Neuromuscular disorders are conditions that affect the structure and function of the peripheral nervous system, as well as all motor and sensory nerves. The predominant symptom of this group of disorders is progressive muscle weakness. Secondary symptoms may include muscular atrophy and disturbances in sensation, which may present as tingling or numbness.

The developments in neuromuscular disorder treatment in the last five to 10 years rapidly have changed the treatment landscape, offering longevity and better quality of life to patients for whom there previously had been neither.

There have been great strides in neuromuscular disorder treatment and overall understanding of these diseases in the last decade, including:

• Deeper understanding of neuromuscular biology
• New or emerging neuromuscular conditions
• Understanding of etiology and pathogenesis of neuromuscular conditions
• Therapeutic and diagnostic advances

What are the types of neuromuscular disease?

This umbrella term encompasses diseases defined by the area of dysfunction, including:

• Anterior horn cells
• Nerve roots, including dorsal root ganglia
• Plexuses, including brachial and lumbosacral
• Peripheral nerve conditions, such as neuropathy
• Neuromuscular junctions
• Muscle fibers

The most common type of neuromuscular disorder is peripheral neuropathy. There are several types and causes of this condition.

“Primary care physicians and specialists often see these neuromuscular disorders in their practices, especially neuropathy,” said Nathaniel R. Beachy, M.D., neuromuscular medicine neurologist at Norton Neuroscience Institute. “The good news is, we can treat more diseases than we could five or 10 years ago, and there are more options available now.”

Treating spinal muscular atrophy

Spinal muscular atrophy (SMA) is a genetic disorder that affects the motor neurons in the spinal cord. It is one of the most prevalent genetic disorders in young children, and though it can strike at any time, is a major cause of infant death. Spinal muscular atrophy is categorized by age of onset, and symptoms are progressive.

SMA is the result of mutations in the SMN1 gene. The nearly identical SMN2 gene serves as a backup: The proteins it produces are shorter and less stable and do not fully compensate for the loss of SMN1 proteins.

There are three drugs introduced in the last eight years that have dramatically altered the treatment landscape for SMA. They all have benefits and drawbacks.

In 2016, the Food and Drug Administration approved nusinersen (Spinraza) for the treatment of SMA. The drug targets the SMN2 gene to encourage the production of normal-length SMN1 proteins.

“This type of gene therapy, or antisense oligonucleotide (ASO) therapy, is designed to modify gene expression,” Dr. Beachy said.

Perhaps the most significant drawback to nusinersen is that after a semimonthly intrathecal loading period, the drug is administered intrathecally monthly.

“It is a long-term commitment that is time-consuming and uncomfortable for the patient,” Dr. Beachy said.

Risdiplam (Evrysdi), approved in 2020, works similarly to nursinersen, but is administered orally daily. In clinical trials, patients of all ages had improved motor function, which was maintained after 24 months of treatment. It was generally well tolerated, and is more comfortable and convenient than nusinersen.

In 2019, onasemnogene abeparvovec-xioi (Zolgensma) was introduced. This is a recombinant adeno-associated virus 9 (AAV)-based gene therapy that delivers a functioning SMN1 gene to the motor neuron cells. This one-time infusion is given to patients under age 2 years.

“It’s a remarkably effective treatment, but it does come with a hefty price tag of about $2.1 million,” Dr. Beachy said.

Hereditary transthyretin amyloidosis treatment

Hereditary transthyretin amyloidosis (TTR or hATTR) is characterized by amyloidosis in the peripheral nerve or autonomic nervous system. Transthyretin transports thyroid hormones and vitamin A to the liver. A mutation in the TTR gene causes unstable proteins that become misfolded and create amyloid deposits. Symptoms of this genetic condition may not present until the early 30s, but most develop later in life. The symptoms of hATTR mimic less-serious conditions, but left untreated, hATTR is fatal.

Typically, hATTR is treated with a liver transplant.

“This is a complex procedure, which eliminates gene expression via the liver, but those genes are still being expressed through other tissues,” Dr. Beachy said. “It’s not an ideal situation.”

Medicines called transthyretin stabilizers prevent the dissociation of tetramers into amyloidogenic monomers by binding to the T4-binding site on TTR. By preventing the creation of unstable monomers, disease progression is slowed or stopped. TTR stabilizers also control protein levels in the heart and peripheral nervous system.

Transthyretin can be silenced via some treatments, including:

• Inotersen
• Eplontersen
• Patisiran
• Vutrisiran

Advanced treatment for amyotrophic lateral sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s Disease, affects control of the muscles needed to move, speak, eat and breathe. The exact cause is unknown, but there is a genetic component. The disease progresses quickly and is fatal.

Since around 1995, treatment for ALS included drugs that slowed the progress of the disease, with a modest extension of life. In 2023, tofersen was developed to treat ALS associated with a mutation in the superoxide dismutase 1 (SOD1) gene.

Tofersen is an ASO, which is a small string of DNA designed to bind to specific molecules of RNA. Tofersen was developed to specifically target the mRNA produced from mutated SOD1 genes to stop toxic SOD1 proteins from being made.

“This method of directly attacking the mutated portion of the mRNA and selectively eradicating the pathogenic protein halts the progression of the disease,” Dr. Beachy said.

Tofersen is administered intrathecally monthly, after an initial loading phase.