A neuropathy is a medical condition that is characterized by damage to or reduced function of the nerves. Nerves are specialized cells that carry messages from one part of the body to another in the form of tiny electrical signals. When the nerves are damaged these messages are not communicated properly, which can cause a variety of symptoms depending on the type of nerve being affected and the location of the nerve in the body. There are different forms of neuropathies and different causes. This patient guide discusses genetic forms of neuropathy or conditions caused by genetic changes that affect the health and function of nerves.
There are different types of nerves in our bodies, motor nerves, sensory nerves and autonomic nerves. Damage to different types of nerves causes different symptoms. For example, motor nerves send messages from the brain and spinal cord to the muscles in the body. Motor nerves allow us to perform activities, such as walking, picking up an object, or catching a ball. Damage to these nerves can result in muscle weakness, difficulty walking, difficulty moving your arms and muscle cramps or spasms.
Sensory nerves send messages from the muscles back to the spinal cord and brain. These nerves allow us to detect if something is sharp, smooth, hot, or cold. Damage to these nerves causes tingling, pain, and numbness. This can affect a person’s ability to feel their extremities causing clumsiness and falls. Injuries can also occur if a person cannot sense heat and suffers a burn.
Autonomic nerves control body functions that are not typically under our conscious control, such as blood pressure, digestion, heart rate and sweating. Damage to these nerves can cause dizziness when a person stands up, can cause too much or too little sweating and can make the heart beat faster or slower than usual. Damage to these nerves can also cause nausea, vomiting, diarrhea, constipation, and difficulty swallowing.
Examples of genetic neuropathies include Charcot-Marie-Tooth disease, hereditary sensory and autonomic neuropathy, hereditary motor neuropathy, small fiber neuropathy and riboflavin transporter deficiency neuronopathy. The symptoms of these conditions overlap and can make it difficult to diagnose the specific type of neuropathy without the assistance of genetic testing.
Charcot-Marie-Tooth (CMT) disease refers to a group of genetic neuropathies which causes progressive muscle weakness and loss of sensation in the arms and legs. These symptoms develop because the peripheral nerves (nerves farthest from the center of the body) are not able to send messages as efficiently as usual. Individuals with CMT may develop clumsiness due to numbness in the feet. As the disease progresses, changes to the structure of the feet can also occur, such as extremely high arches, flat feet or hammertoes. Additionally, individuals with CMT can experience decreased sensation in the hands, which make tasks like writing or buttoning a shirt difficult. There are different subtypes of CMT that are named based on the area of the nerve that is not functioning well. Axonal types of CMT are characterized by damage to the axons. Axons are nerve fibers that conduct electrical impulses from the nerve cell out toward the body. Demyelinating types of CMT are characterized by damage or insufficient quantity of the fatty protective coating, called myelin, that surrounds our nerves and helps electrical impulses travel along them quickly. Some types of CMT can cause damage to both the axons and the myelin sheath.
Another group of genetic neuropathies, called hereditary sensory and autonomic neuropathies (HSAN), mainly affect the sensory nerves, but some types can also affect the autonomic nerves. Loss of sensation in the sensory nerves can lead to frequent injuries. Because the person cannot feel the injury, it can result in slower wound healing. If the wound is not recognized and treated appropriately, there is the risk of bone infection and in rare cases the need to amputate the affected limb. Some forms of HSAN can also cause hearing loss. When autonomic nerves are affected, the person may sweat too much or too little, may have abnormal changes in blood pressure and gastrointestinal complications. Symptoms of HSAN can occur at different ages, depending on the type and the underlying genetic change causing the condition.
Hereditary motor neuropathy (HMN) is a type of genetic neuropathy that develops when the motor neurons in the spinal cord are not working properly. Individuals with HMN have muscle weakness and a breakdown of muscle tissue, called muscle wasting. The symptoms are typically worse in the distal muscles. Distal muscles are those muscles that are furthest away from the midline of the body. However, some people with HMN can have both distal and proximal muscle weakness and wasting. The proximal muscles are those closest to the midline of the body. The muscle weakness and atrophy become gradually more severe over time. Depending on the type of HMN, symptoms can begin as early as infancy, or not until adulthood. Other symptoms that can be part of HSN include, vocal cord paralysis, facial weakness, loss of fine motor skills, and stiffness in joints that decreases their range of motion (arthrogryposis). Many genes associated with HMN can also cause other forms of neuropathy with overlapping symptoms, such as Charcot-Marie-Tooth disease or spinal muscular atrophy.
Hereditary ATTR (hATTR) amyloidosis is an inherited, progressive disease caused by a genetic mutation that results in the buildup of misfolded transthyretin (TTR) protein. This results in the formation of amyloid deposits in the heart, nerves, and gastrointestinal tract. hATTR amyloidosis affects approximately 50,000 people worldwide. Many people remain undiagnosed or misdiagnosed. Invitae has a sponsored testing program where patients suspected of having hATTR amyloidosis can receive a genetic test at no charge. To learn more, click here.
Small fiber neuropathy (SFNP) is caused by genetic changes to genes that play a vital role in generating and transmitting electrical signals from the nerve cells to the spinal cord and brain. SFNP causes an increase in the frequency of pain signals being sent to the spinal cord and brain. This increase makes people with SFNP feel painful sensations in response to stimulation that generally wouldn’t cause pain. Over time, SFNP also causes degeneration of the small fibers, which can lead to the inability to sense temperature differences or feel a pin prick. Symptoms of SFNP usually begin in adolescence or adulthood and include burning, stabbing pain that starts in the hands and feet. Over time, the pain may occur in other parts of the body, as well. Additional symptoms can include heart palpitations, dizziness upon standing, dry eyes and a dry mouth.
Riboflavin transporter deficiency neuronopathy affects the nerve cells in the inner ear and an area of the brainstem called the pontobulbar region. Damage to the nerve cells of the inner ear leads to hearing loss. Damage to the nerve cells in the pontobulbar region affects the ability breathe, speak and move the arms and legs. The condition can also cause muscle stiffness and exaggerated reflexes. The symptoms can begin in infancy or not until young adulthood. If not treated, the symptoms get worse over time, and can lead to death, but when treated with high doses of riboflavin supplementation the symptoms improve.
Genetic neuropathies are caused by changes in the sequence of genes that affect various aspects of nerve cell function. Because the symptoms of many neuropathies can be similar, it is very important to determine the specific diagnosis of the affected person, so that medical care can be specially tailored to their needs.
The diagnosis of neuropathies requires a careful review of the affected person’s medical and family history along with a thorough physical exam by a physician who specializes in treating people with neuropathies, such as a neurologist or geneticist. Additional testing sometimes includes: nerve conduction velocity studies, sensory nerve action potentials, visual evoked potentials, brainstem audiometry evoked response (hearing loss), electroencephalogram, brain magnetic resonance Imaging or a nerve biopsy. More recently, however, comprehensive genetic testing for neuropathies has become available and can be used earlier in the diagnostic process to reduce the need for more painful and invasive tests. Genetic testing can provide a diagnosis in a matter of weeks instead of months or years.
Comprehensive genetic testing for neuropathies can test for multiple types of neuropathies in a single test. This is a tremendous advantage over testing for one condition at a time, or undergoing more invasive test methods (i.e., nerve conduction velocity, nerve biopsy) to achieve a diagnosis. Once a genetic diagnosis is determined, that information can be used to develop the best treatment plan for the affected person, can help to better predict the course of the disease, and can help the family monitor and prepare for any complications associated with the diagnosis. Results of genetic testing can also be used to determine the risks for other family members to be affected with the same condition and their risks to have an affected child. Please speak with your doctor to understand the appropriate role of genetic testing in your diagnosis.
Riboflavin transporter deficiency neuronopathy is treated with high dose riboflavin supplementation, which can help to improve the symptoms and outcome for affected individuals. Symptoms of the other neuropathies are managed through close surveillance and collaboration between medical specialists in genetics, neurology, orthopedics, pulmonology occupational, physical and speech therapy, who work together to meet the needs of the affected individual. Ideally, individuals with neuropathies should be cared for at a multidisciplinary clinic that specializes in these conditions.
Certain medications can be used to help ease the neuropathic pain and other medications, such as baclofen and botox can be used to help reduce spasticity. Orthotics and braces can help improve support when walking and reduce the risk of falls. Careful inspection of the areas of the body that have decreased sensation can help detect unnoticed injuries and treat them quickly to avoid complications.
As researchers and physicians continue to learn more about genetic neuropathies, it will be essential to know an affected individual’s genetic diagnosis. Medications will become available over time that will be targeted to specific genetic changes. Knowing a person’s genetic diagnosis can also help with eligibility to participate in a clinical trial, which are research based trials that are conducted to measure the effectiveness of new treatments and medications. Families can search www.clinicaltrials.gov to monitor for clinical trials that may become available for various forms of genetic neuropathies. You should always discuss any clinical trial with your physician prior to participating. Ultimately, a person’s specific genetic diagnosis will guide decisions about which medications could be helpful and which could be potentially dangerous.
Your physician will assist you in identifying and arranging for the appropriate genetic test(s). If you have specific questions or concerns about the testing, your physician may refer you to a genetic counselor to discuss further. Once you are ready to proceed with genetic testing, you will need to submit either a blood or saliva sample.