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 honorariums from Pfizer for consulting work.)
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 21, 2016; expires November 21, 2019

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.


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-Marie-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 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 downstream-regulated 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 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.

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