Introduction. Overview

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1 Hereditary neuropathy with predisposition to pressure palsy Francisco de Assis Aquino Gondim MD MSc PhD ( Dr. Gondim of Universidade Federal Ceará & Unichristus, Fortaleza, Brazil, received consulting fees from Pfizer and speakers fees from CSL Behring. ) Florian P Thomas MD MA PhD MS ( Dr. Thomas, Chair, Department of Neurology, Seton Hall-Hackensack Meridian School of Medicine, has no relevant financial relationships to disclose. ) Louis H Weimer MD, editor. ( Dr. Weimer of Columbia University has received consulting fees from Roche.) Originally released July 11, 2001; last updated November 14, 2017; expires November 14, 2020 Introduction This article includes discussion of hereditary neuropathy with predisposition to pressure palsy, familial brachial plexus neuropathy, hereditary neuropathy with liability to pressure palsies, and HNPP. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations. Overview Hereditary neuropathy with predisposition to pressure palsy (HNPP) may be considered the genetic opposite of CMT1A, the single most common subtype of Charcot-Marie-Tooth disease, as it is most often caused by a heterozygous deletion of the same gene region containing the PMP22 gene that is duplicated in CMT1A. HNPP may be the inherited neuropathy with the widest phenotypic range. Historical note and terminology Inherited peripheral neuropathies were described independently by Charcot and Marie (Charcot 1886) in France and by Tooth in England (Tooth 1886), but earlier descriptions had been published, including several by Friedreich (Friedreich 1873). Complex forms of Charcot-Marie-Tooth disease are recognized occasionally with associated mental retardation, upper motor neuron signs, deafness, optic atrophy, pigmentary retinal degeneration, and various extraneural manifestations. The heterogeneous nature of the disorder was soon recognized. Thus, Déjérine and Sottas described in Charcot's group more severe cases with onset in infancy (Dejerine and Sottas 1893), and Roussy and Levy described cases associated with tremor, which were defined genetically (Roussy and Levy 1926; Auer-Grumbach et al 1998; Plante-Bordeneuve et al 1999). Allan recognized different forms of inheritance (Allan 1939). With the advent of neurophysiological testing, a stringent classification became possible. Early studies suggested that Charcot-Mari- -Tooth disease patients could be divided into 1 group with slow nerve conduction velocities and pathological evidence of a hypertrophic demyelinating neuropathy, and a second group with relatively normal velocities and axonal or neuronal degeneration (ie, hereditary motor and sensory neuropathy type 2 or Charcot-Marie-Tooth disease type 2) (Dyck and Lambert 1968; Thomas and Calne 1974; Buchthal and Behse 1977). The features of Charcot-Marie-Tooth disease type 1 and type 2 were outlined in 2 landmark publications detailing the genetic and clinical characteristics of more than 200 patients (Harding and Thomas 1980a; Harding and Thomas 1980b). Most Charcot-Marie-Tooth disease patients have an autosomal dominant pattern, whereas other patients inherit the disease through an X-linked recessive or autosomal recessive pattern. De Jong described hereditary neuropathy with predisposition to pressure palsy (HNPP) in a Dutch coal miner, who had been working in a squatting position, and 4 relatives from 3 generations, who grubbed potatoes. De Jong found low vitamin B1 levels in several of these patients and considered this a possible cause of their disorder (De Jong 1947; Koehler 2003). A case of HNPP from this original family has been described (Koehler and Baas 2012). Davies, Wahle, and Tonnis observed pressure sensitive neuropathies in a father and son with recurrent multiple mononeuropathies (Davies 1954; Wahle and Tonnis 1958). Diminished conduction velocity and action potential amplitude along motor and sensory nerves in affected and unaffected nerves with focal conduction slowing or block at common entrapment sites were described in several families with HNPP (Earl et al 1964; Staal et al 1965). A 4-generation Dutch family referred to affected members with transient unilateral peroneal neuropathies as having bulb diggers' palsy (Staal et al 1965). Behse recognized the sausage-like swellings of the myelin sheaths, which later were considered pathognomonic. Madrid and Bradley contributed the ultrastructural changes in HNPP; they proposed several

2 mechanisms for the development of the focal myelin thickening and coined the term tomaculous neuropathy (Madrid and Bradley 1975). Dayan and colleagues reported similar histologic features, termed globular neuropathy, in a family with progressive weakness and numbness of apparent autosomal dominant inheritance (Dayan et al 1968). Larger literature reviews and personally observed series of patients with clinical electrodiagnostic and histological correlation were reported by Roos and Thygesen (Ross and Thygesen 1972), Meier and Moll (Meier and Moll 1982), and Pellissier and colleagues (Pellissier et al 1987). In the 1980s linkages to chromosomes 1, 17, and X were recognized for certain Charcot-Marie-Tooth pedigrees, and Charcot-Marie-Tooth disease was subcategorized to cover hereditary motor and sensory neuropathy type 1A (70% to 80%), type 1B (4% to 5%), and X-linked Charcot-Marie-Tooth disease (Raeymaekers et al 1989; Vance et al 1989; Middleton-Price et al 1990; Lebo et al 1991). In 1991, 2 groups showed that Charcot-Marie-Tooth type 1A, the most common form of the type 1 disease, was associated with a 1.5 mb duplication within chromosome 17p11.2 (Fischbeck et al 1986; Lupski et al 1991; Raeymaekers et al 1991). Ninety percent of these cases result from this duplication (Brice et al 1992; Hallam et al 1992; Wise et al 1993; Patel and Lupski 1994). Mutations in the peripheral myelin protein 22 kd gene, contained within the 1.5 kb duplication on chromosome 17, have been demonstrated to cause demyelinating neuropathies in Trembler and Trembler-J mice (Suter et al 1992a; Suter et al 1992b) and in some Charcot-Marie-Tooth disease type 1 or type 3 patients (Valentijn et al 1992; Roa et al 1993; Nelis et al 1994). Moreover, transgenic mice and rats over-expressing PMP22 develop neuropathies resembling Charcot-Marie-Tooth disease type 1 (Huxley et al 1996; Magyar et al 1996; Sereda et al 1996). An approximately 1.5 mb long deletion of the proximal short arm of chromosome 17 is detected in most families with HNPP (Chance et al 1993; Hoogendijk et al 1994), whereas about 14% to 25% of patients develop the disorder due to other PMP22 mutations (Nicholson et al 1994; Nelis et al 1996). The deletion includes all markers duplicated in Charcot-Marie-Tooth disease type 1A. Several nondeletion mutations have been identified: nonsense mutations with a stop codon at G183A (Trp61stop) and at G372A (Trp124stop); frameshift mutations with a premature termination at 19delAG to 20delAG and 434delT, or with a longer transcript at 281insG to 282insG; splice site mutations at 78+1G>T, 179+1G>C; missense mutations at G208A (Val30Met) in exon 3 (Nicholson et al 1994; Taroni et al 1995; Taroni et al 1996; Bort et al 1997; Young et al 1997; Lenssen et al 1998; Sahenk et al 1998); and small deletion of exon 5 leading to very mild phenotype (Casasnovas et al 2012). A similar condition, hereditary brachial plexus neuropathy (or hereditary neuralgic amyotrophy with predilection for the brachial plexus), is not linked to the PMP22 locus but was mapped to chromosome 17q25 (Chance et al 1994; Gouider et al 1994; Windebank et al 1995; Pellegrino et al 1997). The 1990s also saw the identification of other Charcot-Marie-Tooth genes: myelin protein zero for Charcot-Marie-Tooth disease type 1 and type 3 (Hayasaka et al 1993; Kulkens et al 1993; Su et al 1993) and the gap junction protein connexin 32 or beta 1 on chromosome Xq13.1 (Bergoffen et al 1993). The rare X-linked Charcot-Marie-Tooth disease was mapped to chromosome Xq24 to Xq26 (Priest et al 1995) and the zinc-finger domain containing transcription factor early growth response 2 gene for congenital hypomyelination neuropathy and Charcot-Marie-Tooth disease type 1D (Warner et al 1998). Mutations of all of these genes have been associated with several overlapping clinical phenotypes. For instance, Déjérine-Sottas syndrome is associated with PMP22 or myelin protein zero mutations or deletions (Nelis et al 1996; Warner et al 1996; De Jonghe et al 1997; Reilly 1997). Several new disease linkages and genes have been identified: 2 signal transduction genes; the N-MYC downstreamregulated gene-1 on chromosome 8q24.3 for the Lom form of autosomal recessive motor and sensory neuropathy (hereditary motor sensory neuropathy or Charcot-Marie-Tooth disease type 4D) (Kalaydjieva et al 2000); the gene for the phosphatase myotubularin-related protein-2 on chromosome 11q22 for autosomal recessive Charcot-Marie-Tooth disease type 4B (Bolino et al 2000); a cytoskeletal gene; the neurofilament light subtype gene on chromosome 8p21 for Charcot-Marie-Tooth disease type 2E (Mersiyanova et al 2000); the periaxin gene on chromosome 19q13.1-2, which is regulated by EGR2, for recessive Dejerine-Sottas syndrome (Boerkoel et al 2001); the gene for a serine palmitoyltransferase subunit on chromosome 9q22 for hereditary sensory neuropathy type 1 (Bejaoui et al 2001; Dawkins et al 2001); and the KIF1B-beta gene involved in axonal organelle transport on chromosome 1p36-35 for Charcot-Marie-Tooth disease type A (Zhao et al 2001). A demyelinating neuropathy also results from absent proteolipid protein expression in some Pelizaeus-Merzbacher patients (Garbern et al 1997; Garbern et al 1999). Mutations in the cytoskeletal protein gigaxonin have been linked to giant axonal neuropathy (Bomont et al 2000). A locus for autosomal dominant Charcot-Marie-Tooth disease type 2F was found on chromosome 7q11-q21 (Ismailov et al 2001). Loci with several candidate genes have been identified in 2 families with autosomal dominant Charcot-Marie-Tooth disease and conduction velocities between 24 m/s and 54 m/s. One is on chromosome 19p12-p13.2 (Kennerson et al

3 2001), the other associated with both large fiber loss and regeneration clusters as well as onion bulbs and uncompacted enlarged myelin lamellae on chromosome 10q24.1-q25.1 (Malandrini et al 2001; Verhoeven et al 2001). A recessively inherited severe form of Charcot-Marie-Tooth disease with intermediate conduction velocities has been linked to chromosome 10q23 (Rogers et al 2000). Intermediate conduction velocities also occur with myelin protein zero and neurofilament light subtype gene mutations (De Jonghe et al 1999; De Jonghe et al 2001). Overall, more than 50 genes are known for the different forms of Charcot-Marie-Tooth disease. 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 (Tyson et al 1996). 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. 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. There is typically no neuropathic pain. In a series of 17 HNPP patients, most had transient focal weakness or sensory loss related to activities that may compress nerves (Li et al 2004). 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 (Del Colle et al 2003) 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 3 large series, several other phenotypes have been identified (Pareyson et al 1996; Tyson et al 1996; Pareyson et al 1998; Kumar et al 1999; Mouton et al 1999). In 1 study, 40% were unaware of their condition, and 25% were essentially without symptoms (Pareyson et al 1996). 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 (Simonetti 2000). In a study of 70 patients, the average number of nerve palsies over a lifetime was around 2 (Mouton et al 1999); 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 3 members had brachial plexus palsies as the only clinical manifestation of HNPP (Orstavik et al 2001). 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 (Bosch et al 1980; Martinelli et al 1989; Stogbauer et al 1998). Furthermore, there is no genetic overlap between the 2 conditions (Chance et al 1994; Gouider et al 1994; Windebank et al 1995; Pellegrino et al 1997). In the study by Mouton and colleagues, 10 patients had sensory deficits in addition to palsies (Mouton et al 1999). 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 1 study, ankle jerks were absent in 37.5% of patients, and areflexia occurred in 12.5% (Gouider et al 1994). The second most frequent presentation in 2 series (Pareyson et al 1996; Kumar et al 1999), though rarer in another (Mouton et al 1999), 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

4 as acute or chronic inflammatory demyelinating polyneuropathy (Joy and Oh 1989; Le Forestier et al 1997; Kumar et al 1999). Cranial neuropathies, including deafness (Gabreels-Festen et al 1992), are infrequent and may sometimes represent chance events. Other rare associations of HNPP include CNS demyelination (Amato and Barohn 1996), moving toes and myoclonus (Shaibani et al 1997), fulminant 4-limb weakness possibly related to nerve compression (Crum et al 2000) and amyotrophic lateral sclerosis (Bhatt et al 2009). Lynch and Hennessy (Lynch and Hennessy 2005) reported sciatic neuropathy as the initial presentation of HNPP. Subclinical CNS involvement consists of abnormal blink and jawopening reflexes and acoustic evoked potentials (Tackenberg et al 2006). Normal-appearing white matter in HNPP demonstrated lower fractional anisotropy values by diffusion tensor imaging in the frontal, orbitofrontal, and temporal lobes (Wang et al 2015). The co-occurrence of schwannomas in the median and medial plantar nerves and HNPP led to speculations about a possible common genetic basis (Heckmann et al 2007). Other atypical phenotypes/disease associations and combinations of genetic mutations may delay the diagnosis, such as HNPP and amyotrophic lateral sclerosis (Bhatt et al 2009) and HNPP and oculopharyngeal muscular dystrophy (Marsh and Robinson 2008). 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 (Barisic et al 1990). Only 1 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 1 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 HNPP patients with frame shift, nonsense, or splice site mutations had typical phenotypes, likely because the mutations resulted in a functional deletion (Nicholson et al 1994; Taroni et al 1995; Pareyson et al 1996; Taroni et al 1996), 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 (Lenssen et al 1998). A mild phenotype resulted from a 3' splicesite mutation, preceding coding exon 3 (c G>C) (Meuleman et al 2001). Atypical phenotypes may also result from a combination of mutations. In 1 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 (Pegoraro et al 2005). HNPP rarely presents in childhood. A 2-year old child presented with toe-walking, pain, stiffness, asymmetric weakness, and bilateral upper motor neuron findings (Lonnqvist and Pihko 2003). 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 a progressive polyneuropathy with recurrent episodes of palsy in 1 nerve may be left with significant disability. Foot deformities may be significant. Because the family history may be 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 (Beydoun et al 2008). Prognosis and complications Life expectancy is normal. There is no primary treatment for HNPP. In general, patients with hereditary liability to pressure palsies have 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 (Koike et al 2005).

5 Clinical vignette A 42-year-old man (IV-3) was referred for evaluation of diffuse body aches. 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 2 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 (Reisecker et al 1994). Sixty-eight percent to 90% of these cases (Mariman et al 1994; LeGuern et al 1995; Nelis et al 1996) 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 (Chapon et al 1996) or mutations within the PMP22 gene (Nicholson et al 1994). 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 (Palau et al 1993; Lopes et al 1997; Lopes et al 1998; Boerkoel et al 1999). 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 brainstem and spinal motor neurons. Its 4 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 (Jetten and Suter 2000). PMP22 expression is tightly regulated at the transcriptional level by use of 2 different promoters, of which P1 contains several regulatory elements and appears to function in myelinating Schwann cells (Hai et al 2001). 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 (Muller 1999). 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 2 molecules interact in a heterophilic interaction (D'Urso et al 1999), 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,

6 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 (Friedman et al 1999). The current 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 (Vallat et al 1996; Gabriel et al 1997; Schenone et al 1997), 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 (Adlkofer et al 1995; Adlkofer et al 1997; Maycox et al 1997). 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 (Thomas et al 1994). 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 (Suter and Nave 1999). A naturally occurring disease of cattle is characterized by abnormal gait, gastrointestinal features, and tomaculous neuropathy (Hill et al 1996). 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 1 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 (Ginanneschi et al 2012). 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 (Skre 1974), whereas a worldwide meta-analysis estimated a prevalence of 10 in 100,000 (Emery 1991). On the other hand, the frequency of HNPP is not well documented. A single study of 435,000 individuals in Finland reported prevalence of 16/100,000 for the disorder and of 20/100,000 for Charcot-Marie-Tooth disease in general (Meretoja et al 1997). 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 cross over 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 (Mouton et al 1999). 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 (Kim et al 2004). Of some 1000 individuals with Charcot-Marie-Tooth disease at a single center in the United States, 6% had HNPP (Saporta et al 2011). Men are more severely affected clinically (higher number of nerve palsies) and electrodiagnostically (Manganelli et al 2013). 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 (Bernard et al 2000). 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

7 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 1 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 (Thomas et al 1999). 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 1 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. These include 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. Hereditary neurologic amyotrophy is genetically distinct from HNPP and maps to chromosome 17q25 (Chance et al 1994; Gouider et al 1994; Windebank et al 1995; Pellegrino et al 1997). Familial carpal tunnel syndrome, though rare and often difficult to ascertain, appears to be another entity that must be considered (Gossett and Chance 1998). 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, 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 1 report, 37% of patients had no family history (Tyson et al 1996). Infante and colleagues suggested that in the absence of a 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 (Infante et al 2001). 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 (Malandrini et al 1992; Felice et al 1994; Mancardi et al 1995; Le Forestier et al 1997; Korn-Lubetzki et al 2002), which could also be superimposed on oligosymptomatic or asymptomatic HNPP. 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 a HNPP case manifesting as recurrent polyradiculoneuropathy (Le Forestier et al 1997). 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 CMT1A patients. Patients with more advance 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 (Gallardo et al 2006). Genetic testing. Patients in whom the clinical phenotype, the family history, and electrodiagnostic studies suggest that they might have an inherited neuropathy should be genotyped. This is important because clinical exam and electrodiagnostic studies often cannot definitively establish a precise diagnosis due to the overlap between clinical

8 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. Although fresh 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 (Beckmann and Schroeder 2000). 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 (Mouton et al 1999). 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 a 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 (Gouider et al 1995). Other criteria were proposed by Infante and colleagues (Infante et al 2001). 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 9 and 53 previously reported cases, consistent with a background demyelinative distal polyneuropathy (Andersson et al 2000). 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 (Li et al 2002) disagreed with the concept of a distal myelinopathy and suggested that focal susceptibility to compression was the main culprit. In their study, distal slowing correlated with the exposure to entrapment; there was more slowing in the median and peroneal, 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 (Behse et al 1972; Madrid and Bradley 1975; Gabreels-Festen and van de Wetering 1999; Sander et al 2000). Outside of 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 1 Schwann cell may participate in myelination (Madrid and Bradley 1975). 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 (Jedrzejowska et al 1999). 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 (Sander et al 2000). 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 (Ochoa et al 1971; Vital et al 1985; Vallat et al 1987; Gabreels-Festen et al 1990; Thomas et al 1994; Quattrone et al 1996; Sander et al 2000). An issue with important implications for the molecular pathogenesis is the reason for tomacula formation. Ochoa and colleagues explained pressure-induced myelin abnormalities with slippage of myelin lamellae (Ochoa et al 1971).

9 Gabreels-Festen and van de Wetering proposed that, in HNPP, the genetic defect disturbs adhesion of myelin lamellae and makes them susceptible to displacement (Gabreels-Festen and van de Wetering 1999). 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 every day 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 (Schenone et al 1997). 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 (Gabreels-Festen and van de Wetering 1999; Sander et al 2000). 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 2 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 (Bolino et al 1996; Pellegrino et al 1997). Further insight may result from studies of human nerve xenografts into nude mice (Sahenk et al 1998). There is some evidence that immune dysregulation may play a role in the pathogenesis of hereditary neuropathies, including HNPP (Korn-Lubetzki et al 2002). Sural nerve biopsies in the disorder and other Charcot-Marie-Tooth cases show Mhc class II upregulation, but not inflammatory infiltrates (Stoll et al 1998). 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 (Li et al 2005). Management 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: Adriamycin Alcohol Amiodarone Chloramphenicol Cisplatin Colchicine Dapsone Disulfiram Ethionamide Glutethimide Gold Hydralazine Isoniazid Lithium Metronidazole Misonidazole Nitrofurantoin Nitrous oxide Paclitaxel Penicillamine Penicillin (high doses) Perhexiline Phenytoin Vincristine Vitamin A Vitamin B6 (high doses) Vitamin D

10 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. Introduction of recombinant DNA encoding normal PMP22 into the nerves of knock-out mice is being considered as 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 (Hai et al 2001). The significance of steroid responsive palsies (Barisic et al 1990) is difficult to appreciate in light of the natural history of HNPP, which is remitting. Two studies of transgenic rodent models of PMP22 mutations revealed promising results. Ascorbic acid reduced PMP22 overexpression and ameliorated the phenotype in a transgenic CMT1A mouse model (Passage et al 2004). This approach would, of course, be counterproductive in HNPP, as the gene dosage is already reduced. However, it may open the door to analogous pharmacologic approaches that could increase PMP22 expression. 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 (Sereda et al 2003). 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 HNPP patients. 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 Charcot-Marie-Tooth disease patients, researchers found that the patients had no difficulties tolerating anesthetics, even with succinylcholine (Antognini 1992). 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 (Kinsella and Green 1995). 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. Regional anesthesia is relatively contraindicated in Charcot-Marie-Tooth disorders.