Mutational analysis of Greek patients with suspected hereditary neuropathy with liability to pressure palsies (HNPP): a 15‐year experience

There has been limited information from population studies regarding the overall frequency of the common 1.5‐Mb 17p11.2 deletion and even scarcer data regarding the overall frequency of PMP22 micromutations in patients with a clinical suspicion of hereditary neuropathy with liability to pressure palsies (HNPP). We have analysed 100 consecutive Greek patients referred for HNPP genetic testing over a 15‐year period to our Neurogenetics Unit in Athens, a reference centre for all regions of Greece. All patients were screened for the 1.5‐Mb deletion and a selected subgroup of deletion‐negative patients for PMP22 micromutations. Mutation‐positive and mutation‐negative patients were compared for various clinical parameters. In total, 54 mutation‐positive patients were identified. In index cases, the deletion frequency was 47.8%, and the PMP22 micromutation frequency was 2.2%. Within mutation‐positive patients, the common deletion represented 95.7% and PMP22 micromutations 4.3% of cases. Two previously reported PMP22 micromutations (c.364_365delCC and c.79‐2A>G) were detected. HNPP index cases had a 2.8–1 male‐to‐female ratio, similar to mutation‐negative patients. A typical phenotype (recurrent or isolated palsies) was present in 82.4% of symptomatic HNPP cases, significantly higher than mutation‐negative patients. Sensitivity of proposed electrophysiological diagnostic criteria for HNPP was calculated at 95.7% and specificity at 80.5%. In conclusion, the common HNPP deletion accounts for ～50% and PMP22 micromutations for ～2% of cases in a large consecutive cohort of patients with suspected HNPP. The mutational and phenotypic spectrum of HNPP is similar in the Greek population compared with other populations. Proposed electrophysiological diagnostic criteria perform satisfactorily in everyday clinical practice.     

Prevalence of the 1.5-Mb 17p deletion in families with hereditary neuropathy with liability to pressure palsies

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder of the peripheral nerves leading to increased susceptibility to mechanical traction or compression. Some patients have been shown to be carriers of a 1.5-Mb deletion in chromosome 17p11.2, which corresponds to the duplicated region present in most patients with Charcot-Marie-Tooth disease type 1A. Recently, evidence has been presented that the deletion is not the only cause of HNPP. To determine the prevalence of the 1.5-Mb deletion, we have examined 22 unrelated families with HNPP in the following two ways: by polymerase chain reaction analysis of marker loci D17S122 and D17S261, and by gene dosage measurements with DNA probes for D17S122 (VAW409R3a) and D17S125 (VAW412R3a) and for the PMP-22 gene. The efficiency and sensitivity of these methods is discussed. Our results show that the prevalence of the 17p deletion in our families with HNPP is 68%. One patient, presenting as a sporadic case, was found to be affected by a de novo deletion in the paternal chromosome. Single-strand conformation analysis of the protein-coding region of the PMP-22 gene did not reveal any mutation in patients from the 7 families lacking the 17p deletion. As a group, these families could not be distinguished by clinical, electrophysiological, or morphological features from the families with the deletion.     

Detection of hereditary neuropathy with liability to pressure palsies among patients with acute painless mononeuropathy or plexopathy

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder characterized by recurrent mononeuropathies or brachial plexopathies, commonly associated with a chromosome 17p11.2-12 deletion encompassing the peripheral myelin protein-22 (PMP22) gene. We tried to identify criteria distinguishing HNPP among patients with acute painless mononeuropathy/plexopathy. We investigated by pulsed-field gel electrophoresis the presence of the deletion in 27 patients with isolated or recurrent acute painless mononeuropathy or brachial plexopathy, and no obvious cause of neuropathy. Eight patients carried the deletion, whereas 19 had neither the deletion nor mutations in the PMP22 gene. Age at onset, presenting modality, precipitating events, and rate of recovery did not significantly differ in the two groups. Family history was informative for HNPP diagnosis in 3 cases only. HNPP patients more often showed recurrent episodes, brachial plexopathy, and clinical or electrophysiologic involvement of other nerves. Non-HNPP patients more frequently had peroneal palsy, recent weight loss, and normal electrophysiologic examination in other nerves. Signs of generalized neuropathy and evidence of disease in other family member are often subtle in HNPP and must be thoroughly investigated in patients with acute painless mononeuropathy/plexopathy. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21: 1686–1691, 1998.     

Hereditary neuropathy with liability to pressure palsy

Hereditary neuropathy with liability to pressure palsy (HNPP) is an autosomal dominant disease with sensory and motor nerve palsies usually precipitated by trivial trauma or compression. In the majority of cases HNPP is caused by deletion of the peripheral myelin protein 22 gene (PMP22) on chromosome 17p11.2. The authors present a family case with genetically proven HNPP.     

A novel point mutation in PMP22 gene in an Italian family with hereditary neuropathy with liability to pressure palsies

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant inherited disorder characterized by recurrent sensory or motor dysfunction. In 85% of HNPP cases the genetic defect is a 1.4 Mb deletion on chromosome 17p11.2, encompassing the PMP22 gene. Point mutations in the PMP22 gene responsible for HNPP phenotypes are rare. We investigated a 17-years-old girl who led to our detecting a novel mutation in PMP22 gene. The mutation was also detected in her father and corresponded to a deletion of one tymidine at position 11 in exon2 (c.11delT). This novel mutation creates a shift on the reading frame starting at codon 4 and leads to the introduction of a premature stop at codon 6.     

Hereditary neuropathy with liability to pressure palsies: electrophysiological and genetic study of a family with carpal tunnel syndrome as only clinical manifestation

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disease characterized by recurrent sensory or motor manifestations. The molecular basis of HNPP is a deletion on chromosome 17p11.2. We studied a family (father, 61 years; mother, 55 years; 6 children of mean age 25.3 years) showing symptoms of carpal tunnel syndrome in 4 members (the parents and 2 sons). No one of them reported episodes of nerve palsy. In all the patients, except the mother and the younger son, electrophysiologic evaluation showed a sensorimotor polyneuropathy with delayed sensorimotor latencies. Genetic analysis was carried out in the parents and the eldest son. The 17p11.2 deletion was detected in the father and son, indicating paternal transmission of the disease. Clinical manifestations of HNPP may be atypical. Sometimes there is no history of acute nerve palsy, as in this family. For this reason, the frequence of HNPP might be underestimated. Electrophysiological examination is of great importance for the diagnosis of HNPP. Genetic analysis is a rapid and reliable diagnostic tool that can be combined with simplified electrophysiological examination, avoiding the need for nerve biopsy. In conclusion, the diagnosis of HNPP should be invoked in early onset entrapment neuropathies. Received: 8 November 2002 / Accepted in revised form: 28 March 2003 Correspondence to: R. Del Colle     

The 17p11.2 locus in hereditary neuropathy with liability to pressure palsies,in juvenile and familial carpal tunnel syndrome and in hereditary neuralgic amyotrophy*

The presence of deletions at the CMT-1a locus containing the gene encoding the myelin protein, PMP-22 on chromosome 17p11.2 was assessed in patients with hereditary neuropathy with liability to pressure palsies (HNPP), with hereditary neuralgic amyotrophy and with hereditary carpal tunnel syndrome. Affected members in all families with HNPP, except in one, had a deletion, in one of them a partial one. None of the non-affected relatives, none of the members of the other three groups and none of the controls showed a deletion. These data confirm that the majority of patients with HNPP have a deletion at the PMP-22 gene locus. They do not suggest, however, that such a deletion accounts for a predisposition to the development of hereditary neuralgic amyotrophy or of carpal tunnel syndrome.     

Diagnostic strategy for familial and sporadic cases of neuropathy associated with 17p11.2 deletion

Clinical, electrophysiologic and molecular studies were performed on at-risk members of 14 families with hereditary neuropathy with liability to pressure palsies (HNPP), in order to detect asymptomatic carriers of the 17p11.2 deletion. Sporadic cases due to de novo deletion accounted for 21% of the investigated HNPP families. Approximately one half of deletion carriers were asymptomatic and did not display significant signs on clinical examination. The electrophysiologic hallmark in both symptomatic and asymptomatic deletion carriers was the presence of a nonuniform sensorimotor demyelinating polyneuropathy with conduction abnormalities preferentially located at common entrapment sites and distal nerve segments. A perfect correlation was found between the molecular and electrophysiologic analyses. A reliable screening method to detect clinically unaffected carriers of the deletion in families with HNPP was the evaluation of motor conduction in at least two nerves across usual entrapment sites, especially the ulnar nerve at the elbow, and evaluation of sensory conduction in the sural nerve. In sporadic cases due to a de novo deletion, electrophysiologic studies were suggestive but not sufficient for the diagnosis, and molecular analysis represented the most sensitive diagnostic tool.     

Hereditary neuropathy with liability to pressure palsy: fulminant development with axonal loss during military training

Hereditary neuropathy with liability to pressure palsy (HNPP) is characterised by recurrent mononeuropathies following minor trauma. We describe a case of fulminant HNPP beginning on the first day of military physical training. Protracted weakness, muscle atrophy, hand contractures, and multifocal sensory loss developed during a further three weeks of basic training. Nerve conduction changes were typical of HNPP, but without segmental slowing. Electromyographically, there was prominent acute denervation in muscles of the hands and right shoulder. Sural nerve biopsy demonstrated tomaculae and remyelination. Genetic testing revealed PMP-22 gene deletion. This case report demonstrates that HNPP can present with rapidly progressive peripheral nerve dysfunction and electrophysiological evidence of focal axonal loss.     

Differential electrophysiological features of neuropathies associated with 17p11.2 deletion and duplication

Hereditary neuropathy with liability to pressure palsies (HNPP) and hereditary motor-sensory neuropathy type IA (HMSN IA) are quite distinct clinical entities recently associated to deletion and duplication, respectively, of the 17p11.2 segment including the gene for peripheral myelin protein 22 (PMP-22). We studied the electrophysiological features of 48 HNPP and 62 HMSN IA motor nerves. Conduction velocities (CV) and compound muscle action potential amplitudes were significantly reduced and distal latencies prolonged in HMSN IA compared to HNPP. CV was uniformly slowed in HMSN IA nerves whereas in HNPP it was focally slowed in 80% of ulnar and 12% of peroneal nerves at usual compression sites. Conduction block was present in 6% of HNPP nerves but in none of HMSN IA. In conclusion: (1) HMSN IA with 17p11.2 duplication presents marked, diffuse, and uniform slowing; (2) HNPP with 17p11.2 deletion presents focal electrophysiological abnormalities possibly correlated with the presence of tomaculae; and (3) under-and overexpression of PMP-22 in concurrence with environmental factors might be responsible for the distinctive features of HNPP and HMSN IA. © 1995 John Wiley & Sons, Inc.     

Deletions of chromosome 17p11.2 in multifocal neuropathies

We investigated 51 patients with multifocal neuropathies for the deletion of chromosome 17p11.2 described in families with hereditary neuropathy with liability to pressure palsies (HNPP). The deletion was detected in 24 patients, including 19 patients from 14 of 15 families in whom HNPP had been considered likely on clinical, neurophysiological, and/or pathological grounds. One patient with a deletion had rather unusual clinical features for HNPP, presenting with a progressive scapuloperoneal syndrome. Overall, 7 (37%) of the 19 index patients with the deletion had no affected relatives, and less than half had evidence of a generalized neuropathy on examination. Peripheral nerve lesions were related to pressure in only 15 (62%) of the patients with the deletion. Nerve conduction studies in 23 of 25 patients and relatives studied showed a fairly uniform pattern of moderate prolongation of distal sensory and motor latencies and slowing of conduction velocities, and variable reduction of sensory or evoked muscle action potential amplitudes. The patients investigated who did not have a deletion of 17p11.2 were heterogeneous and included those with recurrent and/or familial neuralgic amyotrophy, two or more peripheral nerve lesions at common sites of entrapment, or a patchy axonal neuropathy of unknown etiology. In 1 patient a diagnosis of HNPP remains most likely. DNA analysis for the deletion of 17p11.2 is clearly useful in establishing the diagnosis of HNPP, which should be considered regardless of family history or clinical evidence of a generalized neuropathy, and in patients with multifocal neuropathies that do not conform to the classic clinical picture of HNPP.     

Epidemiology of hereditary neuropathy with liability to pressure palsies (HNPP) in south western Finland

An epidemiological study of hereditary neuropathy with liability to pressure palsies (HNPP) was carried out in south western Finland, with a population of 435 000. The diagnosis was established in 69 patients from 23 unrelated families through family and medical history, clinical neurological and neurophysiological examinations and with documentation of the deletion at gene locus 17p11.2 in at least one member of each family. This gave a prevalence of at least 16/100 000, which is remarkably high. However, due to the insidious nature of HNPP, most probably it is still an underestimation. This is the first population-based prevalence figure reported for HNPP. The prevalence is somewhat lower than that obtained for CMT in the same population, which agrees with the proposal that HNPP and CMT 1A are reciprocal products of the same unequal crossing-over. The clinical pictures of our patients were, in general, similar to those previously described in HNPP.     

DNA analysis as a tool to confirm the diagnosis of asymptomatic hereditary neuropathy with liability to pressure palsies (HNPP) with further evidence for the occurrence of de novo mutations

We performed DNA analysis in four families with hereditary neuropathy with liability to pressure palsy (HNPP). An interstitial deletion of the 17 p11.2 region was found in typically affected patients as well as in as yet asymptomatic patients. The opportunity for an individual genotyping permitted to ascertain a de novo deletion in one clinically affected case with no relevant familial history. DNA analysis thus becomes the most sensitive tool in diagnosing HNPP, since potentially affected patients may lack either informative familial history, or clinical symptoms or even suggestive EMG or histopathological data (tomaculas).     

Hereditary neuropathy with liability to pressure palsy presenting with an acute inflammatory demyelinating polyneuropathy

INTRODUCTION: Hereditary neuropathy with liability to pressure palsy (HNPP) is an autosomal dominant peripheral neuropathy characterized by compressive focal neuropathies and an underlying sensorimotor demyelinative polyneuropathy. It is usually caused by a 1.5 Mb deletion of the PMP22 gene (17p11.2). CASE REPORT: We describe the case of a 31 year-old woman who presented with acute demyelinative peripheral polyneuropathy affecting the four limbs and elevated cerebrospinal fluid protein content a few days after a viral illness. Acute inflammatory demyelinating polyneuropathy (AIDP, Guillain-Barré syndrome) was suspected. However, electrophysiologic examination suggested HNPP and subsequent genetic testing was confirmatory. CONCLUSION: This case demonstrates that HNPP can present in an acute manner, mimicking AIDP.     

Hereditary neuropathy with liability to pressure palsies caused by 17p11.2 chromosome deletion]

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder characterised by recurrent mononeuropathies. Electrophysiological studies reveal slowed conduction velocity in peripheral nerves. The main histopathological findings are focal thickenings of myelin-tomaculae. In most cases HNPP is associated with a deletion within PMP-22 (peripheral myelin protein; PMP) gene on chromosome 17p11.2. The gene penetration is almost complete but the expression may be variable. DNA analysis is of practical importance in diagnosing HNPP especially in sporadic cases and also in individuals without clinical and electrophysiological signs of neuropathy. We present the first Polish family with HNPP, in which the genetic defect has been confirmed by DNA analysis.     

Hereditary recurrent focal neuropathies: clinical and molecular features

The authors review the molecular genetics and pathophysiology of hereditary recurrent focal neuropathies: hereditary neuropathy with liability to pressure palsies (HNPP) and hereditary neuralgic amyotrophy (HNA). Significant progress in the understanding of HNPP and HNA has been achieved. HNPP and HNA are distinct clinical and pathologic disease entities with autosomal dominant inheritance. Molecular genetic studies have shown that HNPP and HNA are located on chromosome 17 but at distinct genetic loci (17p11.2 for HNPP, 17q25 for HNA). The 1.5 megabase deletion in 17p11.2 is the major cause of HNPP. This interstitial deletion causes the complete loss of one allele of the peripheral myelin protein 22 (PMP22) gene. Interestingly, rare HNPP patients are found without the 1.5 megabase deletion. However, these patients have distinct mutations in the PMP22 gene resulting in altered expression of the PMP22 protein. Current molecular genetic tests and clinical guidelines allow improved diagnosis, prognosis, and genetic counseling for patients with HNPP. Such tests are not available for HNA, because the disease-causing gene remains unknown. Molecular genetic advances in HNPP and HNA, as well as the study of transgenic animal and cellular models, will provide a more precise understanding of the disease mechanisms and will lead to the development of effective therapeutic tools for patients with inherited and sporadic recurrent peripheral neuropathies.     

Hereditary neuropathy with liability to pressure palsies: Association with central nervous system demyelination

Hereditary neuropathy with liability to pressure palsies (HNPP) is usually caused by a 1.5-Mb deletion in chromosome 17p11.2, the inverse mutation to the duplication seen in the majority of Charcot-Marie-Tooth type 1A (CMT 1A) patients. Although most patients with HNPP present with pressure palsies secondary to mild trauma, the clinical heterogeneity of the neuropathy has become more apparent following the discovery of the mutation. There are reports of central conduction abnormalities in CMT 1, however, there have been no previous reports of central nervous system (CNS) demyelination in HNPP. We report a case of HNPP with the typical DNA mutation whose clinical features and MRI of the brain suggested concurrent CNS demyelination. Further studies of possible CNS involvement in HNPP are warranted. © 1996 John Wiley & Sons, Inc.     

Neuropathic scapuloperoneal syndrome (Davidenkow's syndrome) with chromosome 17p11.2 deletion

The nosologic boundary of neuropathic scapuloperoneal syndrome (Davidenkow's syndrome) remains ill defined and its genetic basis is unknown. A case of Davidenkow's syndrome with the monochromosomic 17p11.2 deletion that often is associated with hereditary neuropathy with liability to pressure palsies (HNPP) is described. The other allele at chromosome 17p11.2 locus was of normal length, and direct sequencing of the coding region of the peripheral nerve protein-22 gene in this allele revealed no additional mutation. The deleted allele in the proband was inherited from the paternal line in which the affected members had a late onset Charcot-Marie-Tooth type 1 clinical phenotype. This observation suggests that the rare Davidenkow's syndrome is clinically related to HNPP and its genotype could be a chromosome 17p11.2 deletion.     

经基因诊断确诊的遗传性压迫易感性神经病临床特点分析

目的 研究经基因诊断确诊的遗传性压迫易感性神经病（hereditary neuropathy with liability to pressure palsies，HNPP）患者的临床特点和电生理特征。方法 对来自4个家系的5例HNPP患者进行基因诊断，并总结患者的临床特点，同时分析其电生理特征，包括肌电图（EMG）、运动神经传导速度（MCV）和感觉神经传导速度（SCV）。结果 5例患者均存在周围髓鞘蛋白22（peripheralmyelinationprotein22，PMP22）基因缺失。HNPP临床主要表现为反复发作的肢体麻木、无力，神经传导存在广泛异常。结论电生理检查对HNPP的诊断很重要，基因检测发现PMP22基因缺失是诊断HNPP的金标准。     

Stoichiometric alteration of PMP22 protein determines the phenotype of hereditary neuropathy with liability to pressure palsies

BACKGROUND: Hereditary neuropathy with liability to pressure palsies (HNPP) is caused by a 1.4-megabase deletion at chromosome 17p11.2, which bears the PMP22 gene and other genes. However, whether other genes besides PMP22 contribute to the phenotype is unknown. Whether any mutation within the coding region of the PMP22 gene ultimately causes HNPP by reducing the amount of peripheral myelin protein 22 (PMP22) expressed in myelin is also unknown. OBJECTIVE: To determine whether affected patients develop a phenotype identical to that found in HNPP and whether the leucine 7 frameshift (Leu7fs) mutation reduces PMP22 levels in myelin. DESIGN: We evaluated affected family members by neurological examination, electrophysiology, and skin biopsies. We identified a large family with a Leu7fs mutation of PMP22 (11 affected members across 3 generations) that predicts truncation of the protein prematurely and eliminates PMP22 expression from the mutant allele. RESULTS: We found that PMP22 levels were reduced in peripheral nerve myelin in dermal skin biopsies in patients with an Leu7fs mutation. Through clinical and electrophysiological evaluation, we also found that patients with the Leu7fs mutation were indistinguishable from patients with HNPP caused by deletion. We also found that a length-dependent axonal loss became pronounced in elderly patients with Leu7fs mutations, similar to what has been described in heterozygous knockout mice (pmp22 +/-). CONCLUSIONS: Taken together, these results confirm that the phenotypic expression is identical in patients with Leu7fs mutation and patients with HNPP caused by chromosome 17p11.2 deletion. They also demonstrate that reduction of PMP22 is sufficient to cause the full HNPP phenotype.