HEREDITARY NEUROPATHY WITH LIABILITY TO PRESSURE PALSIES
Jun Li, MD, PhD Professor and Chairman of Neurology Wayne State University School of Medicine Detroit Michigan
Nerve tissues that reside in the skull and spinal canal make up the Central Nervous System (CNS). The CNS extends numerous nerve fibers out of the space of the skull and spinal canal that make contact with muscles, skin, tendons, the gut, and other organs. These nerve fibers outside of the CNS space are collectively called Peripheral Nerves. When the peripheral nerves are damaged by a cause, it is called peripheral neuropathy. If the cause is a genetic mutation in a specific gene, it is called Charcot-Marie-Tooth disease (CMT). There have been over 100 genes identified where a variety of mutations lead to different types of CMT. Hereditary neuropathy with liability to pressure palsies (HNPP) is one type of CMT.
HNPP is caused by missing a DNA segment on chromosome 17. The segment is called c17p12, which contains the Peripheral Myelin Protein-22 (PMP22) gene, as well as others. Scientific evidence supports that loss of one of the two copies of the PMP22 gene (one from mother and one from father) is responsible for HNPP. Genetically, it is called “heterozygous deletion of PMP22”. The remaining genes in the c17p12 segment play a negligible role in the disease. Therefore, HNPP has a 50% chance of being passed to offspring. A small fraction of patients with HNPP may develop this mutation on their own, which is called de nova mutation, and thus would not have any family history of the disease.
Clinical Manifestation: While exceptions do occur, the majority of patients with HNPP develop initial symptoms around the first or second decade of their life. Patients typically present with focal numbness, tingling (pins/needles) and muscular weakness in limbs. These episodes are often brought on by mild physical activities that do not cause symptoms in healthy people. The activities include compression, by sitting with legs crossed, putting pressure on the peroneal nerve, or leaning on elbows against the ulnar nerve, repetitively doing the same movements (stereotypic movements) for a prolonged period, and over-stretching of the arms or legs. It can take anywhere from hours to months to recover from an episode. While most episodes are transient, some patients with HNPP may experience permanent weakness. Some episodes may not have any identifiable triggers.
Peripheral nerves that go to muscles and sensory organs in the head are called cranial nerves and can also be afflicted by HNPP. For instance, partial hearing loss and facial numbness have been reported by patients with HNPP. Many patients with HNPP may also develop generalized symptoms, such as intolerable fatigue and pain. There is a wide range in the severity of these symptoms. Life expectancy for people with HNPP is usually not affected by the disease.
Some patients may be asymptomatic. HNPP may lead to severe limb paralysis when asymptomatic patients are challenged by strenuous physical activities such as running 10 miles a day with a 50lb backpack. An asymptomatic woman developed leg paralysis after prolonged labor of 9 hours to deliver a baby while sitting in birthing position. These possible outcomes could impose a catastrophic risk in the fraction of patients with undiagnosed asymptomatic HNPP.
Upon physical examination, physicians may find sensation loss and muscle weakness in the hands and feet. Unlike other types of CMT, high arching feet or hammer toes are not common in patients with HNPP.
Diagnosis: The diagnosis of HNPP can be quite challenging. This is often due to many physicians’ unfamiliarity with the disease. An HNPP patient may be misdiagnosed with a lacunar stroke, multiple sclerosis, spinal muscular atrophy, chronic inflammatory demyelinating polyneuropathy (CIDP) or idiopathic axonal polyneuropathy, etc. Therefore, a high index of suspicion is often needed to reach the diagnosis in patients with episodes of focal sensory loss or weakness.
Electromyogram/Nerve Conduction Study (EMG/NCS) is an important diagnostic tool for HNPP. It shows changes in areas where peripheral nerves are exposed to mechanical pressure, such as the ulnar nerve at the elbow or median nerve at the wrist. This finding should prompt physicians to seek the diagnosis and perform DNA testing.
DNA testing allows physicians to reach a definitive diagnosis if the loss of one copy of PMP22 is found. There are several issues relating to testing that should be emphasized here: a). Unlike the majority of lab tests, which use blood samples from a red-top tube, blood samples for DNA testing should be collected in a purple-top tube that contains a chemical to prevent the blood from clotting. This is necessary for DNA extraction. If a red-top tube is mistakenly used, clotted samples will be rejected by the lab. The patient may have to return to the clinic for another blood draw. b). The HNPP mutation is usually tested using a technique called multiplex PCR. In rare cases, this technique may not detect the mutation. If the clinical suspicion is strong, alternative techniques would have to be used to clarify the diagnosis. c). There have been a few reported cases that were not caused by a missing copy of PMP22. Instead, their HNPP was caused by an altered DNA sequence in the PMP22 gene that multiplex PCR cannot detect, but DNA sequencing can.
Clinical Management: There is no cure for HNPP at this point. Therefore, clinical management mainly aims to alleviate symptoms and optimize quality of life.
1. Avoid physical triggers: We advise that HNPP patients avoid the physical activities (compression, prolonged stereotypic movements and over-stretch) that may bring on symptoms. However, we do not advocate for a sedentary lifestyle either since this may lead to obesity and metabolic problems. Thus, activities should be tailored for individuals to have adequate exercise without triggering nerve symptoms.
2. Pain control: Many patients with HNPP complain of pain, regardless if focal symptoms are present or not. Those with true neuropathic pain (sharp, burning, tingling, highly sensitive to touch) tend to be responsive to treatments. Others may not show features of neuropathic pain, and the pain may be difficult to control. Physicians may have to carefully seek additional factors contributing to the pain, such as inadequate ankle braces causing overuse of leg muscles, etc.
3. Medication side-effect: Severe side-effects have been reported in patients with CMT1A who took Vincristine and developed limb paralysis. This is a difficult subject to study in patients with HNPP due to ethical issues. However, an HNPP animal model shows slower recovery from nerve damage. We believe that patients with HNPP should be carefully monitored for side-effects when they receive any new medications.
4. Diet: Many patients with HNPP question if they should avoid any foods. We are not aware of any specific dietary restrictions for HNPP patients. A high dose of vitamin C has been shown to reduce PMP22 levels. We recommend that HNPP patients avoid consuming high doses of vitamin C. However, we do not see any problems with a regular dose (75-90mg daily) of vitamin C. This issue needs to be further investigated in carefully designed studies.
Professor and Chairman,
Department of Neurology,
Wayne State University School of Medicine and Detroit Medical Center,
4201 St. Antoine, UHC-8D
Detroit, MI 48201
Tel: 313-577-8824 (Office)
Tel: 313-745-4275 (clinic)