Neuropathy, Hereditary, With Liability To Pressure Palsies

A number sign (#) is used with this entry because hereditary neuropathy with liability to pressure palsies (HNPP) can be caused by deletion of the gene encoding peripheral myelin protein-22 (PMP22; 601097); duplication of PMP22 causes Charcot-Marie-Tooth disease type 1A (CMT1A; 118220). Point mutation in PMP22 may result in HNPP or CMT1A.

Clinical Features

This disorder may have been described first by De Jong (1947) who reported a family in which 1 man and 4 women in 3 generations had recurrent peroneal neuropathy after digging potatoes in a kneeling position. Families were reported by Davies (1954) and by Earl et al. (1964). The latter group found that motor nerve conduction velocity (NCV) was reduced in some clinically normal family members. Staal et al. (1965) studied a family in which members in 4 generations showed transient unilateral peroneal palsies. The neuropathy manifested itself especially after prolonged work in a kneeling position. The family, living in Holland, knew the disease as 'bulb diggers' palsy. Other nerve palsies, such as ulna, occur as well (Davies, 1954). Females are less severely affected. In a Danish family, Roos and Thygesen (1972) observed 19 cases in 5 generations. The usual age of onset was between ages 15 and 20 years. The course of the disorder and the episodic nature of the neuropathy, which often was of mechanical provocation, suggested that it was the same disorder as that reported by Davies (1954), Wahle and Tonnis (1958), Earl et al. (1964), and others. Gabreels-Festen et al. (1992) called attention to atypical presentation of this disorder. Manifestations included pes cavus, scoliosis, and deafness.

Madrid and Bradley (1975) reviewed the pathology, which is distinguished by the presence of sausage-shaped swellings of the myelin sheath, from which the term tomaculous neuropathy (Latin: tomaculum = sausage) was derived. Oda et al. (1990) demonstrated that the tomacula occur not only in sensory nerves but also in motor nerves.

Fewings et al. (1985) reported a family. Sellman and Mayer (1987) reported conduction block in 5 nerves of 4 patients from 2 families with hereditary neuropathy with susceptibility to pressure palsies. Pathologic changes included segmental demyelination and tomaculous swellings. Barisic et al. (1990) described this disorder in monozygotic twin sisters and their father. Only 1 of the twins was clinically affected. She developed unilateral peroneal palsy 20 minutes following local pressure. A 25 to 70% reduction of motor and sensory conduction velocity was recorded in the clinically unaffected twin sister and in the father. Sural nerve biopsy showed 'sausage-like' formations. Cortisone was thought to be beneficial.

Gouider et al. (1995) found mild electrophysiologic abnormalities in all symptomatic and asymptomatic deletion carriers, even in childhood. The most consistent findings were mild increase in the distal motor latency of the median nerve at the wrist, reduced sensory velocity in the palm, and delayed distal motor latency or reduced motor velocity in the peroneal nerve. The authors found that 37.5% of the subjects had absent ankle jerks and 12.5% had global areflexia. However, even these affected subjects did not have the severe slowing or motor nerve conduction velocities that could cause confusion with Charcot-Marie-Tooth disease type 1A.

Sessa et al. (1997) described a father and son with a clinical presentation suggestive of HNPP but without typical tomacula on sural nerve biopsy. Molecular analysis confirmed a deletion at 17p11.2 in both patients. The father, a 45-year-old man, had acute onset of weakness and paresthesia in the right hand after sustained pressure. On examination 3 months later, motor deficit was present in the distribution of the right ulnar and median nerves as well as the right peroneal nerves. Pes cavus and hammertoes were present. The son, an 18-year-old parachutist, reported acute onset of weakness in his left shoulder after parachuting. Sessa et al. (1997) concluded that their observations supported the relevance of DNA analysis for the diagnosis of HNPP.

Stogbauer et al. (1998) described a 29-year-old man who had had 3 episodes of painless palsy of the brachial plexus on either the right or the left side over a period of 6 years. These episodes were not preceded by strenuous use of the affected arm or by infections. Recovery had generally been excellent. Clinical examination showed no signs of generalized neuropathy. There was no pes cavus, and deep tendon reflexes were normal. Nerve conduction velocity studies showed prolonged distal motor latencies as well as prolonged motor nerve conduction velocities of the median and peroneal nerves. Sural nerve biopsy showed demyelination and remyelination, as well as focal myelin thickening (i.e., tomacula). Using intragenic polymorphisms of the PMP22 gene, Stogbauer et al. (1998) demonstrated that the maternal allele was lost, indicating deletion. It appeared to be a de novo deletion.

There are conditions that mimic the symptoms of carpal tunnel syndrome (CTS; 115430) or predispose people to develop it. One such condition is HNNP, which most frequently manifests initially as a peripheral nerve entrapment, including median nerve compression at the carpal canal with delayed nerve conduction velocities. Potocki et al. (1999) described a family with dominantly inherited CTS that was associated with the chromosome deletion in 17p12 that causes HNPP. The authors suggested that HNPP is probably underdiagnosed because it typically has episodic and transient clinical manifestations. Stockton et al. (2001) evaluated 50 patients diagnosed with idiopathic CTS and found no instance of the chromosome 17 microdeletion that causes HNPP.

Cruz-Martinez et al. (1997) reported 2 young females who developed unilateral peroneal nerve palsy after a diet for fashion reasons. Both patients had no previous history of palsies. In both, the palsy developed after nocturnal sleeping. A deletion of the PMP22 gene was demonstrated. Nerve conduction studies showed abnormalities in several relatives, some of whom had had palsies. Conduction block at the fibular head was in agreement with the hypothesis that the peroneal nerve becomes more susceptible to minor injuries, perhaps as a result of the loss of subcutaneous tissue. 'Slimmer paralysis' can occur in persons with HNPP and no history of previous palsy and probably can occur occasionally in individuals without the genetic defect. Weight loss must be added to trivial trauma of attraction or pressure as a precipitating factor in the genetic disorder.

Shaibani et al. (1997) reported the case of a 22-year-old male who awoke with right foot drop and numbness found to be due to HNPP by nerve conduction studies, sural nerve biopsy, and molecular genetic analysis. Two months later he developed involuntary flexion/extension movements of the right toes with associated intermittent dystonic flexion of the right foot. Over the next 2 months these movements spread to the left foot and hand, and myoclonus of the left trapezius and rhomboid muscles appeared. This was thought to be the first case report of moving toes syndrome and segmental myoclonus in association with HNPP. Shaibani et al. (1997) concluded that the temporal and topographic patterns of spread of the abnormal movements suggested a central mechanism probably induced by peripheral pathology.

Felice et al. (1999) described the cases of 2 children with liability to pressure palsies: a 13-year-old girl with a droopy left shoulder that was initially attributed to scoliosis; and a 16-year-old male who presented with right biceps brachii atrophy that was first observed by his pediatrician during a routine physical examination. Nerve conduction studies in both children showed evidence of superimposed diffuse demyelinating polyneuropathy. The girl had frequently carried a heavy backpack on both shoulders.

Ohkoshi et al. (2001) reported a 19-year-old woman who presented with 2 episodes of hand drop and a subsequent episode of aphonia and hoarseness after sleeping in the prone position. Molecular analysis showed a common deletion on 17p11.2, confirming a diagnosis of HNPP. Laryngoscopic findings showed right vocal cord paresis which resolved after 6 weeks. The authors noted that vocal cord paralysis had not previously been reported in patients with HNPP.

Korn-Lubetzki et al. (2002) described a Jewish Kurdish family in which a father and 2 daughters were diagnosed with inflammatory demyelinating polyneuropathy (139393) within a period of 10 years. DNA analysis identified the deletion on chromosome 17 that is typical of HNPP. The authors suggested that screening for the HNPP deletion in patients with atypical, recurrent, or familial inflammatory demyelinating polyneuropathy may be warranted.

Hardon et al. (2002) described a previously healthy 2-year-old boy who presented with radial nerve palsy due to HNPP. He had developed acute severe weakness of his right hand, with no other symptoms. He had the habit of sleeping with his right arm hanging through the bars of his bed. Neurologic examination revealed a paralysis of the wrist and digit extensors and of the abductor pollicis longus muscle on the right. Neurophysiologic study showed a lower right radial nerve compound motor action potential with a normal nerve conduction velocity. The mother experienced numbness in digits I through III of her left hand and was found to have prolonged motor and sensory distal latencies and moderate slowing of the NCVs of the left median nerve compatible with carpal tunnel syndrome. Both mother and son were shown to have the same deletion in the 17p11.2 region. The boy's radial nerve palsy completely recovered in 2 months. Hardon et al. (2002) concluded that even in very young children with a negative family history but otherwise typical compressive nerve palsy, the possibility of HNPP needs to be considered.

Kalfakis et al. (2002) reported a 37-year-old patient with non-Hodgkin lymphoma who was treated with a total of 4 mg vincristine and developed a tetraparesis, inability to walk, and areflexia. Genetic analysis identified the characteristic deletion of the PMP22 gene found in HNPP. Kalfakis et al. (2002) suggested that diagnostic investigations for hereditary neuropathies, including HNPP, should be performed before administration of vincristine.

Studies of patients with HNPP show accentuated distal slowing along with nonuniform conduction abnormalities at segments liable to compression, suggesting a distal myelinopathy as an underlying pathophysiologic mechanism. Li et al. (2002) evaluated 12 patients with HNPP by standard nerve conduction studies and by conduction to more proximal muscles in the arm and leg. Three CMT1A patients and 6 healthy subjects were also evaluated as controls. Li et al. (2002) found accentuated distal slowing primarily in median and peroneal nerve segments liable to pressure palsies or repetitive trauma. However, the ulnar and tibial nerves, which are less liable to compression, had minimal changes. In addition, distal latencies to more proximal muscles in the arm and leg did not have distal slowing. Li et al. (2002) concluded that their findings did not support a distal myelinopathy as a determinant of the conduction abnormalities in HNPP.

Li et al. (2007) reported clinical features of an Australian family with HNPP due to a frameshift mutation in the PMP22 gene (601097.0009); the family had previously been reported by Nicholson et al. (1994). The mean age at onset was 15 years, and all patients reported transient episodes of focal weakness or sensory loss. Nine of 11 patients had mild neurologic abnormalities and mild sensory abnormalities specifically in the feet. Electrophysiologic studies showed a pattern similar to HNPP resulting from the classic PMP22 deletion, with accentuated distal slowing occurring at sites subject to nerve compression. Three patients older than age 65 years had clinical and electrophysiologic evidence of length-dependent axonal loss. Further studies showed a 24% reduction of PMP22 levels in myelinated axons from dermal biopsies. Li et al. (2007) concluded that the phenotype of HNPP due to a PMP22 truncating mutation is indistinguishable from that due to the PMP22 1.5-Mb deletion. The findings indicated that a reduction in PMP22 is sufficient to induce the HNPP phenotype independent of effects from other genes.

Diagnosis

Aarskog and Vedeler (2000) described a quantitative PCR method for detecting both duplication and deletion of the PMP22 gene in CMT1A and HNPP, respectively. Their method of real-time quantitative PCR is a sensitive, specific, and reproducible method allowing 13 patients to be diagnosed in 2 hours. It involves no radioisotopes and requires no post-PCR handling.

Differential Diagnosis

Although HNPP shares clinical features with neuritis with brachial predilection (NAPB; 162100), they are considered distinct disorders (Gouider et al., 1994). Martinelli et al. (1989) described a family in which multiple members had intermittent brachial plexus palsy with the histologic findings of tomaculous neuropathy. Patients showed reduced interpupillary distance (hypotelorism), a finding that has been reported in neuritis with brachial predilection (Airaksinen et al., 1985; Jacob et al., 1961; Gardner and Maloney, 1968). Stogbauer et al. (1997) found linkage of neuritis with brachial predilection to 17q24-q25 in a region distinct from the 17p location of PMP22.

Inheritance

Roos and Thygesen (1972) thought X-linked dominant inheritance could not be excluded; autosomal dominant inheritance is proved, however, by the reports of father-to-son transmission by Davies (1954), Lhermitte et al. (1973), Cruz Martinez et al. (1977), Dubi et al. (1979), and Hinault et al. (1981). Subclinical electrophysiologic abnormalities permit demonstration of autosomal dominant inheritance (Staal et al., 1965; Debruyne et al., 1980).

Molecular Genetics

Using DNA markers, Chance et al. (1993) demonstrated a large interstitial deletion in distal 17p11.2 in persons with HNPP from 3 unrelated pedigrees (601097.0004). In 1 pedigree, de novo genesis of the deletion was documented. The deletion spanned approximately 1.5 Mb and included all markers that were known to be duplicated in CMT1A. The deleted region appeared uniform in all pedigrees and included the gene for peripheral myelin protein-22 (PMP22), the gene that is duplicated or the site of point mutation in CMT1A. Since the breakpoints in HNPP and CMT1A map to the same intervals in 17p11.2, these genetic disorders may be the result of reciprocal products of unequal crossover. The relationship of HNPP to the PMP22 gene was further supported by the demonstration by Mariman et al. (1993) of close linkage to DNA markers in the same region as that to which CMT1A had been mapped. In keeping with this possibility was the finding that D17S122, another marker from the CMT1A region, displayed apparent loss of heterozygosity in the large Dutch family they studied.

Le Guern et al. (1994) found deletion of the D17S122 locus in all affected members of 7 French families with HNPP. In none was an allele contributed to the affected offspring by the affected parent, indicating an interstitial deletion within the 17p11.2 region. Thus, they confirmed the 'mirror image' deletion/duplication relationship of HNPP and CMT1A (see 601097.0004). Reisecker et al. (1994) described an apparently new mutation case due to deletion of the PMP22 gene inherited from the mother, who did not show the mutation. In 3 families with HNPP, Verhalle et al. (1994) confirmed the presence of a deletion on 17p11.2, which included all the markers known to be duplicated in CMT1A.

Silander et al. (1994) found deletions in 17p11.2 in all affected patients in 13 Finnish families with HNPP. Mariman et al. (1994) found the 17p deletion in 15 of 22 Dutch families with HNPP diagnosed clinically, electrophysiologically, and, in all cases but 1, demonstration of tomacula on sural nerve biopsies. Single-strand conformation analysis of the protein coding regions of the PMP22 gene did not reveal mutations in patients from the 7 families without the 17p deletion. Umehara et al. (1995) found deletions in 17p11.2 in 2 unrelated Japanese families with HNPP. Gonnaud et al. (1995) found interstitial deletions of the 17p11.2 region in affected and unaffected members of 4 unrelated families, including an affected woman who did not receive the paternal allele for PMP22.

Most de novo CMT1A duplications and HNPP deletions have been of paternal origin. LeGuern et al. (1996) investigated a rare case of de novo HNPP of maternal origin. Affected individuals in the family carried a deletion corresponding to the CMT1A/HNPP monomer unit. Segregation analysis of 17p12-p11 markers in the family indicated that the deletion was not generated by unequal crossing over between homologous chromosomes 17, as in de novo cases of paternal origin, but rather by an intrachromosomal rearrangement. The authors concluded that 2 distinct mechanisms can, therefore, lead to the same 17p11.2 deletion. Intrachromosomal rearrangement may be specific to maternal transmission.

Lopes et al. (1999) sequenced the crossover hotspot in 28 patients with CMT1A or HNPP. Rearrangements in 3 of 4 HNPP patients were of maternal origin, and 2 of 4 were intrachromosomal in nature. Some patients exhibited chimeric sequences between proximal and distal repeat sequences in the region (CMT1A-REPs), suggesting conversion of DNA segments associated with the crossing-over. The finding of rearrangements supported a double-strand break repair model, which was first described in yeast (Szostak et al., 1983). Successive steps of this model are heteroduplex DNA formation, mismatch correction, and gene conversion. The authors hypothesized that the double-strand break repair model of DNA exchange may apply universally from yeasts to humans.

Kleopa et al. (2004) reported a family from Cyprus in which 4 affected individuals had features of HNPP and/or CMT1A. One patient presented with typical HNPP, which later progressed to severe CMT1, 2 patients had HNPP with features of CMT1, and 1 patient had a chronic asymptomatic CMT1 phenotype. All 4 patients had the same heterozygous point mutation in the PMP22 gene (601457.0019). Kleopa et al. (2004) emphasized the broad phenotypic spectrum resulting from mutations in the PMP22 gene, as well as the phenotypic overlap of HNPP and CMT1A.

Population Genetics

In southwestern Finland, with a population of 435,000, Meretoja et al. (1997) established a diagnosis of HNPP in 69 patients from 23 unrelated families through family and medical history, clinical, neurologic, and neurophysiologic examinations, and demonstration of deletion at 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, this is still probably an underestimation. The prevalence of HNPP was somewhat lower than that for CMT in this population, which agreed with the proposal that HNPP and CMT1A are reciprocal products of the same unequal crossing-over.

Animal Model

Maycox et al. (1997) found that transgenic mice expressing antisense PMP22 RNA exhibited modestly reduced levels of PMP22 together with a phenotype reminiscent of HNPP. Transgenic antisense homozygotes displayed a striking movement disorder and a slowing of nerve conduction that worsened with age. The authors found that a subset of axons had thickened myelin sheaths and tomacula in young adults, with significant myelin degeneration detected in older animals.

History

De Jong (1947) was the first to describe HNPP in a large family; Koehler (2003) reviewed important features of the article and provided a biographic sketch of de Jong (1909-1998).