Spinal muscular atrophy with lower extremity predominance (SMA-LED) is characterized by muscle weakness and wasting (atrophy) in the lower limbs, most severely affecting the thigh muscles (quadriceps). (In SMA-LED, the "D" stands for dominant, which refers to the inheritance pattern of this condition.) The loss of nerve cells that control muscle movement (motor neurons) leads to atrophy of the muscles in the lower limbs. Affected individuals often have a waddling or unsteady walk and walk on the balls of their feet. They may have difficulty rising from a seated position and climbing stairs. Some people with SMA-LED also have weakness in upper limb muscles.

Joint deformities (contractures) in the hips, knees, feet, and ankles can occur in SMA-LED, and in severe cases are present from birth and can impair walking. Some individuals with this disorder have rigidity of joints (arthrogryposis) in their shoulders, elbows, and hands.

In most people with SMA-LED, the muscle problems are apparent in infancy or early childhood; however, about one-quarter of affected individuals do not develop muscle weakness until adulthood. The muscle weakness and related health problems typically do not worsen over time.

SMA-LED is caused by mutations in the DYNC1H1 gene or BICD2 gene. When this condition is caused by mutations in the DYNC1H1 gene, it is often known as SMA-LED type 1 or SMA-LED1, and when it is caused by mutations in the BICD2 gene, the condition is often known as SMA-LED type 2 or SMA-LED2.

The DYNC1H1 gene provides instructions for making a protein that is part of a group (complex) of proteins called dynein. This complex is part of a network that moves (transports) proteins and other materials within cells. The protein produced from the BICD2 gene attaches (binds) to the dynein complex, turning it on (activating it) and helping it bind to other cellular materials for transport. The BICD2 protein and the dynein complex help neighboring neurons communicate by transporting sac-like structures called synaptic vesicles that contain chemical messengers. The BICD2 protein also helps maintain the structure of a cell component called the Golgi apparatus, in which newly produced proteins are modified so they can carry out their functions.

DYNC1H1 and BICD2 gene mutations that cause SMA-LED disrupt the function of the dynein complex. As a result, transport of proteins, synaptic vesicles, and other materials within cells is reduced. Decreased synaptic vesicle transport in motor neurons, leading to impaired growth of neurons, is thought to contribute to the muscle weakness and atrophy experienced by people with SMA-LED. It is unclear why this condition primarily affects the lower limbs.

Additionally, BICD2 gene mutations impair the BICD2 protein's ability to maintain the structure of the Golgi apparatus within cells. As a result, the Golgi apparatus breaks down into small fragments and the altered BICD2 protein becomes trapped within these fragments. Loss of these cell components likely further contributes to the signs and symptoms of SMA-LED.

Normal Function

The BICD2 gene provides instructions for making one of a family of proteins called golgins. Golgins help maintain the structure of a cell component called the Golgi apparatus, in which newly produced proteins are modified so they can carry out their functions.

The BICD2 protein is found in all cells. The protein attaches (binds) to a group of proteins called the dynein complex, turning it on (activating it) and helping it bind to other cellular materials for transport. During transport, BICD2 stabilizes the dynein complex along a track-like system of small tubes called microtubules, similar to a conveyer belt. The BICD2 protein helps the dynein complex with protein transport, positioning of cell compartments, mobility of structures within the cell, and many other cell processes.

In nerve cells (neurons), the BICD2 protein helps the dynein complex transport sac-like structures called synaptic vesicles. These structures contain chemical messengers that allow neighboring cells to communicate with one another.

Health Conditions Related to Genetic Changes

Spinal muscular atrophy with lower extremity predominance

At least six mutations in the BICD2 gene have been found to cause spinal muscular atrophy with lower extremity predominance (SMA-LED). This condition is characterized by muscle weakness and wasting (atrophy) in the lower limbs that often begins in infancy or childhood.

The BICD2 gene mutations that cause SMA-LED replace single protein building blocks (amino acids). One mutation that has been found in multiple affected individuals and families replaces the amino acid serine with the amino acid leucine at position 107 in the BICD2 protein (written as Ser107Leu or S107L). This change and the other BICD2 gene mutations increase the activity of the BICD2 protein. Overactivity of the BICD2 protein changes its ability to bind with the dynein complex, leading to reduced movement of proteins, synaptic vesicles, and other materials within cells. Decreased synaptic vesicle transport in neurons that control muscle movement (motor neurons), leading to impaired growth of neurons, is thought to contribute to the muscle weakness and atrophy experienced by people with SMA-LED. It is unclear why this condition primarily affects the lower limbs.

Additionally, BICD2 gene mutations impair the protein's ability to maintain the structure of the Golgi apparatus within cells. As a result, the Golgi apparatus breaks down into small fragments and the altered BICD2 protein becomes trapped within these fragments. Loss of these cell components likely further contributes to the signs and symptoms of SMA-LED.

Other Names for This Gene

• bA526D8.1
• bic-D 2
• bicaudal D homolog 2
• coiled-coil protein BICD2
• cytoskeleton-like bicaudal D protein homolog 2
• homolog of Drosophila bicaudal D
• KIAA0699

Genomic Location

Normal Function

The DYNC1H1 gene provides instructions for making a protein that is part of a group (complex) of proteins called dynein. This complex is found in the fluid inside cells (cytoplasm). Dynein is turned on (activated) by attaching (binding) to another complex called dynactin. This dynein-dynactin complex binds to various materials within cells. Using energy provided by molecules called ATP, the dynein-dynactin complex moves material along a track-like system of small tubes called microtubules, similar to a conveyer belt. The dynein-dynactin complex is necessary for protein transport, positioning of cell compartments, movement of structures within the cell, and many other cell processes. Dynein helps neighboring nerve cells (neurons) communicate by transporting sac-like structures called synaptic vesicles that contain chemical messengers. When synaptic vesicles are passed from one neuron to another, the dynein-dynactin complex transports the vesicle from the edge of the cell to the nucleus, where the chemical message is received.

The parts (subunits) of a dynein complex are classified by weight as heavy, intermediate, light intermediate, or light chains. Two heavy chain proteins bind together to form the core of the dynein complex. Combinations of intermediate, light intermediate, and light chains make up the rest of the complex. The protein produced from the DYNC1H1 gene is a heavy chain. Other subunits are produced from different genes.

Health Conditions Related to Genetic Changes

Charcot-Marie-Tooth disease

MedlinePlus Genetics provides information about Charcot-Marie-Tooth disease

Spinal muscular atrophy with lower extremity predominance

At least eight mutations in the DYNC1H1 gene have been found to cause a condition called spinal muscular atrophy with lower extremity predominance (SMA-LED). This condition is characterized by muscle weakness and wasting (atrophy) in the lower limbs that often begins in infancy or childhood. The DYNC1H1 gene mutations that cause SMA-LED replace single protein building blocks (amino acids) in the heavy chain subunit of the dynein complex. These changes alter the core of the dynein complex and impair its function. As a result, the movement of proteins, synaptic vesicles, and other materials within cells is reduced. Decreased synaptic vesicle transport in neurons that control muscle movement (motor neurons), leading to impaired neuronal growth, is thought to contribute to the muscle weakness and atrophy experienced by people with SMA-LED. It is unclear why this condition primarily affects the lower limbs.

Other disorders

DYNC1H1 gene mutations have been identified in some people who have intellectual disability. These affected individuals often have a brain malformation called polymicrogyria. Normally, the surface of the brain has many ridges or folds, called gyri. In people with polymicrogyria, the brain develops too many folds, and the folds are unusually small. In addition to intellectual disability, some affected individuals develop seizures and movement problems.

The DYNC1H1 gene mutations that cause intellectual disability are typically in a different region of the gene than those that cause SMA-LED (described above). It is unclear whether the site of the mutation is associated with the location in the body most affected by the disease, with SMA-LED-associated mutations primarily affecting motor neurons and intellectual disability-associated mutations primarily affecting neurons in the brain.

Other Names for This Gene

• cytoplasmic dynein 1 heavy chain 1
• cytoplasmic dynein heavy chain 1
• DHC1
• DHC1a
• DNCH1
• Dnchc1
• DNCL
• DNECL
• DYHC
• DYHC1_HUMAN
• dynein heavy chain, cytosolic
• dynein, cytoplasmic 1, heavy chain 1
• dynein, cytoplasmic, heavy polypeptide 1
• HL-3
• p22

Genomic Location

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

In some cases, an affected person inherits the mutation from one affected parent. Other cases result from new mutations in the gene and occur in people with no history of the disorder in their family.

SMA-LED is thought to be a rare condition; its prevalence is unknown.

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.