Hereditary Neuropathy with Liability to Pressure Palsies

Actionability Adult Summary Report

Secondary Findings in Adult Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Mode(s) of Inheritance: Autosomal Dominant
• Literature Search: 05/13/2014
• Curation Status: Released (2.0.2)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
No assertions found.

Actionability Assertion Rationale

• This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Neuropathy / Avoidance of triggers	1	3C	0C	3	7CC

Severity of Outcome

Prevalence of the Genetic Condition

The prevalence of hereditary neuropathy with liability to pressure palsies (HNPP) is not well known, though it has been estimated between 1/50,000 and 1/14,000. The actual prevalence may be higher because of under diagnosis. A study of the Finnish population found that prevalence may be as high as 1/6,250.

Clinical Features (Signs / symptoms)

HNPP is characterized by episodic focal motor and sensory peripheral neuropathies in the hands and feet. These attacks are typically painless. The nerve palsies often recur over a period of many years, but some individuals have a single episode and others with a pathogenic variant remain asymptomatic. In many cases these symptoms are triggered by mechanical stresses to the nerve, such as compression, repetitive movement and/or stretching of the affected limbs. Common clinical manifestations include carpal tunnel syndrome and peroneal palsy with foot drop. In 50% of cases, recovery from the acute neuropathy is complete within a few days to months. Incomplete recovery is common, though the resulting disability rarely severe. Chronic motor deficits after nerve palsies are noted in 10-15%. In rare cases, strenuous activities can lead to severe and prolonged limb paralysis. Atypical presentations of HNPP are common and can include: recurrent positional short-term sensory symptoms, progressive mononeuropathy, Charcot-Marie-Tooth like polyneuropathy, chronic sensory polyneuropathy, and chronic inflammatory demyelinating polyneuropathy-like disorder.

Natural History (Important subgroups & survival / recovery)

Most individuals with HNPP typically experience their first episode in the second or third decade at a mean age of 37 years, but with a large range from birth through the eighth decade. The most common presenting symptom is acute onset of a focal neuropathy of a single nerve (mononeuropathy). Males and females are equally affected. Occasional episodes have been reported during pregnancy, likely related to physiological changes. Older patients often develop a symmetric sensory motor polyneuropathy. HNPP is not life threatening, and patients have a normal life expectancy.

Likelihood of Outcome

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

1-2 in 50000

The prevalence of pathogenic variants in PMP22 associated with HNPP was unavailable. However, PMP22 accounts for an estimated 100% of HNPP cases and thus the prevalence of pathogenic variants in PMP22 is expected to be similar to the prevalence of HNPP, or between 1/50,000 and 1/20,000.

Tier 4

Penetrance (Includes any high-risk racial or ethnic subgroups)

>= 40 %

Studies screening relatives of index patients have identified that 6-23% of family members may be asymptomatic. These rates are not reported within the context of the exposure to potential triggers.

Tier 3

Relative Risk (Includes any high-risk racial or ethnic subgroups)

Unknown

Information regarding relative risk was unavailable.

Expressivity

Large intrafamilial clinical variability has been noted.

Tier 4

Intervention Effectiveness

Patient Management

To establish the extent of disease following diagnosis the following evaluations are recommended:

• History of focal nerve symptoms

• Family history

• Neurologic examination

• Electromyography/nerve conduction velocity

• Clinical genetics consultation.

Tier 4

Protective pads at the elbows or knees may prevent pressure and trauma to local nerves.

Tier 4

Surveillance

Circumstances to Avoid

Patients are advised to avoid prolonged sitting with legs crossed, prolonged leaning on the elbows, occupations requiring repetitive movements of the wrist, and rapid weight loss as these have been reported in case reports as being associated with the onset of HNPP symptoms.

Tier 3

Vincristine, used in chemotherapy, has been reported to exacerbate HNPP. A single case report related to this exposure was identified. No studies were identified reporting the rate of developing HNPP symptoms following vincristine exposure

Tier 3

An overview of case reports addressing Charcot Marie Tooth (CMT) and toxic medication effects identified 22 reports (30 patients) addressing vincristine toxicity; however it is unclear whether this evidence may apply to HNPP. 18 of 30 patients developed marked sensory symptoms or new onset weakness, with some developing dysarthria and dysphagia. Nearly all reports describe eventual improvement, but frequently not to baseline levels. These cases occurred in both adults (15) and children (15). Most individuals having a reaction were previously unsuspected or undiagnosed with CMT (26 of 30) and were only recognized following administration of vincristine; however, 10 cases, in retrospect, had overt clinical signs or a close relative with known CMT.

Tier 5

Nature of Intervention

Nature of Intervention

The interventions identified in this report include wearing protective pads and avoidance of potential triggers including vincristine.

Context: Adult

Chance to Escape Clinical Detection

Individuals with HNPP are typically identified after their first episode and diagnosed via genetic testing and/or electrophysiological studies. Thus, patients are likely to escape detection prior to their first episode. Given pain is often a presenting symptom, individuals with HNPP are often clinically misdiagnosed with fibromyalgia upon presentation.

Context: Adult

Tier 4

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers

References List

Hereditary neuropathy with liability to pressure palsies. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=640

TD Bird. Hereditary Neuropathy with Liability to Pressure Palsies. (1998) [Updated Sep 25 2014]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1392/

van Paassen BW, van der Kooi AJ, van Spaendonck-Zwarts KY, Verhamme C, Baas F, de Visser M. (2014) PMP22 related neuropathies: Charcot-Marie-Tooth disease type 1A and Hereditary Neuropathy with liability to Pressure Palsies. Orphanet journal of rare diseases. 9(1750-1172):38.

Weimer LH, Podwall D. (2006) Medication-induced exacerbation of neuropathy in Charcot Marie Tooth disease. Journal of the neurological sciences. 242(1-2):47-54.