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.     

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     

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.     

Molecular diagnosis of PMP22-associated neuropathies using fluorescence in situ hybridization (FISH) on archival peripheral nerve tissue preparations

Charcot-Marie-Tooth (CMT) syndrome type 1 and tomaculous neuropathy, also called hereditary neuropathy with liability to pressure palsies (HNPP), represent two groups of neurological disorders with different subtypes, which can be distinguished at the molecular level. It is known that a 1.5-mb region on chromosome 17p11.2– 12, which includes the gene for the peripheral myelin protein 22 kDa (PMP22), is duplicated in more than 95% of patients with CMT type 1A (CMT1A; gene dosage 3) and is deleted in about 90% of subjects suffering from HNPP (gene dosage 1). This duplication/deletion can be detected reliably by interphase-two-color fluorescence in situ hybridization (FISH). We report here a technique for extraction of nuclei from paraffin-embedded and cryofixed sural nerve biopsies for precise molecular diagnosis, employing interphase-two-color FISH in clinically diagnosed CMT1 or HNPP patients. Following this technique we were able to identify six CMT1A duplications in 13 clinically diagnosed CMT1 cases and five HNPP deletions in 6 clinically diagnosed HNPP cases; 8 control persons were included in this study. This is the first report on the use of FISH in the detection of 17p11.2–12 duplication and deletion in archival biopsy material. Received: 10 January 1997 / Revised, accepted: 3 March 1997     

A Family Harboring CMT1A Duplication and HNPP Deletion

Charcot-Marie-Tooth disease type 1A (CMT1A) is associated with duplication of chromosome 17p11.2-p12, whereas hereditary neuropathy with liability to pressure palsies (HNPP), which is an autosomal dominant neuropathy showing characteristics of recurrent pressure palsies, is associated with 17p11.2-p12 deletion. An altered gene dosage of PMP22 is believed to the main cause underlying the CMT1A and HNPP phenotypes. Although CMT1A and HNPP are associated with the same locus, there has been no report of these two mutations within a single family. We report a rare family harboring CMT1A duplication and HNPP deletion.     

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.     

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.     

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.     

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.     

HNPP Associated With An Alternatively-Sized Deletion At Chromosome 17p11.2-p12

Chromosome 17p11.2-p12 is prone to unequal crossing-over events associated with inherited neuropathies (17p12) and with forms of mental retardation known as Smith Magenis Syndrome (SMS) (17p11.2). A 1.5 megabase (Mb) duplication or deletion encompassing the PMP22 gene causes respectively Charcot-Marie-Tooth neuropathy type 1A (CMT1A) and Hereditary Neuropathy with liability to Pressure Palsies (HNPP); the unequal crossing over is caused by misalignment of two low-copy repeat elements named CMT1A-REP which flank the duplicated/deleted region. HNPP is genetically homogenous; only exceptional cases have been associated with non-sense mutations of PMP22. In a four-generation pedigree five individuals were affected with a clinically and pathologically typical HNPP (tomaculous neuropathy). PFGE analysis with SacII endonuclease and probe pNEA101, which maps to the proximal CMT1A-REP, failed to detect the 770 and 820 kb junction fragments associated with the 1.5-Mb deletion. Restriction by SacII and NotI showed respectively two novel junction fragments of ≅1.1 and 1.25 Mb, suggesting the presence of a shorter deletion. Nucleotide sequencing of PMP22 was normal. Linkage analysis using the markers D17S1921, D17S839, D17S1357, D17S12, D17S261, D17S953 and D17S1843 confirmed the results of PFGE by demonstrating loss of heterozygosity for D17S1357 and D17S122. The report underlines the high instability of chromosome 17p11.2-p12 and prompts to investigate other mechanisms of genetic rearrangement in that region.     

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.     

Deletion in the CMT1A locus on chromosome 17p11.2 in hereditary neuropathy with liability to pressure palsies

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disease of peripheral nerves, characterized by recurrent focal neuropathies often with an underlying asymptomatic polynuropathy. We report the clinical, electrophysiological, and histopathological findings in three families with HNPP and confirm the presence of a deletion on chromosome 17p11.2, including all the markers known to be duplicated in Charcot-Marie-Tooth disease type 1A. This deletion appears to be the underlying molecular deficit in this disease and provides additional evidence for the importance of this locus for peripheral nerve function.     

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.     

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.     

DNA analysis in Finnish patients with hereditary neuropathy with liability to pressure palsies (HNPP).

Hereditary neuropathy with liability to pressure palsies (HNPP) is a dominantly inherited disorder that presents as recurrent mononeuropathies precipitated by apparently trivial traumas. The presence of a deletion in 17p11.2 was analysed in 13 Finnish families with HNPP. The deletion was found in all patients who were neurologically and neurophysiologically confirmed to have HNPP. In the problematic cases the detection of the gene defect is the method of choice in the diagnosis of HNPP. Analysis of DNA can also be used to detect clinically unaffected family members.     

Ultrastructural PMP22 expression in inherited demyelinating neuropathies

Charcot-Marie-Tooth type 1A (CMT-1A) disease results from a duplication of the PMP22 gene on chromosome 17p11.2. A deletion of the same region causes hereditary neuropathy with liability to pressure palsies (HNPP). We examined the expression of PMP22 in sural nerve biopsies from 2 unrelated patients with CMT-1A, 2 unrelated patients with HNPP, and control patients. The ultrastructural immunocytochemical quantitative analysis of cases of CMT-1A and HNPP showed, respectively, an elevated and reduced expression of PMP22 level compared with controls.     

A novel 3'-splice site mutation in peripheral myelin protein 22 causing hereditary neuropathy with liability to pressure palsies

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant, demyelinating peripheral neuropathy. Clinical hallmarks are recurrent painless focal neuropathies mostly preceded by minor trauma or compression at entrapment sites of peripheral nerves. In the majority of the patients, HNPP is caused by a 1.5 Mb deletion on chromosome 17p11.2-p12 containing the peripheral myelin protein 22 (PMP22) gene. Point mutations within this gene are reported in only a few families. We report a novel mutation in the PMP22 gene in a Spanish family with HNPP. The mutation is a 3' splice-site mutation, preceding coding exon 3 (c.179-1 G>C), causing a mild HNPP phenotype.     

Uncompacted myelin in hereditary neuropathy with liability to pressure palsies with the 17 p11.2 deletion

A 16-year-old girl with a typical features of hereditary neuropathy with liability to pressure palsies (HNPP) and deletion on chromosome 17p11.2 was described. In the mother who was asymptomatic the same genetic defect was found. In a sural nerve biopsy obtained from the girl myelin thickenings characteristic for this disease and de- and remyelination in nerve fibers were found. Special attention was paid to the occurrence of uncompacted myelin, which was present in diffuse and focal forms. It is concluded that high amount of uncompacted myelin is characteristic for HNPP and it is probably related to the under-expression of peripheral myelin protein 22.     

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.