onset of weakness in patients with SMA type 2 usually 6 to 12 months. Sick children can sit on their own at an early stage of development, but cannot even walk 3 meters on their own. Tremor is almost always observed in type 2 SMA (tremor) fingers. Approximately 70% of those affected do not have deep tendon reflexes. Those with type 2 SMA usually cannot sit up on their own by mid-teens or later.

Patients with SMA type 3 (Kugelberg-Welander syndrome) learn to walk, but often fall and have difficulty climbing and descending stairs at the age of 2–3 years. Legs are more affected than arms. The long-term prognosis depends on the degree of motor function achieved during childhood.

The onset of muscle weakness in people with SMA type 4 comes after 10 years; these patients are usually in outpatient care for up to 60 years.

Complications of SMA include:

• scoliosis;
• joint contractures;
• pneumonia;
• metabolic disorders such as severe metabolic acidosis and dicarboxylic aciduria.

Causes

Spinal muscular atrophy of all types is inherited as an autosomal recessive genetic disorder and is associated with abnormalities (mutations) in genes SMN1 and SMA2 on chromosome 5 at chromosomal locus 5q11-q13. SMA1 considered to be the main gene causing the disease. Approximately 95-98% of patients have gene deletions SMA1 and 2-5% have specific mutations in the gene SMA1that lead to decreased production of SMN protein. When three or more copies of the gene are also present SMA2, the disease may be more mild.

Genetic diseases are defined by a combination of genes for a specific trait that are found on chromosomes received from the father and mother.

Recessive genetic disorders occur when a person inherits the same abnormal gene for the same trait from each parent. If a person receives one normal gene and one gene for the disease, they will be a carrier of the disease, but usually asymptomatic. The risk for two carrier parents of passing on the defective gene and therefore having a sick child is 25% with each pregnancy. The risk of having a child who will be a carrier, like the parents, is 50% with every pregnancy. The probability that a child will receive normal genes from both parents and be genetically normal for this trait is 25%. The risk is the same for men and women.

Affected populations

The incidence of SMA is approximately 1 in 10,000 live births.

Diagnostics

A diagnosis of SMA is suspected when symptoms are present and is confirmed by molecular genetic testing. Molecular genetic testing is used to determine the presence of a mutation in a gene SMN1. SMA types 0, 1, 2, 3, and 4 are caused by partial or complete loss of a gene SMN1, and about 95% of affected patients will show deletion of both copies of a particular portion (exon 7 or exon 8) of the gene. About 5% of those affected will have an exon 7 deletion in one copy of the gene SMN1 and another mutation in a different copy of the gene SMN1. Molecular genetic testing can also be used to determine the copy number of a gene SMN2.

Before the advent of molecular testing, neurophysiological studies were used for diagnosis and muscle biopsy, but these tests are rarely used today, unless there are problems with molecular genetic testing.

Standard treatments

- Nusinersen.

In December 2016, the Food and Drug Administration (FDA) The Food and Drug Administration (FDA) has approved nusinersen (Spinraza), the first drug approved for the treatment of children (including newborns) and adults with spinal muscular atrophy. Nusinersen is an antisense oligonucleotide developed for the treatment of SMA caused by mutations on chromosome 5q that lead to a deficiency in the SMN protein. Using in vitro assays and studies in transgenic animal models of SMA, it has been shown that nusinersen increases the incorporation of exon 7 into SMN2 ribonucleic acid (mRNA) transcripts and full-length protein production SMN.

Nusinersen's endorsement was based on ENDEAR research. The ENDEAR Study (n = 121) is a randomized, double-blind, sham-controlled phase 3 study in patients with infantile onset (most likely to develop type 1) SMA. In a planned interim analysis, a greater percentage of infants who received nusinersen achieved a motor response compared to those who did not receive treatment (40% versus 0%; p <0.0001) according to Hammersmith Infant Neurological Examination (HINE). In addition, a smaller percentage of patients died in the nusinersen group (23%) compared with untreated patients (43%).

Interim data from another phase 3 study, CHERISH, included 126 non-ambulatory patients with late-onset SMA (corresponds to type 2), including patients with signs and symptoms onset> 6 months of age and 2 to 12 years of age at the time of screening. A pre-defined interim analysis showed a difference of 5.9 points (p = 0.0000002) at 15 months between treatment groups (n = 84) and sham-controlled (n = 42) examination as measured by the Hammersmith Extended Functional Motor Scale (HFMSE). From baseline to 15 months of treatment, patients in the nusinersen group achieved an average improvement of 4.0 points on HFMSE, while patients who did not receive treatment decreased by an average of 1.9 points.

- She is completely abeparvec.

Onsemnogen abeparvovec (Zolgensma) is a recombinant gene therapy based on AAV9, designed to deliver a copy of a gene encoding a human survival motor neuron protein (eng. Survival of motor neuron [SMN]). It is indicated for gene replacement therapy in children 2 years of age and younger with type 1 spinal muscular atrophy. (also called Werdnig-Hoffmann disease) who have a biallelic mutation in the survival motor neuron 1 gene (SNM1).

The approval was based on the ongoing phase 3 study STR1VE and the completed phase 1 START study. Fifteen patients with SMA type 1 received a single dose of intravenous serotype 9 adeno-associated virus carrying complementary SMN DNA encoding the missing SMN protein. At the time of data clipping, all 15 patients were alive and free of complications at 20 months of age, compared with a survival rate of 8% in the historical cohort. In the high-dose cohort, a rapid increase from baseline in CHOP INTEND scores after gene delivery with an increase of 9.8 points after 1 month and 15.4 points after 3 months compared with a decrease in this indicator in the historical cohort. Of the 12 high-dose patients, 11 sat unaided, 9 rolled over, 11 ate and could speak independently, and 2 walked on their own.

An interim analysis of data from the ongoing phase 3 study STR1VE showed that 21 of 22 (95%) patients were alive and free of complications. The median age was 9.5 months, with 6 out of 7 (86%) patients aged 0.5 months and older surviving without any complications. Interim results also showed permanent improvement in motor milestones (eg, keeping the head straight, rolling over, sitting unsupported).

- Risdiplam.

Risdiplam (Eurydie) is a survival motor neuron 2 (SMN2) mRNA modifier designed to treat mutations on chromosome 5q that lead to a deficiency of the SMN protein. It is indicated for spinal muscular atrophy, including types 1, 2, and 3, in adults and children 2 months of age and older. The approval was confirmed by the results of several Phase 3 trials (FIREFISH, SUNFISH, JEWELFISH, RAINBOWFISH).

FIREFISH is an open-label, two-part pivotal clinical trial in infants 2–7 months of age with type 1 SMA. The results showed that 41% (7/17) of infants achieved the ability to sit without support for at least 5 seconds, and 90% (19/21) remained alive without constant ventilation after 12 months. After a minimum of 23 months of treatment and reaching the age of 28 months or older, 81% (17/21) of all patients survived without constant artificial ventilation.

The SUNFISH study was a double-blind, placebo-controlled baseline clinical a two-part study in children and young adults (ages 2 to 25) with SMA 2 or 3 types. There was a clinically significant and statistically significant improvement in motor function in children and adults, as measured by the change in the overall MFM-32 score from baseline. Improvement in motor function of the upper limbs from baseline, as measured by the revised upper module extremities (RULM), a secondary independent endpoint of motor function study, also showed statistically significant improvement.

JEWELFISH is an open-label study in patients with type 1, 2, or 3 SMA aged 6 months to 60 years who have previously received SMA therapy, gene therapy, or olesoxim. The study included 174 people.

RAINBOWFISH is an open-label, one-stage, multicenter study dedicated to the study of efficacy, safety, pharmacokinetics and pharmacodynamics risdiplama in infants (~ n = 25) from birth to 6 weeks of age (at first dose) with a genetically diagnosed SMA who do not yet have symptoms. At the time of this writing, recruitment is still underway.

- Other treatments.

In laboratory studies, it has been found that drugs such as valproic acid, phenylbutyrate, hydroxyurea and albuterol, increase SMN transcription, but clinical trials have not shown significant improvement in progression diseases. SMA CARNIVAL studies (Parts 1 & 2) have shown that valproic acid and L-carnitine are ineffective in with regard to improvement in strength or functionality after 6 and 12 months in both outpatient and general children. Side effects were reported in 85% of patients. Gabapentin, riluzole and olesoxim have been studied for their putative neuroprotective properties, but without significant clinical benefits. Treatment with creatine, phenylbutyrate, gabapentin, thyrotropin-releasing hormone, and hydroxyurea also proved ineffective.

A randomized, double-blind, placebo-controlled study in men with genetically confirmed spinobulbar muscular atrophy (Kennedy disease) with oral dutasteride (a 5-alpha reductase inhibitor that lowers dihydrotestosterone) has not shown significant effects on muscle weakness and development. The failure of this study to treat spinal bulbar muscular atrophy may be due in part to insufficient study power and a relatively short period during which the effect of the treatment can be accurately measured due to the slowly progressive nature of this diseases. These results also suggest that the role of androgens in spinal bulbar muscle atrophy is complex.

Supportive care should be aimed at improving the quality of life of patients and minimizing disability, especially in patients with slow progression. The goals are to maximize patient independence and improve quality of life at every stage of the disease.

Treatment of patients with spinal muscular atrophy onset in adults is similar to treatment for amyotrophic lateral sclerosis (ALS), except that the course and duration of life with spinal muscular atrophy is much longer.

An interdisciplinary approach is important. Once the diagnosis is made, nocturnal oximetry, respiratory muscle function tests, cough efficacy, forced vital capacity (for patients> 5 yr), video swallowing examination, physical and occupational therapy assessment, ancillary equipment assessment and radiography hip / spine. Recognizing mandibular dysfunction such as limited mouth opening is an important factor in preventing aspiration.

Interventions such as chest physiotherapy, assisted cough, night (+/- daytime) non-invasive ventilation and Nissen fundoplication for non-seated patients. A gastrostomy tube is often done when diagnosed with type 1 SMA.

The use of splints, braces and orthoses for the spine can be individually tailored to each patient. The use of wheelchairs should be determined by the patient's level of fatigue while moving, as well as the speed at which they fall.

Pregnant women with spinal muscular atrophy do not have an increased risk of miscarriage or hypertension. There were higher rates of cesarean section (42.5%) and premature birth (29.4%). About a third of patients reported worsening symptoms during pregnancy.

Genetic counseling is recommended for patients and their families.

Forecast

In the absence of pharmacological treatment, the condition of patients with spinal muscular atrophy worsens over time. Recently, survival has increased in patients with severe SMA with active and regular respiratory and nutritional support.

If left untreated, most children diagnosed with SMA types 0 and 1 do not reach 4 years of age because recurrent respiratory problems are the leading cause of death. With proper care, milder cases of type 1 SMA (which account for approximately 10% of all cases of type 1 SMA) survive into adulthood. Long-term survival in type 1 SMA is insufficiently proven; however, recent advances in respiratory support appear to have reduced mortality.

In untreated SMA type 2, the disease progresses more slowly and life expectancy is reduced than in the healthy population. Death often occurs before the age of 20, although many people with SMA survive to the age of their parents and grandparents. Type 3 SMA has a normal or near-normal life expectancy if the standards of care are met. Type 4 SMA in adults usually causes mobility impairment and does not affect life expectancy.