Inherited focal, episodic neuropathies

Hereditary neuropathy with liability to pressure palsies (HNPP; also called tomaculous neuropathy) is an autosomal-dominant disorder that produces a painless episodic, recurrent, focal demyelinating neuropathy. HNPP generally develops during adolescence, and may cause attacks of numbness, muscular weakness, and atrophy. Peroneal palsies, carpal tunnel syndrome, and other entrapment neuropathies may be frequent manifestations of HNPP. Motor and sensory nerve conduction velocities may be reduced in clinically affected patients, as well as in asymptomatic gene carriers. The histopathological changes observed in peripheral nerves of HNPP patients include segmental demyelination and tomaculous or “sausage-like” formations. Mild overlap of clinical features with Charcot-Marie-Tooth (CMT) disease type 1 (CMT1) may lead patients with HNPP to be misdiagnosed as having CMT1. HNPP and CMT1 are both demyelinating neuropathies, however, their clinical, pathological, and electrophysiological features are quite distinct. HNPP is most frequently associated with a 1.4-Mb pair deletion on chromosome 17p12. A duplication of the identical region leads to CMT1A. Both HNPP and CMT1A result from a dosage effect of the PMP22 gene, which is contained within the deleted/duplicated region. This is reflected in reduced mRNA and protein levels in sural nerve biopsy samples from HNPP patients. Treatment for HNPP consists of preventative and symptom-easing measures. Hereditary neuralgic amyotrophy (HNA; also called familial brachial plexus neuropathy) is an autosomal-dominant disorder causing episodes of paralysis and muscle weakness initiated by severe pain. Individuals with HNA may suffer repeated episodes of intense pain, paralysis, and sensory disturbances in an affected limb. The onset of HNA is at birth or later in childhood with prognosis for recovery usually favorable; however, persons with HNA may have permanent residual neurological dysfunction following attack(s). Episodes are often triggered by infections, immunizations, the puerperium, and stress. Electrophysiological studies show normal or mildly prolonged motor nerve conduction velocities distal to the affected brachial plexus. Pathological studies have found axonal degeneration in nerves examined distal to the plexus abnormality. In some HNA pedigrees there are characteristic facial features, including hypotelorism. The prognosis for recovery of normal function of affected limbs in HNA is good, although recurrent episodes may cause residual deficits. HNA is genetically linked to chromosome 17q25, where mutations in the septin-9 (SEPT9) gene have been found.     

Peripheral Myelin Protein 22 gene duplication with atypical presentations: A new example of the wide spectrum of Charcot-Marie-Tooth 1A disease

Charcot-Marie-Tooth type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP) are both autosomal-dominant disorders linked to peripheral myelin anomalies. CMT1A is associated with a Peripheral Myelin Protein 22 (PMP22) duplication, whereas HNPP is due to a PMP22 deletion on chromosome 17. In spite of this crucial difference, we report three observations of patients with the 1.4 megabase CMT1A duplication and atypical presentation (electrophysiological, clinical or pathological): a 10 year-old girl with tomaculous lesions on nerve biopsy; a 26 year-old woman with recurrent paresthesiae and block conduction on the electrophysiological study; a 46 year-old woman with transient recurrent nerve palsies mimicking HNPP. These observations highlight the wide spectrum of CMT1A and the overlap between CMT1A and HNPP (both linked to the PMP22 gene), and finally illustrate the complexity of the genotype–phenotype correlations in Charcot-Marie-Tooth diseases.     

Variable phenotypes are associated with PMP22 missense mutations

Charcot-Marie-Tooth disease (CMT) is the commonest hereditary neuropathy encompassing a large group of clinically and genetically heterogeneous disorders. The commonest form of CMT, CMT1A, is usually caused by a 1.4 megabase duplication of chromosome 17 containing the PMP22 gene. Mutations of PMP22 are a less common cause of CMT. We describe clinical, electrophysiological and molecular findings of 10 patients carrying PMP22 missense mutations. The phenotype varied from mild hereditary neuropathy with liability to pressure palsies (HNPP) to severe CMT1. We identified six different point mutations, including two novel mutations. Three families were also found to harbour a Thr118Met mutation. Although PMP22 point mutations are not common, our findings highlight the importance of sequencing the PMP22 gene in patients with variable CMT phenotypes and also confirm that the PMP22 Thr118Met mutation is associated with a neuropathy albeit with reduced penetrance.     

The prevalence of hereditary neuropathy with liability to pressure palsies in patients with multiple surgically treated entrapment neuropathies

PURPOSE: Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal-dominant peripheral neuropathy that results from deletion of a 1.5-Megabase pair (Mb) segment of the short arm (p) of chromosome 17. Hereditary neuropathy with liability to pressure palsies increases susceptibility of peripheral nerves to pressure and trauma and can be associated with symptoms at multiple anatomic entrapment sites. Many patients present with multiple upper-extremity entrapment neuropathies and the etiology is uncertain. We hypothesized that some of these patients have an underlying hereditary neuropathy. The purpose of this study was to determine the prevalence of HNPP in patients with multiple surgically treated upper-extremity entrapment neuropathies. METHODS: The inclusion criterion for the study was history of more than 1 carpal tunnel release and/or ulnar nerve transposition. The exclusion criteria were history of diabetes or history of Charcot-Marie-Tooth neuropathy. Fifty-nine patients were in the study group. Two patients known to have the 17p11.2 deletion were used as controls. Genomic DNA was extracted from peripheral blood. Each sample was genotyped using polymerase chain reaction (PCR) amplification with short tandem repeat polymorphism markers within the 1.5-Mb region of 17p deleted in HNPP. Markers were scored as homozygous or heterozygous after resolution by polyacrylamide gel electrophoresis and silver staining. RESULTS: The 2 control patients were homozygous for 11 markers. None of the 59 study patients were homozygous for all markers tested in the deleted region. No study patient had the 17p deletion diagnostic for HNPP. Based on the sample size of 59 patients the 95% confidence interval for the prevalence of the 17p11.2 deletion in this population is 0% to 5%. CONCLUSIONS: We found no evidence for an association between HNPP and patients who have multiple surgical releases for upper-extremity entrapment neuropathies.     

Co-segregation of LMNA and PMP22 gene mutations in the same family

We report here clinical, electrophysiological, and molecular findings in a family affected with two inherited genetic diseases: limb girdle muscular dystrophy type 1B (LGMD1B) and hereditary neuropathy with liability to pressure palsies (HNPP). Members of the family carry a novel missense mutation in the LMNA gene and a nonsense mutation in the PMP22 gene. Interestingly, the double LMNA/PMP22 mutations carriers showed clinical features more severe than usually seen in HNPP, and electrophysiological findings suggesting an axonal loss in addition to a typical myelinopathy. This study provides further insights into the relevance of lamin A/C in muscle and nerve.     

Improved testing for CMT1A and HNPP using multiplex ligation-dependent probe amplification (MLPA) with rapid DNA preparations: comparison with the interphase FISH method

Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP) are the two most common peripheral neuropathies, with incidences of about 1 in 2,500. Several techniques can be used to detect the typical 1.5-Mb duplication or deletion associated with these respective conditions, but none combines simplicity with high sensitivity. MLPA is a new technique for measuring sequence dosage. We have assessed its performance for the detection of the specific 1.5-Mb duplication/deletion by prospectively testing 50 patients referred with differential diagnoses of CMT or HNPP. Probes were designed to evaluate the TEKT3, PMP22, and COX10 genes within the CMT1A/HNPP region. We have compared the results with our existing fluorescence in situ hybridization (FISH) assay, which was performed in parallel. There was concordance of results for 49 patients. Of note, one patient showed an intermediate multiplex ligation-dependent probe amplification (MLPA) result with an abnormal FISH result, which is consistent with mosaicism. The assay works equally well with either purified DNA or rapid DNA preparations made by direct cell lysis. The use of the latter significantly reduces the cost of the assay. MLPA is a sensitive, specific, robust, and cost-effective technique suitable for fast, high-throughput testing and offers distinct advantages over other testing methods.     

Hereditary neuropathy with liability to pressure palsy combined with schwannomas of the median and medial plantar nerves

A 42-year-old woman was surgically treated for carpal tunnel syndrome, revealing schwannoma of the median nerve. A year later, she developed a tarsal tunnel syndrome. At time of this diagnosis, hereditary neuropathy with liability to pressure palsies (HNPP) was diagnosed genetically and a schwannoma of the medial plantar nerve was treated surgically. The occurrence of HNPP and schwannomas in the same patient might be purely coincidental, but it is tempting to speculate that they share a common genetic basis.     

Ciliary neurotrophic factor null alleles are not a risk factor for Charcot-Marie-Tooth disease, hereditary neuropathy with pressure palsies and amyotrophic lateral sclerosis

Growth factors, such as ciliary neurotrophic factor (CNTF), have been implicated in neuronal survival and proliferation. About 2% of the human population is homozygous for a polymorphism that induces truncated and biologically inactive CNTF but does not obviously change the phenotype. In a population of patients with hereditary neuropathy, a higher rate of the CNTF null mutation would indicate greater susceptibility for clinically significant disease, and a recent report attributes early onset and rapid deterioration in a case of familial ALS (FALS) to this mutation. We have, therefore, genotyped the CNTF polymorphism in a large group of patients with CMT 1a, HNPP, sporadic ALS, in one pedigree with FALS, and controls. All groups exhibited a similar distribution of the polymorphism. We conclude that absence of CNTF does not increase susceptibility for these disorders and confirm that it does not affect onset and course of familial and sporadic ALS.     

Moving toes and myoclonus associated with hereditary neuropathy with liability to pressure palsy (HNPP)

A 22-year-old male awoke with right foot drop and numbness. Nerve conduction studies, sural nerve biopsy, and molecular genetic analysis were consistent with hereditary neuropathy with liability to pressure palsy (HNPP). Two months later he developed involuntary flexion/extension movements of the right toes with associated intermittent dystonic flexion of the right foot. Over the next 2 months these movements spread to the left foot and hand and myoclonus of the left trapezius and rhomboid appeared. This is the first case report of moving toes syndrome and segmental myoclonus in association with HNPP. The temporal and topographic patterns of spread of the abnormal movements suggest a central mechanism probably induced by peripheral pathology. © 1997 John Wiley & Sons, Inc. Muscle Nerve 20: 881–883, 1997