Autosomal dominant hereditary demyelinating motor and sensory neuropathy
-Rare genetic disease
-Rare neurologic disease
Partial monosomy of the short arm of chromosome 17
-Rare developmental defect during embryogenesis
-Rare genetic disease
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 ... 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.
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 ... 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.
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 ... 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.
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 ... 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.
The diagnosis of hereditary neuropathy with liability to pressure palsies (HNPP) is established in an adult with (1) recurrent focal compression neuropathies and (2) family history consistent with autosomal dominant inheritance....
DiagnosisClinical DiagnosisThe diagnosis of hereditary neuropathy with liability to pressure palsies (HNPP) is established in an adult with (1) recurrent focal compression neuropathies and (2) family history consistent with autosomal dominant inheritance.Findings that support the diagnosis include the following:Mild polyneuropathy, with or without symptomsEvidence on physical examination of previous nerve palsy such as focal weakness, atrophy, or sensory lossAbsent ankle reflexes (50%-80%)Diffusely reduced tendon reflexes (15%-30%)Mild to moderate pes cavus foot deformity (20%)Electrophysiologic studies are usually abnormal:Prolongation of distal nerve conduction latencies (e.g., of the median nerve at the wrist) occurs in essentially all individuals whether symptomatic or asymptomatic.According to Mouton et al [1999], the key electrophysiologic diagnostic features are bilateral slowing of sensory and motor nerve conduction at the carpal tunnel with at least one additional abnormal finding for motor conduction in one peroneal nerve. Infante et al [2001] emphasize the need to evaluate sensory conduction in the sural nerve and motor conduction in at least two nerves across usual entrapment sites, especially the ulnar nerve at the elbow. Li et al [2002] found evidence for prolonged distal motor latencies in the median and peroneal nerves but not ulnar or tibial nerves.Nerve conduction velocity (NCV) may be delayed at the site of compression.General motor NCVs are usually normal (>40 m/s); a few individuals have electrical evidence of a mild diffuse polyneuropathy.Sural nerve biopsy often shows evidence of demyelination and "tomaculous" (focal, sausage-like enlargement of the nerve) change. Tomaculous change is not specific and has been noted occasionally in other neuropathies.Molecular Genetic TestingGene. PMP22 is the only gene in which mutation is known to cause HNPP.Clinical testingDeletion/duplication analysis. A 1.5-Mb deletion at 17p11.2 (including PMP22) is detected in approximately 80% of individuals with HNPP. Methods to detect this specific deletion and novel deletions including PMP22 are variable (Table 1, footnote 2). Selected published studies include:Long polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) [Lorentzos et al 2003, Thiel et al 2003]Southern blot analysis (pulse field gel electrophoresis) to detect large-scale PMP22 deletionsMultiplex ligation-dependent probe amplification (MLPA) Note: In one study MPLA was used to detect smaller deletions [Sutton et al 2004].Fluorescence in situ hybridization (FISH) [Mohammed & Shaffer 2003]Sequence analysis. Sequence analysis of PMP22 detects point mutations and small deletions in approximately 20% of individuals with HNPP.Table 1. Summary of Molecular Genetic Testing Used in HNPPView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityPMP22Deletion / duplication analysis 21.5-Mb deletion including PMP22~80%Clinical Sequence analysis 3Point mutations and small deletions~20%1. The ability of the test method used to detect a mutation that is present in the indicated gene.2. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.3. Small intragenic deletions/insertions, missense, nonsense, and splice site mutations.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm/establish the diagnosis in a proband requires detection of a PMP22 mutation using molecular genetic testing. If the PMP22 deletion test is normal in a person with the typical HNPP phenotype, the next step is PMP22 sequence analysis.Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutations in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersThe other phenotypes associated with alterations of PMP22 are Charcot-Marie-Tooth neuropathy type 1A (CMT1A) and Charcot-Marie-Tooth neuropathy type 1E (CMT1E) (see CMT Overview).
Hereditary neuropathy with liability to pressure palsies (HNPP) is characterized by recurrent sensory and motor neuropathy in a single nerve beginning in adolescence or young adulthood. The most common presenting symptom of HNPP is the acute onset of a non-painful focal sensory and motor neuropathy in a single nerve (mononeuropathy) [Pareyson et al 1996, Kumar et al 2002, Li et al 2004]. Some individuals experience transient sensory phenomena without weakness. History of actual physical compression of the nerve may or may not be present....
Natural HistoryHereditary neuropathy with liability to pressure palsies (HNPP) is characterized by recurrent sensory and motor neuropathy in a single nerve beginning in adolescence or young adulthood. The most common presenting symptom of HNPP is the acute onset of a non-painful focal sensory and motor neuropathy in a single nerve (mononeuropathy) [Pareyson et al 1996, Kumar et al 2002, Li et al 2004]. Some individuals experience transient sensory phenomena without weakness. History of actual physical compression of the nerve may or may not be present.Occasional episodes have been reported during pregnancy, perhaps related to physiologic changes such as soft tissue swelling and edema. The nerve palsies often recur over a period of many years, but some individuals have a single episode and some individuals who have a disease-causing mutation are asymptomatic.The first attack is usually in the second or third decade (mean age: 37 years), although the age range extends from two to 70 years. Radial nerve palsy has been reported in a two-year-old with HNPP [Hardon et al 2002] and peroneal nerve palsies have been reported shortly after birth [Goikhman et al 2003].Males and females are equally affected.The following are the most common sites of focal neuropathy (in decreasing order of frequency):The peroneal nerve at the fibular head causing foot dropThe ulnar nerve at the elbow, causing hypothenar and interossei muscle weakness and atrophy with sensory loss over the lateral aspect of the handThe median nerve at the wrist causing carpal tunnel syndrome with thenar muscle weakness and atrophy and sensory loss over the thumb and index finger [Del Colle et al 2003]The brachial plexus and radial nerve, causing transient sensory symptoms and hand pain [Marriott et al 2002].Full recovery over a period of days to months occurs in approximately 50% of episodes. Incomplete recovery is fairly common, but the remaining symptoms are rarely severe. Poor recovery correlates with a history of prolonged focal compression of the nerve [Koike et al 2005].Symptomatic individuals have the frustration and disability associated with recurrent pressure palsies, although the degree of handicap in performing activities of daily living is usually not severe.In addition to the typical presentation of HNPP, Mouton et al [1999] described five other phenotypes:Recurrent positional short-term sensory symptomsProgressive mononeuropathyCMT-like polyneuropathyChronic sensory polyneuropathyChronic inflammatory demyelinating polyneuropathy-like disorder [Korn-Lubetzki et al 2002]Note: Some individuals may be asymptomatic.Other findings reported in a few individuals:Motor brachial paralysis [Kumar et al 2002, Makela et al 2006]Proximal muscle atrophy and severe respiratory insufficiency [Asahina et al 2000]CNS white matter lesions that are usually asymptomatic [Dackovic et al 2001, Sanahuja et al 2005, Tackenberg et al 2006]Hypoglossal nerve paralysis of the tongue, including after carotid endarterectomy [Corwin & Girardet 2003, Winter & Juel 2003]Rapid onset and progression of neuropathy early in military physical training [Horowitz et al 2004]Scapuloperoneal syndrome [Verma 2005]
Persons with the PMP22 frameshift mutation (p.Arg95Glyfs*128) have a typical HNPP phenotype but are also more likely to have an associated clinically evident motor/sensory neuropathy mimicking Charcot-Marie-Tooth Neuropathy Type 1 (CMT1) [Lenssen et al 1998]. Other point mutations in PMP22 with a similar phenotype have been described [Bellone et al 2006, Li et al 2007, Muglia et al 2007, Moszyńska et al 2009]....
Genotype-Phenotype CorrelationsPersons with the PMP22 frameshift mutation (p.Arg95Glyfs*128) have a typical HNPP phenotype but are also more likely to have an associated clinically evident motor/sensory neuropathy mimicking Charcot-Marie-Tooth Neuropathy Type 1 (CMT1) [Lenssen et al 1998]. Other point mutations in PMP22 with a similar phenotype have been described [Bellone et al 2006, Li et al 2007, Muglia et al 2007, Moszyńska et al 2009].Shy et al [2006] described an HNPP phenotype associated with the p.Thr118Met mutation in PMP22.Al-Thihli et al [2008] reported a severely affected child with a two abnormal PMP22 alleles: a PMP22 deletion inherited from the mother and deletion of exons 2 and 3 of PMP22 inherited from the father.
Pressure palsies are most commonly the result of environmentally acquired physical compression of peripheral nerves. The most common are the carpal tunnel syndrome with compression of the median nerve at the wrist, peroneal pressure palsy with compression of the superficial peroneal nerve at the fibular head, and ulnar nerve compression at the elbow. The signs and symptoms of compression neuropathy in hereditary neuropathy with liability to pressure palsies (HNPP) are the same as those of the acquired type. Thus, HNPP is part of the broad differential diagnosis of both compression neuropathies and general peripheral neuropathies, including the hereditary neuropathies and Charcot-Marie-Tooth (CMT) syndrome (see CMT Overview)....
Differential DiagnosisPressure palsies are most commonly the result of environmentally acquired physical compression of peripheral nerves. The most common are the carpal tunnel syndrome with compression of the median nerve at the wrist, peroneal pressure palsy with compression of the superficial peroneal nerve at the fibular head, and ulnar nerve compression at the elbow. The signs and symptoms of compression neuropathy in hereditary neuropathy with liability to pressure palsies (HNPP) are the same as those of the acquired type. Thus, HNPP is part of the broad differential diagnosis of both compression neuropathies and general peripheral neuropathies, including the hereditary neuropathies and Charcot-Marie-Tooth (CMT) syndrome (see CMT Overview).Persons with an underlying polyneuropathy, such as those with diabetes mellitus, are at increased risk for compression neuropathies.HNPP is not a common cause of isolated idiopathic carpal tunnel syndrome [Stockton et al 2001, Sander et al 2005].The proportion of individuals with a single episode of compression neuropathy who have a 17p11 deletion or PMP22 point mutation is not known. However, because some individuals with HNPP may have no family history of neuropathy, a single episode of nerve compression, or a de novo mutation, some authors have advocated molecular genetic testing of individuals with a negative family history who have compression neuropathy. A more selective approach is to test only those individuals with either:More than one episode of compression neuropathy,One episode of compression neuropathy and an unexplained polyneuropathy, orOne episode of compression neuropathy and a family history of neuropathy.HNPP sometimes involves the brachial plexus, thus overlapping with hereditary neuralgic amyotrophy, a distinct disorder that maps to 17q. Stogbauer et al [2000] contrast the clinical features of HNPP and hereditary neuralgic amyotrophy.
To establish the extent of disease in an individual diagnosed with hereditary neuropathy with liability to pressure palsies (HNPP), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with hereditary neuropathy with liability to pressure palsies (HNPP), the following evaluations are recommended:History of focal nerve symptomsFamily historyNeurologic examinationElectromyography / nerve conduction velocity (EMG/NCV)Treatment of ManifestationsTransient bracing, such as with a wrist splint or ankle-foot orthosis (AFO), may be useful. Some individuals with residual foot drop may permanently use an AFO.Prevention of Primary ManifestationsProtective pads at elbows or knees may prevent pressure and trauma to local nerves.Prevention of Secondary ComplicationsBracing of weak muscles, such as ankle-foot-orthosis for foot drop, may prevent injury.Agents/Circumstances to AvoidRisk factors for pressure palsies (and thus activities to avoid) include prolonged sitting with legs crossed, occupations requiring repetitive movements of the wrist, prolonged leaning on elbows, and rapid weight loss [Cruz-Martinez et al 2000, Marriott et al 2002].Vincristine, commonly used in the chemotherapy of lymphoma, has been reported to exacerbate HNPP [Kalfakis et al 2002].Evaluation of Relatives at RiskRelatives at risk may wish to clarify their genetic status by undergoing molecular genetic testing; if found to have the PMP22 mutation identified in an affected family member, they can choose to avoid the aforementioned agents and circumstances.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.OtherControversy exists as to whether surgical decompression of nerves is of benefit. Because spontaneous recovery is common and because no systematic controlled study of surgical intervention has been done, this decision must be made on an individual basis, taking into consideration knowledge of the natural history of the disease. There is a developing consensus that surgical repair of carpal tunnel syndrome is of little benefit to individuals with HNPP and that transposition of the ulnar nerve at the elbow may actually produce poor results [Lazar et al 2007].No specific treatment for the underlying genetic or biochemical defect exists and no special diet or vitamin regimen is known to alter the natural course of HNPP.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Hereditary Neuropathy with Liability to Pressure Palsies: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDPMP2217p12Peripheral myelin protein 22IPN Mutations, PMP22 PMP22 homepage - Leiden Muscular Dystrophy pagesPMP22Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Hereditary Neuropathy with Liability to Pressure Palsies (View All in OMIM) View in own window 162500NEUROPATHY, HEREDITARY, WITH LIABILITY TO PRESSURE PALSIES; HNPP 601097PERIPHERAL MYELIN PROTEIN 22; PMP22Normal allelic variants. PMP22 spans approximately 5 kb and has four exons.Pathologic allelic variants. The molecular defect present in 80% of affected individuals is a 1.5-Mb deletion at 17p11.2 that includes PMP22. This is the reciprocal of the 1.5-Mb duplication that occurs in Charcot-Marie-Tooth neuropathy type 1A (see CMT1). These rearrangements are the result of unequal crossing over following misalignment of flanking repeat sequences at this chromosomal location. HNPP is likely to be the result of a gene dosage effect.Approximately 20% of families with HNPP have a variety of PMP22 point mutations that produce frameshifts, premature termination of translation, or other abnormalities [Young et al 1997, Lenssen et al 1998, Stogbauer et al 2000, van de Wetering et al 2002, Kleopa et al 2004]. The clinical and molecular aspects of other point mutations associated with the HNPP phenotype are reviewed by Stogbauer et al [2000] and van de Wetering et al [2002]. These include mutations resulting in frameshifts, premature termination translation, 5' splice-site mutation, and a mutation affecting the junction of the extracellular loop and the first transmembrane domain of PMP22. Additionally, Meuleman et al [2001] have reported a 3' splice-site mutation, preceding coding exon 3, resulting in a mild HNPP phenotype. The p.Arg95Glyfs*128 mutation not only results in a frameshift at residue 95 but also creates a new translation termination site, thereby adding 61 more amino acids to the length of the protein. See Table 2.Table 2. Selected PMP22 Pathologic Allelic VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid Change (Alias 1)Reference Sequencesc.281_282insGp.Arg95Glyfs*128 2(Gly94fs)NM_000304.2 NP_000295.1 c.353C>Tp.Thr118Met 2See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). 1. Variant designation that does not conform to current naming conventions2. See Genotype-Phenotype Correlations.Normal gene product. Peripheral myelin protein 22 is a 160-amino acid protein that is present in compact myelin and has four transmembrane domains.Abnormal gene product. HNPP is associated with decreased mRNA message for PMP22 and decreased peripheral myelin protein 22 in peripheral nerve [Gabriel et al 1997, Schenone et al 1997a, Schenone et al 1997b].