Clinical manifestations

Presentation and course

Onset of neuropathies associated with PMP22 deletions or mutations typically occurs during the third or fourth decade but ranges from the first to the eighth; palsy may be present at birth (175). Due to its insidious onset, some patients are unaware of their disease or seek medical attention only late in life; others remain asymptomatic. The condition may occasionally be revealed in later life when individuals develop an acquired unrelated neuropathy due to metabolic derangements, autoimmunity, or neurotoxic drugs.

In typical HNPP, motor symptoms predominate over sensory symptoms. Patients often report that after resting on a limb in an awkward position, the resulting weakness and dysesthesias last weeks to months, rather than seconds to minutes. Rarely, the condition may mimic stroke-like episodes (66). Slight compression of peripheral nerves and repeated local exercise leads to episodes of weakness with decreased perception to touch and pain. Most attacks are of sudden onset, painless, and initially followed by recovery. Attacks most often present with a single nerve involvement, with onset on awakening. They are usually triggered by mild compression that resolves in days to months. Patients with frequent episodes may have persistent neurologic abnormalities. Precipitating trauma, such as carrying heavy loads, writing, or playing musical instruments, may be minimal and unavoidable. Although pain was long considered a minor symptom of HNPP, it appears to affect 42.1% of patients (45). In a series of 17 patients with HNPP, most had transient focal weakness or sensory loss related to activities that may compress nerves (97). None had a symmetric CMT1A-like phenotype. The authors postulated that PMP22 may stabilize myelin and protect nerves from repetitive, minor trauma. Del Colle and colleagues (44) reported carpal tunnel syndrome without episodes of nerve palsy as the presentation in a PMP22 deletion family; electrodiagnostic testing revealed a sensorimotor polyneuropathy with delayed sensorimotor latencies.

HNPP is not the only manifestation of PMP22 deletions. In multiple case reports and three large series, several other phenotypes have been identified (129; 175; 130; 91; 120). It is important to keep in mind that atypical presentations occur and that HNPP must be considered in the differential diagnosis of many different forms of neuropathy. In a study, 40% were unaware of their condition, and 25% were essentially without symptoms (129). The most common presentation is recurrent acute mononeuropathy often related to minor nerve compression. Sites of compression are often those of anatomic vulnerability: the fibular neck for the peroneal nerve; the cubital tunnel for the ulnar nerve; the spiral groove of the humerus for the radial nerve; and the carpal tunnel for the median nerve. Many other sites may exist, however, as evidenced by the report of a lesion of the anterior branch of the axillary nerve. This is likely due to compression against the surgical neck of the humerus (159). In a study of 70 patients, the average number of nerve palsies over a lifetime was around two (120); the most commonly affected structure was the peroneal nerve, followed by the ulnar, the brachial plexus, and the radial and median nerves; and weakness persisted for more than 3 months in 15% of patients. Orstavik and colleagues reported a family in which three members had brachial plexus palsies as the only clinical manifestation of HNPP (127). The brachial plexopathy form of HNPP may be recurrent, isolated, or part of other multiple mononeuropathies and is painless, which differentiates it from hereditary neurologic amyotrophy (23; 113; 162). Furthermore, there is no genetic overlap between the two conditions (28; 65; 187; 134). In the study by Mouton and colleagues, 10 patients had sensory deficits in addition to palsies (120). In patients with the recurrent pattern, the exam between episodes may be normal or mildly abnormal. There may be distal and mild pansensory loss. Reflexes are normal in about two thirds of patients. In one study, ankle jerks were absent in 37.5% of patients, and areflexia occurred in 12.5% (65). The second most frequent presentation in two series (129; 91), though rarer in another (120), was a largely symmetric, slowly progressive polyneuropathy, giving rise to a misdiagnosis of Charcot-Marie-Tooth disease. With this subtype, high arches and hammertoes are common. Scoliosis is rarely seen. Some patients have recurrent, sensory symptoms lasting minutes to hours triggered by limb position or nerve compression. Others present with a chronic sensory polyneuropathy. Rarely, patients present with subacute recurrent or confluent demyelinating multiple mononeuropathies and are misdiagnosed as acute or chronic inflammatory demyelinating polyneuropathy (80; 93; 91). Cranial neuropathies, including recurrent Bell palsy (137), deafness (55), laryngeal (126; 33) and swallowing dysfunction (102), bilateral successive hypoglossal nerve injuries following carotid endarterectomies with only partial recovery (34), phrenic nerve involvement (33), and lumbosacral radiculopathies (31) have been reported. Greater occipital neuropathy was observed by Dr. Florian P Thomas in three members of one family (143). Association with autonomic involvement has been observed by Dr. Florian P Thomas and others (150; 186).

Other rare associations of HNPP include CNS demyelination (04), moving toes and myoclonus (158), fulminant 4-limb weakness possibly related to nerve compression (35) and amyotrophic lateral sclerosis (15). Lynch and Hennessy (104) reported sciatic neuropathy as the initial presentation of HNPP. Subclinical CNS involvement consists of abnormal blink and jaw-opening reflexes and acoustic evoked potentials (168). Normal-appearing white matter in HNPP demonstrated lower fractional anisotropy values by diffusion tensor imaging in the frontal, orbitofrontal, and temporal lobes (183). The co-occurrence of schwannomas in the median and medial plantar nerves and HNPP led to speculations about a possible common genetic basis (72). Other atypical phenotypes/disease associations and combinations of genetic mutations may delay the diagnosis, such as HNPP and amyotrophic lateral sclerosis (15) and HNPP and oculopharyngeal muscular dystrophy (112).

Some patients are oligosymptomatic or asymptomatic, but their exam during evaluations may reveal subtle abnormalities such as distal hyporeflexia or Tinel signs. This is illustrated by a study of monozygotic twin sisters and their father (08). Only one twin was clinically affected. Significant conduction slowing in motor and sensory nerves was recorded in the clinically unaffected twin and the father. Not surprisingly, patients may evolve from one phenotype to another, and different phenotypes may coexist in a family. These are the phenotypic presentations associated with PMP22 deletions, but rare instances of mutations other than PMP22 deletion result in additional specific phenotypes. Although several patients with HNPP and frameshift, nonsense, or splice site mutations had typical phenotypes, likely because the mutations resulted in a functional deletion (124; 169; 129; 170), several families with the disorder due to base insertions leading to an altered longer protein that could disturb Schwann cell function and normal myelin formation have additional features reminiscent of Charcot-Marie-Tooth disease type 1 (95). A mild phenotype resulted from a 3' splice-site mutation, preceding coding exon 3 (c.179-1 G> C) (118). Atypical phenotypes may also result from a combination of mutations. In one family, Pegoraro reported co-segregation of Lamin A/C and PMP22 mutations, leading to a more severe phenotype with unusual axonal involvement in addition to a typical myelinopathy (133).

HNPP rarely presents in childhood. A 2-year-old child presented with toe-walking, pain, stiffness, asymmetric weakness, and bilateral upper motor neuron findings (99). Five years later, the patient developed episodic numbness and weakness in the arms and borderline conduction velocities, and HNPP was diagnosed.

Undiagnosed HNPP in an oligosymptomatic patient may complicate the treatment and diagnosis of an acquired neuromuscular disease later in life. For instance, a person with the disorder may, in his sixties, become diabetic and develop diabetic amyotrophy. A patient with HNPP may also acquire chronic inflammatory demyelinating polyneuropathy. Such a patient's clinical and electrical presentation may be unusual and difficult to understand unless a diagnosis of HNPP is also considered. Even more importantly, such a patient's spontaneous recovery or positive treatment response may be disappointing and far less complete than expected, had the acquired neuropathy been the only condition.

Given the short recovery time and oligosymptomatic or asymptomatic nature of diseases associated with PMP22 deletions in many patients, the course is often mild, and disability is subtle. However, patients with progressive polyneuropathy with recurrent episodes of palsy in one nerve may be left with significant disability. Foot deformities may be significant. Because the family history may be truly or falsely negative, a clinical history of transient or recurrent neurologic symptoms with clinical and electrodiagnostic abnormalities in affected and unaffected sites can guide further genetic testing (14).

Prognosis and complications

Life expectancy is usually normal. There is no primary treatment for HNPP. In general, patients with hereditary liability to pressure palsies have an excellent quality of life. About 10% of patients make an incomplete recovery from episodes of nerve palsy. Koike and colleagues reported progressive age-related irreversible motor axonal damage at entrapment sites, whereas sensory involvement did not change with age (87). Although direct and indirect health care calculations cannot typically be easily transposed from one country to another, the first study to ever assess the average cost of Charcot-Marie-Tooth disease provided an estimate of $22,362 per patient in Germany, with the cost of HNPP much lower at $7928. Cost predictors included disease severity, age, Charcot-Marie-Tooth disease subtype, comorbidities, body mass index, and employment status (155). Quality of life was impaired in HNPP to the same degree as in CMT1A (16). Fatigue can lead to decreased quality of life, even with mild neurologic impairment (54).

Clinical vignette

A 42-year-old man (IV-3) was referred for evaluation of diffuse body aches. He gave a history of episodic bilateral wrist drop, intermittent limb numbness (after repetitive movements in particular), and frequent muscle cramps since the age of 20. His examination showed fairly subtle abnormalities. Sensation was diminished to all modalities in a right ulnar and peroneal as well as left median and ulnar distribution. Power, bulk, gait, and coordination were intact, but there was distal hyporeflexia in the arms and legs. Tinel signs were present at the wrists and elbows. No nerves could be palpated. Hammertoes and high arches were present. Routine labs, erythrocyte sedimentation rate, B12, folate, rapid plasma reagin, antinuclear antibodies, rheumatoid factor, thyroid function, HgA1c, creatine kinase, and HIV antibodies were noncontributory, but hepatitis C serology was positive. His 65-year-old mother gave a history of finger numbness and post-partum arm weakness and had distal hyporeflexia and decreased sensation. His 81-year-old great-aunt was similarly affected. His daughter, 18 years of age, had numbness and tingling in the back of her legs during gym class and middle finger numbness when holding a pen but denied episodic weakness; symptom onset was at the age of 13. She had high arches and hammertoes, slightly weak finger extension, mild distal pansensory impairment, and a Romberg sign. Her 15-year-old sister was reluctant to attend gym class because of foot numbness; symptoms improved when she shook her legs. Either hand occasionally went numb, especially the right thumb when writing. Once after sitting on her cousin's shoulders, both legs were weak for some 20 minutes. Her examination was remarkable only for weak interossei in both hands. Two younger children were asymptomatic but had distal pinprick and vibratory sense loss with normal proprioception, strength, and reflexes.

Electrodiagnostic studies in 1987, 1988, and 1996 in the father revealed multiple nerve entrapments at both median and ulnar nerves at the wrists, the ulnar nerves at the elbows, the right radial nerve at the spiral groove, and the right peroneal nerve at the fibular head. Conduction velocities were normal or low normal except for slowing in the demyelinative range at areas of nerve entrapment, where amplitudes were also low. There was no significant change over time in nerves studied repeatedly.

Light and electron microscopy of the father's sural nerve biopsy showed a prominent sausage-shaped expansion of the myelin sheath in the perinodal and internodal regions, the classical finding that gives this condition its other name, tomaculous neuropathy, thinly myelinated fibers, and reduction in large myelinated fiber density with a shift of fiber diameters to small sizes. There were areas of incomplete myelin compaction and of redundant loops of the myelin sheath.

Genetic testing revealed a deletion of the 1.5 MB gene region that harbors the PMP22 gene in all affected family members and in the two asymptomatic younger daughters.

This family illustrates the typical presentation of PMP22 deletions, but the diagnosis is not always as straightforward. They had the classic history of recurrent pressure-related mononeuropathies at common entrapment points as well as typical clinical, electrodiagnostic, histological, and genetic findings. Symptoms were often induced by relatively minor trauma. Onset was in the second or third decade. Most episodes were of rapid onset, painless, and usually followed by complete recovery. They noticed that the nerve palsies, instead of clearing in seconds to minutes, persisted for days or weeks. Adults and children in this family realize this susceptibility and avoid situations from which pressure palsies may result. Only the father sought medical attention on his own. Not only the symptomatic relatives, but even the asymptomatic younger children had evidence of more generalized neuropathic disease with hyporeflexia, distal sensory loss, or subtle weakness, and several had skeletal deformities.

Biological basis

Etiology and pathogenesis

PMP22 mutation diseases are typically inherited in an autosomal dominant fashion, but de novo mutations have been documented for HNPP (145). Sixty-eight percent to 90% of these cases (111; 94; 123) are caused by a 1.5 mB deletion that includes the PMP22 gene within chromosome 17p11.2, the same region that is duplicated in Charcot-Marie-Tooth disease type 1A, although some do result from smaller deletions (29) or mutations within the PMP22 gene (124). The fact that both PMP22 deletions and frameshift or nonsense mutations are associated with HNPP suggests a loss of function mechanism. This notion is supported by the finding of PMP22 underexpression in patient and transgenic mouse nerve tissue and of a similar clinical and histological phenotype in humans and animal models. Deletions of paternal origin make up 87% and are caused by unequal meiotic cross-over between both chromosome 17 homologs, whereas the much rarer maternal deletions result from an intrachromosomal process (128; 101; 100; 17). The 1.5 mB gene region is flanked by homologous replication gene sequences, which serve as substrates for the recombination step required for deletion. These replication gene sequences contain regions homologous to so-called mariner insect transposons. Although these regions do not encode a transposase, this enzyme function provided from elsewhere in the genome could act on the mariner insect transposons and, thus, could explain the unexpectedly high frequency of recombination at this hotspot and of the PMP22 gene region duplication. Other genes reside in the 1.5 mB region, and their monosomy in HNPP could conceivably contribute to the phenotype.

PMP22 is a 160 amino acid peptide with an apparent molecular weight of 18 kD (22 kD after glycosylation) that is highly conserved in evolution. It is most highly expressed in Schwann cells, where it localizes to compact myelin, but is also expressed in the brainstem and spinal motor neurons. Its four membrane-spanning domains may indicate a pore function; however, the presence of the L2/HNK-1 carbohydrate epitope suggests a role in cell adhesion, as is the case for myelin protein zero, myelin-associated glycoprotein, and neural cell adhesion molecule (79). PMP22 expression is tightly regulated at the transcriptional level by the use of two different promoters, of which P1 contains several regulatory elements and appears to function in myelinating Schwann cells (67). It is conceivable that mutations in such elements could be responsible for some cases of inherited neuropathies; however, this is not yet commercially testable. PMP22 expression is also controlled at the translational level, possibly through axonal signaling, with decreased expression in the distal nerve stump following injury and the reverse during regeneration. It also plays a role in the cell cycle (as indicated by its other name, growth arrest-specific gene). In vitro, PMP22 overexpression not only delays Schwann cell progression through the cell cycle into division, but also causes programmed cell death or apoptosis. Underexpression accelerates cell proliferation (121).

Likely mutations of individual myelin genes do not act in isolation to cause the different forms of Charcot-Marie-Tooth disease; they interact with each other. Colocalization and complex formation of myelin protein zero and PMP22 in compact myelin, as well as the presence of the L2/HNK-1 carbohydrate epitope on both, may indicate that these two molecules interact in a heterophilic interaction (46), an attractive hypothesis given their similar expression and gene regulation and the clinical and histological analogies between Charcot-Marie-Tooth disease type 1A and type B and HNPP. This interaction could be disrupted by PMP22 or myelin protein zero overexpression, underexpression, or point mutations. However, myelin gene mutations have further far-reaching consequences. For instance, it was shown that Trembler mouse Schwann cells are deficient in glial cell-derived neurotrophic factor, nerve growth factor, and brain-derived neurotrophic factor, which could lead to impaired axonal and myelin maintenance (52).

The focus of active research is the process by which PMP22 deletions, duplications, and other mutations cause HNPP, Charcot-Marie-Tooth disease type 1A, and other conditions. The gene deletion is responsible for diminished PMP22 mRNA and protein (178; 58; 154), but PMP22 nonsense and point mutations result in an early stop codon and a truncated protein and, thus, also cause neuropathy by protein underexpression. Several transgenic mouse studies have addressed the role of PMP22 underexpression. Animals under-expressing PMP22 as a result of a heterozygous knock-out or an antisense PMP22 transgene resemble HNPP (02; 01; 114). Heterozygous knock-out mice display mild neurophysiological changes and focal, often perinodal, hypermyelination when younger. However, these changes appear to be unstable and evolve into a predominantly demyelinating appearance in older animals. This overlap obviously appears analogous to the manifestations in humans that can range from typical HNPP to typical Charcot-Marie-Tooth disease. The seeming instability of tomacula may also be an explanation of the transient nature of symptoms in HNPP, although the same histologic hallmarks are also characteristic of some myelin protein zero mutations in a nonrecurrent hereditary neuropathy, Charcot-Marie-Tooth disease type 1B (172). Homozygous PMP22-deficient animals have delayed myelination and weakness at 2 weeks, frequent tomacula at 3 weeks, severe nerve conduction slowing, onion bulbs and other signs of demyelination or remyelination when older than 2 months, and axonal atrophy at 1 year of age (166). A naturally occurring disease of cattle is characterized by abnormal gait, gastrointestinal features, and tomaculous neuropathy (73).

Although myelin abnormalities are the pathological hallmark of PMP22 deletions, axonal loss likely contributes to the clinical manifestations that are especially late during the disease course. The process by which Schwann cell mutations induce axonal degeneration is one of the most exciting areas of investigation.

Nerve ultrasound suggests that the disproportional distal slowing in HNPP may result from a combination of mechanical insults and an axon-initiated process in the distal nerves leading to conduction failure. Increased distal motor latencies occurred independently of nerve enlargement seen by ultrasound (62).

Epidemiology

Charcot-Marie-Tooth disorders are among the most common inherited neurologic disorders, but estimates of their frequency vary. An exhaustive study from Norway indicated a prevalence of 36 per 100,000 (160), whereas a worldwide meta-analysis estimated a prevalence of 10 in 100,000 (49). On the other hand, the frequency of HNPP is not well documented. A single study of 435,000 individuals in Finland reported a prevalence of 16/100,000 for the disorder and of 20/100,000 for Charcot-Marie-Tooth disease in general (116). Although this is less than the previously reported frequency of Charcot-Marie-Tooth disease of 36/100,000 in Norway, it is an indication that HNPP is not a rare condition. As both diseases result from unequal crossover during meiosis, similar epidemiological data are to be expected. Likely diseases associated with PMP22 gene deletions or protein truncations are underdiagnosed due to the variable phenotype, the insidious nature of the disease, and the many mildly affected patients. HNPP may be more common, with an earlier age of onset in men, possibly due to environmental (nerve trauma) or X-linked genetic factors (120). Epidemiologic features were similar in a Korean series compared to Western countries; disease onset appeared to be earlier in patients with recurrent nerve palsies versus those with single attacks (83). Among 11,885 Korean newborns tested by next-generation sequencing-based copy number variation analysis, 17p11.2 deletions were found in 7, for an estimated prevalence of 58.9 per 100,000 (131). Of some 1000 individuals with Charcot-Marie-Tooth disease at a single center in the United States, 6% had HNPP (153). Men are more severely affected clinically (higher number of nerve palsies) and electrodiagnostically (110).

Prevention

At present, inherited neuropathies cannot be prevented, unless affected parents choose not to have children. As the clinical disease, in most instances, does not shorten a person's life span, affect the intellect, or prevent a person from maintaining an independent lifestyle, many patients decide to have families despite the chance that their children may ultimately have difficulties with their feet or hands. In the future, prenatal detection of a 17p11.2 duplication or deletion could become available commercially (13). In addition, these deletion and duplication mutations occur relatively frequently as a new mutation. Thus, even if patients had no children, HNPP would remain a prevalent disorder. Secondary preventive measures focus on education and awareness and avoidance of intercurrent medical problems or interventions that can lead to systemic or focal neuropathies (eg, diabetes mellitus, hypothyroidism, vitamin deficiencies, neurotoxic drugs, and prolonged immobilization of limbs during surgery). It is also important to recognize rare patients who may have more than one hereditary disorder. Therefore, patients with an unusual progression of clinical signs of a known genetic disease need to be evaluated for acquired and additional hereditary disorders (171). Employment or recreational activities with exposure to repetitive motion injury must be avoided as much as possible. Contact sports are inadvisable. Adolescents and adults benefit from counseling when choosing a profession. Patients also need to learn how to protect their nerves from compression.

Differential diagnosis

Recurrent pressure palsy originating at typical entrapment sites and involving one or more nerves warrants the diagnostic consideration of HNPP. Hereditary neurologic amyotrophy is another autosomal dominant condition with recurrent mononeuropathies. It shares a predominance of tomaculous changes with HNPP, although axonal changes distal to the plexus suggest a strong axonal component. Hereditary neurologic amyotrophy is distinguished by several factors, including prominent, often severe, movement-dependent pain that typically precedes other symptoms; abnormalities that typically affect the brachial plexus in an isolated fashion; occasional dysmorphic features of the face and short stature; and the absence of an associated polyneuropathy. This condition is genetically distinct from HNPP and maps to chromosome 17q25 (28; 65; 187; 134). Familial carpal tunnel syndrome, though rare and often difficult to ascertain, appears to be another entity that must be considered (63). Patients with other phenotypes of PMP22 deletions are more difficult to diagnose. In these, the first challenge may be to demonstrate that a patient's weakness and sensory loss do indeed result from peripheral nerve disease and not from abnormalities elsewhere. Proof can usually be accomplished by a clinical examination revealing focal or distal weakness, muscle wasting, sensory loss, and hyporeflexia. If the patient has a neuropathy and a positive family history, a Charcot-Marie-Tooth disorder becomes likely. Pedigree analysis can clarify inheritance patterns. However, the absence of a family history does not eliminate consideration of a hereditary PMP22 mutation, because relatives may be oligosymptomatic or asymptomatic, or disease may result from a de novo mutation. In one report, 37% of patients had no family history (175). Infante and colleagues suggested that in the absence of familial history, HNPP should be strongly considered in patients with nerve palsies or atypical clinical presentations as well as generalized abnormalities of nerve conduction preferentially at common entrapment sites and distal nerve segments (76).

Other conditions that may directly or indirectly lead to recurrent or isolated painless mononeuropathies or plexopathy must be excluded. These conditions include alcohol abuse, trauma, diabetes mellitus, porphyria, hypothyroidism, uremia, vasculitis, and ischemia. Furthermore, HNPP can mimic chronic inflammatory demyelinating polyneuropathy (108; 50; 109; 93; 88), which could also be superimposed on oligosymptomatic or asymptomatic HNPP. Although highly unlikely to be misdiagnosed as Guillain-Barré syndrome, challenging and atypical cases can be considered psychiatric disease, and misdiagnosis of HNPP as Guillain-Barré syndrome has been reported (191).

Diagnostic workup

The purpose of studies in patients with a possible inherited neuropathy is to confirm or refute this working diagnosis and to ascertain the presence of a treatable condition (eg, nerve entrapment that might be amenable to surgery or a superimposed acquired neuropathy). This workup should include tests that address causes of neuropathies such as endocrinological, infectious, and immunological abnormalities, vitamin and nutritional deficiencies, and nerve compression.

Cerebrospinal fluid analysis is usually normal, but protein levels may be elevated, as documented in an HNPP case manifesting as recurrent polyradiculoneuropathy (93).

MRI of the leg and foot muscles may be useful in the evaluation of disease progression. Gallardo found that early involvement was restricted to intrinsic foot muscles in a cohort of 11 patients with CMT1A. Patients with more advanced disease also had variable involvement of proximal leg muscles. Findings included atrophy, fatty infiltration, edema, and contrast enhancement. Abnormalities were also found in clinically normal muscles (59). MRI parameters may be useful biomarkers to evaluate disease progression in HNPP (138).

Genetic testing. Patients in whom the clinical phenotype, family history, and electrodiagnostic studies suggest that they might have an inherited neuropathy should be genotyped. This is important because clinical examination and electrodiagnostic studies often cannot definitively establish a precise diagnosis due to the overlap between clinical syndromes and the significant variability between family members with an identical genotype. Genotyping permits sound genetic and prognostic counseling and advances the scientific understanding of phenotypes. In a study, de novo mutations accounted for 21% of HNPP families (76). Although oral mucosal swabs or saliva or blood samples are usually required for DNA analysis, a report documented that chromosomal changes of the PMP22 gene can be diagnosed in up to 12-year-old highly degraded DNA from sural nerve biopsies (09).

Electrodiagnostic studies. These can separate HNPP from other inherited or acquired neuropathies. Typically there is background polyneuropathy independent of superimposed entrapment neuropathy. The variability within families may be considerable. Stringent criteria have been proposed to facilitate the distinction between HNPP and other causes. In a series of 99 patients with a PMP22 deletion, Mouton and colleagues found a multifocal polyneuropathy with diffusely increased distal motor latencies, more normal motor conduction velocities, diffuse reduction if sensory nerve action potentials, and multiple instances of focal slowing at anatomical entrapment sites (120). These features, including focal slowing, were also observed in several patients with a Charcot-Marie-Tooth phenotype without recurrent nerve palsies. This indicates that neurophysiologic testing can lead to an HNPP diagnosis, even when the clinical features do not suggest it. Neurophysiologic findings were similar in oligosymptomatic and asymptomatic patients and became characteristic as early as the second decade. EMG is normal in proximal muscles but may show distal changes with increased duration and amplitude motor unit potentials. Signs of active denervation such as increased insertional activity and fibrillation potentials are not prominent in muscles unaffected by weakness. Diagnostic criteria for the disorder have been proposed based on bilaterally delayed median distal motor latencies, slowed median sensory conduction at the wrist, and prolonged distal motor latencies or motor conduction slowing in the peroneal nerves (64). Other criteria were proposed by Infante and colleagues (76). Bilaterally normal median distal motor latencies and sensory velocities at the wrist appear to exclude HNPP.

Andersson and colleagues found diffuse sensory conduction slowing independent of nerve entrapment in the vast majority of their own nine and 53 previously reported cases, consistent with a background of demyelinative distal polyneuropathy (05). Slowed motor conduction was less common in HNPP, although distal motor latencies were frequently prolonged in the study’s own and previously published patients, indicating that there is a distal motor polyneuropathy, similar to that seen in IgM monoclonal gammopathy against myelin-associated glycoprotein or sulfated glucuronyl paragloboside. The authors suggested that a profile of conduction velocity slowing in most sensory nerves, relatively less frequent and more minor motor slowing, and prolonged distal motor and F-wave latencies were characteristic of HNPP. However, Li and colleagues disagreed with the concept of distal myelinopathy and suggested that focal susceptibility to compression was the main culprit (98). In their study, distal slowing correlated with exposure to entrapment; there was more slowing in the median and peroneal and less in the ulnar and peroneal.

Neuropathologic studies. Both motor and sensory fibers in most nerves show segmental demyelination and remyelination; variable, secondary, and axonal loss; and focal thickening of the myelin sheath or tomacula (10; 105; 57; 152). Outside of the tomacula the ratio of axon and fiber diameter (g ratio) is normal. Onion bulb formation and increase in endoneurial connective tissue are limited. Tomacula are more often perinodal than internodal. Nodes of Ranvier are often obscured, probably by transnodal myelin. There may be branching and duplication of the mesaxons, and more than one Schwann cell may participate in myelination (105). Ultrastructurally, tomacula appear as redundant myelin loops, both external and internal, with intramyelinic folds. Uncompacted myelin is typically rare but was prominent in diffuse and focal forms in the sural nerve of a 16-year-old girl with HNPP due to a PMP22 gene deletion (78).

A teased fiber analysis of 37 biopsies found features of demyelination and remyelination as well as tomacula in all cases. About 23% of fibers were normal, 52% showed evidence of demyelination or remyelination; 54% of the fibers had tomacula with a mean diameter and length of 16.3 µm and 83.7 µm, respectively (152). Focal myelin thickening, although a hallmark of HNPP, is not restricted to this condition. It occurs to various degrees with Charcot-Marie-Tooth disease type 1B, immune-mediated neuropathies, hereditary neuropathies with myelin outfolding, and others. It can occur experimentally from pressure injury (125; 181; 177; 56; 172; 140; 152).

An issue with important implications for molecular pathogenesis is the reason for tomacula formation. Ochoa and colleagues explained pressure-induced myelin abnormalities with slippage of myelin lamellae (125). Gabreels-Festen and van de Wetering proposed that, in HNPP, the genetic defect disturbs adhesion of myelin lamellae and makes them susceptible to displacement (57). The susceptibility of nerve biopsies from patients and PMP22 deletion transgenic mice to artifacts supports the exquisite sensitivity to mechanical forces. Gabreels-Festen and van de Wetering suggested that tomacula are accumulated due to everyday injuries that patients may not notice, whereas more intense or longer injuries displace sufficient myelin lamellae to cause demyelination and conduction block with palsies.

Interestingly, several conditions in which tomacula occur result from either antibodies binding to proteins in compact myelin carrying the L2/HNK-1 epitope or from genetic defects in the proteins themselves. This is the case for myelin protein zero, PMP22, and myelin-associated glycoprotein (myelin protein zero may be a binding partner for L2/HNK-1). Mutations in these genes and myelin-associated glycoprotein antibodies are also associated with widening of the myelin lamellae. Although altered PMP22 function may play a role in some mutations, PMP22 deletion results in underexpression of PMP22 mRNA that correlates with disease severity, axon diameter, and g ratio, but not with myelin thickness, number of tomacula, or nerve conduction parameters (154). Mutations of the connexin32 gene that are not expressed in compact myelin and do not carry the L2/HNK-1 epitope are not associated with tomacula formation in Charcot-Marie-Tooth disorder type X. Sander and colleagues, Gabreels-Festen, and van de Wetering proposed that myelin proteins expressing or reacting with HNK-1 are crucial in myelin adhesion and tomacula formation (57; 152). However, it remains unexplained why tomacula, indistinguishable histologically, are associated with liability to pressure palsies in some conditions but not others. It is likely that additional genes expressed in peripheral nerves are also involved, as the gene in two other conditions with focal myelin thickening, hereditary neurologic amyotrophy, and hereditary motor and sensory neuropathy with myelin outfolding have not been identified, although gene linkages have been established to chromosomes 17q25 and 11q23, respectively (19; 134). Further insight may result from studies of human nerve xenografts into nude mice (151).

There is some evidence that immune dysregulation may play a role in the pathogenesis of hereditary neuropathies, including HNPP (88). Sural nerve biopsies in the disorder and other Charcot-Marie-Tooth cases show major histocompatibility complex (MHC) class II upregulation, but not inflammatory infiltrates (163).

Li and colleagues advocate skin biopsies as a less invasive alternative in the evaluation of myelin-related neuropathies and have shown myelin abnormalities in all patients with CMT diseases. PMP22 mRNA and protein levels were increased in CMT1A and decreased in HNPP (96).

Management

Supportive measures are discussed in Peripheral neuropathies: supportive measures and rehabilitation.

It is important to prevent, look for, and treat acquired neuropathies as well as to avoid compression neuropathies. This may require adjustments in lifestyle and avoidance of job-related nerve injury.

Patients, family members, and physicians need to be aware of drugs and vitamin supplements that can affect the peripheral nervous system. Drugs and vitamins with various degrees of neurotoxicity include the following:

Nutritional and vitamin deficiencies. Patients should maintain a well-balanced diet and avoid obesity, which can contribute to spinal root disease and certain entrapment neuropathies (meralgia paresthetica).

Physical therapy and prosthetics. Physical therapy may be useful during episodes of nerve palsy to maintain range of motion and prevent joint deformities and contractures. Physical therapy can be beneficial for the long term in PMP22 deletion or mutation patients with prominent features of an inherited polyneuropathy. Prosthetic devices such as ankle-foot orthoses can prevent Achilles tendon shortening and extend near normal ambulation. At times, boots can delay the need for such ankle braces. In case of arm and hand weakness, thick-handle tools and cutlery can render certain activities of daily living easier. Shoe inserts to relieve pressure of pressure points, together with scheduled foot inspections, may prevent the development of foot ulcers in patients who progress to a chronic polyneuropathy.

Pain. Although HNPP is typically pain-free, pain may result from joint deformities or compensatory overuse of certain muscle groups during episodes of nerve palsy. Some types of pain may respond to nonsteroidal anti-inflammatory drugs. Dysesthetic pain may occur; it responds to antidepressants such as amitriptyline, desipramine, or paroxetine as well as to anticonvulsants such as gabapentin or carbamazepine.

Surgery. In rare cases of foot deformities, patients with HNPP or other PMP22 deletion mutations may benefit from Achilles tendon lengthening, tendon transfers, hammer toe correction, and release of the plantar fascia. The response to nerve entrapment surgery is often suboptimal, and surgeons must be aware of the diagnosis because, as discussed above, the nerves are exquisitely sensitive to trauma. Treatment of carpal tunnel syndrome but not of ulnar entrapment has been recommended for HNPP (32).

Treatment. The introduction of recombinant DNA encoding normal PMP22 into the nerves of knock-out mice is being considered a therapeutic strategy. Another approach explores neurotrophin gene transfer into the spine. The identification of regulatory PMP22 promoter sequences might open venues for therapeutic intervention if drugs could be designed to allow modulation of gene expression (67). The significance of steroid-responsive palsies (08) is difficult to appreciate in light of the natural history of HNPP, which is remitting. In a rat model of CMT1A, a selective progesterone antagonist improved the CMT phenotype, whereas administration of progesterone increased PMP22 and MPZ mRNA expression and Schwann cell pathology and led to clinical progression (157). Of course, sex hormones cannot easily be used in humans in this fashion, but drugs could be engineered to increase PMP22 expression selectively in nerve for use by patients with HNPP.

Special considerations

Pregnancy

Some Charcot-Marie-Tooth patients report faster deterioration during pregnancy, usually but not always, with recovery. Worsening of HNPP during the puerperium is not uncommon. As with surgical procedures, prolonged positioning of the body and limbs in particular positions can result in nerve compression, which could make any underlying neuropathy worse. Therefore, obstetricians, midwives, and nurses must be aware of a diagnosis of HNPP. However, deterioration can occur in the absence of any identifiable trauma during delivery. Furthermore, due to the variability of clinical manifestations, couples who both have symptomatic or asymptomatic HNPP might have homozygous offspring with more severe disease.

Anesthesia

In a series of 161 surgical procedures on 86 patients with Charcot-Marie-Tooth disease, researchers found that the patients had no difficulties tolerating anesthetics, even with succinylcholine (06). The Charcot-Marie-Tooth disease association cites this reference in its handbook for primary care physicians. They state, however, that in patients who are rapidly becoming weak from Charcot-Marie-Tooth disease, it may be inadvisable to use succinylcholine. Nitrous oxide, by inactivating the cobalamin-dependent enzyme methionine synthase, may be neurotoxic (84). Other risks, including sensitivity to neuromuscular blocking agents and malignant hyperthermia, are said to be minimal. Prolonged body and limb positions must be avoided as much as possible, due to the risk of nerve compression (89). Regional anesthesia is relatively contraindicated in Charcot-Marie-Tooth disorders.