What is hereditary neuropathy with predisposition to pressure palsy (HNPP) in Charcot-Marie-Tooth (CMT) disease?

Updated: Feb 19, 2019
  • Author: Francisco de Assis Aquino Gondim, MD, PhD, MSc, FAAN; Chief Editor: Nicholas Lorenzo, MD, MHA, CPE  more...
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Answer

Onset of neuropathies associated with PMP22 deletions or mutations is typically in the third or fourth decades of life, but it ranges from the first to the eighth decades of life; palsy may be present at birth. Because of its insidious onset, some patients are unaware of their disease or seek medical attention only late in life, whereas others remain asymptomatic.

In one study of patients with PMP22 deletions, 40% were unaware of their condition; 25% were essentially without symptoms. Monozygotic twins have been reported of which only 1 was affected clinically, although both and their father had slowed nerve conduction.

The most common presentation is recurrent acute mononeuropathy often related to minor nerve compression. In typical HNPP, motor symptoms predominate over sensory symptoms. Patients often report that after resting on a limb in an awkward position, the resulting weakness and dysesthesias last weeks to months, rather than seconds to minutes.

Slight compression of peripheral nerves and repeated local exercise leads to episodes of weakness with decreased perception to touch and pain. Most attacks are of sudden onset, are painless, and are initially followed by recovery. Attacks most often occur with a single nerve involvement, with onset on awakening. They are usually triggered by mild compression that resolves in days to months. Patients with frequent episodes may have persistent neurologic abnormalities. Precipitating trauma, such as carrying heavy loads, writing, or playing musical instruments, may be minimal and unavoidable. Other precipitating events include prolonged immobilization during surgery or childbirth. Typically, no neuropathic pain is present, but tingling is a frequent symptom.

In patients with the recurrent pattern, the examination findings between episodes may be normal or mildly abnormal. Distal and mild pansensory loss may be present. Reflexes are normal in approximately two thirds of patients. In one study, ankle jerks were absent in 37.5%, and areflexia occurred in 12.5%.

Sites of compression are often those of anatomic vulnerability, including the fibular neck for the peroneal nerve, the cubital tunnel for the ulnar nerve, the spiral groove of the humerus for the radial nerve, and the carpal tunnel for the median nerve. However, many other sites may exist, as evidenced by the recent report of a lesion of the anterior branch of the axillary nerve, likely caused by compression against the surgical neck of the humerus.

In a study of 70 patients, the average number of nerve palsies over a lifetime was approximately 2; the most commonly affected structure was the peroneal nerve, followed by the ulnar, the brachial plexus, and the radial and median nerves; weakness persisted for over 3 months in 15%. The second most frequent presentation in 2 series was a largely symmetric slowly progressive polyneuropathy, causing a misdiagnosis of CMT in the narrow sense. With this subtype, high arches and hammertoes are common. Scoliosis is rarely observed.

Some patients have recurrent sensory symptoms lasting minutes to hours triggered by limb position, nerve compression, or holding a phone, whereas others present with a chronic sensory polyneuropathy. Rarely, patients can present with subacute recurrent or confluent demyelinating multiple mononeuropathies, and they are misdiagnosed with acute or chronic inflammatory demyelinating polyneuropathy. Cranial neuropathies, including deafness, are infrequent and may sometimes represent chance events. One of the authors' patients provided a history of 3 episodes of Bell palsy over 3 years.

The brachial plexopathy form of HNPP may be recurrent, isolated, or part of other multiple mononeuropathies, and it is painless, which serves to differentiate it from HNA. Furthermore, no genetic overlap exists between the 2 conditions.

Rare associations of PMP22 deletions include CNS demyelination, moving toes and myoclonus, and fulminant 4-limb weakness possibly related to nerve compression. Some patients are oligosymptomatic or asymptomatic, but their examination findings during family evaluations may reveal subtle abnormalities such as distal hyporeflexia or Tinel signs. Not surprisingly, conditions may evolve, with patients expressing one phenotype and progressing to another, and different phenotypes may coexist in a given family.

The condition may occasionally manifest in later life when individuals develop an acquired unrelated neuropathy due to metabolic derangements, autoimmunity, or neurotoxic drugs. Undiagnosed PMP22 deletions in an oligosymptomatic patient may complicate the treatment and diagnosis of an acquired neuromuscular disease. For instance, a person with the disorder may, in the seventh decade of life, become diabetic and develop diabetic amyotrophy. Alternately, such a patient may require neurotoxic drugs such as platinum or vincristine in the treatment of a malignancy. Some HNPP patients might develop chronic inflammatory demyelinating polyneuropathy. Such patients' clinical and electrical presentations may be unusual and difficult to understand, unless a diagnosis of HNPP is also considered. Even more importantly, such a patient's spontaneous recovery or positive treatment response may be disappointing and far less complete than expected if the acquired neuropathy were the only condition.


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