Spinal Muscular Atrophy With Progressive Myoclonic Epilepsy (SMA-PME)

Spinal muscular atrophy with progressive epilepsy (SMA-PME) is a very rare type of SMA. SMA-PME is also an inherited neuromuscular disorder. However, it is caused by different gene mutations than the major types of SMA. Only about a dozen families have been reported to carry SMA-PME.

People with SMA-PME show typical symptoms of SMA, including progressive muscle weakness. They also experience epileptic seizures. There is no cure for SMA-PME. The focus is on managing symptoms and preventing complications.

What is progressive myoclonic epilepsy?

Progressive myoclonic epilepsy (PME) is a group of rare diseases that show epileptic seizures and “myoclonus.” Myoclonus is a brief and involuntary twitch or jerk. Occasional myoclonic jerks occur for everyone, especially while falling asleep. But frequent and widespread myoclonic jerks can be a sign of neurological disorders.¹

PME diseases usually get worse over time and can be fatal. PME can occur on its own, such as in Lafora disease. PME can also be associated with other disorders, such as SMA-PME.¹

What causes SMA with PME?

SMA-PME is a very rare type of SMA. It was first described in the 1970s. It does not have the same genetic cause as the major types of SMA. This means it is not caused by alterations in the SMN1 gene. Instead, SMA-PME is caused by mutations in the ASAH1 gene.^1,2

SMA-PME is inherited in a “recessive” pattern. This means that children must inherit 2 copies of mutated ASAH1 (1 from each parent) to have SMA-PME. Children who inherit 1 copy of the normal ASAH1 gene and 1 copy of the mutated ASAH1 gene are “carriers.” A child of 2 carriers has a 25 percent chance of having SMA-PME.¹

The ASAH1 gene provides instructions for cells to make an enzyme called “acid ceramidase.” This enzyme breaks down a special type of lipid (fat) called ceramide. The breakdown products of ceramide are used to produce “myelin.” Myelin is a fatty substance that surrounds neurons to help them communicate.³

Low levels of “acid ceramidase” in SMA-PME cause low myelin production. This leads to nerve cell damage. Farber disease is also caused by mutations in the ASAH1 gene. Farber disease seems to reduce acid ceramidase function further than SMA-PME. This causes symptoms to start earlier and be more severe than in SMA-PME.^4,5

What are symptoms of SMA with progressive myoclonic epilepsy?

People with SMA-PME usually start showing symptoms of SMA before age 6. This includes progressive muscle weakness and wasting. Usually, children with SMA-PME lose the ability to sit or stand. They may show other symptoms and complications of SMA, including:⁵

• Difficulty controlling their head
• Difficulty swallowing
• Tongue twitches
• Scoliosis
• Breathing problems, which is a common cause of death

Symptoms of myoclonic epilepsy then appear afterwards, usually before age 12. These symptoms include:^5,6

• Brief seizures
• Myoclonic jerks
• Trouble walking or speaking
• Cognitive decline

Doctors can diagnose SMA-PME with a genetic test for ASAH1 mutations. They may also perform tests such as magnetic resonance imaging (MRI) and electroencephalograms (EEGs).^1,6

How is progressive myoclonic epilepsy treated?

There is no cure for SMA-PME. The disease-modifying treatments for SMA are also not suitable for children with SMA-PME. Those treatments work by fixing the lack of “survival of motor neuron” (SMN) protein that causes the major SMA types.⁷

Some research is being done to develop drugs that increase the amount of acid ceramidase. Until then, treatment is focused on managing symptoms. This may include:⁴

• Anti-inflammatory drugs to address pain
• Physical therapy
• Nutritional support
• Breathing support
• Anti-epileptic drugs, though myotonic seizures may be resistant to these drugs