Inherited focal, episodic neuropathies: hereditary neuropathy with liability to pressure palsies and hereditary neuralgic amyotrophy

Hereditary neuropathy with liability to pressure palsies (HNPP; also called tomaculous neuropathy) is an autosomal-dominant disorder that produces a painless episodic, recurrent, focal demyelinating neuropathy. HNPP generally develops during adolescence, and may cause attacks of numbness, muscular weakness, and atrophy. Peroneal palsies, carpal tunnel syndrome, and other entrapment neuropathies may be frequent manifestations of HNPP. Motor and sensory nerve conduction velocities may be reduced in clinically affected patients, as well as in asymptomatic gene carriers. The histopathological changes observed in peripheral nerves of HNPP patients include segmental demyelination and tomaculous or "sausage-like" formations. Mild overlap of clinical features with Charcot-Marie-Tooth (CMT) disease type 1 (CMT1) may lead patients with HNPP to be misdiagnosed as having CMT1. HNPP and CMT1 are both demyelinating neuropathies, however, their clinical, pathological, and electrophysiological features are quite distinct. HNPP is most frequently associated with a 1.4-Mb pair deletion on chromosome 17p12. A duplication of the identical region leads to CMT1A. Both HNPP and CMT1A result from a dosage effect of the PMP22 gene, which is contained within the deleted/duplicated region. This is reflected in reduced mRNA and protein levels in sural nerve biopsy samples from HNPP patients. Treatment for HNPP consists of preventative and symptom-easing measures. Hereditary neuralgic amyotrophy (HNA; also called familial brachial plexus neuropathy) is an autosomal-dominant disorder causing episodes of paralysis and muscle weakness initiated by severe pain. Individuals with HNA may suffer repeated episodes of intense pain, paralysis, and sensory disturbances in an affected limb. The onset of HNA is at birth or later in childhood with prognosis for recovery usually favorable; however, persons with HNA may have permanent residual neurological dysfunction following attack(s). Episodes are often triggered by infections, immunizations, the puerperium, and stress. Electrophysiological studies show normal or mildly prolonged motor nerve conduction velocities distal to the affected brachial plexus. Pathological studies have found axonal degeneration in nerves examined distal to the plexus abnormality. In some HNA pedigrees there are characteristic facial features, including hypotelorism. The prognosis for recovery of normal function of affected limbs in HNA is good, although recurrent episodes may cause residual deficits. HNA is genetically linked to chromosome 17q25, where mutations in the septin-9 (SEPT9) gene have been found.     

Brachial plexus involvement as the only expression of hereditary neuropathy with liability to pressure palsies.

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal-dominant focal neuropathy characterized by recurrent entrapment neuropathies. Single members of families with HNPP and brachial plexus involvement have been reported previously. We describe a family with three affected members and in which the only symptom of entrapment was recurrent brachial plexopathy. The diagnosis of HNPP in this family was confirmed by both neurophysiological methods and DNA analysis. The distinction between HNPP and hereditary neuralgic amyotrophy is discussed.     

Recurrent familial brachial plexus palsies as the only clinical expression of 'tomaculous' neuropathy

Two familial cases of recurrent brachial plexus are described and similar episodes were noticed in other members of the family. Electrophysiological investigations found impaired motor and sensory nerve conduction velocity in affected and nonaffected members. Tomaculous neuropathy was found at biopsy of peripheral nerve in more than 40% of dissected fibers. In addition, two affected members showed a reduced interpupillary distance, i.e. the most common dysmorphic feature found in the hereditary neuralgic amyotrophy (HNA). A literature review showed only two other instances of recurrent familial brachial plexus palsies as the only manifestation of tomaculous neuropathy (hereditary neuropathy with liability to pressure palsy, HNPP). The dysmorphic feature found in our cases in addition to the clinical, electrophysiological and anatomical data support the hypothesis that these cases of HNPP and the HNA may represent the same disease.     

遗传性压迫易感性神经病（附一家系2例报告）

本文报告遗传性压迫易感性神经病一家系母女 2例患者的临床及电生理资料。2例均在 2 5岁起病 ,呈常染色体显性遗传。临床表现为反复肢体麻木、乏力 ,多于用力、提重物或轻度外伤后出现 ,数日至半个月左右自行好转。电生理检查有弥漫性神经传导速度减慢。周围神经病理特点为节段性脱髓鞘及腊肠样结构形成。已发现大部分本病家系均有 17p11.2上一 1.5Mb片段 (含有 PMP- 2 2基因 )的大缺失 ,少数家系为 PMP- 2 2基因碱基缺失。及时诊断 ,避免重体力劳动和外伤 ,可明显改善患者的预后     

Peripheral Myelin Protein 22 gene duplication with atypical presentations: A new example of the wide spectrum of Charcot-Marie-Tooth 1A disease

Charcot-Marie-Tooth type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP) are both autosomal-dominant disorders linked to peripheral myelin anomalies. CMT1A is associated with a Peripheral Myelin Protein 22 (PMP22) duplication, whereas HNPP is due to a PMP22 deletion on chromosome 17. In spite of this crucial difference, we report three observations of patients with the 1.4 megabase CMT1A duplication and atypical presentation (electrophysiological, clinical or pathological): a 10 year-old girl with tomaculous lesions on nerve biopsy; a 26 year-old woman with recurrent paresthesiae and block conduction on the electrophysiological study; a 46 year-old woman with transient recurrent nerve palsies mimicking HNPP. These observations highlight the wide spectrum of CMT1A and the overlap between CMT1A and HNPP (both linked to the PMP22 gene), and finally illustrate the complexity of the genotype–phenotype correlations in Charcot-Marie-Tooth diseases.     

Inherited peripheral neuropathy

Hereditary disorders of the peripheral nerves constitute a group of frequently encountered neurological diseases. Charcot-Marie-Tooth neuropathy type 1 (CMT1) is genetically heterogeneous and characterized by demyelination with moderately to severely reduced nerve conduction velocities, absent muscle stretch reflexes and onion bulb formation. Genetic loci for CMT1 map to chromosome 17 (CMT1A), chromosome 1 (CMT1B), and another unknown autosome (CMT1C). CMT1A is most often associated with a tandem 1.5-megabase (Mb) duplication in chromosome 17p11.2-12, or in rare patients may result from a point mutation in the peripheral myelin protein-22 (PMP22) gene. CMT1 B result from point mutations in the myelin protein zero (Po or MPZ) gene. The molecular defect in CMT1 C is unknown. Mutations in the early growth response 2 gene (EGR2) are also associated with demyelinating neuropathy. Other rare forms of demyelinating peripheral neuropathies map to chromosome 8q, 10q, and 11q. X-linked Charcot-Marie-Tooth neuropathy (CMTX), which has clinical features similar to CMT1, is associated with mutations in the connexin32 gene. Charcot-Marie-Tooth neuropathy type 2 (CMT2) is characterized by normal or mildly reduced nerve conduction velocity with decreased amplitude and axonal loss without hypertrophic features. One form of CMT2 maps to chromosome 1 p36 (CMT2A), another to chromosome 3p (CMT2B) and another to 7p (CMT2D). Dejerine-Sottas disease (DSD), also called hereditary motor and sensory neuropathy type III (HMSNIII), is a severe, infantile-onset demyelinating polyneuropathy that may be associated with point mutations in either the PMP22 gene or the Po gene and shares considerable clinical and pathological features with CMT1. Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder that results in a recurrent, episodic demyelinating neuropathy. HNPP is associated with a 1.5-Mb deletion in chromosome 17p11.2-12 and results from reduced expression of the PMP22 gene. CMT1A and HNPP are reciprocal duplication/deletion syndromes originating from unequal crossover during germ cell meiosis.     

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     

Screening for Charcot-Marie-Tooth type 1A and hereditary neuropathy with liability to pressure palsy in archival nerve biopsy samples by direct-double-differential PCR

Chromosomal imbalance of the peripheral myelin protein-22 gene (PMP22) is known to be the most frequent genetic abnormality in Charcot-Marie-Tooth disease type 1 (CMT1) and hereditary neuropathy with liability to pressure palsy (HNPP). We applied a new quantitative PCR method, the direct-double-differential PCR (dddPCR), to the gene dosage determination of PMP22. The method allows the quantification of the PMP22 gene copy number independently from DNA fragmentation, even in highly degraded DNA from up to 12-year-old sural nerve biopsy samples. Chromosomal imbalance of the PMP22 gene, which had been detected by examination of four microsatellites located directly adjacent to the PMP22 gene, between the CMT1A-repetition (CMT1A-REP) elements was reliably confirmed by the dddPCR. Using this method we unexpectedly identified two cases with PMP22 imbalance, although morphologically the neuropathies were of a neuronal or axonal type and not of a demyelinating type as usual. One sural nerve biopsy was from a 58-year-old male diabetes mellitus patient with a disproportionately severe polyneuropathy showing a heterozygous duplication of PMP22. The second biopsy exhibiting a heterozygous deletion of PMP22 was from a 58-year-old female patient with a more axonal than demyelinating type of neuropathy without typical tomaculous changes seemingly altered by exogenous, possibly traumatic factors other than diabetes mellitus. Thus, the dddPCR provides a fast and reliable diagnostic tool for the screening and identification of CMT1A and HNPP cases, which is fast and may be essential even when nerve biopsies show morphologically atypical changes. Received: 10 April 2000 / Accepted: 7 June 2000     

Hereditary neuropathy with liability to pressure palsies: the same molecular defect can result in diverse clinical presentation

Hereditary neuropathy with liability to pressure palsies (HNPP) is a peripheral nerve disorder characterized by autosomal dominant inheritance, recurrent pressure palsies, reduced motor and sensory conduction velocities and sausage-like swellings (tomacula) of myelin sheaths in nerve biopsy. Two young adult patients are reported as index cases of two families in which HNPP was diagnosed. The first patient presented with recurrent pressure palsies, whereas the second suffered from fasciculations and myokymias in his right hand, with difficulty in writing, and upper and lower limb paraesthesias of 3 years' duration. Electrodiagnostic studies revealed slowing of conduction primarily in common sites of compression in both patients. Sural nerve biopsy revealed the characteristic tomaculous swellings in both patients. DNA analysis showed that both patients have a deletion in chromosome 17p11.2 which is found in the majority of HNPP cases. In light of the common molecular defect, the different clinical symptomatology of the two patients is discussed.     

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.     

Cation binding at the node of Ranvier in biopsied peripheral nerves of patients with Charcot-Marie-Tooth disease type 1A and hereditary neuropathy with liability to pressure palsies

The node of Ranvier in myelinated fibers is known to have an affinity to bind cations. Demyelination and remyelination due to abnormal expression of a myelin protein may affect cation binding or vice versa under pathological conditions. To study the cation binding at the node of Ranvier in inherited demyelinating neuropathies associated with over- and under-expression of the peripheral myelin protein 22 (PMP-22), the reaction with ferric ion and ferrocyanide was used to visualize the cation binding sites in biopsied nerves of four patiens with Charcot-Marie-Tooth disease type 1A (CMT1A) and two patients with hereditary neuropathy with liability to pressure palsies (HNPP), and the results were compared with those of four patients having acquired neuropathies with normal PMP-22 expression. In CMT1A, nodal widening or paranodal demyelination was associated with dense precipitates focally on both sides of the widened node. Although fainter precipitates were present at the node between remyelinated internodes, the percentage of nodes exhibiting the reaction product between normal and remyelinated internodes was not statistically different from that between normal internodes in CMT1A. In acquired neuropathies, on the other hand, the difference was significant between the two (P < 0.05), with reduction between normal and remyelinated internodes. At the nodes neighboring demylinated internodes, the percentage of nodes exhibiting the reaction product was reduced significantly in both CMT1A and acquired neuropathies, but to a lesser degree in CMT1A. Precipitates were clearly seen at the nodes neighboring a tomaculum in HNPP. The results suggest that preserved cation binding at the node may allow nerves to keep the electrical excitability in CMT1A and HNPP where myelin remodeling takes place at high frequency. Received: 6 June 1995 / Revised: 28 September 1995 / Revised, accepted: 29 November 1995     

Recurrent polyradiculoneuropathy with the 17p11.2 deletion

Hereditary neuropathy with liability to pressure palsies (HNPP) classically occurs as recurrent focal neuropathy. We report the first known instance of HNPP manifesting, over a 15-year period, as a recurrent sensorimotor polyneuropathy and confirmed by the presence of the PMP-22 gene deletion. We suggest that the molecular study of the 17p11.2 region could be an effective non invasive investigative tool in cases of chronic recurrent polyneuropathy associated with episodes of nerve palsy. © 1997 John Wiley & Sons, Inc. Muscle Nerve 20:1184–1186, 1997     

The phenotype of the Gly94fsX222 PMP22 insertion

Point mutations in PMP22 are relatively rare and the phenotype may vary from mild hereditary neuropathy with liability to pressure palsies (HNPP) to severe Charcot-Marie-Tooth type 1 (CMT1). We describe the phenotype of the Gly94fsX222 mutation in the PMP22 gene. Medical records of all patients were reviewed and 11 patients were re-examined. EMG was carried out in nine patients and nerve biopsy in one. Thirteen patients originating from seven families with a Gly94fsX222 mutation were included and consisted of 10 women and 3 men with a median age of 41 years (range 7-67). Five index patients were originally suspected of CMT1. Ten patients had abnormal motor skills during childhood. Nine patients had a history of pressure palsies. Involvement of the olfactory, trigeminal, facial, and pudendal nerves occurred in three patients. Twelve patients had pes cavus and one scoliosis. Distal anterior leg and distal arm weakness were found in 12 and 4 patients, respectively. Twelve patients had distal leg sensory abnormalities. Electrophysiological examination revealed a demyelinating sensorimotor neuropathy, both resembling CMT1 and HNPP. Sural nerve biopsy showed demyelinating neuropathy with presence of tomacula. More than three-fourths of the patients with Gly94fsX222 mutation demonstrated a CMT1 phenotype combined with transient deficits. Clinicians should test for this mutation in those patients exhibiting a generalised neuropathy combined with compressive like episodes.     

遗传性压力敏感性周围神经病

遗传性压力敏感性周围神经病（HNPP）是一种常染色体显性遗传的周围神经病。HNPP的分子基础是染色体17p11．2区的一个1．5Mb片段缺失。临床特点为反复发作的在易卡压部位神经受压后，受累神经所支配区域出现运动感觉障碍。本病早期准确诊断后采取预防措施可减少发作。本文就HNPP的病因、临床特点及诊断等作一综述。     

Major histocompatibility complex class II expression and macrophage responses in genetically proven Charcot–Marie–Tooth type 1 and hereditary neuropathy with liability to pressure palsies

This study examined major histocompatibility complex (MHC) class II expression and macrophage infiltration in sural nerve biopsies from patients with genetically proven Charcot–Marie–Tooth (CMT) 1A and 1B and hereditary neuropathy with liability to pressure palsies (HNPP) by immunocytochemistry. In both young and older patients with duplication of the PMP22 gene, MHC class II expression was consistently up-regulated and not closely related to the extent of macrophage infiltration. On the other hand, MHC class II expression was more variable in CMT1A and CMT1B caused by point mutations and in HNPP. The extent of nerve pathology as assessed by teased fiber preparations or electron microscopy was not predictive for the degree of MHC class II expression in CMT1/HNPP. We conclude that MHC class II up-regulation is a common feature in hereditary neuropathies. As shown for the animal model of globoid cell dystrophy, it is conceivable that increased expression of MHC class II molecules in CMT1 and HNPP accelerates nerve pathology. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21: 1419–1427, 1998     

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     

Report of a novel mutation in the PMP22 gene causing an axonal neuropathy

Introduction: Point mutations in the peripheral myelin protein 22 (PMP22) gene rarely cause the hereditary neuropathies Charcot–Marie–Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP), both of which show a demyelinating phenotype. Methods: In this study we characterized a family with an axonal neuropathy. Results: Three family members carried a heterozygous point mutation of the PMP22 gene, resulting in amino acid substitution R159C. Screening of 185 healthy controls did not reveal the R159C allele in any case. Discussion: The novel R159C mutation represents a very rare case of a dominant PMP22 mutation causing an axonal neuropathy. Muscle Nerve, 2011     

Hereditary neuralgic amyotrophy

Hereditary neuralgic amyotrophy (HNA) belongs to the group of recurrent focal neuropathies, the other major representative being hereditary neuropathy with liability to pressure palsies. The search for the HNA gene has now focused on a locus on chromosome 17q24-q25. Most HNA families show linkage to this locus, but recent evidence indicates that HNA is genetically heterogeneous. Detailed analysis of these unlinked families has broadened our perception of the HNA phenotype, and currently two different clinical courses can be discerned: the classical relapsing-remitting course and a chronic undulating course. After 5 years of molecular genetic research, this disease remains enigmatic. At present, we can only speculate how such very diverse stimuli as immunizations, childbirth, infections, strenuous exercise, and immobilization can trigger painful attacks of brachial plexus palsies in genetically susceptible individuals. Electronic Publication     

Tomaculous neuropathy. A histopathological study and electroclinical correlates in 10 cases

Among 980 sural nerve biopsies, the nerves of 10 patients showed a great number of focal sausage-shaped thickenings of the myelin sheaths and were investigated by light and electron microscopy, teasing and quantitative studies. Single teased nerve fibres revealed myelin thickening in more than 25 p. 100 of internodes. This condition defined the tomaculous neuropathy and differed from other degenerative or toxic neuropathies which displayed a small number of internodes with myelin thickenings, in less than 5 p. 100. Segmental demyelination and remyelination were found in 12 p. 100 to 65 p. 100 of myelinated fibres. Tomaculous swellings were observed in the internodes of these fibres. Except axonal constriction within the sausage-shaped thickenings, no fibers with axonal degeneration was observed. The density of myelinated and unmyelinated fibres was normal. The loss of large myelinated fibres was interpreted as resulting from the myelinic changes. Clinical and electrophysiological data were similar in the ten cases of tomaculous neuropathies and in hereditary neuropathy with liability to pressure palsies, i.e.: autosomal dominant inheritance, higher incidence in males, recurrent nerve trunck and/or brachial plexus involvement related to compression, slowing of nerve conduction velocities in clinically affected and unaffected nerves more pronounced in anatomical narrow sites and increased F wave latencies. One patient (case 10) showed a mixed sensory motor progressive neuropathy but signs of widespread neuropathy were noted in more advanced cases. A great number of tomaculous swellings of myelin sheaths is considered as a specific but non constant change of hereditary neuropathy with liability to pressure palsies.     

Hereditary recurrent brachial plexus neuropathy with dysmorphic features

A Finnish pedigree comprising 13 members in 3 generations with recurrent brachial plexus neuropathy is described. The disease was characterized by repeated attacks of pain in the upper limb/shoulder region, followed by muscle weakness and atrophy. The first episode usually occurred in childhood after a mild infection. Symptoms varied in intensity and seldom left marked neurological deficiencies. Patients had typical features including hypotelorism, small palpebral fissures and a small oral opening. The distribution of the affected members in the pedigree was compatible with autosomal dominant inheritance with high penetrance. Despite the limitation of the symptoms to the upper limbs, sural nerve biopsy showed tomaculous neuropathy in an affected member of the family. The structural changes of tomaculous neuropathy probably reflect a genetically determined generalized abnormality of the Schwann cells predisposing the patients to the recurrent palsies by exogenous factors.