Identification of a Dutch founder mutation in MUSK causing fetal akinesia deformation sequence

Fetal akinesia deformation sequence (FADS) refers to a clinically and genetically heterogeneous group of disorders with congenital malformations related to impaired fetal movement. FADS can result from mutations in CHRNG, CHRNA1, CHRND, DOK7 and RAPSN; however, these genes only account for a minority of cases. Here we identify MUSK as a novel cause of lethal FADS. Fourteen affected fetuses from a Dutch genetic isolate were traced back to common ancestors 11 generations ago. Homozygosity mapping in two fetuses revealed MUSK as a candidate gene. All tested cases carried an identical homozygous variant c.1724T>C; p.(Ile575Thr) in the intracellular domain of MUSK. The carrier frequency in the genetic isolate was 8%, exclusively found in heterozygous carriers. Consistent with the established role of MUSK as a tyrosine kinase that orchestrates neuromuscular synaptogenesis, the fetal myopathy was accompanied by impaired acetylcholine receptor clustering and reduced tyrosine kinase activity at motor nerve endings. A functional assay in myocytes derived from human fetuses confirmed that the variant blocks MUSK-dependent motor endplate formation. Taken together, the results strongly support a causal role of this founder mutation in MUSK, further expanding the gene set associated with FADS and offering new opportunities for prenatal genetic testing.     

5q — syndrome in a child

A boy aged 8 years, 10 months presented with refractory anemia. Bone marrow investigation revealed monolobular megakaryocytes. Cytogenetic analysis showed a clonal abnormality: 46, XY, del(5)(q14q32). This is the youngest individual ever reported with this disorder. A year after diagnosis, while on treatment with human recombinant erythropoietin, the bone marrow showed an excess of blasts. No bone marrow donor could be found. Transformation to acute myelomonocytic leukemia occurred 3 months later. In spite of intensive chemotherapy, the child died of progressive disease with massive splenomegaly and jaundice. The case illustrates that the 5q- syndrome can occur de novo in children. The outcome in this child was poor, which may reflect a difference from the adult 5q- syndrome or may possibly be related to the erythropoietin the child received.     

Evaluation of the Appropriateness of Pacemaker Mode Selection in Bradycardia Pacing:

Although guidelines for selection of the appropriate pacing mode have been published, little data is available on how closely these are followed in the clinical setting. All 738 patients (men 412, women 326; age 73.4 +/- 0.46 years; range 19-101 years) who underwent pacemaker implantation from 1996 to 2000 were reviewed to determine if the appropriate mode was selected based on the ACC/AHA guidelines with the data collected prospectively. Demographic, investigational, and implantation data including the presence of sinus disease and/or atrioventricular block, diagnosis, indication for pacing, ACC/AHA class indication for device therapy, recommended ACC/AHA mode, implanted mode, and reason for not using the recommended mode were entered into an SPSS data base. Of 738 patients, 708 were cross-tabulated for a match to the guidelines of which 358 (50.6%) had a mode selected that did not conform. The reasons were advanced physical disability (16%), physician choice without identifiable reason (21%), rate modulation selected without identifiable indication (16%), DDD implanted instead of VDD (25%), advanced age (9%), rare need for pacing (6%), a need for specific device features (5%), and unstable stimulation thresholds or difficult venous access (2%). In the treatment of bradyarrhythmias, deviation from the ACC/AHA indicated mode occurred in a substantial proportion of pacing system implantations. However, in many, the deviation appeared appropriate considering the patient's clinical status. Nevertheless, in a smaller proportion of patients the deviation appeared inappropriate requiring rectification. The two outstanding categories were: (1) elderly denied a dual chamber system with no clinical explanation and (2) selection of rate-modulated devices without any indication of chronotropic incompetence.     

Increased Risk of HIV in Women Experiencing Physical Partner Violence in Nairobi,Kenya

As part of a study on etiology of sexually transmitted infections (STI) among 520 women presenting at the STI clinic in Nairobi, data on partner violence and its correlates were analyzed. Prevalence of lifetime physical violence was 26%, mainly by an intimate partner (74%). HIV seropositive women had an almost twofold increase in lifetime partner violence. Women with more risky sexual behavior such as early sexual debut, number of sex partners, history of condom use and of STI, experienced more partner violence. Parity and miscarriage were associated with a history of lifetime violence. We found an inverse association between schooling and level of violence. Six percent of the women had been raped. Gender-based violence screening and services should be integrated into voluntary counseling and testing programs as well as in reproductive health programs. Multi-sector approaches are needed to change prevailing attitudes towards violence against women. An erratum to this article can be found at     

Old measures and new scores in spinal muscular atrophy patients

Introduction: A recent Rasch analysis performed on the Hammersmith Functional Motor Scale—Expanded (HFMSE) in patients with spinal muscular atrophy (SMA) identified issues impacting scale validity, redundant items, and disordered thresholds on some items. Methods: We modified the HMFSE scoring based on the Rasch analysis and on expert consensus to establish whether the traditional scoring overestimated the number of patients with changes within 2 points from baseline. Data were collected retrospectively from multicenter data sets in 255 type 2 and 3 SMA patients. Results: The mean 12‐month changes using the new and the traditional scoring system did not differ significantly (P > 0.05). The numbers of patients who improved or decreased by >2 points were also similar. Conclusions: The presence of outliers using the traditional scoring system was not due to overestimation of changes in activities that were tested bilaterally or to discrepancies in the scoring hierarchy of individual items. Muscle Nerve 52:435–437, 2015     

Cuprizone‐induced demyelination and demyelination‐associated inflammation result in different proton magnetic resonance metabolite spectra

Conventional MRI is frequently used during the diagnosis of multiple sclerosis but provides only little additional pathological information. Proton MRS (¹H‐MRS), however, provides biochemical information on the lesion pathology by visualization of a spectrum of metabolites. In this study we aimed to better understand the changes in metabolite concentrations following demyelination of the white matter. Therefore, we used the cuprizone model, a well‐established mouse model to mimic type III human multiple sclerosis demyelinating lesions. First, we identified CX₃CL1/CX₃CR1 signaling as a major regulator of microglial activity in the cuprizone mouse model. Compared with control groups (heterozygous CX₃CR1^+/? C57BL/6 mice and wild type CX₃CR1^+/+ C57BL/6 mice), microgliosis, astrogliosis, oligodendrocyte cell death and demyelination were shown to be highly reduced or absent in CX₃CR1^?/? C57BL/6 mice. Second, we show that ¹H‐MRS metabolite spectra are different when comparing cuprizone‐treated CX₃CR1^?/? mice showing mild demyelination with cuprizone‐treated CX₃CR1^+/+ mice showing severe demyelination and demyelination‐associated inflammation. Following cuprizone treatment, CX₃CR1^+/+ mice show a decrease in the Glu, tCho and tNAA concentrations as well as an increased Tau concentration. In contrast, following cuprizone treatment CX₃CR1^?/? mice only showed a decrease in tCho and tNAA concentrations. Therefore, ¹H‐MRS might possibly allow us to discriminate demyelination from demyelination‐associated inflammation via changes in Tau and Glu concentration. In addition, the observed decrease in tCho concentration in cuprizone‐induced demyelinating lesions should be further explored as a possible diagnostic tool for the early identification of human MS type III lesions. Copyright © 2015 John Wiley & Sons, Ltd.     

PROP sensitivity affects macronutrient selection

The objective was to study the effect of 6-n-propylthiouracyl (PROP) taster status on macronutrient selection. Thirteen PROP nontasters (PNT) and 23 PROP tasters (PT) were offered three ad libitum lunches in a random order: a high-fat (HF; CHO/P/F: 30/10/60), a high-carbohydrate (HCHO; 80/10/10), and a mixed (MIX) lunch consisting of products of the HF and HCHO lunch. PT compared to PNT ate relatively more fat (47+/-9 vs. 38+/-10%, P<.05) and less carbohydrate (45+/-9 vs. 53+/-10%, P<.05) from the MIX lunch. When dividing PT into supertasters (PST) and medium tasters (PMT), the same relation between PT status and macronutrient selection was observed (P<.05). The energy density of the food consumed was higher for PT than for PNT (P<.05). Protein, food (g) and energy (kJ) intake, appetite, and hedonic value were not different between PT and PNT. At the HCHO as well as HF lunch, no differences with respect to macronutrient selection, food and energy intake, appetite levels, and hedonic value between PT and PNT were observed. However, at the HF lunch, energy density of the food consumed was higher for PT than for PNT, but this effect was not observed during the HCHO lunch. Hunger and satiety scores did not differ between PT and PNT. The hedonic value was higher for the MIX lunch compared to the HCHO and HF lunch for PT as well as for PNT.In conclusion, PT ingest more of the HF foods than of the HCHO foods from a mixed lunch compared to PNT.