Hereditary recurrent focal neuropathies: Clinical and molecular features

Klinik and Poliklinik für Neurologie, Westfälische Wilhelms Universität, Münster, Germany.
Neurology (Impact Factor: 8.29). 03/2000; 54(3):546-51. DOI: 10.1212/WNL.54.3.546
Source: PubMed


The authors review the molecular genetics and pathophysiology of hereditary recurrent focal neuropathies: hereditary neuropathy with liability to pressure palsies (HNPP) and hereditary neuralgic amyotrophy (HNA). Significant progress in the understanding of HNPP and HNA has been achieved. HNPP and HNA are distinct clinical and pathologic disease entities with autosomal dominant inheritance. Molecular genetic studies have shown that HNPP and HNA are located on chromosome 17 but at distinct genetic loci (17p11.2 for HNPP, 17q25 for HNA). The 1.5 megabase deletion in 17p11.2 is the major cause of HNPP. This interstitial deletion causes the complete loss of one allele of the peripheral myelin protein 22 (PMP22) gene. Interestingly, rare HNPP patients are found without the 1.5 megabase deletion. However, these patients have distinct mutations in the PMP22 gene resulting in altered expression of the PMP22 protein. Current molecular genetic tests and clinical guidelines allow improved diagnosis, prognosis, and genetic counseling for patients with HNPP. Such tests are not available for HNA, because the disease-causing gene remains unknown. Molecular genetic advances in HNPP and HNA, as well as the study of transgenic animal and cellular models, will provide a more precise understanding of the disease mechanisms and will lead to the development of effective therapeutic tools for patients with inherited and sporadic recurrent peripheral neuropathies.

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    • "In CMT1Apatients the altered number of genomic PMP22 copies determines the type of neuropathy and correlates with disease severity. Loss of one functional PMP22 allele results in a reduced gene dosage (0.5-fold) and in hereditary neuropathy with liability to pressure palsies (HNPP) (Stogbauer et al., 2000) (Fig. 2). A 1.5-fold increased copy number of PMP22 causes CMT1A. "
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    ABSTRACT: Charcot-Marie-Tooth (CMT) disease is a common hereditary neuropathy that causes progressive distally pronounced muscle weakness and can lead to life-long disability in patients. In most cases, the disorder has been associated with a partial duplication of human chromosome 17 (CMT1A), causing 1.5-fold overexpression of the peripheral myelin protein 22 kDa (PMP22). Increased PMP22 gene dosage results in demyelination, sectiondary axonal loss, and neurogenic muscle atrophy. Experimental therapeutic approaches based on the role of progesterone and ascorbic acid in myelin formation recently have reached preclinical proof-of-principle trials in rodents. It was shown that progesterone receptor antagonists can reduce PMP22 overexpression and clinical severity in a CMT1A rat model. Furthermore, ascorbic acid treatment reduced premature death and demyelination in a CMT1A mouse model. Thus, basic research has opened up new vistas for the understanding and treatment of hereditary neuropathies.
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    ABSTRACT: ABSTRACT Introduction: Hereditary Neuralgic Amyotrophy (HNA), also known asBrachial Plexus Neuropathy, is a rare hereditary disease that is characterized,by recurrent,episodes,of severe,arm,and,shoulder,pain
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