Adult Summary Report

Secondary Findings in Adult Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Adult): Passed (Consensus scoring is Complete)
• Curation Status (Adult): Released 1.0.1
• GENE/GENE PANEL: PMP22
• Condition: Hereditary Neuropathy with Liability to Pressure Palsies
• Mode(s) of Inheritance: Autosomal Dominant

Actionability Assertion

• PMP22 ⇔ 162500: Assertion Pending

Actionability 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.

Final Consensus Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Neuropathy / Avoidance of triggers	1	3C	1C	3	8CC

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

The prevalence of HNLPP is not well known, though it has been estimated between 1/50,000 and 1/20,000. A study of the Finnish population found that prevalence may be as high as 1/6,250. [1, 2]

Clinical Features

HNLPP is characterized by episodic focal motor and sensory peripheral neuropathies. These attacks are painless and may be episodic. 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. [1, 2, 3]

Natural History

Most individuals with HNLPP 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, though occasional episodes have been reported during pregnancy, likely related to physiological changes. Older patients often develop a symmetric sensory motor polyneuropathy. HNLPP is not life threatening, and patients have a normal life expectancy. [1, 2, 3]

2. How effective are interventions for preventing harm?

Patient Management

Protective pads at the elbows or knees may prevent pressure and trauma to local nerves. Information on the effectiveness of this intervention was not provided. (Tier 4) [1, 2]

Surveillance

No surveillance recommendations have been provided for the Adult context.

Circumstances to Avoid

Information on the effectiveness of these interventions was not provided.
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. (Tier 3) [1, 3]

Vincristine, used in chemotherapy, has been reported to exacerbate HNLPP. (Tier 3) [1, 3]

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

The prevalence of PMP22 mutations associated with HNLPP was unavailable. PMP22 is the only gene known to cause HNLPP, with deletions of PMP22 and mutations within PMP22 accounting for 100% of cases. (Tier 4) [1, 2]

Penetrance

The penetrance of PMP22 mutations for HNLPP phenotypes is unknown, though it is likely incomplete as some individuals carrying a disease-causing mutation are asymptomatic. (Tier 4) [1, 3]

Other evidence for incomplete penetrance may be derived from studies which have found the percentages of asymptomatic family members of index patients varied from 6-23%. (Tier 3) [3]

Information on the penetrance of variants was not available for the Adult context.

Relative Risk

Information regarding relative risk was unavailable.

Expressivity

Large intrafamilial clinical variability has been noted, with variability in the number and severity of episodes. In addition, some individuals may exhibit additional symptoms, including mild to moderate peripheral neuropathy or pes cavus. (Tier 4) [1, 3]

4. What is the Nature of the Intervention?

Nature of Intervention

The intervention identified in this report (wearing protective pads) is of low risk and intensity.

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

Individuals with HNLPP 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. (Tier 4) [1, 3]

Date of Search: 05.13.2014

Reference List

1. TD Bird. Hereditary Neuropathy with Liability to Pressure Palsies. 1998 Sep 28 [Updated 2014 Sep 25]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1392

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

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