Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) is a neurological condition that begins in childhood. SMA-PME causes muscle weakness and wasting (atrophy) and a combination of seizures and uncontrollable muscle jerks (myoclonic epilepsy).

In individuals with SMA-PME, spinal muscular atrophy results from a loss of specialized nerve cells, called motor neurons, in the spinal cord and the part of the brain that is connected to the spinal cord (the brainstem). After a few years of normal development, affected children begin experiencing muscle weakness and atrophy in the lower limbs, causing difficulty walking and frequent falls. The muscles in the upper limbs are later affected, and soon the muscle weakness and atrophy spreads throughout the body. Once weakness reaches the muscles used for breathing and swallowing, affected individuals develop life-threatening breathing problems and increased susceptibility to pneumonia.

A few years after the muscle weakness begins, affected individuals start to experience recurrent seizures (epilepsy). Most people with SMA-PME have a variety of seizure types. In addition to myoclonic epilepsy, they may have generalized tonic-clonic seizures (also known as grand mal seizures), which cause muscle rigidity, convulsions, and loss of consciousness. Affected individuals can also have absence seizures, which cause loss of consciousness for a short period that may or may not be accompanied by muscle jerks. In SMA-PME, seizures often increase in frequency over time and are usually not well-controlled with medication. Individuals with SMA-PME may also have episodes of rhythmic shaking (tremors), usually in the hands; these tremors are not thought to be related to epilepsy. Some people with SMA-PME develop hearing loss caused by nerve damage in the inner ear (sensorineural hearing loss).

Individuals with SMA-PME have a shortened lifespan; they generally live into late childhood or early adulthood. Near the end of their lives, affected individuals often have limited mobility, difficulty swallowing, and decline in cognitive functioning. The cause of death is often respiratory failure or pneumonia.

SMA-PME is caused by variants (also called mutations) in the ASAH1 gene. This gene provides instructions for making an enzyme called acid ceramidase. This enzyme is found in lysosomes, which are cell compartments that digest and recycle materials. Within lysosomes, acid ceramidase breaks down fats called ceramides into a fat called sphingosine and a fatty acid. These two breakdown products are recycled to create new ceramides for the body to use. Ceramides have several roles within cells. For example, they are a component of a fatty substance called myelin that insulates and protects nerve cells.

ASAH1 gene variants that cause SMA-PME result in a reduction of acid ceramidase activity to a level less than one-third of normal. Inefficient breakdown of ceramides and impaired production of its breakdown products likely play a role in the nerve cell damage that leads to the features of SMA-PME, but the exact mechanism is unknown.

Normal Function

The ASAH1 gene provides instructions for making an enzyme called acid ceramidase. This enzyme is found in lysosomes, which are cell compartments that digest and recycle materials. Within lysosomes, acid ceramidase breaks down fats (lipids) called ceramides. Ceramides are typically found within the membranes that surround cells and play a role in regulating cell maturation (differentiation), growth and division of cells (proliferation), and controlled cell death (apoptosis). Additionally, ceramides are a component of a fatty substance called myelin that insulates and protects nerve cells. Ceramides also serve as building blocks for more complex lipids. When ceramides need to be replaced, they travel to lysosomes where acid ceramidase breaks them down into a fat called sphingosine and a fatty acid. These two breakdown products are recycled to create new ceramides for the body to use.

Health Conditions Related to Genetic Changes

Farber lipogranulomatosis

Variants (also known as mutations) in the ASAH1 gene have been found to cause Farber lipogranulomatosis. This condition is characterized by the buildup of ceramides and other fats in cells throughout the body, particularly around the joints. Most of the variants associated with Farber lipogranulomatosis change a single protein building block (amino acid) in acid ceramidase, which severely reduces the activity of the enzyme, typically to less than one-tenth of normal. As a result, the enzyme cannot break down ceramides properly and they build up in the lysosomes of various cells, including in the lungs, liver, muscles, brain, cartilage, and bone. It is unclear how an accumulation of ceramides impairs the normal functioning of cells, but damage to the affected cells leads to the voice, skin, and joint problems that are characteristic of Farber lipogranulomatosis. Ceramides influence various cell functions, and it is likely that abnormal regulation of these processes also contributes to the features of this condition.

Spinal muscular atrophy with progressive myoclonic epilepsy

Variants in the ASAH1 gene have been found to cause spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME). This condition is characterized by muscle weakness and wasting (atrophy) and a combination of seizures and uncontrollable muscle jerks (myoclonic epilepsy) that begin in childhood. The ASAH1 gene variants that cause SMA-PME result in a reduction of acid ceramidase activity to a level less than one-third of normal. The decrease in acid ceramidase activity leads to inefficient breakdown of ceramides and impaired production of its breakdown products sphingosine and fatty acids. The increase in ceramides and reduction in sphingosine and fatty acids likely play a role in the development of the features of SMA-PME, but the exact mechanism is unknown.

The reduction in acid ceramidase activity associated with SMA-PME is less than what occurs in another condition called Farber lipogranulomatosis (described above). Researchers suspect that the small amount of enzyme activity in SMA-PME allows some ceramide breakdown to occur, so the ceramides do not accumulate and damage cells as extensively as seen in Farber lipogranulomatosis. However, because SMA-PME is so rare, the effects of the enzyme changes are still unclear.

Other Names for This Gene

• AC
• ACDase
• acylsphingosine deacylase
• ASAH
• ASAH1_HUMAN
• FLJ21558
• FLJ22079
• N-acylsphingosine amidohydrolase (acid ceramidase) 1
• PHP
• PHP32

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have variants. The parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition.

SMA-PME is a rare disorder; approximately 50 affected individuals have been described in the scientific literature.

What is spinal muscular atrophy?

Spinal muscular atrophy (SMA) refers to a group of hereditary diseases that can damage and kill specialized nerve cells in the brain and spinal cord (motor neurons). Motor neurons control movement in the arms, legs, face, chest, throat, and tongue, as well as skeletal muscle activity, such as speaking, walking, swallowing, and breathing.

The most common form of SMA is caused by a mutated or missing gene known as the survival motor neuron gene 1 (SMN1), which is typically responsible for the production of a protein essential to motor neurons. There are four types of this form of SMA:

1. Type l (also known as Werdnig-Hoffman disease or infantile-onset SMA) is usually evident before 6 months of age. The most severely affected children will have reduced movement and chronic shortening of muscles or tendons (contractures). Other children may have symptoms including reduced muscle tone, lack of tendon reflexes, twitching, skeletal abnormalities, and problems with swallowing and feeding. Without treatment, many affected children die before age 2.
2. SMA Type ll is usually first noticed between 6 and 18 months of age. Children can sit without support but are unable to stand or walk without help. Children may also have respiratory difficulties. Life expectancy is reduced but most individuals live into adolescence or young adulthood.
3. SMA Type lll (also known as Kugelberg-Welander disease) is seen after age 18 months. Children can walk independently but may have difficulty doing so or when running, rising from a chair, or climbing stairs. Other complications may include curvature of the spine, contractures, and respiratory infections. With treatment, most individuals can have an average lifespan.
4. SMA Type IV develops after 21 years of age, with mild to moderate leg muscle weakness and other symptoms.

Who is more likely to get spinal muscular atrophy?

The most common form of SMA is caused by a mutated or missing gene known as the survival motor neuron gene 1 (SMN1). The SMN1 gene is located on chromosome 5q and produces the survival motor neuron (SMN) protein which maintains the health and normal function of motor neurons.

People living with SMA have insufficient levels of the SMN protein, which leads to loss of motor neurons in the spinal cord and causes weakness and wasting of the skeletal muscles. The weakness is often more severe in the trunk (chest) and upper leg and arm muscles than in muscles of the hands and feet.

Many types of spinal muscular atrophy are caused by changes in the same genes. Less common SMA forms are caused by changes in other genes including the:

• VAPB gene on chromosome 20
• DYNC1H1 gene on chromosome 14
• BICD2 gene on chromosome 9
• UBA1 gene on the X chromosome

Except in rare cases, SMA is inherited in an autosomal recessive manner, meaning that the affected individual has two mutated genes, often inheriting one from each parent. Those who carry only one mutated gene are carriers of the disease who will not have any symptoms.

How is spinal muscular atrophy diagnosed and treated?

Diagnosing SMA

A blood test is available to look for mutations or deletions of the SMN1 gene. This test identifies at least 95 percent of SMA Types I, II, and III, and also may reveal if a person is a carrier. If the SMN1 gene is not found to be problematic or the individual's history and examination are not typical of SMA, other diagnostic tests may include:

• Electromyography to record the electrical activity of the muscles during contraction and at rest
• Nerve conduction velocity studies to measure the nerve's ability to send an electrical signal
• Muscle biopsy to diagnose many neuromuscular disorders
• Other blood tests

Treating SMA

There is no complete cure for SMA. Treatment consists of managing the symptoms and preventing complications.

Medications

• The U.S. Food and Drug Administration (FDA) approved nusinersen (Spinraza™) as the first drug approved to treat children and adults with SMA. The drug is designed to increase production of the SMN protein, which is critical for the maintenance of motor neurons.
• The FDA approved onasemnogene abeparovec-xioi (Zolgensma ™) gene therapy for children less than two years old who have infantile-onset SMA. A safe virus delivers a fully functional human SMN gene to the targeted motor neurons, which in turn improves muscle movement and function and survival.
• The FDA approved the orally-administered drug risdiplam (Evrysdi) to treat patients age two months of age and older with SMA.

Physical therapy, occupational therapy, and rehabilitation may help to improve posture, prevent joint immobility, and slow muscle weakness and atrophy. Stretching and strengthening exercises may help reduce contractures, increase range of motion, and keeps circulation flowing. Some individuals require additional therapy for speech and swallowing difficulties. Assistive devices such as supports or braces, orthotics, speech synthesizers, and wheelchairs may be helpful to improve functional independence.

Proper nutrition and calories are essential to maintaining weight and strength, while avoiding prolonged fasting. People who cannot chew or swallow may require insertion of a feeding tube. Non-invasive ventilation at night can improve breathing during sleep, and some individuals also may require assisted ventilation during the day due to muscle weakness in the neck, throat, and chest.

What are the latest updates on spinal muscular atrophy?

The National Institute of Neurological Disorders and Stroke (NINDS), a component of the National Institutes of Health (NIH), conducts basic, translational, and clinical research on SMA in laboratories at the NIH and also supports research through grants to major medical institutions across the country.

Scientists have developed model systems in animals and cells to study disease processes and speed up the testing of potential therapies, including the following:

• Gene therapy and specific drugs have been shown to halt motor neuron destruction and slow disease progression in mouse models and individuals with SMA. NINDS supports research to establish these methods and to provide a path toward clinical tests. Clinical trials for gene therapy in SMA are ongoing.
• Animal models of SMA represent critical tools in discovering and developing new therapies for SMA. Scientists developed zebrafish, mouse, and pig models, including models of less severe SMA types 2 and 3, which may greatly aid the identification of new therapeutic targets and candidate therapies.

Additionally, NIH-supported scientists have collected data on pre-symptomatic or recently diagnosed children with SMA types I, II, or III, and their healthy siblings. The goal of this study is to provide counselling and education to parents about possible clinical trial opportunities.

NINDS established the NeuroNext (NINDS Network for Excellence in Neuroscience Clinical Trials) clinical trials network to promote the rapid development and implementation of trials for neurological disorders that affect adults and/or children. The network is designed to develop early-phase trials aimed at identifying biomarkers—usually a physical trait or substance in the blood or other bodily fluids that can be measured to determine the presence and severity of a disease—and testing emerging therapies. One such project was to identify biomarkers for SMA and to understand the cause and mechanisms underlying the disease. Data gained through this study led to the approval decision for nusinersen (Spinraza™). Knowledge acquired from this study has also enhanced the design of additional clinical trials in SMA.