Cerebral cavernous malformation: novel mutation in a Chinese family and evidence for heterogeneity

Familial cerebral cavernous malformation (CCM) is an autosomal dominant disorder producing vascular anomalies throughout the central nervous system associated with seizures and hemorrhagic stroke. Linkage analysis has shown evidence for at least three genetic loci underlying this disorder with a founder mutation in the Mexican/Hispanic community. We report the first family of Chinese ethnic origin with CCM having a novel mutation in the CCM1 gene. The mutation in exon 19 causes a premature stop codon (Q698X) predicted to produce a truncated Krev1 interaction-trapped 1 (KRIT1) protein. Members of the family with this mutation have a wide range in age of onset with seizures, ataxia, spinal cord vascular malformation, headaches and skin lesions. An additional unrelated sporadic subject with brain lesions compatible with CCM as well as vascular skin findings suggesting the blue rubber bleb nevus (BRBN) syndrome has no mutation detected in the CCM1 gene. These findings expand the phenotype of and demonstrate further evidence for the heterogeneity in the CCM syndrome.     

Neuropeptide expression following constriction or section of the inferior alveolar nerve in the ferret

Some of the sensory abnormalities that follow peripheral nerve injury may result from the development of ectopic discharge from the damaged axons. Previous studies in our laboratory have shown that, following tight ligation of the inferior alveolar nerve (IAN), there is a close association between the time-course of this neural activity and the accumulation of neuropeptides at the injury site. In this study we investigated whether the type of injury has any effect on the time-course or level of neuropeptide expression. In 36 adult ferrets, the IAN was either loosely constricted or sectioned, and the animals left to recover for 3 days, 3 weeks, or 3 months. The tissue was processed using indirect immunofluorescence and image analysis was used to quantify levels of substance P, calcitonin gene-related peptide, vasoactive intestinal polypeptide, enkephalin, galanin, and neuropeptide Y. Immunoreactivity to all of the neuropeptides was present within the injured nerve 3 days after both types of injury, and decreased to lower levels by 3 weeks and 3 months. Comparisons between the levels of neuropeptide immunoreactivity in each group revealed that the pattern of accumulation was similar following loose constriction or section, and also similar to that found in our previous study on tight ligation. For each injury the time-course of neuropeptide expression was similar to that of the spontaneous activity we had previously recorded. These data support the suggestion that neuropeptide accumulation may be linked to the development of ectopic neural activity but indicate that the type of injury has little effect on the extent of expression.     

Involvement of deprivation and environmental lead in neural tube defects: a matched case-control study

OBJECTIVE: To analyse the prevalence of neural tube defects in small geographical areas and seek to explain any spatial variations with reference to environmental lead and deprivation. SETTING: The Fylde of Lancashire in the north west of England. DESIGN: Cases were ascertained as part of a prospective survey of major congenital malformations in babies born in the Fylde to residents there between 1957 and 1981. A matched case-control analysis used infants with cardiovascular system, alimentary tract, and urinary system malformations as controls. Conditional logistic regression was used to assess the effects of more than 10 micrograms/l lead in drinking water and the Townsend deprivation score. RESULTS: The prevalence of neural tube defects in 1957-73 was higher in Blackpool, Fleetwood, and North Fylde, whereas the three control groups showed no significant spatial variation. In 1957-81 mothers living in electoral wards with either a higher proportion of houses with more than 10 micrograms/l lead in the water or a higher deprivation score had a greater risk of having a baby with a neural tube defect. For spina bifida and cranium bifidum alone, this was also true. For anencephaly, deprivation was less important although the effect of lead was still seen. In some neural tube defects, lead may act independently of other possible factors associated with deprivation. It seemed unlikely that lead levels changed significantly during the survey. The percentage of houses with 10 micrograms/l or more of lead in the water in 1984-5 was similar to that found in Great Britain 10 years previously. CONCLUSION: There is evidence to suggest that lead is one cause of neural tube defects, especially anencephaly. This could link the known preventive actions of hard water and folic acid. Calcium is a toxicological antagonist of lead. One cause of a deficiency of folic acid is impaired absorption secondary to zinc deficiency, which may be produced or exacerbated by lead.     

Blood-brain barrier and blood volume imaging of cerebral glioma using functional CT: A pictorial review

Five cases of cerebral glioma are presented here that illustrate the benefit of functional CT imaging of blood-brain barrier permeability and cerebral blood volume. Functional CT uses Patlak analysis of a single location dynamic sequence to extract physiological information that is useful clinically in the assessment of cerebral gliomas. Functional CT offers distinct advantages over other functional modalities including clearer delineation of tumour, tumour grading, measurement of tumour activity and monitoring response to therapy.     

Parkinson's disease, CYP2D6 polymorphism, and age

OBJECTIVE: PD may be caused by genetic susceptibility to neurotoxins. CYP2D6 is a candidate gene for PD because it regulates drug and toxin metabolism, but association studies have been inconsistent. The aim of this study was to test if the CYP2D6*4 allele (poor metabolizer phenotype) is associated with earlier age at onset. METHODS: Five hundred seventy-six patients with PD and 247 subjects without PD were studied using standard diagnostic, genotyping, and statistical techniques. RESULTS: Surprisingly, mean onset age was significantly later in *4-positive patients. Frequency of *4 was significantly higher in late-onset PD than early-onset PD. When early- and late-onset PD were analyzed separately, *4 had no effect on onset age; hence, the association with delayed onset was likely an artifact of an elevated *4 frequency in late-onset PD. Contrary to a common assumption that CYP2D6 frequencies do not change with age, *4 frequency rose significantly with advancing age, both in patients with PD (from 0.16 at mean age of 56.5 years to 0.21 at mean age of 72) and subjects without PD (from 0.09 at mean age of 45.5 years to 0.21 at mean age of 72). *4 Frequencies in patients with early- and late-onset PD, although different from each other, were in agreement with similarly aged subjects without PD, suggesting the elevated *4 frequency in late-onset PD was likely an age effect, unrelated to PD. CONCLUSION: The CYP2D6*4 allele is not associated with earlier PD onset. *4 May be associated with survival. Inconsistent results from allelic association studies may have been due to an unrecognized age effect.     

The effect of altering eligibility criteria for entry onto a kidney transplant waiting list.

BACKGROUND: This paper concerns the allocation of kidneys from cadaveric donors to patients with end-stage renal disease (ESRD). Currently, the decision as to whether or not a particular patient should go onto the renal transplant waiting list is left to the discretion of the local dialysis centre, and is usually based almost entirely upon consideration of each case on its individual merits. Would this person like to have a renal transplant, is this possible, and would it seem reasonable to give them a chance? It could be argued that such an approach may not make best use of a scarce national resource. In this study we explore the effects of altering the eligibility criteria for transplantation to take explicit and quantitative account of the fact that some patients are more likely to die than others. METHODS: We performed a survey of one unit's dialysis patients to ascertain the characteristics used in practice to determine who should go onto the transplant waiting list and who should not. We then created a computer model to simulate a cohort of ESRD patients, initially of the same size and characteristics as that in the unit surveyed, receiving renal replacement therapy over a period of 10 years. Using this model, we compared four strategies for defining eligibility for transplantation: (1) all patients eligible; (2) standard and medium risk patients eligible; (3) only standard risk patients eligible; and (4) no regrafts performed (standard and medium risk according to definitions in the Renal Association Standards Document). RESULTS: Strategies of allowing only standard or standard and medium risk patients onto the waiting list most closely reflected the current decisions made regarding eligibility. The different strategies considered in the models necessarily gave rise to very considerable variation in the size of the waiting list at the end of the 10 year period (range 98-368), which would have important practical implications. The predicted mean time of kidney function varied from 9.8 years for strategy 4 (no regrafts) to 10.8 years for strategy 3 (only standard risk patients eligible). However, the different strategies had very little effect on other parameters, such as numbers of deaths and the size of the dialysis population. CONCLUSIONS: Variation in decision making from centre to centre regarding access to renal transplantation could make up to a 10% (1 year) difference in the expected half-life of renal transplants performed. Information about recipient characteristics is therefore required when making comparisons between outcome in one transplant unit with that in another, or when comparing one immunosuppressive regime with another.     

Reflexes and somatic responses as predictors of ejaculation by penile vibratory stimulation in men with spinal cord injury

STUDY DESIGN: Retrospective chart review. OBJECTIVE: To identify factors in addition to level of injury (LOI) that may predict ejaculation by penile vibratory stimulation (PVS) in spinal cord injured males. SETTING: Major urban medical school and teaching hospital. MATERIALS AND METHODS: Presence of a bulbocavernosus response (BCR) and a hip flexor response (HR) before PVS (n=123 patients), and somatic responses during PVS (n=204 trials performed on a subset of 44 patients) were evaluated for their frequency of occurrence on trials with and without ejaculation. RESULTS: Overall ejaculation success rates for cervical, T1-T6, and T7-T12 LOI were 71%, 73%, and 35%, respectively. Eighty per cent of patients who were positive for both BCR and HR ejaculated with PVS, while only 8% of patients who were negative for both BCR and HR ejaculated with PVS. For cervical injuries, BCR and HR were no more predictive of ejaculation by PVS than LOI alone. T1-T6 patients were more likely to ejaculate when at least one reflex was present. T7-T12 patients with no BCR were unlikely to ejaculate by PVS. Except for abdominal contractions, somatic responses were not present in the majority of PVS trials. When they were present, however, they occurred in a high percentage of ejaculation trials: withdrawal response (hip flexion, knee flexion and thigh adduction) (90%), piloerection (84%), extremity spasms (83%), thigh abduction (80%), and thigh adduction (72%). CONCLUSION: We recommend that patients with cervical injuries initially undergo PVS. Patients with T1-T6 LOI with at least one reflex present, and patients with T7-T12 LOI with both reflexes, or only BCR present, may undergo PVS. Certain somatic/autonomic responses, when seen, may help in deciding whether to continue with a given trial, or give a repeat trial, of PVS. SPONSORSHIP: The Miami Project to Cure Paralysis and the State of Florida Specific Appropriations.     

Approaches to the patient with neurogenetic disease

The approach to a patient with a possible neurogenetic disorder is a complex process that challenges the physician's knowledge, diagnostic acumen and counseling abilities. This article focuses on six aspects of the process: 1. Clues suggesting the presence of a genetic disease, 2. The importance of family history, 3. The interpretation of sporadic cases, 4. Genetic counseling, 5. Genetic testing and 6. Available resources.