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  • Updated 02.01.2021
  • Released 07.11.2001
  • Expires For CME 02.01.2024

Hereditary neuropathy with predisposition to pressure palsy



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 (30) in France and by Tooth in England (172), but earlier descriptions had been published, including several by Friedreich (52). 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, Dejerine and Sottas described in Charcot's group more severe cases with onset in infancy (38), and Roussy and Levy described cases associated with tremor, which were defined genetically (147; 07; 134). Allan recognized different forms of inheritance (03). 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) (46; 171; 25). 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 (68; 69). 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 (39; 84). A case of HNPP from this original family has been described (85). Davies, Wahle, and Tonnis observed pressure sensitive neuropathies in a father and son with recurrent multiple mononeuropathies (35; 180). 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 (47; 159). A 4-generation Dutch family referred to affected members with transient unilateral peroneal neuropathies as having bulb diggers' palsy (159). 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 (103). Dayan and colleagues reported similar histologic features, termed “globular neuropathy,” in a family with progressive weakness and numbness of apparent autosomal dominant inheritance (37). Larger literature reviews and personally observed series of patients with clinical electrodiagnostic and histological correlation were reported by Roos and Thygesen (146), Meier and Moll (113), and Pellissier and colleagues (133).

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 (139; 177; 117; 90). 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 (50; 101; 140). Ninety percent of these cases result from this duplication (24; 67; 186; 130). 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 (163; 165) and in some Charcot-Marie-Tooth disease type 1 or type 3 patients (174; 144; 120). Moreover, transgenic mice and rats over-expressing PMP22 develop neuropathies resembling Charcot-Marie-Tooth disease type 1 (74; 104; 154). An approximately 1.5 mB long deletion of the proximal short arm of chromosome 17 is detected in most families with HNPP (27; 73), whereas about 14% to 25% of patients develop the disorder due to other PMP22 mutations (122; 121). 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 (122; 167; 168; 22; 187; 93; 149); and small deletion of exon 5 leading to very mild phenotype (26). 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 (28; 64; 185; 132).

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 (70; 88; 162) and the gap junction protein connexin 32 or beta 1 on chromosome Xq13.1 (12). The rare X-linked Charcot-Marie-Tooth disease was mapped to chromosome Xq24 to Xq26 (137) and the zinc-finger domain containing transcription factor early growth response 2 gene for congenital hypomyelination neuropathy and Charcot-Marie-Tooth disease type 1D (183). Mutations of all of these genes have been associated with several overlapping clinical phenotypes. For instance, Dejerine-Sottas syndrome is associated with PMP22 or myelin protein zero mutations or deletions (121; 182; 42; 142).

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) (80); the gene for the phosphatase myotubularin-related protein-2 on chromosome 11q22 for autosomal recessive Charcot-Marie-Tooth disease type 4B (20); a cytoskeletal gene; the neurofilament light subtype gene on chromosome 8p21 for Charcot-Marie-Tooth disease type 2E (115); the periaxin gene on chromosome 19q13.1-2, which is regulated by EGR2, for recessive Dejerine-Sottas syndrome (18); the gene for a serine palmitoyltransferase subunit on chromosome 9q22 for hereditary sensory neuropathy type 1 (11; 36); and the KIF1B-beta gene involved in axonal organelle transport on chromosome 1p36-35 for Charcot-Marie-Tooth disease type A (188). A demyelinating neuropathy also results from absent proteolipid protein expression in some Pelizaeus-Merzbacher patients (60; 59). Mutations in the cytoskeletal protein gigaxonin have been linked to giant axonal neuropathy (21). A locus for autosomal dominant Charcot-Marie-Tooth disease type 2F was found on chromosome 7q11-q21 (76).

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 (81), 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 (105; 178). A recessively inherited severe form of Charcot-Marie-Tooth disease with intermediate conduction velocities has been linked to chromosome 10q23 (145). Intermediate conduction velocities also occur with myelin protein zero and neurofilament light subtype gene mutations (41; 40).

Overall, more than 100 genes are known for the different forms of Charcot-Marie-Tooth disease.

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