Patients homozygous for the 17p 11.2 duplication in charcot-marie-tooth type 1A Disease

Charcot-Marie-Tooth type 1A disease is an inherited sensorimotor neuropathy that is most often associated with a duplication of chromosome 17p11.2. This region contains the gene of the peripheral myelin protein 22 (PMP22), which is responsible by a gene dosage effect for the Charcot-Marie-Tooth type 1A phenotype with 17p11.2 duplication. We performed a clinical, electrophysiological, and genetic study of a consanguinous Charcot-marie-Tooth type 1A family with 4 affected siblings, 3 of whom were homozygous for the 17p11.2 duplication, the other a heterozygote. Comparison of phenotypes showed that the severity of the disease was more severely affected than the heterozygous sibling who was pausiymptomatic. These results suggest that the severity of the disease is not determined solely by the number of copies of the PMP22 gene.     

Retrorenal colon: implications for percutaneous diskectomy

It has been recommended that computed tomography (CT) with the patient prone be performed in every patient undergoing percutaneous diskectomy; this would enable detection of a retrorenal location of the colon, which could interfere with the percutaneous procedure. In this evaluation of 346 prone CT studies, only one patient (0.29%) was found to have retrorenal or retropsoas bowel that would have been perforated at diskectomy. Because of this extremely low prevalence, the performance of prone CT in every patient undergoing percutaneous lumbar diskectomy is not believed to be necessary.     

Safety and efficacy of interferon alpha-2b following prednisone withdrawal in the treatment of chronic viral hepatitis B. A case-controlled, randomised study.

The therapeutic effects of interferon alpha-2b (Intron A; Scherag) in patients with chronic active hepatitis caused by hepatitis B virus (HBV) were assessed in a randomised, case-controlled clinical trial conducted between January 1988 and June 1990. Treatment involved a short course of prednisone followed by interferon alpha-2b, initially 10 million U by subcutaneous injection, 3 times a week for 16 weeks. All patients were symptomatic, were known to have had hepatitis B surface antigen and hepatitis B e antigen (HBeAg) in their blood for at least 6 months, and had elevated serum aminotransferase activities with histological evidence of chronic active hepatitis. Patients with carcinoma, renal or haematological abnormalities or decompensated cirrhosis were excluded. In 6 of 10 patients randomised to receive interferon and 1 of 10 controls, HBeAg and HBV DNA were cleared from the blood during the 12-month study period (P < 0.05). An indeterminate response with clearance of HBV DNA but persistence of HBeAg was noted in 1 patient receiving interferon. Serum aminotransferase levels decreased only in those patients who had responded to treatment, but this did not reach statistical significance for the group as a whole. Histological studies, where available, showed decreased hepatic periportal necrosis in patients who underwent treatment. Two patients relapsed to HBeAg-positive status 2 months after their initial seroconversion; 1 became clear again during a repeat course of interferon. Side-effects of treatment were common and included fever, malaise, myalgias and myelosuppression. One patient developed hypothyroidism.(ABSTRACT TRUNCATED AT 250 WORDS)     

Construction and validation of a Parkinson's disease mutation genotyping array for the Parkin gene.

Parkin mutations account for the majority of familial and sporadic early onset Parkinson's disease (EOPD) cases with a known genetic association. More than 100 mutations have been described in the Parkin gene that includes homozygous, compound heterozygous, and single heterozygous mutations. We have designed a Parkin mutation genotyping array (gene chip) that includes published Parkin sequence variants and allows their simultaneous detection. The chip was validated by screening 85 PD cases and 47 controls previously tested for Parkin mutations. Similar genotyping microarrays have been developed for other genetically heterogeneous diseases including age-related macular degeneration. Here, we show the utility of a genotyping array for Parkinson's disease by analysis of 60 subjects from the Genetic Epidemiology of Parkinson Disease (GEPD) study that includes 15 early-onset PD case probands and 45 relatives.     

Early stress tests following an uncomplicated myocardial infarct: a comparison between symptom-limited and submaximal tests

To compare the diagnostic and prognostic usefulness of symptom-limited versus load-limited submaximal stress testing, 76 patients, during the first week post acute non-complicated myocardial infarction, were submitted to a symptom-limited Naughton-modified protocol stress test. At 2 METs, 3 METs and maximal effort levels, the tests were classified as positive or negative following the currently used criteria. After a mean follow-up of 15 months, the symptom-limited protocol showed the best sensitivity (95%), specificity (78%), positive (64%) and negative (98%) predictive value, and also the highest risk ratio (27.4) for prediction of subsequent coronary events (2p less than 0.01 vs 2 METs, 3 METs and 2D-Echocardiogram results). Forward stepped multiple correlation analysis indicated independent prognostic value for the results of the symptom-limited stress test (R2: .52 p less than 0.01) and for the location of the myocardial infarction (R2: .05 p less than 0.05) only. In addition, the discriminant prognostic power of the symptom-limited protocol was significant after the fourth month of follow-up (2p less than 0.05 vs submaximal tests and 2D-Echo). Therefore, we recommend the performance of a symptom-limited stress test during the first week post acute non-complicated myocardial infarction, provided that all coronary active medication has been withheld 24 hours before the test.     

SMN gene analysis of the spinal form of Charcot-Marie-Tooth disease.

The spinal form of Charcot-Marie-Tooth disease (spinal CMT) is a rare genetic disorder of the peripheral nervous system, the genetic basis of which remains unknown. To test the hypothesis that a defect of survival motor neuron (SMN), the determining gene for spinal muscular atrophy (SMA), would result in spinal CMT, 18 unrelated spinal CMT patients were studied. Nine of them were sporadic cases and the other nine belonged to unrelated autosomal dominant pedigrees. None of the 18 patients showed deletions involving SMN exons 7 or 8, the most frequent gene alteration found in SMA. In addition, haplotype analysis in two large autosomal dominant pedigrees showed that the 5q13 locus was not segregating with the spinal CMT locus. Therefore, neither the sporadic nor the familial cases of spinal CMT are associated with a SMN gene deletion, nor are the familial cases linked to the 5q13 region, indicating that this neuropathy is genetically different from SMA.     

Ovarian hormones and cognition in the aged female rat: II. progesterone supplementation reverses the cognitive enhancing effects of ovariectomy

The authors hypothesized that the progesterone component of some hormone replacement therapies in women is detrimental to cognition. A previous study showed that ovariectomy (ovx) in aged rats enhanced spatial working memory and decreased elevated progesterone levels. The current study evaluated whether progesterone administration counteracts these cognitive enhancing effects of ovx. Aged sham and aged ovx rats given progesterone exhibited compromised learning of the working and reference memory components of the task, and made more working memory errors on the latter testing days compared with aged ovx rats not given progesterone. Results suggest that whereas ovx of the aged female rat enhances learning and the ability to handle numerous items of spatial working memory information, progesterone is detrimental to these aspects of performance. These findings may speak to studies in menopausal women which suggest that combination hormone therapies have a negative impact on cognition.     

Xq22.3q23 microdeletion harboring TMEM164 and AMMECR1 genes: Two case reports confirming a recognizable phenotype with short stature,midface hypoplasia,intellectual delay,and elliptocytosis

The AMME syndrome defined as the combination of Alport syndrome, intellectual disability, midface hypoplasia, and elliptocytosis (AMME) is known to be a contiguous gene syndrome associated with microdeletions in the region Xq22.3q23. Recently, using exome sequencing, missense pathogenic variants in AMMECR1 have been associated with intellectual disability, midface hypoplasia, and elliptocytosis. In these cases, AMMECR1 gene appears to be responsible for most of the clinical features of the AMME syndrome except for Alport syndrome. In this article, we present two unrelated male patients with short stature, mild intellectual disability or neurodevelopmental delay, sensorineural hearing loss, and elliptocytosis harboring small microdeletions identified by array‐CGH involving TMEM164 and AMMECR1 genes and SNORD96B small nucleolar RNA for one patient, inherited from their mothers. These original cases further confirm that most specific AMME features are ascribed to AMMECR1 haploinsufficiency. These cases reporting the smallest microdeletions encompassing AMMECR1 gene provide new evidence for involvement of AMMECR1 in the AMME phenotype and permit to discuss a phenotype related to AMMECR1 haploinsufficiency: developmental delay/intellectual deficiency, midface hypoplasia, midline defect, deafness, and short stature.     

Sequencing of the alpha-synuclein gene in a large series of cases of familial Parkinson's disease fails to reveal any further mutations. The European Consortium on Genetic Susceptibility in Parkinson's Disease (GSPD)

A mutation in exon 4 of the human alpha-synuclein gene was reported recently in four families with autosomal dominant Parkinson's disease (PD). In order to examine whether mutations in this exon or elsewhere in the gene are common in familial PD, all seven exons of the alpha- synuclein gene were amplified by PCR from index cases of 30 European and American Caucasian kindreds affected with autosomal dominant PD. Each product was sequenced directly and examined for mutations in the open reading frame. No mutations were found in any of the samples examined. We conclude that the A53T change described in the alpha- synuclein gene is a rare cause of PD or may even be a rare variant. Mutations in the regulatory or intronic regions of the gene were not excluded by this study.