Neurofibromatosis 1 (NF 1) is an autosomal dominant disorder affecting approx 1/3500 individuals. It is characterized by tumors of neural crest origin. Predominant manifestations include cafe au lait spots and cutaneous or subcutaneous neu-rofibromas (benign tumors of peripheral nerves). Other findings include axillary freckling, Lisch nodules (iris hamartomas), sco-liosis, plexiform neurofibromas, macrocephaly, short stature, seizures, and localized hypertrophy. Over half of individuals report learning problems. Patients are at increased risk for malignant tumors, including neurofibrosarcoma, astrocytoma, pheochromocytoma, embryonic rhabdomyosarcoma, and leukemia. Affected individuals could have cafe au lait spots at birth, and 97% of these individuals are symptomatic by age 20. Cutaneous neurofibromas appear in the second decade.

Neurofibromatosis 2 or central NF is a separate disorder mapped to 22q12. It is characterized by acoustic neuromas and meningiomas. Cafe au lait spots and neurofibromas are not prominent features of NF 2. This discussion will focus on NF 1.

5.1. GENETICS The gene for NF 1 is mapped to 17q11.2. The gene is extremely large, spanning 350 kb and containing at least 51 exons (58). The introns range in size from 6 bp to more than 40 kb. Intron 27 contains genes for three other proteins whose role in NF 1, if any, has not been determined (59). The mutation rate for the NF 1 gene is 1 x 10-4 per generation (approx 50% of the affected individuals have a new mutation).

Neurofibromin, the 2818-amino-acid protein encoded by NF 1, contains a domain that shares sequence homology with mammalian Ras p21 GTPase-activating protein (GAP) (59). This domain is denoted NF1GRD for the GTPase-activity protein-related domain of the human NF type 1 protein. GAP functions to stimulate the conversion of the active GTP-bound form of Ras (p21 ras-GTP) to the inactive GDP bound form (p21 ras-GDP) (60); Ras p21 proteins stimulate DNA synthesis and changes in cell morphology in response to mitogenic growth factors. Thus, NF1GRD is believed to act as a tumor suppressor gene by stimulating the conversion of p21 ras to its inactive form. Observations of increased ras activity and the loss of het-erozygosity (LOH) for polymorphic DNA markers at the NF 1 locus in NF 1-associated tumors further support its role as a tumor suppressor gene (61).

5.2. MOLECULAR DIAGNOSIS Screening the neuro-fibromin gene from affected patients has resulted in the detection of a number of mutations. The mutations include translocations, deletions, insertions, and nonsense and missense mutations (62). "Hot spots" for mutation have been identified in exons 10a-10c and exon 37. Together these might account for 30% of the mutations seen in NF 1 patients (62). A consortium was formed in 1993 to consolidate NF 1 mutation data (59). In 2000, the consortium reported 278 mutations in screening over 500 NF 1 patients. The size of the NF 1 gene has hindered development of direct mutation analysis for use in the clinical setting.

Some laboratories have focused on the protein truncation test (PTT) for the molecular diagnosis of NF 1. The PTT assay involves generation of NF1 cDNA from cellular mRNA. This is accomplished through the use of overlapping primer sets. Coupled in vitro transcription/translation reactions generate a protein product that is then analyzed by electrophoresis. The location of the protein truncation can be estimated by comparing the migration patterns of the aberrantly migrating polypeptides with proteins of known molecular weight. Subsequent sequencing of the cDNA can be done through the use of primers designed for the region of the suspected mutation. Heim et al. (63) reported a 60% mutation detection rate with the NF 1 PTT assay. A significant improvement in the detection rate of NF 1 mutations (95%) was recently accomplished using a tiered approach that includes a combination of PTT, hetero-duplex analysis, Southern blot, and cytogenetic analysis of patients with a possible diagnosis of NF 1 (62).

Linkage analysis is available for those individuals who are part of an NF 1 pedigree. However, for the 50% of affected individuals representing sporadic cases, linkage analysis cannot be utilized. New techniques and technologies will hopefully allow for the efficient and accurate detection of mutations in affected and at-risk individuals, as well as to assist in the understanding of the function and regulation of the NF 1 gene.

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