Spinal muscular atrophy 1
Alternate names[edit | edit source]
Werdnig-Hoffmann disease; Werdnig Hoffmann disease; Muscular atrophy, infantile; SMA1; SMA, infantile acute form; Proximal spinal muscular atrophy, type 1; Proximal spinal muscular atrophy type 1; SMA type 1; SMA type I; SMA-I
Definition[edit | edit source]
Spinal muscular atrophy 1 (SMA1), also known as Werdnig Hoffmann disease, is a genetic neuromuscular disorder that affects the nerve cells that control voluntary muscles (motor neurons).
Epidemiology[edit | edit source]
- Spinal muscular atrophy affects 1 per 8,000 to 10,000 people worldwide.
- Spinal muscular atrophy type I is the most common type, accounting for about half of all cases.
Cause[edit | edit source]
- SMA1 is caused by changes (pathogenic variants also called mutations) in the SMN1 gene.
- The SMN1 gene provides instructions for making a protein called the survival motor neuron (SMN) protein.
- The SMN protein is one of a group of proteins called the SMN complex, which is important for the maintenance of motor neurons.
- Motor neurons transmit signals from the brain and spinal cord that tell skeletal muscles to tense (contract), which allows the body to move.
- Most people with spinal muscular atrophy are missing a piece of the SMN1 gene, which impairs SMN protein production.
- A shortage of SMN protein leads to motor neuron death, and as a result, signals are not transmitted between the brain and muscles.
- Muscles cannot contract without receiving signals from the brain, so many skeletal muscles become weak and waste away, leading to the signs and symptoms of spinal muscular atrophy.
Inheritance[edit | edit source]
- Spinal muscular atrophy 1 (SMA1) is inherited in an autosomal recessive manner.
- This means that to be affected, a person must have a change (mutation) in both copies of the responsible gene in each cell.
- The parents of an affected person usually each carry one mutated copy of the gene and are referred to as carriers.
- Carriers are typically unaffected and do not have any signs or symptoms of the condition.
When two carriers of an autosomal recessive condition have children, each child has a:
- 25% chance to have the condition
- 50% chance to be an unaffected carrier like each of the parents
- 25% chance to not have the condition and not be a carrier.
An unaffected sibling of a person with SMA1 has a 2/3 chance to be a carrier. Approximately 2% of cases of SMA1 are not inherited from both parents. In these cases, the affected person inherits one mutated copy of the gene from one carrier parent, and has a new mutation that occurs for the first time in the other copy of the gene.
Signs and symptoms[edit | edit source]
- Infants with spinal muscular atrophy 1 (SMA1) experience severe weakness before 6 months of age.
- Muscle weakness, lack of motor development and poor muscle tone (hypotonia) are the major features of SMA1.
- Infants with the poorest outlook have problems with breathing and feeding (sucking and/or swallowing).
- Some children develop scoliosis (curvature of the spine) or other skeletal abnormalities.
- Intellectual development is usually normal.
- Affected children are not able to sit up or stand, and the vast majority do not survive past 2 years of age due to respiratory failure.
Diagnosis[edit | edit source]
- Genetic testing for spinal muscular atrophy 1 (SMA1) is available.
- Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible, if the disease-causing mutations in the family have been identified.
- SMA1 is caused by mutations in the SMN1 gene, and extra copies of the SMN2 gene affect the severity of the condition.
- In some cases, interpreting results of carrier testing for SMA is difficult.
- Approximately 6% of parents of a child with SMA due to deletions in each copy of the gene have normal results of SMN1 dosage testing (carrier testing) for one of two reasons.
- Most people have one copy of SMN1 on each chromosome.
- However, about 4% of carriers have two copies of SMN1 on a single chromosome and a deletion on the other chromosome.
- These carriers with two copies of SMN1 on one chromosome are misdiagnosed as non-carriers by the SMN1 dosage test (they have a false negative test result).
- The second reason is that a new (de novo) deletion on one copy of the SMN1 gene occurs in 2% of people with SMA; in these cases, only one parent is a carrier.
Treatment[edit | edit source]
- In December 2016, nusinersen (Spinraza) became the first FDA approved treatment for SMA1.
- Continued treatment with nusinersen is allowing many babies with SMA1 to reach and maintain age appropriate developmental milestones, including sitting, crawling, and walking.
- On average, breathing problems, nutrition problems, and hospital admissions have also decreased.
- However, response to treatment does vary.
- Some babies with SMA1 may not respond to the nusinersen at all or may have medical complications that prevent use of the treatment.
- Other treatments remain supportive.
The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition.
- Risdiplam (Brand name: Evrysdi)was approved for the treatment of spinal muscular atrophy (SMA) in patients 2 months of age and older.
- Nusinersen (Brand name: Spinraza) was approved for the treatment of spinal muscular atrophy in pediatric and adult patients.
- Onasemnogene abeparvovec (Brand name: Zolgensma) was approved for the treatment of pediatric patients less than 2 years of age with spinal muscular atrophy (SMA) with bi-allelic mutations in the survival motor neuron 1 (SMN1) gene.
NIH genetic and rare disease info[edit source]
Spinal muscular atrophy 1 is a rare disease.
Spinal muscular atrophy 1 Resources | |
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Contributors: Prab R. Tumpati, MD