Accumulation of peripheral myelin protein 22 in onion bulbs and Schwann cells of biopsied nerves from patients with Charcot-Marie-Tooth disease type 1A

Peripheral myelin protein 22 (PMP-22) is a glycoprotein expressed in the myelin sheath of myelinated Schwann cells. Duplication of the PMP-22 gene and its gene dosage effect have been postulated to be involved in the pathogenesis in the majority of individuals with Charcot-Marie-Tooth disease type 1A (CMT1A). Northern blot analysis has demonstrated that the mean relative ratio of PMP-22 mRNA/β-actin mRNA in biopsied nerves of patients with CMT1A is significantly higher than that in disease controls. To investigate whether the elevated expression of PMP-22 mRNA is reflected in the amount and the localization of PMP-22, we analyzed PMP-22, myelin basic protein (MBP), protein zero (P0), and S-100 immunoreactivities in biopsied nerves from six patients with CMT1A, five patients with other types of CMT, five patients with acquired demyelinating neuropathies, and two normal subjects. In all patients with CMT other than CMT1A and acquired demyelinating neuropathy, as well as in normal subjects, the myelin sheath was immunoreactive for PMP-22, MBP, and P0, while the Schwann cell cytoplasm was immunoreactive only for S-100. In five out of six patients with CMT1A, however, the PMP-22 immunoreactivity was present not only on the myelin sheath but also in the Schwann cell cytoplasm and onion bulbs (OBs). Although OBs are nonspecific and also seen in other inherited or acquired demyelinating neuropathies, the PMP-22-positive OBs were seen exclusively in CMT1A.The finding suggested that the expression of PMP-22 was abnormal for its localization and probably for the amount in patients with CMT1A carrying duplication of the PMP-22 gene. Received: 5 February 1996 / Revised, accepted: 20 May 1996     

VASCULITIC NEUROPATHY - 8 YEARS FOLLOW-UP STUDY ON PATIENTS ADMITTED TO HOSPITAL

Tenascin-C (TN-C) is an extracellular matrix glycoprotein synthesized by glial cells that is involved in neuron–glia interactions. During development of peripheral nerve (PN), TN-C is abundantly expressed by myelinating Schwann cells, while in the adult its synthesis is down-regulated and its localization restricted to the node of Ranvier in myelinated nerve fibers.
Interestingly, TN-C expression is up-regulated in the PN of some animal models of inherited human demyelinating neuropathies. Moreover, in TN-C-deficient mice, important morphological alterations of PN have been demonstrated.
We have therefore studied the expression of TN-C in sural nerve biopsies of patients with inherited demyelinating neuropathies such as CMT1 and HNPP, using immunoperoxidase and immunofluorescence methods. At variance with control nerves, where TN-C immunoreactivity was localized only in the perineurium and at the node of Ranvier, in all pathological nerves TN-C was present also in a variable number of Schwann cells and myelin sheaths, sometimes marking whole myelin internodes.
These data suggest that TN-C expression by Schwann cells in human pathologic nerves may be a marker of active demyelination and/or remyelination. These events may be modulated by TN-C by mediating adhesive interactions between axons and Schwann cells, in a way similar to that observed in the developmental stage.     

Novel PCR-based diagnostic tools for Charcot-Marie-Tooth type 1A and hereditary neuropathy with liability to pressure palsies.

The majority of cases of Charcot-Marie-Tooth type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP) are the result of DNA duplications and deletions respectively of a 1.5 Mb region on 17p11.2. The region contains the peripheral myelin protein 22 gene (PMP-22) and is flanked by homologous proximal and distal CMT1A-REP elements. The majority of duplications and deletions arise during meiotic recombination following misalignment and unequal crossing-over between the proximal and distal CMT1A-REP elements. The cross-over breakpoints are most frequently located within a 1.7 Kb hotspot of recombination and produce novel duplication or deletion junctional CMT1A-REPs with unique restriction patterns. Here we describe the use of PCR based tests, which amplify a 3.6 Kb region including the 1.7 Kb hotspot from specific CMT1A-REPs, for the rapid diagnosis of CMT1A and HNPP patients. In an analysis of 96 CMT1A and 30 HNPP patients, duplication and deletion events were detected in all samples with cross-over breakpoints known to be within the region amplified by PCR.     

Correlation between PMP-22 messenger mRNA expression and phenotype in hereditary neuropathy with liability to pressure palsies

Hereditary neuropathy with liability to pressure palsies (HNPP) is associated with a deletion in chromosome 17p 11.2, which includes the gene for the peripheral myelin protein 22 (PMP-22). A “gene dosage” effect is probably the mechanism underlying HNPP, but the amount of PMP-22 mRNA in sural nerves of HNPP patients is highly variable and the role of PMP-22 underexpression in impairing myelination has yet to be clarified. We have studied 6 genetically proven HNPP patients, to evaluate the relationship between PMP-22 mRNA levels, and clinical, neurophysiological, and neuropathological findings. Underexpression of PMP-22 mRNA correlates with disease severity and with mean axon diameter and g ratio, but not with myelin thickness, number of “tomacula,” or nerve conduction parameters. Our findings further confirm that underexpression of PMP-22 is the main pathogenetic mechanism underlying the severity of clinical symptoms and signs in HNPP. Smaller axons in sural nerves of HNPP patients with lower PMP-22 levels suggests that underexpression of PMP-22 may also affect axon development.     

Differential electrophysiological features of neuropathies associated with 17p11.2 deletion and duplication

Hereditary neuropathy with liability to pressure palsies (HNPP) and hereditary motor-sensory neuropathy type IA (HMSN IA) are quite distinct clinical entities recently associated to deletion and duplication, respectively, of the 17p11.2 segment including the gene for peripheral myelin protein 22 (PMP-22). We studied the electrophysiological features of 48 HNPP and 62 HMSN IA motor nerves. Conduction velocities (CV) and compound muscle action potential amplitudes were significantly reduced and distal latencies prolonged in HMSN IA compared to HNPP. CV was uniformly slowed in HMSN IA nerves whereas in HNPP it was focally slowed in 80% of ulnar and 12% of peroneal nerves at usual compression sites. Conduction block was present in 6% of HNPP nerves but in none of HMSN IA. In conclusion: (1) HMSN IA with 17p11.2 duplication presents marked, diffuse, and uniform slowing; (2) HNPP with 17p11.2 deletion presents focal electrophysiological abnormalities possibly correlated with the presence of tomaculae; and (3) under-and overexpression of PMP-22 in concurrence with environmental factors might be responsible for the distinctive features of HNPP and HMSN IA. © 1995 John Wiley & Sons, Inc.     

LONG-TERM EFFECT OF INTRAVENOUS IMMUNOGLOBLIN THERAPY (IVIg) IN MULTIFOCAL MOTOR NEUROPATHY (MMN)

Peripheral myelin protein 22 (PMP22) plays a dual role in regulating cells growth and peripheral myelin compaction. Charcot‐Marie‐Tooth 1A neuropathy (CMT1A) and Hereditary Neuropathy with liability to Pressure Palsies (HNPP) are respectively due to a duplication and a deletion of the PMP22 gene, leading to over and underexpression of the protein. It is unknown how the altered PMP22 dosage impairs peripheral myelination. By means of transmission electron microscopy (TEM) morphometry we found that myelin periodicity is significantly increased in CMT1A patients (9.79 ± 0.9 nm) and compared to normal sural nerves (9.1 ± 0.7 nm). Conversely, myelin periodicity was slightly reduced in HNPP patients (8.9 ± 0.7 nm). Interestingly, the difference between CMT1A and HNPP patients was highly significant. Moreover, we found an increased myelin periodicity in sciatic nerves of a transgenic rat model of CMT1A (8.9 ± 0.08) and in organotypic dorsal root ganglia cultures (10.1 ± 0.1 nm) established from this rat line, compared to control animals (8.6 ± 0.1) and cultures (9.6 ± 0.1 nm). Since TEM studies suffer considerably from radiation damage, we also used small‐angle X‐ray scattering (SAXS) with a synchrotron radiation microbeam (5 m diameter) for in‐situ experiments on single sural nerves of CMT 1A and HNPP patients and of normal controls. For comparison with the TEM‐data, the periodicities were divided by two. Myelin periodicities ranged from 8.4 to 8.9 nm (mean: 8.7 ± 0.3) in CMT 1A nerves, from 8.0 to 8.4 nm (mean: 8.1 ± 0.3) in normal controls, and from 6.9 to 7.2 nm (mean 7.1 ± 0.3) in HNPP. In conclusion, altered PMP22 levels induce significant changes in myelin lamellae spacing, which may be recorded by appropriate morphometric techniques, and in particular by microbeam SAXS. Differences in term of myelin periodicity between TEM morphometry and x‐ray microbeam analysis may be due to the higher resolution and accuracy of the latter technique to measure periodic structures. Having an altered myelin period could lead to demyelination and subsequent remyelination. Therefore, the pathomechanism of both CMT1A and HNPP may be also related to a dysfunction of PMP22 as a structural protein of peripheral myelin.     

Quantitative examination of internodal length of remyelinated nerve fibres in the central nervous system

The internodal length of remyelinated internodes was examined by observations on teased CNS nerve fibres following primary demyelination induced by intraspinal injections of lysolecithin into the white matter of cats. A remyelinated internode was identified as a thinly-myelinated internode, where a node of Ranvier was bounded by a thickly-myelinated internode on one side and a less-thicklymyelinated internode on the other; as an internode of less than 100 μm in length or below 2 standard deviations from the normal regression line of internodal length against fibre diameter; as an internode joined to one of similar myelin sheath thickness which fulfilled either or both of the previous two criteria.Using the above criteria, remyelinated internodes were found to be shorter than normal; some were very short with no relationship to axon diameter while others were longer, falling within the predicted range for a given fibre diameter.This study illustrates that examination of teased CNS fibres in pathological situations can yield valuable information. However, sampling and technical difficulties are far greater than in comparable studies on peripheral nerve fibres.     

Dosage effects of PMP22 on nonmyelinating Schwann cells in hereditary neuropathy with liability to pressure palsies

Focal thickening of the myelin sheath, also known as tomacula, is a characteristic pathological feature of patients with hereditary neuropathy with liability to pressure palsies (HNPP). However, a deeper understanding of the pathology underlying unmyelinated fibers and nonmyelinating Schwann cells is required. Electron microscopic examination of sural nerve biopsy specimens was performed for 14 HNPP patients with peripheral myelin protein 22 (PMP22) deletion, and their results were compared to 12 normal controls and 14 Charcot–Marie–Tooth disease type 1A (CMT1A) patients with PMP22 duplication. The number of unmyelinated axons in a single axon-containing nonmyelinating Schwann cell subunit in the HNPP group significantly increased compared with that in normal controls (1.99 ± 0.66 vs. 1.57 ± 0.52, p < 0.05). Conversely, these numbers significantly decreased in the CMT1A group compared with those in normal controls (1.16 ± 0.16, p < 0.05). Some unmyelinated axons in patients with HNPP were incompletely surrounded by the cytoplasm of Schwann cells, almost as if the Schwann cells failed to form mesaxons; such failure in mesaxon formation was not observed in normal controls or in patients with CMT1A. These findings suggest that PMP22 dosage affects nonmyelinating as well as myelinating Schwann cells.     

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     

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.     

IgM deposits at nodes of Ranvier in a patient with amyotrophic lateral sclerosis, anti-GM1 antibodies, and multifocal motor conduction block

We studied a patient with amyotrophic lateral sclerosis, multifocal motor conduction block, and IgM anti-GM1 antibodies. A sural nerve biopsy demonstrated deposits of IgM at nodes of Ranvier by direct immunofluorescence. The deposits were granular and located in the nodal gap between adjacent myelin internodes, and in some instances, they extended along the surface of the paranodal myelin sheath. When injected into rat sciatic nerve, the serum IgM bound to the nodes of Ranvier, and the binding activity was removed by preincubation with GM1. These observations suggest that anti-GM1 antibodies may have caused motor dysfunction by binding to the nodal and paranodal regions of peripheral nerve.     

Molecular and pathological studies in Charcot-Marie-Tooth disease 1A

We analyzed a 1.5-Mb duplication of the p11.2–12 region of chromosome 17, including the PMP-22 gene (CMT1A duplication), seven families with Charcot-Marie-Tooth disease type I (CMT I) and six sporadic patients with suspected CMT I by Southern blot analysis. In order to detect the CMT 1A duplication, probe pVAW409R3a, probe PMP-22 cDNA and reference probe SF85 were used for Southern hybridization. In six out of seven families with CMT I, CMT1A duplication was identified. One of six sporadic CMT patients had CMT1A duplication. The probe pVAW409R3a was more informative than PMP-22 cDNA and SF85 for detecting CMT1A duplication. In pathological study of biopsied sural nerve, thickened myelin sheath was observed in some myelinated fibers in patients with CMT1A duplication.     

Elevated expression of messenger RNA for peripheral myelin protein 22 in biopsied peripheral nerves of patients with Charcot-Marie-Tooth disease type 1A

The human peripheral myelin protein 22 (PMP-22) gene has been mapped to chromosome 17p11.2 in the duplicated region associated with Charcot-Marie-Tooth disease type 1A. Southern blot analysis using PMP-22 as a probe indicated that the PMP-22 gene was duplicated in 5 patients from unrelated Japanese families with Charcot-Marie-Tooth disease type 1. In order to investigate whether or not an extra copy of PMP-22 has an effect on its gene expression, we analyzed relative expression of messenger RNA for PMP-22 and protein 0 (P0) against beta-actin by Northern blotting in biopsied nerves of the patients with type 1A disease, and compared the results with those of patients having other demyelinating neuropathies and the autopsied nerves of patients without neuropathies. The relative expression of PMP-22 messenger RNA in 5 patients with Charcot-Marie-Tooth disease type 1A was significantly higher than that in 5 patients with other demyelinating neuropathies (p < 0.05). There was no statistically significant difference in P0 expression between them. This study provided direct evidence for elevated expression of PMP-22 in peripheral nerves of patients with Charcot-Marie-Tooth disease type 1A as the result of a gene dosage effect. However, the relation between elevated expression of PMP-22 and the mechanism causing demyelination remains undetermined.     

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.     

Remyelination following viral-induced demyelination: ferric ion-ferrocyanide staining of nodes of Ranvier within the CNS

Ferric ion-ferrocyanide (Fe-FeCN) staining was used to stain nodes of Ranvier in remyelinating central nervous system (CNS) axons following viral-induced demyelination. As at normal nodes, Fe-FeCN staining was observed on the cytoplasmic surface of the nodal axolemma of remyelinated fibers. These fibers were identified on the basis of inappropriately short internode lengths and thin myelin sheaths. Thus, newly formed nodes along remyelinated CNS axons recapitulate at least one normal nodal membrane property.     

Characterisation of autoantibodies to peripheral myelin protein 22 in patients with hereditary and acquired neuropathies

To investigate the possibility that an autoimmune mechanism may play a role in the hereditary neuropathy Charcot-Marie-Tooth type 1A (CMT1A), sera were analysed by Western blot for anti-peripheral myelin protein 22 (PMP22) autoantibodies. These sera were compared with sera from patients with CMT type 2 (CMT2), acquired peripheral neuropathies such as chronic inflammatory demyelinating neuropathy (CIDP), anti-MAG IgM neuropathy, Miller-Fisher syndrome (MFS), diabetic neuropathy and with control blood donors. Anti-PMP22 positive sera were detected in 70% of patients with CMT1 and unexpectedly in 60% of patients with CMT2. Interestingly, 44% of the patients with other peripheral neuropathies and 23% of the apparently healthy controls showed also anti-PMP22 antibody reactivity. Immunohistochemical analysis of the human anti-PMP22 antisera on healthy sural nerve sections and on PMP22-expressing COS cells revealed that these sera did not recognise endogenous PMP22. Our results indicate that anti-PMP22 autoantibodies are found in sera of patients with different types of peripheral neuropathies, but their role in the pathogenesis of these diseases remains to be determined.     

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.     

Clinical syndromes associated with tomacula or myelin swellings in sural nerve biopsies

OBJECTIVES: To describe the neuropathological features of clinical syndromes associated with tomacula or focal myelin swellings in sural nerve biospies and to discuss possible common aetiopathological pathways leading to their formation in this group of neuropathies. METHODS: Fifty two patients with sural nerve biopsies reported to show tomacula or focal myelin swellings were reviewed, light and electron microscopy were performed, and tomacula were analysed on teased fibre studies. Molecular genetic studies were performed on those patients who were available for genetic testing. RESULTS: Thirty seven patients were diagnosed with hereditary neuropathy with liability to pressure palsies (HNPP), four with hereditary motor and sensory neuropathy type I (HMSN I) or Charcot-Marie-Tooth disease type 1 (CMT1), four with HMSN with myelin outfolding (CMT4B), three with IgM paraproteinemic neuropathy, three with chronic inflammatory demyelinating polyneuropathy (CIDP), and one with HMSN III (CMT3). CONCLUSIONS: Most of these syndromes were shown to be related to genetic or immunological defects of myelin components such as peripheral myelin protein 22 (PMP22), myelin protein zero (P0), or myelin associated glycoprotein (MAG). These proteins share the HNK-1 epitope which has been implicated in cell adhesion processes. Impaired myelin maintenance may therefore contribute to the formation of tomacula and subsequent demyelination.     

A novel homozygous variant extending the peripheral myelin protein 22 by 9 amino acids causes early‐onset Charcot‐Marie‐Tooth disease with predominant severe sensory ataxia

Peripheral myelin protein 22 (PMP22) related neuropathies account for over 50% of inherited peripheral neuropathies. A gene copy variation results in CMT1A (duplication) and hereditary neuropathy with liability to pressure palsies (HNPP; single deletion). Point mutations comprise both phenotypes. The underlying pathological mechanisms are incompletely understood and biallelic mutations of PMP22 are very rare. We describe a 9‐year‐old girl who presented before the age of 1 year with severe locomotor delay. She now requires support for standing and walking in view of her severe sensory ataxia. Strikingly, her muscle power and bulk are close to normal in all segments. Nerve conduction studies showed sensory‐motor velocities below 5 m/s. Genetic analysis revealed a homozygous sequence change in the PMP22 gene causing the loss of termination codon (c.483A > G; p.[*161Trpext*10]), extending the protein by 9 amino acids. Both heterozygous parents have neurophysiological abnormalities consistent with HNPP, consistent with this being a loss‐of‐function mutation. PMP22‐deficient human models are rare but important to decipher the physiological function of the PMP22 protein in vivo. The predominance of large fiber sensory involvement in this and other rare similar cases suggests a pivotal role played by PMP22 in the embryogenesis of dorsal root ganglia in humans.