Hereditary Neuropathy Disorders

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Hereditary motor, sensory or autonomic neuropathies refer to a group of nerve disorders that lead to weakness, sensory abnormalities or autonomic dysfunction that are due to genetic abnormalities. The genetic abnormality sometimes can be passed on from parents to children. For several of these conditions, the genetic defect is known, and tests are available for the diagnosis and prenatal counseling.

Charcot-Marie-Tooth disease (CMT) is a broad term used to describe a group of inherited neurological disorders characterized by a slowly progressive degeneration of the muscles in the foot, lower leg, hand, and forearm, and a mild loss of sensation in the limbs, fingers, and toes.

Three doctors, Jean-Marie Charcot, Pierre Marie, and Howard Henry Tooth, described for the first time CMT in 1886. Although CMT is one of the most common inherited neuromuscular disorders, it is often misdiagnosed. The number of people in the United States that have CMT is currently estimated to be 125,000 and 2.6 million worldwide.

The symptoms of CMT depend on which form of the disease is inherited, but generally start between mid-childhood and early adulthood. The first signs are usually foot deformities, such as an unusually high arch or flexed “hammer” toes. People with CMT often trip on curbs. Sprained ankles and fractures of the ankles and lower legs are not uncommon. As the disease progresses, muscle weakness and wasting leads to difficulties with walking, running and balance. If the hands are affected, daily activities such as turning doorknobs, fastening buttons, or writing can become difficult.

The disease is slowly progressive and, although many patients need to wear a brace to prevent their feet from dragging, the leg and foot problems are rarely disabling enough to require a wheelchair in the most common forms of CMT. CMT is not a fatal disease, and the disorder does not normally affect normal life expectancy.

CMT is usually divided into types 1 and 2, depending on which part of the peripheral nerve is affected. Most people have type 1, which affects the myelin sheath (the protective covering of the nerve). About one-third of people with CMT have type 2, which affects the nerve fibers (axons) themselves.

How is it inherited? Today, around 100 different genes are known to cause CMT. However, the PMP22 gene accounts for almost 50% of CMT diagnosis. CMT usually is inherited in an autosomal dominant pattern (as is the case for the PMP22 gene), which means that each child from a parent with CMT has a 50% chance of inheriting the disease. CMT can also be inherited in a recessive or an X-linked pattern.

Symptoms

CMT symptoms in patients can range from very mild to severe weakness, as well as a degree of sensory disturbances. The more severe symptoms are frequently related to an earlier age of onset. CMT can progress to severe weakness, atrophy, and loss of sensation over time. Not all symptoms and signs may be present in a given person, and the severity of the disease can vary between patients, even within the same family.

Some specific symptoms are:

  • Foot drop (foot can’t be picked up or held horizontally)
  • Progressive thinning of muscles of the leg (“inverted champagne bottle”) or the foot, with abnormally high arched feet, flat feet and/or hammer toes.
  • Decreased sensation or numbness in the foot or leg
  • Problems with gait and balance
  • Poor hand coordination
  • Diminished or absent ankle reflexes

CMT Tests & Evaluations

Several tests and evaluations can be performed to help correctly diagnose CMT disease and guide the genetic testing.

CMT tests and evaluations include:

Other blood tests such as measuring of the muscle enzyme (CK) or lumbar puncture for cerebrospinal fluid analysis in rare, selected cases

Physical examination

  • Neurological exam
  • Electromyography and a Nerve conduction velocity test
  • Nerve and or muscle imaging (echography or magnetic resonance)
  • A nerve and/or muscle biopsy may confirm the diagnosis and be performed in selected cases
  • Genetic testing is available for most forms of the disease
  • Other blood tests such as measuring of the muscle enzyme (CK) or lumbar puncture for cerebrospinal fluid analysis in rare, selected cases

Tests

Although currently there is no cure for CMT, physical therapy, occupational therapy, and moderate physical activity may help maintain muscle strength and endurance. Lightweight lower leg braces, special shoes or shoe inserts can ameliorate gait, prevent ankle sprains and maximize independence. Surgery may be used to correct foot deformities in some patients.

Other treatment options may include:

  • Over-the-counter pain medicationfor mild pain
  • For moderate-to-severe pain, analgesia specific for neuropathic pain inperipheral neuropathy can be prescribed by your physician
  • Shoe inserts can also compensate for loss of sensation

Hereditary neuropathy with liability to pressure palsies (HNPP) is a relatively common, though under-diagnosed, hereditary disorder in which a fairly mild pressure or trauma to a single nerve results in episodes or periods of numbness and weakness, similar to an arm or leg going to sleep. 

Unlike a limb going to sleep for a few seconds, each episode of numbness can last from several minutes to several days or months. The most common sites are the wrists, with carpal tunnel syndrome, the elbows or knees. HNPP is inherited in an autosomal dominant manner, which means that each child of a person with HNPP has a 50% chance of inheriting the genetic mutation. It may be misdiagnosed as Charcot-Marie-Tooth disease, an isolated pressure palsy or Bell’s Palsy.

Symptoms

HNPP can a progressive hereditary disorder, but the symptoms can be so mild that they go unnoticed. For some people, there are years between episodes, while others have mild symptoms that progress at a steady rate.

(Not all symptoms and signs may be present.)

  • Partial or total weakness of a limb
  • Unable to use certain muscles of the arm (can’t reach, wash hair, eat) or hand (difficulty gripping things or grasping small objects) or face
  • Episodes of numbness or tingling that do not go away
  • Diminished or absent ankle reflexes
  • Other symptoms such as fatigue, muscle cramps or leg/ankle foot swelling may be associated

Tests

(Not all evaluation and tests may be necessary)

To test for pre-diabetes:

  • Physical examination
  • Neurological exam
  • Electromyography and Nerve conduction velocity test
  • Nerve imaging
  • Nerve biopsy
  • Genetic blood tests

Treatments

Avoiding positions that can create pressure on a nerve, such as leaning on elbows, crossing legs or ankles, or sitting for too long without changing position is the principal measure to prevent episodes of weakness and tingling. In this line a person with HNPP should avoid:

  • Prolonged activity on hands and knees that could cause nerve compression
  • Sitting with legs crossed, tailor-style
  • Sitting in one position too long without readjusting
  • Holding the telephone in one position too long
  • Tying shoes too tight or using tight shoe straps
  • High heels, which can make toes numb

An adaptation of the environment, specially at work, can also be beneficial in reducing episodes of palsy. Take safety measures to compensate for loss of sensation and ask your doctor about special therapeutic shoes (which may be covered by Medicare and other insurance).

Symptomatic treatment of pain with over-the-counter pain killers or specific analgesia for neuropathic pain can also be helpful in patients experiencing sensory disturbances.

The first sign of diabetic neuropathy is usually numbness, tingling or pain in the feet, legs or hands.

Over a period of several years, the neuropathy may lead to muscle weakness in the feet and a loss of reflexes, especially around the ankle.

As the nerve damage increases, the loss of sensation in the feet can reduce a person’s ability to detect temperature or to notice pain. Because the person can no longer notice when his/her feet become injured, people with diabetic neuropathy are more likely to develop foot problems such as skin lesions and ulcers that may become infected.

Diabetic neuropathy may suddenly flare up and affect a specific nerve or group of nerves. When this occurs, the result may be weakness and muscle atrophy in various parts of the body, such as involvement of the eye muscles or eyelid (e.g., causing double vision or a drooping eyelid) or thigh muscles. Alternatively, neuropathy caused by diabetes may slowly progress over time. It also can interfere with the normal functioning of the digestive system and sexual organs.

Symptoms

(Not all symptoms and signs may be present)

  • Numbness, tingling, or pain in the toes, feet, legs, hands, arms, and fingers
  • Indigestion, nausea, or vomiting
  • Diarrhea or constipation
  • Dizziness or faintness due to a drop in blood pressure especially when rising to a standing position
  • Problems with urination
  • Erectile dysfunction (impotence) or vaginal dryness

Tests

(Not all evaluation and tests may be necessary)

  • Comprehensive foot exam
  • Physical examination
  • Neurological exam
  • Electromyography
  • Nerve conduction velocity test
  • Quantitive sensory testing (QST)
  • Nerve or skin biopsy
  • Blood studies (to verify diabetes (e.g., HbA1C) and to rule out other potential causes)

Treatments

(Not all treatments and therapies may be indicated)

The goal of treatment for diabetic neuropathy is to relieve discomfort and to prevent further tissue damage. The first step is to bring blood sugar levels under control by diet and medication. Another important part of treatment involves taking special care of the feet.

  • Over-the-counter pain medication for mild pain
  • For severe pain, take over-the-counter pain medication or prescription drugs used for peripheral neuropathy, on a regular basis—rather than waiting until nighttime when symptoms can become more severe
  • Keep blood sugar levels in normal range
  • Get regular exercise
  • Maintain a healthy weight
  • Antidepressants (for pain relief)
  • Foot care: inspect your feet daily for injuries
  • Special Therapeutic shoes (which may be covered by Medicare and other insurance)
  • Take safety measures to compensate for loss of sensation
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