Hereditary neuropathy with liability to pressure palsies (ORPHA:640)
A rare neurologic disease characterized by recurrent mononeuropathies usually triggered by minor physical activities innocuous to healthy people.
Epidemiology
Hereditary neuropathy with liability to pressure palsies (HNPP) actual prevalence is unknown due to under-diagnosis but estimates range between 1/50,000 -1/20,000 worldwide. In Finland, the prevalence is reported to be 1/6250.
Clinical description
Disease onset usually occurs in the 2nd to 3rd decade of life, but may present in childhood. Some patients are asymptomatic and never diagnosed. The most common presenting symptom is the sudden onset of focal sensory loss and muscle weakness in the distribution of a single nerve. In many cases, these acute focal symptoms are triggered by mechanical stresses to the nerve, such as compression, repetitive movement or stretching of the affected limbs. Commonly affected nerves include the peroneal nerve at the fibular head, ulnar nerve at the elbow, median nerve at the wrist, brachial plexus and radial nerve. Clinical manifestations caused by these mononeuropathies include foot drop, hand numbness and weakness, arm weakness, and sensory loss over the index finger and thumb or lateral aspect of the hand. In 50% of cases, patients recover from these episodes within a few days to months but others have incomplete recovery and suffer from recurrent focal sensory and motor deficits. In rare cases, brachial plexopathy with unilateral painless arm paralysis and sensory loss may be a presenting symptom. Occasionally, mild impairments of cranial nerve functions may be seen. Absent deep tendon reflexes and pes cavus foot deformity are seen in some patients but not in others. The phenotype of HNPP often evolves into a symmetric sensory motor polyneuropathy in aged patients. Many patients with HNPP complain of diffuse pain and severe fatigue. HNPP may cause severe limb paralysis when asymptomatic patients with unknown diagnosis of HNPP are challenged by strenuous physical activities. This imposes a catastrophic risk in a fraction of patients with HNPP.
Etiology
HNPP is due to a mutation in the chromosome 17p12 containing PMP22 and other genes. PMP22 encodes the peripheral myelin protein-22 (PMP22) that is predominantly expressed in the compact myelin of the peripheral nervous system. In 80% of cases, a 1.4Mb deletion at 17p11.2 that includes the PMP22 gene is found, and in the remaining 20%, patients may carry a point mutation or small deletion in PMP22 or mutations in as yet unidentified genes.
Diagnostic methods
Diagnosis of HNPP is typically suggested by the presence of recurrent focal mononeuropathies and the evidence of a family history. Electrophysiologic testing shows prolonged distal latency at the sites susceptible to mechanical stress. Conduction velocities out of these sites are often either normal or only mildly slowed. Tomacula (focal thickening of the myelin sheath) is the characteristic histological finding in sural nerve biopsies. It may however be seen in other types of neuropathies. A DNA test showing the PMP22 heterozygous deletion confirms the diagnosis.
Differential diagnosis
Differential diagnosis includes both compression induced mononeuropathies and generalized polyneuropathies. HNPP can sometimes be mistaken for neuralgic amyotrophy, stroke or multiple sclerosis.
Antenatal diagnosis
Prenatal testing is theoretically possible in families where the disease causing gene has been identified.
Genetic counseling
The disorder is inherited autosomal dominantly. Genetic counseling should be done for individuals having the disease and informing them that there is 50% risk of passing the mutation to offspring.
Management and treatment
Consultation should be provided to the patient about physical activities that may trigger the sensory/motor deficits. Those with foot drop or wrist drop may benefit from an ankle-foot orthosis or a wrist splint. Protective pads for the elbows and knees can alleviate nerves from mechanical stresses. Activities that involve prolonged sitting with crossed legs, leaning on elbows and repetitive movements of the wrists, as well as rapid weight loss should be avoided. Vincristine should equally be avoided. Cautions should be taken when new medications are prescribed with potential side-effect to the peripheral nerves.
Prognosis
HNPP is not life threatening and does not appear to affect longevity. However, many patients may have incomplete recovery in their sensory moto deficits. In some cases, severe and prolonged limb paralysis can occur, particularly after strenuous physical activities. Many patients with HNPP suffer from pain and fatigue. Unfortunately, these issues have not been well studied and should be addressed in future investigations.

                            Last update: 
                            March 2020


                            - Expert reviewer(s): 
                            Pr Jun LI