Guidelines for diagnosis of hereditary neuropathy with liability to pressure palsies.

Abstract

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant peripheral neuropathy [1]. HNPP patients present with variously located recurrent peripheral nerve palsies, or sensory loss, often precipitated by minor trauma or compression. The dysfunction is painless, distinguishing HNPP from another inherited recurrent focal neuropathy, namely hereditary neuralgic amyotrophy [2,3]. Usually the onset is acute, but progressive weakness may occur. In most cases, patients recover within days or weeks, but relapses are frequent, and paresis may last for long periods. A number of patients show signs of a symmetrical distal neuropathy without acute nerve palsies [3,4]. Neurological examination reveals weakness and sensory loss in the distribution of affected nerves; tendon re exes are often depressed or abolished, pes cavus is infrequent, scoliosis is rare, and there is no nerve hypertrophy or CNS involvement [1]. HNPP is probably underdiagnosed because of its usually benign course. In addition, about 10±15% of mutation carriers remain clinically asymptomatic, suggesting incomplete penetrance [4,5]. Given the poverty of the clinical ®ndings in HNPP, electrophysiological examination is of great importance for its diagnosis. Nerve conduction studies reveal a characteristic pattern of mildly decreased motor nerve conduction velocities (MNCV), prolonged distal motor latencies (DML) predominantly at nerve entrapment sites, and altered sensory nerve action potentials, even in clinically nonaffected nerves or in asymptomatic at-risk individuals [6]. A simple standardized electrophysiological examination is suf®cient to identify adult gene carriers: bilaterally delayed median DML and reduced sensory velocity in the palmwrist segment, and a delayed DML or reduced MNCV in the peroneal nerve, are highly suggestive of the disease when there is a family history of HNPP [4]. Peripheral nerve biopsies show a characteristic focal sausage-shaped thickening of the myelin sheath in about 25% or less of the internodes [7], which were designated by Madrid and Bradley as `tomacula' [8,9]. The tomaculous changes are not speci®c to HNPP and can occur, even in a higher frequency in Charcot±Marie±Tooth disease or Dejerine±Sottas phenotype [10]. Some patients do not show these speci®c changes, but rather non-speci®c ®ndings with either extensive loss of ®bers, or excessive variability in thickness and length of myelin internodes [1]. However, molecular analysis has not yet been performed in these HNPP patients. An interstitial deletion in the 17p11.2 region is associated with the disorder in most HNPP families [11±16]. This is the same region, designated CMT1A monomer unit, which contains the gene encoding the peripheral myelin protein 22 (PMP22), which is duplicated in the more frequently diagnosed neuropathy, Charcot±Marie±Tooth disease type 1A (CMT1A) [11±16]. Thus, it was hypothesized that unequal crossing-over between chromosome 17 homologues would generate a duplication that could lead to CMT1A, or a deletion that could result in HNPP. This hypothesis was reinforced by the existence of de novo deletions in HNPP patients without affected parents, most of them with a paternal origin [11,13,15], but sometimes with a maternal origin [17±20]. Investigators have postulated a gene dosage effect of PMP22 contained in the CMT1A monomer unit. This hypothesis has been con®rmed by the demonstration that PMP22 protein level expression in myelin correlates with the number of gene copies [21,22]. Moreover, it has recently been shown that PMP22 mRNA level is lower in the sural nerve of HNPP patients compared with normal controls, and correlates with disease severity [23,24]. The causative role of the PMP22 gene has been de®nitely proven by the existence, in rare HNPP patients, of mutations in this gene, probably causing a loss of function Neuromuscular Disorders 10 (2000) 206±208