Abstract
Objective: To study the clinical and electrophysiologic features of a large series of carriers of the 17p11.2 deletion.
Background: The 17p11.2 deletion is associated in most patients with recurrent acute nerve palsies, which is the typical presentation of hereditary neuropathy with liability to pressure palsies (HNPP). Nevertheless, a few other phenotypes have been reported.
Methods: On the basis of clinical and electrophysiologic data, the authors conducted a retrospective study of 99 individuals with the 17p11.2 deletion referred to their neurogenetic department between 1993 and 1997.
Results: In addition to the typical presentation of HNPP, they describe five other phenotypes in 15 patients: recurrent positional short-term sensory symptoms, progressive mononeuropathy, Charcot–Marie–Tooth disease-like polyneuropathy, chronic sensory polyneuropathy, and chronic inflammatory demyelinating polyneuropathy-like, recurrent subacute polyneuropathy; and 14 asymptomatic patients. In all the deletion carriers, regardless of their phenotype and by the second decade, the authors found a characteristic, multifocal electrophysiologic neuropathy consisting of a diffuse increase in distal motor latencies contrasting with normal or moderately reduced motor nerve conduction velocities, a diffuse reduction in sensory nerve action potential, and multiple focal slowing of nerve conduction at the usual sites of entrapment. The key diagnostic criterion is a bilateral slowing of sensory and motor nerve conduction at the carpal tunnel with at least one abnormal parameter for motor conduction in one peroneal nerve.
Conclusion: The authors confirm the clinical phenotypic heterogeneity of the 17p11.2 deletion and suggest that electrophysiologic examination is a reliable tool for screening suspected HNPP patients in its various clinical presentations.
Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder presenting typically as recurrent, painless monofocal palsies usually triggered by minor compression at the usual anatomic sites of nerve entrapment.1-4 Focal thickening of the myelin sheath, also named tomacula, are the main pathologic characteristic of HNPP on nerve biopsy,5,6 although they have been shown to be nonspecific and insufficiently sensitive for diagnostic purposes. Diffuse motor and sensory nerve conduction abnormalities are found in patients with HNPP and lead to an electrophysiologic, multifocal neuropathy occurring predominantly at the usual sites of entrapment.3-5,7 A 1.5 mega-base deletion on chromosome 17p11.2 was found in a great majority of HNPP families with common clinical presentation characterized by recurrent nerve palsies,8-14 but was later reported in patients with other phenotypes, including a few cases of chronic polyneuropathy mimicking Charcot–Marie–Tooth disease (CMT).15-21 The 17p11.2 deletion involves the same region as that duplicated in CMT type 1A and encompasses the peripheral myelin protein-22 (PMP22) gene.8 Direct implication of the PMP22 gene in the pathogenesis of HNPP was demonstrated when point mutations of this gene resulting in truncated protein were identified in the few HNPP families without the 17p11.2 deletion.22-26
Genetic testing for the 17p11.2 deletion has now become a valuable tool in diagnosing HNPP, even in isolated cases.14 However, in a study of 13 HNPP families with the 17p11.2 deletion, Gouider et al.27 delineated the electrophysiologic characteristics of this entity and suggested electrophysiologic examination as a reliable and more accessible tool for diagnosis in patients at risk for HNPP.
To extend our knowledge of the clinical phenotypic heterogeneity of HNPP and to define key electrophysiologic parameters for the diagnosis of the disorder in its various clinical presentations, we studied the clinical and electrophysiologic features of a group of 99 patients with the 17p11.2 deletion.
Methods.
The 17p11.2 deletion was identified in 99 individuals referred to the neurogenetic department for genetic analysis between 1993 and 1997. Medical history, neurologic examination, and electrophysiologic study were available for all these deletion carriers. Thirty-six of these patients had been included in a previous study by Gouider et al.27
Electrophysiologic study.
Nerve conduction studies were performed with surface stimulating and recording electrodes. Distal motor latency (DML) was measured for the median, ulnar, peroneal, and tibial nerves. Motor nerve conduction velocity (MNCV) was measured for the median, ulnar, and peroneal nerves. For the ulnar and peroneal nerves, particular attention was given to the motor nerve conduction study across the elbow and fibular head respectively. Motor conduction block was defined as a decrease in amplitude of 30% or more of the compound muscle action potential ratio across the site of compression. Focal motor slowing across the site of compression was considered significant when a decrease of 10 m/sec or more was present in comparison with the distal MNCV. Sensory nerve action potential (SNAP) was recorded for the median, ulnar, radial, and sural nerves. Sensory nerve conduction velocity (SNCV) was measured for the median nerve across the carpal tunnel with palmar stimulation, digit stimulation, or both. Focal sensory slowing across the carpal tunnel was considered significant under 40 m/sec.
Molecular study.
Deletions in 17p11.2 were detected by EcoRI-Sac1 Southern blots hybridized with a pJ7.8 probe corresponding to a 7.8-kb EcoRI-EcoRI fragment from proximal CMT1A-repetition (REP). The presence of the deletion was assumed by the visualization of a 7.8-kb junction fragment or a gene dosage, 1:2 or 2:1 copies, between proximal and distal CMT1A-REP.28 These results were confirmed by a gene dosage experiment using a VAW409R3a probe located in the CMT1A monomer and the reference probe SF85 (chromosome 21).12
Statistical analysis.
Percentages and means were compared using the χ2 test and Student’s t-test respectively. Differences were considered significant at p ≤ 0.05.
Results.
Familial and sporadic cases.
Of the 99 carriers with the 17p11.2 deletion, 74 (belonging to 34 families) had a clear family history of peripheral nervous system disease consistent with HNPP. Twenty-five patients were apparently isolated cases, based on family medical history reported by the proband. In four of the latter patients, systematic screening of at-risk first-degree family members revealed asymptomatic deletion carriers. All familial patients were consistent with autosomal dominant inheritance.
Neurologic presentation and clinical findings.
We distinguished three main groups of patients according to clinical presentation: 1) common clinical features of HNPP, 2) uncommon clinical features of HNPP, and 3) asymptomatic patients.
Group 1: patients with common clinical features of HNPP.
A total of 70 individuals (40 men and 30 women) presented with at least one acute peripheral nerve palsy. The main clinical features are shown in table 1 . Mean age at examination was 38 ± 14 years (range, 14 to 73 years). Mean age at first symptom was significantly earlier (p = 0.047) in men (mean ± SD, 20.3 ± 9 years; range, 7 to 43 years) than in women (26.5 ± 16.4 years; range, 7 to 73 years). Age at onset of symptoms was between 10 and 30 years in 70% of patients. In three patients, the first symptom occurred after 50 years of age, including a woman with an inaugural partial ulnar nerve palsy at the age of 73. Number of palsies was not significantly different between men (1.78 ± 1.35) and women (2 ± 1.5). Six patients, five men and one woman, experienced so many palsies that they were not able to remember the exact number. In the other patients, a total of 143 acute palsies were identified. Palsies involving the peroneal (36%) and ulnar (28%) nerves were by far the most commonly encountered of all palsies, followed by the brachial plexus (20%) and the radial nerve (13%). Acute palsy of the median nerve was rare (4%), and was not observed for the tibial posterior nerve. Two individuals had a peripheral facial nerve palsy. Approximately one-third of patients experienced at least one brachial plexus palsy, with a significantly higher prevalence (p = 0.02) in women than in men. Pure acute sensory symptoms were experienced in 10 patients in addition to the motor deficits. Two of these 10 patients had paresthesias lasting a few hours or days involving the femoral and the lateral femoral cutaneous nerves, and eight patients had recurrent short-term positional paresthesias in truncal territories including sensory carpal tunnel syndrome in five patients. We considered as a significant neurologic sequela a residual motor deficit equal or worse than 3 of 5 points on the Medical Research Council rating scale for muscle strength. Such motor deficits were observed in 15% of patients, at least 3 months after the last acute palsy.
Clinical findings in the different groups of 17p11.2 deletion carriers
Group 2: patients with uncommon clinical features of HNPP.
Fifteen patients did not present with the usual acute nerve palsies. In Group 2a, five patients (three men and two women) had recurrent short-term positional sensory symptoms involving truncal territories and triggered by positions such as crossing the legs or leaning on the elbow. In one of these patients, the only symptom was a chronic sensory carpal tunnel syndrome. Mean age at examination was 38 ± 9 years (range, 27 to 47 years) and mean age at onset was 25 ± 13 years (range, 10 to 41 years). No patient had pes cavus, and tendon reflexes were normal. In Group 2b, two patients (a 56-year-old woman and a 29-year-old man) experienced a progressive sensorimotor mononeuropathy involving the peroneal nerve. Both had pes cavus and ankle jerk areflexia. The older patient had surgery for chronic sensory carpal tunnel syndrome, and reported a “dropping hand” episode in her sister. In Group 2c, three patients, all women (age, 37 to 46 years), presented with a chronic sensory polyneuropathy. For several years they had experienced chronic paresthesias in the four extremities. Pes cavus and areflexia in the lower limbs were observed in two patients. No familial history of HNPP was found, but in one patient CMT had been diagnosed clinically in a brother. Because the three patients were negative for the usual causes of acquired neuropathies, and because tomacula were found in two patients on nerve biopsy, they were investigated for the 17p11.2 deletion. In Group 2d, four patients presented with a chronic sensorimotor polyneuropathy and had an initial diagnosis of CMT. They had pes cavus, tendon areflexia in the lower limbs, and mild to severe peroneal atrophy. Age at onset was 3 years in a 14-year-old girl and approximately 60 years in the other three patients (two men, one woman). Nerve biopsy performed in a 65-year-old man showed tomacula. A few years later his grandson experienced acute nerve palsies consistent with HNPP, although his son remained asymptomatic. The other male patient had exhibited acute nerve palsies in childhood long before he started to complain of chronic motor weakness in the lower limbs. The 14-year-old girl had no family history of peripheral nerve disease and her 40-year-old deletion carrier mother was asymptomatic but presented ankle jerk areflexia. In Group 2e, one patient experienced several subacute peripheral quadriparetic episodes over a period of 15 years and was initially misdiagnosed as having chronic idiopathic demyelinating polyneuropathy. The patient’s protein level was increased to 90 mg/100 mL in CSF without pleiocytosis. Nerve biopsy showed focal thickening of the myelin sheath. This patient has already been reported.21
Group 3: asymptomatic patients.
Genetic testing in 22 families allowed us to detect 14 asymptomatic patients (six men and eight women). Mean age at examination was 28.7 ± 20.3 years (range, 5 to 67 years). Eight patients were less than 30 years of age and two were older than 60 years. Neurologic examination showed ankle jerk areflexia in four patients. These four patients included a 47-year-old man with generalized areflexia and pes cavus, and a 9-year-old boy with generalized areflexia and symmetric distal amyotrophy of the lower limbs.
Electrophysiologic findings.
Electrophysiologic findings for all 99 deletion carriers are shown in tables 2 and 3⇓. In Group 1, the parameters that were found to be abnormal in all patients older than 15 years were 1) increased DML in both median nerves, 2) slowed SNCV in both median nerves across the carpal tunnel in a palm–wrist segment, and 3) either an increased DML or a slowed MNCV for at least one peroneal nerve. In younger patients, these parameters were also abnormal for their age. There was a marked increase in mean DML in all the nerves studied in contrast to the MNCV, which in most patients remained normal in the upper limbs and moderately reduced in the lower limbs. Only two median MNCVs were less than 38 m/sec and six peroneal MNCVs were less than 30 m/sec. A diffuse decrease in SNAPs was found in approximately 60% of patients. In nerves usually involved in entrapment neuropathies (ulnar, median) the values were not more frequently abnormal than in the others (radial, sural, superficial peroneal). Focal slowing of ulnar MNCV at the elbow was observed in 80% of patients. In contrast, focal motor slowing of the peroneal nerve at the knee was found in only 18% of patients. Conduction blocks were also uncommon, either at the elbow (14% of patients) or at the knee (12%). In Groups 2 and 3, all deletion carriers older than 15 years had the same multifocal neuropathy as that defined in Group 1. In Group 3, which included many young patients, reduced SNAPs and focal motor slowing at the elbow were less frequently observed than in the symptomatic patients. ⇓ ⇓
Electrophysiologic findings in 99 carriers of the 17p11.2 deletion: Motor conduction parameters
Electrophysiologic findings in 99 carriers of the 17p11.2 deletion: Sensory conduction parameters
Clinical and electrophysiologic variations within the same family.
Of the 34 HNPP families, two were heterogeneous phenotypically. The first family included the proband with a CMT-like syndrome and a relative with typical HNPP. In the second family, one relative had recurrent short-term positional sensory symptoms whereas the others had typical HNPP. Most of the patients with sensory or CMT-like polyneuropathy were seemingly isolated patients. In contrast, in families with typical HNPP, the localization and number of acute nerve palsies, and the age at onset varied considerably within families. No family presented isolated brachial plexus palsies. Electrophysiologic parameters varied within families independent of age. For example, in the four largest families including 18 deletion carriers, the mean difference between the highest and lowest median nerve DML values in each family was 4.3 msec (difference range, 2.4 to 6.5 msec).
Discussion.
We report a group of 99 individuals carrying the 17p11.2 deletion—the molecular characteristic of most patients with HNPP. A total of 70 of these patients presented one or more nerve palsies—the typical clinical presentation of HNPP. In this study, which to our knowledge is the largest undertaken to date, we confirm and extend most of the previous clinical findings14,16,20,26,27,29 (see table 1). Two patients experienced a peripheral facial nerve palsy, which is consistent with reports suggesting that cranial nerve involvement in HNPP is very rare or may be coincidental.7,30 The 4:3 ratio of men to women and the significantly earlier age at onset in men observed in our study suggest a higher expression of the disease in men than in women, in line with previous reports on tomaculous neuropathy.7,31 Possible explanations for this apparent difference between men and women include a genetic factor linked to chromosome X and environmental factors leading to repeated traumas. Another significant gender-related difference was the higher prevalence of brachial plexus palsy in women than in men. We would suggest that anatomic features in the thoracic outlet are responsible for this higher prevalence in women, for the same reason that the classic thoracic outlet syndrome related to a cervical rib is far more frequent in women than in men.
In addition to the common clinical phenotype, we have described five other clinical presentations encountered in 15 patients, representing 17% of our symptomatic patients: recurrent positional short-term sensory symptoms, progressive mononeuropathy, CMT-like polyneuropathy, chronic sensory polyneuropathy, and chronic inflammatory demyelinating polyneuropathy-like, recurrent subacute polyneuropathy. Most of these patients were misdiagnosed initially, and the diagnosis was rectified some years later following detailed electrophysiologic examination (n = 8), nerve biopsy (n = 4), or molecular detection of 17p11.2 rearrangement (n = 3). Our study confirms the phenotypic heterogeneity of the 17p11.2 deletion15-21,26 and extends its spectrum to include a pure chronic sensory polyneuropathy presentation not reported previously.
The observation of distinct phenotypes within the same family seems to be uncommon. However, we observed only one family that included two members, one who presented with typical HNPP and one who presented with a CMT-like polyneuropathy. No such families have been reported previously. In contrast, age at onset as well as localization and number of acute nerve palsies were variable for members of the same family with the typical HNPP phenotype.
HNPP cannot be excluded by an absence of family history or a normal clinical examination because, in our study, more than 40% of probands were isolated cases and, as previously reported,29 fewer than 20% of deletion carriers presented with pes cavus or generalized areflexia. Interestingly, in HNPP families with the PMP22 frame shift mutation at nucleotide 276-281, the phenotype is more severe and clinical signs of generalized polyneuropathy are highly frequent.25,29
In contrast with family and clinical findings, this study demonstrates that a characteristic, multifocal electrophysiologic neuropathy is present in all deletion carriers, regardless of their clinical phenotype, including asymptomatic individuals, and as early as the second decade. In agreement with other studies of HNPP with the 17p11.2 deletion,26,27,29,32 we found a diffuse increase in DMLs contrasting with normal or moderately reduced MNCVs, diffuse reduction in SNAPs, and multiple focal slowing of nerve conduction at the usual sites of entrapment. Moreover, we confirm the key diagnostic criteria previously delineated by Gouider et al.,27 which consist of bilateral slowing of sensory and motor median nerve conduction at the carpal tunnel with at least one abnormal parameter for motor conduction in one peroneal nerve.
Although DNA analysis remains the most reliable tool for diagnosis of HNPP,14 our study confirms that electrophysiologic examination represents an easy and reliable method for selecting subjects for genetic analysis of the 17p11.2 region. The presence of the same pattern of electrophysiologic abnormalities in HNPP patients with uncommon phenotype is of great interest, especially in chronic polyneuropathy patients, in whom clinical presentation may be highly confusing. The seven patients with chronic polyneuropathy had normal or moderately slowed MNCVs consistent with the diagnosis of CMT2 or CMT-X, but the more marked slowing of distal motor conduction and the occurrence of multiple electrophysiologic entrapment neuropathies have never been reported in CMT. A diffuse increase in DMLs contrasting with normal or moderately decreased MNCVs and multiple electrophysiologic entrapment neuropathies should lead one to suspect HNPP. No other hereditary neuropathy presents this electrophysiologic pattern. The only acquired polyneuropathy known to mimic certain aspects of the electrophysiologic findings in HNPP is polyneuropathy with immunoglobulin M monoclonal gammopathy, which can be diagnosed easily.
Given the molecular mechanism that makes HNPP with 17p11.2 deletion the genetic counterpart of CMT1A with 17p11.2 duplication,8,28 a similar prevalence for these two hereditary neuropathies might be expected. However, the estimated prevalence of HNPP appears to be well below that of CMT1A.33 On the basis of our results, we propose that the frequency of HNPP has been underestimated due to the existence of a significant number of asymptomatic or only slightly symptomatic patients, and an as yet unknown proportion of atypical phenotypes that are often misdiagnosed. At a time when our knowledge of these latter phenotypes is improving, this study provides strong evidence that electrophysiologic examination is a reliable tool for screening suspected HNPP patients. A minimal electrophysiologic examination and its correct interpretation can lead to a diagnosis that may be confirmed easily by molecular analysis. This examination must include DMLs and MNCVs for both median and peroneal nerves, and a search for focal conduction slowing of the motor ulnar nerve at the elbow and the sensory median nerve at the carpal tunnel. This strategy would avoid performing more aggressive investigations (e.g., nerve biopsy), especially in patients with atypical clinical presentation.
Acknowledgments
Acknowledgment
The authors thank Odette Lacroix, Nicole Blanc, Jacqueline Boissinot, and Nathalie Le Hénaff for technical assistance, and Nicolas Barton for his critical reading of the manuscript.
- Received November 9, 1998.
- Accepted in final form January 9, 1999.
References
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