Neuropathy in a human without the PMP22 gene.

BACKGROUND: Haploinsufficiency of PMP22 causes hereditary neuropathy with liability to pressure palsies. However, the biological functions of the PMP22 protein in humans have largely been unexplored owing to the absence of patients with PMP22-null mutations. OBJECTIVE: To investigate the function of PMP22 in the peripheral nervous system by studying a boy without the PMP22 gene and mice without the Pmp22 gene. DESIGN: The clinical and pathological features of a patient with a PMP22 homozygous deletion are compared with those of Pmp22-null mice. SETTING: Clinical evaluation was performed at tertiary hospitals in the United Kingdom. Molecular diagnosis was performed at the West Midlands Regional Genetics Laboratory. Immunohistochemistry and electron microscopy analyses were conducted at Wayne State University, Detroit, Michigan. Analysis of the Pmp22 +/- and null mice was performed at Vanderbilt University, Nashville, Tennessee. PARTICIPANT: A 7-year-old boy without the PMP22 gene. RESULTS: Motor and sensory deficits in the proband were nonlength-dependent. Weakness was found in cranial muscles but not in the limbs. Large fiber sensory modalities were profoundly abnormal, which started prior to the maturation of myelin. This is in line with the temporal pattern of PMP22 expression predominantly in cranial motor neurons and dorsal root ganglia during embryonic development, becoming undetectable in adulthood. Moreover, there were conspicuous maturation defects of myelinating Schwann cells; these defects were more significant in motor nerve fibers than in sensory nerve fibers. CONCLUSIONS: Taken together, the data suggest that PMP22 is important for the normal function of neurons that express PMP22 during early development, such as cranial motor neurons and spinal sensory neurons. Moreover, PMP22 deficiency differentially affects myelination between motor and sensory nerves, which may have contributed to the unique clinical phenotype in the patient with an absence of PMP22.

Conduction block in PMP22 deficiency.

Patients with PMP22 deficiency present with focal sensory and motor deficits when peripheral nerves are stressed by mechanical force. It has been hypothesized that these focal deficits are due to mechanically induced conduction block (CB). To test this hypothesis, we induced 60-70% CB (defined by electrophysiological criteria) by nerve compression in an authentic mouse model of hereditary neuropathy with liability to pressure palsies (HNPP) with an inactivation of one of the two pmp22 alleles (pmp22(+/-)). Induction time for the CB was significantly shorter in pmp22(+/-) mice than that in pmp22(+/+) mice. This shortened induction was also found in myelin-associated glycoprotein knock-out mice, but not in the mice with deficiency of myelin protein zero, a major structural protein of compact myelin. Pmp22(+/-) nerves showed intact tomacula with no segmental demyelination in both noncompressed and compressed conditions, normal molecular architecture, and normal concentration of voltage-gated sodium channels by [(3)H]-saxitoxin binding assay. However, focal constrictions were observed in the axonal segments enclosed by tomacula, a pathological hallmark of HNPP. The constricted axons increase axial resistance to action potential propagation, which may hasten the induction of CB in Pmp22 deficiency. Together, these results demonstrate that a function of Pmp22 is to protect the nerve from mechanical injury.

Discordant expression of familial amyloid polyneuropathy in monozygotic Brazilian twins.

Discordant expression of Familial Amyloid Neuropathy (FAP) in monozygotic twins is a rare event. Only five such cases have been described in the literature so far. We report the clinical, neurophysiologic and autonomic findings of Brazilian monozygotic twins discordant for the expression of FAP type I. Twin I first presented symptoms at the age of 21, when his brother was completely asymptomatic. Twin 2 only presented symptoms at the age of 25, almost four years after his brother. Both brothers eventually developed the complete phenotype of FAP type I. The occurrence of monozygotic twins discordant for the expression of FAP type I suggests that other factors beside TTR gene mutations should play an important role in the pathogenesis of this condition. Environmental factors, as well as modifier genetic loci are likely to modulate the expression of FAP type I and the study of cases such as the one presented here may help to identify some of these factors.

Prevalência e custos indiretos das cefaléias em uma empresa brasileira / Prevalence and indirect costs of headache in a Brazilian Company

Funcionários de uma empresa (n=993) foram entrevistados quanto à ocorrência de cefaléias durante um período retrospectivo de 30 dias. A prevalência foi 49,8 por cento, com frequência de 4,3+7,0 episódios e duraçao de 12,2+21,4 horas. Os diagnósticos baseados na classificaçao da Sociedade Internacional de Cefaléias, foram enxaqueca (5,5 por cento), cefaléia do tipo tensao (CTT) episódica (26,4 por cento), CTT crônica (1,7 por cento) e outras cefaléias (16,2 por cento). As mulheres foram mais acometidas e tiveram proporcionalmente mais enxaquecas que os homens. Cerca de 10 por cento dos pacientes relataram dor suficientemente intensa a ponto de prejudicar seu desempenho no trabalho, o que representou 538,75 horas nao trabalhadas. O custo indireto proporcionado pela interferência no trabalho foi estimado para cada cefaléia. O potencial prejuízo projetado à empresa devido às cefaléias é R$ 145,64 por funcionário, ou R$ 144 682,39 por ano. Como a enxaqueca é a cefaléia de maior custo, seu controle é particularmente importante no ambiente de trabalho. Há meios eficazes para reduzir sua frequência, com reflexos positivos no bem-estar e na produtividade do indivíduo. A relaçao custo-benefício favorece claramente a instituiçao de programas de prevençao e tratamento contra cefaléias crônicas.