Evidence for a recessive PMP22 point mutation in Charcot-Marie-Tooth disease type 1A.

Charcot-Marie-Tooth disease type 1A (CMT1A) is an autosomal dominant neuropathy that can be caused by dominant point mutations in PMP22 which encodes a peripheral nerve myelin protein. Usually, CMT1A is caused by the duplication of a 1.5-megabase (Mb) region on chromosome 17p11.2-p12 containing PMP22. Deletion of a similar 1.5-Mb region is associated with hereditary neuropathy with liability to pressure palsies (HNPP), a clinically distinct neuropathy. We have identified a severely affected CMT1 patient who is a compound heterozygote for a recessive PMP22 point mutation, and a 1.5 Mb deletion in 17p11.2-p12. A son heterozygous for the PMP22 point mutation had no signs of neuropathy, while two others heterozygous for the deletion had HNPP, suggesting that point mutations in PMP22 can result in dominant and recessive alleles contributing to CMT1A.

Clinical phenotypes of different MPZ (P0) mutations may include Charcot-Marie-Tooth type 1B, Dejerine-Sottas, and congenital hypomyelination.

Hereditary demyelinating peripheral neuropathies consist of a heterogeneous group of genetic disorders that includes hereditary neuropathy with liability to pressure palsies (HNPP), Charcot-Marie-Tooth disease (CMT), Dejerine-Sottas syndrome (DSS), and congenital hypomyelination (CH). The clinical classification of these neuropathies into discrete categories can sometimes be difficult because there can be both clinical and pathologic variation and overlap between these disorders. We have identified five novel mutations in the myelin protein zero (MPZ) gene, encoding the major structural protein (P0) of peripheral nerve myelin, in patients with either CMT1B, DSS, or CH. This finding suggests that these disorders may not be distinct pathophysiologic entities, but rather represent a spectrum of related "myelinopathies" due to an underlying defect in myelination. Furthermore, we hypothesize the differences in clinical severity seen with mutations in MPZ are related to the type of mutation and its subsequent effect on protein function (i.e., loss of function versus dominant negative).

Screening mammogram utilization in women with diabetes.

OBJECTIVE: To determine whether women with diabetes undergo fewer screening mammograms than matched control subjects. RESEARCH DESIGN AND METHODS: A total of 424 women with diabetes aged 50-75 years who received their primary care from general internists at a large Midwestern multispecialty group practice were retrospectively studied for frequency of mammography from August 1997 to January 2000. Two control subjects without diabetes (n = 845) were matched to each case by age, sex, provider, and date of visit. The main outcome measure was the percentage of subjects undergoing mammography 1 year before and 30 days after an index date, defined as the most recent health care visit after August 1997 and before January 2000. RESULTS: Analysis by conditional logistic regression demonstrated that women with diabetes had significantly lower rates of mammograms than control subjects (78.1 vs. 84.9%, respectively; odds ratio 0.63, P = 0.002). After adjusting for insurance status and race, women with diabetes continued to have significantly lower rates of mammography (odds ratio 0.70, P = 0.027). CONCLUSIONS: Women with diabetes were significantly less likely to undergo screening mammography than control subjects. Considering the increasing incidence of diabetes and the equal incidence of malignancy in women with and without diabetes, it would be beneficial to improve breast cancer screening in this population.

Controlled pilot trial of monthly intravenous cyclophosphamide in multiple sclerosis.

Monthly intravenous cyclophosphamide treatment was compared with placebo treatment for one year in a controlled trial of 14 patients with relapsing/remitting multiple sclerosis. Eight patients received placebo and six patients received cyclophosphamide. The cyclophosphamide group showed a definite trend to have less frequent and less prolonged episodes than the placebo group. When each group served as their own controls, the cyclophosphamide group had a significant decrease in episodes while the placebo group did not. When the placebo group was then given cyclophosphamide, they also had a significant decrease in episodes. When all patients who were receiving cyclophosphamide were combined for analysis, the decrease in episodes was even more evident. Complications were minimal. These results suggest that monthly intravenous doses of cyclophosphamide may influence the frequency and duration of episodes of relapsing/remitting multiple sclerosis.

Glossopharyngeal neuralgia, asystole, and seizures.

Glossopharyngeal neuralgia, asystole, and seizures occurred in a patient with an internal carotid occlusion and external carotid stenosis. Swallowing was the triggering mechanism for these events. Mechanical stimulation of the pharynx failed to reproduce the symptoms. An ischemic injury to the glossopharyngeal nerve in the region of the jugular foramen that resulted in an artificial synapse is the proposed etiology.

Familial tic disorder, parkinsonism, motor neuron disease, and acanthocytosis: a new syndrome.

We report two brothers who were of consanguineous parents and who displayed a unique association of motor and vocal tics, parkinsonism, distal muscular atrophy, and acanthocytosis. In the older brother, leg weakness and muscle wasting started at age 13, and he became wheelchair bound at 40. Electrophysiologic studies and muscle biopsy confirmed diffuse denervation. Involuntary vocalizations and facial tics began at age 36, but within 5 years the tics were replaced by progressive parkinsonism with supranuclear ophthalmoparesis. CSF studies implied impaired central dopamine and serotonin turnover. In the younger brother, orofacial tics started at age 36, vocalizations and fasciculations in the legs began 1 year later, and parkinsonian findings were present at age 40. This is the first report of an association of Tourettism, parkinsonism, motor neuron disease, and acanthocytosis occurring as an autosomal recessive syndrome.

Interferon beta induces T-helper 2 immune deviation in MS.

OBJECTIVE: To define the in vitro effects of interferon beta la (IFN-beta1a) on myelin basic protein (MBP)-reactive T cells and to determine its regulatory mechanism on cytokine networks in patients with MS. METHODS: The proliferation and cytokine production of MBP-reactive T-cell clones were measured in thymidine uptake assays and ELISA respectively. The precursor frequency of MBP-reactive T cells was estimated in a microwell culture system. RESULTS: IFN-beta inhibited the proliferation of established MBP-reactive T-cell clones, which correlated with enhanced production of anti-inflammatory interleukin (IL)-4 and IL-10, and a decrease in tumor necrosis factor alpha (TNF-alpha) and IFN-gamma. When examined with peripheral blood mononuclear cells (PBMCs), IFN-beta was found to reduce the in vitro T-cell responses to MBP, as indicated by the significantly decreased frequency of MBP-reactive T cells. The decreased frequency of MBP-reactive T cells corresponded to an augmented production of IL-4 and IL-10. Although the level of TNF-alpha and IFN-gamma was generally unaltered or decreased, IFN-beta appeared to enhance the production of IFN-gamma in PBMCs derived from some individuals with MS. CONCLUSION: Interferon beta la (IFN-beta) suppresses myelin basic protein (MBP)-reactive T cells and induces immune deviation toward the production of T-helper 2 cytokines, which may contribute to its therapeutic benefit in MS. The study also suggests some heterogeneity in MBP-reactive T-cell responses to IFN-beta in different individuals with MS.

Time trends in the prevalence of atherosclerosis: a population-based autopsy study.

PURPOSE: Mortality from coronary heart disease is declining but little is known about trends in the prevalence of atherosclerosis. Autopsy rates in Olmsted County, Minnesota, are higher than the national average, offering an opportunity to address this matter. In this study, we determined the prevalence of anatomic coronary disease among autopsied Olmsted County residents and examined the generalizability of these findings. SUBJECTS AND METHODS: Reports of the 2,562 autopsies performed between 1979 and 1994 on Olmsted County residents > or =20 years of age were reviewed for the presence of coronary disease. RESULTS: Among autopsied decedents less than 60 years old at death and among coroner's cases, the prevalence of anatomic coronary disease declined with time (P for trend = 0.05); no trend was detected among older persons or noncoroner's cases. By logistic regression analysis, the crude odds ratio ([OR] per 5 years) for the association between time and anatomic coronary disease was 0.94 (95% confidence interval [CI]: 0.86 to 1.03; P = 0.18]. Age, sex, and antemortem diagnosis of heart disease were also strongly related to the presence of disease. After adjustment for sex and antemortem diagnosis of heart disease, the prevalence of anatomic coronary disease decreased more in younger people than in older people (age 40 years: OR 0.43 [95% CI: 0.24 to 0.80]; age 60 years: OR 0.62 [95% CI: 0.45 to 0.87]; age 80 years: OR 0.89 [95% CI: 0.64 to 1.23]). CONCLUSION: The prevalence of anatomic coronary disease at autopsy decreased between 1979 and 1994, particularly among younger people, supporting the notion that the burden of coronary disease has shifted toward the elderly. These results suggest that the decreased incidence of coronary artery disease has contributed to the recent decrease in coronary mortality, particularly among younger people.

Motor neuron destruction in guinea pigs immunized with bovine spinal cord ventral horn homogenate: experimental autoimmune gray matter disease.

Guinea pigs immunized with bovine spinal cord ventral horn homogenate develop muscle weakness with electromyographic and morphologic evidence of denervation. Pathological examination demonstrates a loss of motoneurons and scattered inflammatory foci primarily localized to the spinal cord. Immunohistochemical techniques document the presence of immunoglobulin G at the motor end plate and around the external membrane and within the cytoplasm of motoneurons. This syndrome of experimental autoimmune gray matter disease (EAGMD) differs from experimental autoimmune motor neuron disease induced by inoculation with purified motoneurons and also differs from experimental autoimmune encephalomyelitis. The existence of two different forms of immune-mediated motoneuron destruction suggests that a number of cytoplasmic and membrane antigens may give rise to an immunologically based attack on the motor system.

Clinical, cytogenetic, and molecular evidence for an infant with Smith-Magenis syndrome born from a mother having a mosaic 17p11.2p12 deletion.

We describe an infant with del(17) (p11.2p12) whose deleted chromosome was inherited from a mosaic mother. The child had manifestations consistent with Smith-Magenis syndrome. The mother appeared to be of normal intelligence and she had minimal findings of Smith-Magenis syndrome. Separation of chromosome 17 homologues in somatic cell hybrids and molecular studies confirmed the cytogenetic diagnoses and the fact that the mother was mosaic. Furthermore, molecular analysis demonstrated novel breakpoints in this family, with the deletion extending into and completely encompassing the markers duplicated in Charcot-Marie-Tooth (CMT) disease. Although this Smith-Magenis syndrome patient is completely deleted for the CMT region, her electrophysiological findings are different from those found in CMT. This is the only reported case of Smith-Magenis syndrome with transmission from a partially affected mosaic mother. Transmission of interstitial deletions from mosaic parents may be more common than thought; therefore, parental chromosomes should be examined when interstitial deletions are identified.

Cerebral infarction: diagnosis and assessment of prognosis by using 123IMP-SPECT and CT.

A multicenter prospective study was performed in 49 patients with 77 regions of cerebral infarction. Each patient was evaluated in the acute (0-5 days) and subacute (6-17 days) phases by (1) clinical neurologic examination, (2) CT scans, and (3) N-isopropyl-p-123I-iodoamphetamine (123IMP) single-photon emission CT (SPECT) scans. The abilities of the scans to (1) detect a lesion and (2) predict the clinical outcome were assessed. For lesion detection, 123IMP-SPECT was superior to CT in the first 2 days, but the scans were equally effective 3-5 days after onset. In the subacute phase, IV contrast-enhanced CT was superior to 123IMP-SPECT and unenhanced CT. The clinical outcome was only mildly correlated with the results of the acute and subacute 123IMP-SPECT and the acute CT scans. Reduction in lesion size on the subacute scans did not correlate with clinical improvement. We conclude that the parameters measured by CT and 123IMP-SPECT in patients with acute cerebral infarction cannot reliably be used to predict clinical outcome. 124I contamination of 123IMP and the use of low-energy collimators may have decreased lesion detectability.

Diagnosis of acute cerebral infarction: comparison of CT and MR imaging.

The appearance of acute cerebral infarction was evaluated on MR images and CT scans obtained in 31 patients within 24 hr of the ictus; follow-up examinations were performed 7-10 days later in 20 of these patients and were correlated with the initial studies. Acute infarcts were visible more frequently on MR images than on CT scans (82% vs 58%). Proton density- and T2-weighted scans usually demonstrated regions of hyperintensity corresponding to acute infarcts, but proton density-weighted scans often showed better definition of the lesion in terms of regional anatomy. Follow-up MR images and CT scans identified approximately 88% of subacute strokes, 54% of which were better defined and/or larger than on the initial examination. In 20% of lesions, "hemorrhagic" characteristics were seen on at least one examination. CT and MR imaging were comparable in delineating acute hemorrhage, but MR detected more cases with evidence of hemorrhage on follow-up examinations. MR appears to be more sensitive than CT in the imaging of acute stroke.

Elevated frequencies of 6-thioguanine-resistant lymphocytes in multiple sclerosis patients treated with cyclophosphamide: a prospective study.

An autoradiographic assay for 6-thioguanine-resistant (TGr) lymphocytes was used to determine the frequency of in vivo derived variant T lymphocytes in peripheral blood from multiple sclerosis (MS) patients treated with monthly intravenous infusions of 750 mg/m2 of cyclophosphamide (CP). To analyze the time-course of response to CP, the MS patients were studied prospectively. Samples were obtained from the patients before the beginning of CP therapy, 4-5 times during the course of treatment, and, finally, 2 or 3 months after the completion of therapy. 2 weeks after the first CP infusion, the variant frequencies (Vfs) of the MS patients were significantly increased (p less than 0.05) above their pre-treatment values, but by 4 weeks following the first CP infusion the Vfs had fallen to normal or near-normal levels. After subsequent treatments, the frequencies of variant TGr cells were again higher than pre-treatment Vfs. However, within 7-13 weeks after the cessation of CP therapy, the Vfs of all subjects had returned to normal levels. The transient nature of the response indicates rapid in vivo selection against CP-induced TGr mutant cells. The mean pre-treatment Vf of the 4 MS patients who were cigarette smokers was 6.56 X 10(-6) which was significantly greater (p less than 0.05) than the mean Vf (1.52 X 10(-6) of the 4 MS patients who were non-smokers. The mean Vf from 8 assays of healthy non-smokers was 1.92 X 10(-6).

Homozygous expression of a dominant gene for Charcot-Marie-Tooth neuropathy.

A kindred of 68 French Acadians who were heterozygous for a dominant gene of Charcot-Marie-Tooth disease associated with peripheral nerve hypertrophy are described. Marriage between 2 heterozygotes resulted in 2 homozygous offspring. Clinical features of the homozygotes were similar to the classic description of Dejerine-Sottas disease. Laboratory studies in this family revealed no chemical, metabolic, or chromosomal abnormalities in either the homozygotes or the heterozygotes.

Clinical utility of dorsal sural nerve conduction studies.

A technique of testing sensory nerve conduction of the dorsal sural nerve in the foot was used in 38 normal subjects and 70 patients with peripheral neuropathies. The normal dorsal sural sensory nerve action potential (SNAP) had a mean amplitude of 8.9 microV (range 5-15 microV), mean latency to negative peak of 4.0 ms (range 3.2-4.7 ms), and mean conduction velocity of 34.8 m/s (range 30-44 m/s). Optimal placement of the recording electrodes to obtain a maximal nerve action potential was proximal to digits 4 and 5. Cooling to below 25 degrees C prolonged the latency but did not decrease the SNAP amplitude. Among the patients with peripheral neuropathy, dorsal sural SNAP was absent in 68 (97%), whereas only 54 (77%) showed abnormalities of sural sensory conduction. The diagnostic sensitivity of sensory nerve conduction studies in peripheral neuropathies may be significantly improved by the use of this technique for evaluating the action potential of the dorsal sural nerve.

Experimental autoimmune motoneuron disease.

An animal model of disease of the lower motoneurons has been developed by inoculating guinea pigs with bovine motoneurons. Four of 9 immunized female animals and 4 of 5 immunized male animals developed symptoms of neuromuscular degeneration marked by weakness, evidence of denervation by electromyographic and morphological criteria, and a loss of motoneurons within the spinal cord. No inflammatory foci were noted within parenchyma or meninges of the central nervous system. The immunized guinea pigs developed high serum titers of IgG class antibodies to motoneurons. Immunohistochemical studies demonstrated the presence of IgG within spinal cord motoneurons and at the end-plates of immunized animals. This experimental autoimmune motoneuron disease may provide important insights into the cause and pathogenesis of amyotrophic lateral sclerosis, a human motoneuron disease.