Swiss national guideline for reimbursement of enzyme replacement therapy in late-onset Pompe disease.

Glycogen storage disease type II is a rare multi-systemic disorder characterised by an intracellular accumulation of glycogen due a mutation in the acid alpha glucosidase (GAA) gene. The level of residual enzyme activity, the genotype and other yet unknown factors account for the broad variation of the clinical phenotype. The classical infantile form is characterised by severe muscle hypotonia and cardiomyopathy leading to early death. The late-onset form presents as a limb girdle myopathy with or without pulmonary dysfunction. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA) in infants is life saving. In contrast, therapeutic efficacy of rhGAA in the late-onset form is modest. High expenses of rhGAA, on-going infusions and poor pharmacokinetic efficacy raised a discussion of the cost effectiveness of ERT in late-onset Pompe disease in Switzerland. This discussion was triggered by a Swiss federal court ruling which confirmed the reluctance of a health care insurer not to reimburse treatment costs in a 67-year-old female suffering from Pompe disease. As a consequence of this judgement ERT was stopped by all insurance companies in late-onset Pompe patients in Switzerland regardless of their clinical condition. Subsequent negotiations lead to the release of a national guideline of the management of late-onset Pompe disease. Initiation and limitation of ERT is outlined in a national Pompe registry. Reimbursement criteria are defined and individual efficacy of ERT with rhGAA is continuously monitored.

Subjective pubertal timing and health compromising behaviors among on- time Swiss adolescent girls

AIM: The aim of this research is to assess the associations between subjective pubertal timing (SPT) and onset of health-compromising behaviours among girls reporting an on-time objective pubertal timing (OPT). METHODS: Data were drawn from the Swiss SMASH 2002 survey, a self-administered questionnaire study conducted among a nationally representative sample of 7548 adolescents aged 16-20 years. From the 3658 girls in the initial sample, we selected only those (n = 1003) who provided information about SPT and who reported the average age at menarche, namely 13, considering this as an on-time OPT. Bivariate and logistic analyses were conducted to compare the early, on-time and late SPT groups in terms of onset of health-compromising behaviours. RESULTS: A perception of pubertal precocity was associated with sexual intercourse before age 16 [adjusted odds ratio (AOR): 2.10 (1.30-3.37)] and early use of illegal drugs other than cannabis [AOR: 2.55 (1.30-5.02)]. Conversely, girls perceiving their puberty as late were less likely to report intercourse before age 16 [AOR: 0.30 (0.12-0.75)]. CONCLUSION: Faced with an adolescent girl perceiving her puberty as early, the practitioner should investigate the existence of health-compromising behaviours even if her puberty is or was objectively on-time.

Terrestrial and submarine evidence for the extent and timing of the Last Glacial Maximum and the onset of deglaciation on the maritime-Antarctic and sub-Antarctic islands

This paper is the maritime and sub–Antarctic contribution to the Scientific Committee for Antarctic Research (SCAR) Past Antarctic Ice Sheet Dynamics (PAIS) community Antarctic Ice Sheet reconstruction. The overarching aim for all sectors of Antarctica was to reconstruct the Last Glacial Maximum (LGM) ice sheet extent and thickness, and map the subsequent deglaciation in a series of 5000 year time slices. However, our review of the literature found surprisingly few high quality chronological constraints on changing glacier extents on these timescales in the maritime and sub–Antarctic sector. Therefore, in this paper we focus on an assessment of the terrestrial and offshore evidence for the LGM ice extent, establishing minimum ages for the onset of deglaciation, and separating evidence of deglaciation from LGM limits from those associated with later Holocene glacier fluctuations. Evidence included geomorphological descriptions of glacial landscapes, radiocarbon dated basal peat and lake sediment deposits, cosmogenic isotope ages of glacial features and molecular biological data. We propose a classification of the glacial history of the maritime and sub–Antarctic islands based on this assembled evidence. These include: (Type I) islands which accumulated little or no LGM ice; (Type II) islands with a limited LGM ice extent but evidence of extensive earlier continental shelf glaciations; (Type III) seamounts and volcanoes unlikely to have accumulated significant LGM ice cover; (Type IV) islands on shallow shelves with both terrestrial and submarine evidence of LGM (and/or earlier) ice expansion; (Type V) Islands north of the Antarctic Polar Front with terrestrial evidence of LGM ice expansion; and (Type VI) islands with no data. Finally, we review the climatological and geomorphological settings that separate the glaciological history of the islands within this classification scheme.

Patterns and Correlates of Expressed Emotion, Perceived Criticism, and Rearing Style in First Admitted Early-Onset Schizophrenia Spectrum Disorders

The aim of this study was to assess patterns and correlates of family variables in 31 adolescents treated for their first episode of a schizophrenia spectrum disorder (early-onset schizophrenia [EOS]). Expressed emotion, perceived criticism, and rearing style were assessed. Potential correlates were patient psychopathology, premorbid adjustment, illness duration, quality of life (QoL), sociodemographic variables, patient and caregiver "illness concept," and caregiver personality traits and support. Families were rated as critical more frequently by patients than raters (55% vs. 13%). Perceived criticism was associated with worse QoL in relationship with parents and peers. An adverse rearing style was associated with a negative illness concept in patients, particularly with less trust in their physician. Future research should examine perceived criticism as a predictor of relapse and indicator of adolescents with EOS who need extended support and treatment. Rearing style should be carefully observed because of its link with patients' illness concept and, potentially, to service engagement and medication adherence

Exposure to stallion accelerates the onset of mares' cyclicity.

Horses (Equus caballus) belong to the group of seasonally polyestrous mammals. Estrous cycles typically start with increasing daylight length after winter, but mares can differ greatly in the timing of onset of regular estrus cycles. Here, we test whether spatial proximity to a stallion also plays a role. Twenty-two anestrous mares were either exposed to one of two stallions (without direct physical contact) or not exposed (controls) under experimental conditions during two consecutive springs (February to April). Ovarian activity was monitored via transrectal ultrasound and stallion's direct contact time with each mare was determined three times per week for one hour each. We found that mares exposed to a stallion ovulated earlier and more often during the observational period than mares that were not exposed to stallions. Neither stallion identity nor direct contact time, mare age, body condition, size of her largest follicle at the onset of the experiment, or parasite burden significantly affected the onset of cyclicity. In conclusion, the timing of estrous cycles and cycle frequency, i.e., crucial aspects of female reproductive strategy, strongly depend on how the mares perceive their social environment. Exposing mares to the proximity of a stallion can therefore be an alternative to, for example, light programs or elaborated hormonal therapies to start the breeding season earlier and increase the number of estrous cycles in horses.

Impact of early-onset seizures on grading and outcome in patients with subarachnoid hemorrhage

OBJECT After subarachnoid hemorrhage (SAH), seizure occurs in up to 26% of patients. The impact of seizure on outcome has been studied, yet its impact on grading is unknown. The authors evaluated the impact of early-onset seizures (EOS) on grading of spontaneous SAH and on outcome. METHODS This retrospective analysis included consecutive patients with SAH who were treated at the NeuroCenter, Inselspital, University Hospital Bern, Switzerland, between January 2005 and December 2010. Demographic data, clinical data, and reports of EOS were recorded. The EOS were defined as seizures occurring within 24 hours after ictus. Patients were graded according to the World Federation of Neurosurgical Societies (WFNS) scale pre- and postresuscitation and dichotomized into good (WFNS I-III) and poor (WFNS IV-V) grades. Outcome was assessed at 6 months by using the modified Rankin Scale (mRS); an mRS score of 0-3 was considered a good outcome and an mRS score of 4-6 was considered a poor outcome. RESULTS Forty-one of 425 patients with SAH had EOS. Twenty-seven of those 41 patients (65.9%) had a poor WFNS grade. Twenty-eight (68.3%) achieved a good outcome, 11 (26.8%) had a poor outcome, and 2 (4.9%) were lost to followup. Early-onset seizures were proven in 9 of 16 electroencephalograms. The EOS were associated with poor WFNS grade (OR 2.81, 97.5% CI 1.14-7.46; p = 0.03) and good outcome (OR 4.01, 97.5% CI 1.63-10.53; p = 0.03). Increasing age, hydrocephalus, intracerebral hemorrhage, and intraventricular hemorrhage were associated with poor WFNS grade, whereas only age, intracerebral hemorrhage (p < 0.001), and poor WFNS grade (p < 0.001) were associated with poor outcome. CONCLUSIONS Patients with EOS were classified significantly more often in a poor grade initially, but then they significantly more often achieved a good outcome. The authors conclude that EOS can negatively influence grading. This might influence decision making for the care of patients with SAH, so grading of patients with EOS should be interpreted with caution.

An ARHGEF10 deletion is highly associated with a juvenile-onset inherited polyneuropathy in Leonberger and Saint Bernard dogs

An inherited polyneuropathy (PN) observed in Leonberger dogs has clinical similarities to a genetically heterogeneous group of peripheral neuropathies termed Charcot-Marie-Tooth (CMT) disease in humans. The Leonberger disorder is a severe, juvenile-onset, chronic, progressive, and mixed PN, characterized by exercise intolerance, gait abnormalities and muscle atrophy of the pelvic limbs, as well as inspiratory stridor and dyspnea. We mapped a PN locus in Leonbergers to a 250 kb region on canine chromosome 16 (Praw = 1.16×10-10, Pgenome, corrected = 0.006) utilizing a high-density SNP array. Within this interval is the ARHGEF10 gene, a member of the rho family of GTPases known to be involved in neuronal growth and axonal migration, and implicated in human hypomyelination. ARHGEF10 sequencing identified a 10 bp deletion in affected dogs that removes four nucleotides from the 3'-end of exon 17 and six nucleotides from the 5'-end of intron 17 (c.1955_1958+6delCACGGTGAGC). This eliminates the 3'-splice junction of exon 17, creates an alternate splice site immediately downstream in which the processed mRNA contains a frame shift, and generates a premature stop codon predicted to truncate approximately 50% of the protein. Homozygosity for the deletion was highly associated with the severe juvenile-onset PN phenotype in both Leonberger and Saint Bernard dogs. The overall clinical picture of PN in these breeds, and the effects of sex and heterozygosity of the ARHGEF10 deletion, are less clear due to the likely presence of other forms of PN with variable ages of onset and severity of clinical signs. This is the first documented severe polyneuropathy associated with a mutation in ARHGEF10 in any species.

Early-onset Crohn's disease is a risk factor for smaller final height.

OBJECTIVES Growth retardation is a frequent complication of paediatric inflammatory bowel disease (IBD). Only a few studies report the final height of these patients, with controversial results. We compared adult height of patients with paediatric IBD with that of patients with adult-onset disease. METHODS Height data of 675 women 19-44 years of age and 454 men 23-44 years of age obtained at inclusion in the Swiss IBD cohort study registry were grouped according to the age at diagnosis: (a) prepubertal (men≤13, women≤11 years), (b) pubertal (men 13-22, women 11-18 years) and (c) adult (men>22, women>18 years of age), and compared with each other and with healthy controls. RESULTS Male patients with prepubertal onset of Crohn's disease (CD) had significantly lower final height (mean 172±6 cm, range 161-182) compared with men with pubertal (179±6 cm, 161-192) or adult (178±7 cm, 162-200) age at onset and the general population (178±7 cm, 142-204). Height z-scores standardized against heights of the normal population were significantly lower in all patients with a prepubertal diagnosis of CD (-0.8±0.9) compared with the other patient groups (-0.1±0.8, P<0.001). Prepubertal onset of CD emerged as a risk factor for reduced final height in patients with prepubertal CD. No difference for final height was found between patients with ulcerative or unclassified IBD diagnosed at prepubertal, pubertal or adult age. CONCLUSION Prepubertal onset of CD is a risk for lower final height, independent of the initial disease location and the necessity for surgical interventions.

Sporadic late-onset nemaline myopathy with MGUS: long-term follow-up after melphalan and SCT.

OBJECTIVE Sporadic late-onset nemaline myopathy (SLONM) is a rare, late-onset myopathy that progresses subacutely. If associated with a monoclonal gammopathy of unknown significance (MGUS), the outcome is unfavorable: the majority of these patients die within 1 to 5 years of respiratory failure. This study aims to qualitatively assess the long-term treatment effect of high-dose melphalan (HDM) followed by autologous stem cell transplantation (SCT) in a series of 8 patients with SLONM-MGUS. METHODS We performed a retrospective case series study (n = 8) on the long-term (1-8 years) treatment effect of HDM followed by autologous SCT (HDM-SCT) on survival, muscle strength, and functional capacities. RESULTS Seven patients showed a lasting moderate-good clinical response, 2 of them after the second HDM-SCT. All of them had a complete, a very good partial, or a partial hematologic response. One patient showed no clinical or hematologic response and died. CONCLUSIONS This case series shows the positive effect of HDM-SCT in this rare disorder. Factors that may portend an unfavorable outcome are a long disease course before the hematologic treatment and a poor hematologic response. Age at onset, level and type of M protein (κ vs λ), and severity of muscle weakness were not associated with a specific outcome. CLASSIFICATION OF EVIDENCE This study provides Class IV evidence that for patients with SLONM-MGUS, HDM-SCT increases the probability of survival and functional improvement.

Late onset and pregnancy-induced congenital thrombotic thrombocytopenic purpura.

UNLABELLED We report on our patient (case 2) who experienced a first acute episode of thrombotic thrombocytopenic purpura (TTP) at the age of 19 years during her first pregnancy in 1976 which ended in a spontaneous abortion in the 30th gestational week. Treatment with red blood cell concentrates was implemented and splenectomy was performed. After having suffered from several TTP episodes in 1977, possibly mitigated by acetylsalicylic acid therapy, an interruption and sterilization were performed in 1980 in her second pregnancy thereby avoiding another disease flare-up. Her elder sister (case 1) had been diagnosed with TTP in 1974, also during her first pregnancy. She died in 1977 during her second pregnancy from a second acute TTP episode. DIAGNOSIS In 2013 a severe ADAMTS13 deficiency of <10% without detectable ADAMTS13 inhibitor was repeatedly found. Investigation of the ADAMTS13 gene showed that the severe ADAMTS13 deficiency was caused by compound heterozygous ADAMTS13 mutations: a premature stop codon in exon 2 (p.Q44X), and a missense mutation in exon 24 (p.R1060W) associated with low but measurable ADAMTS13 activity. CONCLUSION Genetic analysis of the ADAMTS13 gene is important in TTP patients of all ages if an ADAMTS13 inhibitor has been excluded.

15q26.1 microdeletion encompassing only CHD2 and RGMA in two adults with moderate intellectual disability, epilepsy and truncal obesity

We report two patients with microdeletions in chromosomal subdomain 15q26.1 encompassing only two genes, CHD2 and RGMA. Both patients present a distinct phenotype with intellectual disability, epilepsy, behavioral issues, truncal obesity, scoliosis and facial dysmorphism. CHD2 haploinsufficiency is known to cause intellectual disability and epilepsy, RGMA haploinsufficiency might explain truncal obesity with onset around puberty observed in our two patients.

Clinical importance of risk variants in the dihydropyrimidine dehydrogenase gene for the prediction of early-onset fluoropyrimidine toxicity.

We investigated the clinical relevance of dihydropyrimidine dehydrogenase gene (DPYD) variants to predict severe early-onset fluoropyrimidine (FP) toxicity, in particular of a recently discovered haplotype hapB3 and a linked deep intronic splice site mutation c.1129-5923C>G. Selected regions of DPYD were sequenced in prospectively collected germline DNA of 500 patients receiving FP-based chemotherapy. Associations of DPYD variants and haplotypes with hematologic, gastrointestinal, infectious, and dermatologic toxicity in therapy cycles 1-2 and resulting FP-dose interventions (dose reduction, therapy delay or cessation) were analyzed accounting for clinical and demographic covariates. Fifteen additional cases with toxicity-related therapy delay or cessation were retrospectively examined for risk variants. The association of c.1129-5923C>G/hapB3 (4.6% carrier frequency) with severe toxicity was replicated in an independent prospective cohort. Overall, c.1129-5923G/hapB3 carriers showed a relative risk of 3.74 (RR, 95% CI = 2.30-6.09, p = 2 × 10(-5)) for severe toxicity (grades 3-5). Of 31 risk variant carriers (c.1129-5923C>G/hapB3, c.1679T>G, c.1905+1G>A or c.2846A>T), 11 (all with c.1129-5923C>G/hapB3) experienced severe toxicity (15% of 72 cases, RR = 2.73, 95% CI = 1.61-4.63, p = 5 × 10(-6)), and 16 carriers (55%) required FP-dose interventions. Seven of the 15 (47%) retrospective cases carried a risk variant. The c.1129-5923C>G/hapB3 variant is a major contributor to severe early-onset FP toxicity in Caucasian patients. This variant may substantially improve the identification of patients at risk of FP toxicity compared to established DPYD risk variants (c.1905+1G>A, c.1679T>G and c.2846A>T). Pre-therapeutic DPYD testing may prevent 20-30% of life-threatening or lethal episodes of FP toxicity in Caucasian patients.