Abstracts & Commentary
Synopsis: Peripheral neuropathy in NF-1 patients is a marker for poorer prognosis and mandates heightened vigilance for malignancy and spinal cord complications.
Source: Drouet A, et al. Neurofibromatosis-Associated Neuropathies: A Reappraisal. Brain. 2004;127;1993-2009.
Among 688 neurofibromatosis type-1 (NF-1) patients followed in 2 NF clinics in France between 1995-2002 and satisfying established National Institutes of Health (NIH) Consensus criteria for NF-1, 18 (2.3%) demonstrated diffuse peripheral neuropathy. None had diabetes, vasculitis, paraproteinemia, renal insufficiency, thyroidopathy, B12, folate deficiency, human immunodeficiency virus (HIV), hepatitis B or C virus, or Charcot Marie Tooth type 1. Of the 14 men and 4 women, 3 had severe, and 5 had moderate, sensorimotor neuropathy. Mild sensory neuropathy was present in 2, and 8 were minimally or non-symptomatic, and were diagnosed electrodiagnostically. All but 2 were chronic in nature. Seventy-seven percent (n = 14) demonstrated demyelinating neuropathy, half of which showed concomitant axonal changes, either severe (n = 3) or mild to moderate (n = 4). Four of the 18 patients had axonal neuropathy. Subcutaneous and large nerve root neurofibromas was strongly associated with peripheral neuropathy, and morbidity and mortality was much higher than expected in the NF-1 neuropathy patients, compared to the non-neuropathy group. Twenty-two percent (n = 4) developed a malignant peripheral nerve sheath tumor, and 2 died. Peripheral neuropathy in NF-1 patients is a marker for poorer prognosis, and mandates heightened vigilance for malignancy and spinal cord complications.
Tumor suppression appears to be the raison d’etre of the NF-1 gene. Neurofibromin, the 2818 amino acid protein product of this gene, shows a striking sequence similarity to the catalytic domain of proteins that negatively regulate Ras guanosine triphosphate (GTP)ase proteins (Arun D, et al. Curr Opin Neurol. 2004;17;101-105). Ras is an effective growth promoter, and loss of NF-1 gene function allows Ras activity to run amok, resulting in cell proliferation and tumorigenesis. NF-1 gene dysfunction also impairs cyclic adenosine monophosphate (cAMP) formation necessary for modulation of cell growth, suggesting another mechanism whereby the NF-1 mutation allows unbridled cell growth.
Neurofibromas are the most common tumor in NF-1 individuals, and up to 13% of patients develop malignant peripheral nerve sheath tumors. Significantly, these highly invasive and metastatic tumors have recently been shown to demonstrate an abnormal proliferation-promoting triad of NF-1 deletion, aberrant epidermal growth factor receptor expression, and homozygous p16 tumor suppression gene deletion.
Optic pathway gliomas are the 2nd most common NF-1 associated tumor, but are symptomatic in only a third. Typically arising in the optic nerve and chiasm, hypothalamus, brainstem, and cerebellum, their main management challenge remains how to predict which will need intervention and which will not. Annual ophthalmologic evaluation is recommended for all NF-1 children younger than 10 years of age. Michael Rubin
Michael Rubin, MD Professor of Clinical Neurology, New York Presbyterian Hospital-Cornell Campus is Assistant Editor of Neurology Alert.