Sign In
Individual Sign In
Create an Account
Institutional Sign In
OpenAthens Shibboleth
December 2005

Central Nervous System Involvement in Hereditary Neuropathy With Liability to Pressure PalsiesDescription of a Large Family With This Association

Author Affiliations

Author Affiliations: Departments of Neurology (Drs Sanahuja and Granés) and Neurophysiology (Dr Franco), Hospital Universitari Arnau de Vilanova, and Institut de Diagnòstic per la Imatge (Dr Begué), Lleida; Department of Neurology, Neuromuscular Unit and Laboratory of Experimental Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona (Drs Rojas-García, Gallardo, and Illa); and Department of Neurology, Hospital Universitario Marqués de Valdecilla, Santander (Dr Combarros), Spain.


Copyright 2005 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.2005

Arch Neurol. 2005;62(12):1911-1914. doi:10.1001/archneur.62.12.1911

Objective  To describe a large family with hereditary neuropathy with liability to pressure palsies associated with central nervous system demyelination.

Design  We examined the 18 members of a pedigree. Genetic analysis was performed on 15 subjects, standard nerve conduction studies on 10 subjects, and brain magnetic resonance imaging studies on 8 subjects.

Results  Hereditary neuropathy with liability to pressure palsies was confirmed in 9 patients of the pedigree. Brain magnetic resonance imaging findings showed multiple areas of demyelination in 6 of 6 affected members and were normal in 2 of 2 healthy relatives. Magnetic resonance imaging abnormalities were predominantly located in the subcortical frontal white matter. All patients had acute and recurrent nerve palsies, while clinical features of central nervous system involvement were not a characteristic of this pedigree.

Conclusions  We demonstrate that this association, previously reported in sporadic cases, is not coincidental. Therefore, patients with hereditary neuropathy with liability to pressure palsies can present central nervous system white matter lesions, and the role of the PMP22 (peripheral myelin protein 22) gene deletion in the central nervous system should be further studied.

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder typically presenting as acute recurrent nerve palsies.1,2

Most HNPP families have a 1.5-megabase deletion on chromosome 17p11.2, an area that contains the PMP22 (peripheral myelin protein 22) gene; PMP22 is an integral membrane glycoprotein of uncertain function. It is mainly localized in the compact part of peripheral myelin.3 Its expression in central nervous system (CNS) myelin has not been clearly established,4 although it has been described in rat and mouse brain and spinal cord motoneurons.5 Central nervous system involvement has previously been reported in several isolated patients, suggesting an association between central demyelinating lesions and HNPP.68

We describe a large family with HNPP caused by a 17p11.2 deletion, demonstrating that the association is not fortuitous.


We describe 18 members of a family (Figure 1). In all subjects, a standardized neurological examination was performed. Fifteen subjects gave their informed consent for genetic analysis.

Figure 1.
Image not available

Pedigree of the family with hereditary neuropathy with liability to pressure palsies and central nervous system involvement. Squares indicate male subjects; circles, female subjects; black circles and squares, affected individuals; white circles and squares, healthy family members; symbol with a diagonal line, deceased individual; asterisk, a neurophysiological study was performed; white triangle, genetic study results were normal; black triangle, the individual had a 17p11.2 deletion; section mark, brain magnetic resonance imaging was performed; and numbers under each symbol, the current age (in years) of the member of the pedigree.


Nerve conduction studies were performed on 6 patients and 4 healthy relatives. Distal motor latency, motor conduction velocity, and sensory nerve action potentials were recorded for the median, ulnar, and fibular nerves. Normal values from our laboratory and those from another laboratory were used.9


Molecular diagnosis of HNPP was performed using polymerase chain reaction amplification of 3 new, highly polymorphic, short tandem repeats covering 0.55 megabase in the center of the Charcot-Marie-Tooth type 1A–duplicated region, including the PMP22 sequence, as previously described.10,11


Cranial magnetic resonance imaging (MRI) was performed using a 0.5-T magnet with a head coil in 8 subjects, 6 patients and 2 healthy relatives with a confirmed genetic study. Imaging sequences consisted of the following: (1) T1-weighted spin-echo sequence in the sagittal and axial planes (repetition time/echo time, 490/25 milliseconds), (2) axial T2-weighted spin-echo sequence (repetition time/echo time, 2450/25.90 milliseconds), and (3) sagittal and axial fluid-attenuated inversion recovery images (repetition time/echo time, 6950/120 milliseconds).


The proband (III:1) was referred at the age of 24 years for investigation into the cause of an abnormal MRI. The neuroradiological study was performed because she complained of acute right arm weakness and because a cousin (III:4) with similar neurological symptoms was diagnosed as having possible multiple sclerosis (MS). She had experienced recurrent episodes of weakness and/or sensory symptoms in the upper and lower extremities since childhood. The episodes resolved within 1 to 4 weeks and could be related to mononeuropathies. The neurological examination findings were normal, except for right radial hypoesthesia. Signs of generalized neuropathy or CNS pathological features were carefully excluded. Visual, brainstem auditory, and somatosensory-evoked potentials showed no abnormalities. Fluid-attenuated inversion recovery and T2-weighted MRI clearly revealed several foci of a high-intensity signal in the supratentorial white matter, predominantly in the corticomedullary junction (Figure 2C).

Figure 2.
Image not available

Magnetic resonance imaging fluid-attenuated inversion recovery sequences (repetition time/echo time, 6950/120 milliseconds) of 4 patients of the pedigree (A, patient II:3, aged 50 years; B, patient II:4, aged 48 years; C, patient III:1, aged 24 years; and D, patient III:4, aged 27 years) showing multifocal areas of hyperintense signal in the subcortical white matter.

Nerve conduction studies demonstrated prolonged distal latencies of the motor nerves and focal motor conduction velocity slowing at the wrist in the median nerve, while study results were normal in the ulnar or fibular nerves across the usual entrapment sites. Sensory potentials could not be elicited in the fibular nerve, but they were of normal amplitude in the median and ulnar nerves. Genetic study confirmed the deletion on chromosome 17p11.2.


Clinical and/or electrophysiological studies confirmed the neuropathy in 8 other members of the family in addition to our proband (Figure 1).

Clinical features were similar in all these patients. They complained of episodes of sensory disturbance and/or weakness, which developed suddenly and resolved within several days or weeks. In all patients, the onset of the disease occurred between the second and the third decade of life.

Central nervous system involvement was investigated in all subjects. When she was 27 years of age, patient II:3 complained of right hemiparesis, with complete recovery in 2 weeks (the episode was not monitored by a physician). A second episode, of left hemiparesis and hypoesthesia, occurred when she was 48 years of age. The initial diagnosis was of a probable lacunar infarct because she had a long-standing history of untreated arterial hypertension. She recovered, and her neurological examination findings are normal. Another patient, III:4, had previously been diagnosed as having possible MS when she was 25 years of age, because of punctuate lesions in the supratentorial white matter revealed by MRI after an episode of weakness and paresthesia of the left arm, with complete remission after several weeks. Before and after the episode motivating the brain MRI, she complained of several episodes of mononeuropathies. Her neurological examination showed no central involvement and the evoked potentials were normal. In summary, the patient did not fulfill the criteria for MS.12


Genetic study of 15 subjects of the pedigree established the association with the 17p11.2 deletion in all the symptomatic members in whom the study was performed (6 patients). Genetic analysis was not performed in patients II:1, II:7, and II:8 with clinical involvement and electrophysiological confirmation (Figure 1).


Ten members of the family were studied, and the results in the 4 nonsymptomatic relatives were normal. In the 6 patients with confirmed deletion of 17p11.2, the studies showed prolongation of distal motor latencies and abnormal sensory nerve conduction as the most prominent features.


The MRI performed on 6 patients with a deletion of PMP22 showed bilateral supratentorial multifocal lesions in the subcortical white matter in all of them (Figure 2). These hyperintense signals were predominant in the frontal areas. Apparently, the number of lesions did not correlate with the age of the individuals because some members of the second generation presented fewer lesions than members from the third generation, and vice versa. Furthermore, in one patient, the MRI was repeated after 4 years, and the number of lesions remained the same. The results of MRI were normal (not shown) in the only 2 members of the pedigree (III:2 and III:7) who accepted the neuroradiological study and had normal genetic study results and no clinical history of peripheral nerve involvement.


To our knowledge, we describe the first family with HNPP caused by a 17p11.2 deletion in which the affected members present peripheral involvement and CNS demyelination. This association, corroborated by the absence of lesions in the brain MRI of unaffected family members, indicates that the PMP22 deletion may affect myelin not only in the peripheral nervous system but also in the CNS. Of clinical relevance, sensory symptoms and an abnormal MRI result could evoke the diagnosis of MS; this happened in one of our young patients.

Clinically, the disease corresponds to the classic form, with liability to pressure palsy. None of our patients developed generalized polyneuropathy. The results of electrophysiological tests were in agreement with those of previous studies.13 Central nervous system lesions were silent in most of our patients. The patient with clinical CNS involvement had 2 episodes of hemiparesis; however, we cannot prove if this was due to the mutation in the PMP22 gene or to ischemic episodes due to a history of arterial hypertension. The functional outcome of this family over the years is similar to that seen in most HNPP patients, and the CNS involvement has caused no functional involvement in any of the members of the different generations of this family. Furthermore, the number of multifocal areas of increased signal was no larger in patients of the second generation than in those of the third.

This family confirms previously reported isolated cases of HNPP associated with CNS involvement.68 However, in these patients, some clinical symptoms, signs, or pathological test results could be attributed to CNS involvement. Speculating on the pathophysiological mechanism(s) involved in these CNS signs and symptoms is difficult. No brain autopsy description is available from patients with HNPP and, unfortunately, no pathological substrate is available from pmp22 0/0 or 0/+ mice.14,15 In fact, in the peripheral nerves, tomaculous structures are diffusely distributed in the nerve fibers and the mechanism(s) involved in the multifocal clinical and electrophysiological findings are not fully understood.

Of clinical interest is that one patient in our family had been diagnosed as having possible MS. Although isolated cases of definite MS in association with some inherited neuropathies, including HNPP, have been reported,1618 we consider that MRI lesions in our young patient with numbness confused the diagnosis.

Evidence for CNS demyelination has been seen in many patients with chronic inflammatory demyelinating polyneuropathy.19 Therefore, in the absence of a family history, chronic inflammatory demyelinating polyneuropathy also has to be considered in the differential diagnosis.

This family and the previously described patients indicate that this is not an isolated MRI finding in those with HNPP. Therefore, this neuropathy should be included in the differential diagnosis when a pattern of multifocal lesions in the subcortical white matter is found on brain MRI.

Central nervous system demyelination has also been described in other hereditary neuropathies.20,21 The researchers concluded that central and peripheral involvement was caused by the same genetic disorder. Our family seems to confirm that this would also be the case for HNPP. To our knowledge, the role of PMP22 in the CNS has not been studied in humans. According to the MRI findings in this family, CNS demyelination may be associated with the underexpression of PMP22. It is not known if this finding is a direct consequence of the absence of protein or a defect in gene dosage. Furthermore, whether there is a phenomenon of compensation by other members of the PMP22 gene family22 or by other associated proteins remains to be elucidated.

Back to top
Article Information

Correspondence: Isabel Illa, MD, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Padre Claret 167, 08025 Barcelona, Spain (

Accepted for Publication: March 2, 2005.

Author Contributions:Study concept and design: Sanahuja and Illa. Acquisition of data: Sanahuja, Franco, Rojas-García, Combarros, Begué, Granés, and Illa. Analysis and interpretation of data: Sanahuja, Franco, Rojas-García, Gallardo, Begué, and Illa. Drafting of the manuscript: Sanahuja, Franco, Rojas-García, Gallardo, Begué, and Illa. Critical revision of the manuscript for important intellectual content: Rojas-García, Gallardo, Combarros, Granés, and Illa. Statistical analysis: Illa. Obtained funding: Illa. Administrative, technical, and material support: Sanahuja, Franco, Gallardo, and Begué. Study supervision: Sanahuja, Franco, Begué, and Granés.

Gouider  RLeGuern  EGugenheim  M  et al.  Clinical, electrophysiologic, and molecular correlations in 13 families with hereditary neuropathy with liability to pressure palsies and a chromosome 17p11.2 deletion. Neurology 1995;452018- 2023
Amato  AAGronseth  GSCallerame  KJKagan-Hallet  KSBryan  WWBarohn  RJ Tomaculous neuropathy: a clinical and electrophysiological study in patients with and without 1.5-Mb deletions in chromosome 17p11.2. Muscle Nerve 1996;1916- 22
Snipes  GJSuter  UWelcher  AAShooter  EM Characterization of a novel peripheral nervous system myelin protein (PMP-22/SR13). J Cell Biol 1992;117225- 238
Baechner  DLiehr  THameister  H  et al.  Widespread expression of the peripheral myelin protein-22 gene (PMP22) in neural and non-neural tissues during murine development. J Neurosci Res 1995;42733- 741
Parmantier  ECabon  FBraun  CD’Urso  DMuller  HWZalc  B Peripheral myelin protein-22 is expressed in rat and mouse brain and spinal cord motoneurons. Eur J Neurosci 1995;71080- 1088
Amato  AABarohn  RJ Hereditary neuropathy with liability to pressure palsies: association with central nervous system demyelination. Muscle Nerve 1996;19770- 773
Schneider  CReiners  KFriedl  WEbner  RToyka  KV Involvement of the visual pathway in hereditary neuropathy with liability to pressure palsies. J Neurol 2000;247222- 223
Dackovic  JRakocevic-Stojanovic  VPavlovic  S  et al.  Hereditary neuropathy with liability to pressure palsies associated with central nervous system myelin lesions. Eur J Neurol 2001;8689- 692
Kimura  J Electrodiagnosis in Diseases of Nerve and Muscle: Principles and Practice. 2nd ed. Philadelphia, Pa: FA Davis Co Publishers; 1984
Latour  PBoutrand  LLevy  N  et al.  Polymorphic short tandem repeats for diagnosis of the Charcot-Marie-Tooth 1A duplication. Clin Chem 2001;47829- 837
Infante  JGarcia  ACombarros  O  et al.  Diagnostic strategy for familial and sporadic cases of neuropathy associated with 17p11.2 deletion. Muscle Nerve 2001;241149- 1155
McDonald  WICompston  AEdan  G  et al.  Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50121- 127
Li  JKrajewski  KShy  MELewis  RA Hereditary neuropathy with liability to pressure palsy: the electrophysiology fits the name. Neurology 2002;581769- 1773
Adlkofer  KMartini  RAguzzi  AZielasek  JToyka  KVSuter  U Hypermyelination and demyelinating peripheral neuropathy in Pmp22-deficient mice. Nat Genet 1995;11274- 280
Adlkofer  KNaef  RSuter  U Analysis of compound heterozygous mice reveals that the Trembler mutation can behave as a gain-of-function allele. J Neurosci Res 1997;49671- 680
Schoene  WCCarpenter  SBehan  POGeschwind  N “Onion bulb” formations in the central and peripheral nervous system in association with multiple sclerosis and hypertrophic polyneuropathy. Brain 1977;100755- 773
Frasson  EPolo  ADi Summa  A  et al.  Multiple sclerosis associated with duplicated CMT1A: a report of two cases. J Neurol Neurosurg Psychiatry 1997;63413- 414
Almsaddi  MBertorini  TESeltzer  WK Demyelinating neuropathy in a patient with multiple sclerosis and genotypical HMSN-1. Neuromuscul Disord 1998;887- 89
Mendell  JRKolkin  SKissel  JTWeiss  KLChakeres  DWRammohan  KW Evidence for central nervous system demyelination in chronic inflammatory demyelinating polyradiculoneuropathy. Neurology 1987;371291- 1294
Inoue  KTanabe  YLupski  JR Myelin deficiencies in both the central and the peripheral nervous systems associated with a SOX10 mutation. Ann Neurol 1999;46313- 318
Hisama  FMLee  HHVashlishan  A  et al.  Clinical and molecular studies in a family with probable X-linked dominant Charcot-Marie-Tooth disease involving the central nervous system. Arch Neurol 2001;581891- 1896
Taylor  VWelcher  AAProgram  AESuter  U Epithelial membrane protein-1, peripheral myelin protein 22, and lens membrane protein 20 define a novel gene family. J Biol Chem 1995;27028824- 28833