IntroductionInfertility treatment prior to 1978 proved challenging to both patients and their physicians. The birth of Louise Brown through in vitro fertilization (IVF) was the result of decades-long research in both the basic and clinical sciences and followed hundreds of failed attempts at human IVF [1]. With IVF's successful introduction, related and supportive technologies soon emerged including IVF and the use of donor eggs, cryopreservation and frozen embryo transfer (FET), gamete intra-fallopian transfer (GIFT), zygote intra-fallopian transfer (ZIFT), intra-cytoplasmic sperm injection (ICSI) and less invasive procedures aided by enhancements in equipment, such as transvaginal ultrasound guided oocyte retrieval. It may be hard to recall now that technologies such as IVF, the use of donor eggs, and ICSI were, at first, controversial but so successful in improving outcomes that they were most often adopted into clinical practice without any demonstrated benefit in randomized controlled clinical trials [2].Despite the technical enhancements introduced over time that have resulted in unprecedented cumulative IVF pregnancy rates, a significant percentage of women continue to fail repeated attempts at IVF. While cumulative pregnancy rates increase with increasing cycle number (approximately 75% of women will achieve a live birth by the sixth IVF cycle), per cycle IVF success rates tend to decrease with increasing cycle number. The age blended probability of a live birth is approximately 25% in a woman's first cycle (range [9-33%]), 20% per cycle during her second and third cycles and decreases to less than 20% per cycle during cycles four through six [3]. IVF success rates drop dramatically as women age. Therefore, a patient population exists that will fail to respond to all lines of treatment, including repeated cycles of IVF. For this patient population, IVF using a donor egg or adoption have, until recently, represented the only remaining option(s) [4].The causes of repeated IVF failure are often complex and poorly understood. In contrast, the decrease in fertility observed in women with increasing maternal age has been attributed to a decline in egg and embryo quality as well as increased rates of aneuploidy [5]. Other causes of poor egg/embryo quality beyond age-related factors include medical conditions such as type II diabetes, obesity, polycystic ovary syndrome (PCOS), as well as other genetic and environmental factors [6,7]. Over the past 25 years, an increasing body of clinical and preclinical data has demonstrated that the decline in egg quality is largely due to a reduction in energy production [8][9][10][11]. In the 1990s, there were attempts at improving egg and embryo quality by injecting cytoplasm from young,
BACKGROUND The disease gene for hypertrophic cardiomyopathy (HCM) has been identified as the beta-myosin heavy chain (beta-MHC) gene in some HCM families. We describe extensive clinical evaluations in two kindreds with two distinct point mutations in the beta-MHC gene. METHODS AND RESULTS We used single-strand confirmation polymorphism (SSCP) gel analysis of polymerase chain reaction-amplified products capturing each of the 40 beta-MHC gene exons to identify distinct missense mutations in two HCM kindreds. Clinical, ECG, and echocardiographic studies were performed in the two kindreds: kindred 2755 with amino acid 908Leu----Val mutation and kindred 2002 with amino acid 403Arg----Gln mutation. The morphological appearances of HCM were similar in these two kindreds. However, the two kindreds differed with respect to disease penetrance, age of onset of disease, and incidence of premature sudden death. Twelve of 31 adults (greater than or equal to 17 years) with the disease gene in kindred 2755 did not have left ventricular hypertrophy (LVH), and only five of these had ECG abnormalities. Thus, the disease penetrance in adults with this mutation was only 61%. None of 11 children aged less than 16 years had LVH. The 908 mutation was associated with a low incidence of cardiac events: Only two sudden deaths and one syncope occurred in 46 individuals with the mutant allele. In contrast, LVH was present in all 11 adults in kindred 2002 with the 403 mutation (100% disease penetrance). In addition, three of four affected children were symptomatic and had clinical evidence of HCM. The disease in this kindred was severe and resulted in six premature sudden deaths. Seven additional patients had syncope or presyncope. CONCLUSIONS In some kindreds, the HCM disease gene is more prevalent than indicated by echocardiography and ECG. Some point mutations may be associated with a more malignant prognosis. Preclinical identification of children with mutations associated with a high incidence of sudden death and syncope provides the opportunity to evaluate efficacy of early therapeutic interventions.
Enzyme replacement therapy is the standard of care for symptomatic Gaucher disease. Velaglucerase alfa is a human -glucocerebrosidase produced in a wellcharacterized human cell line. A 9-month phase 1/2 open-label, single-center trial and ongoing extension study were conducted to evaluate safety and efficacy of velaglucerase alfa. Twelve symptomatic adult type 1 Gaucher patients (intact spleens) received velaglucerase alfa (60 U/kg per infusion) during phase 1/2. An extension study was offered to patients completing the trial; step-wise dose reduction (to 30 U/kg per infusion) was instituted. Eleven patients completed phase 1/2; 10 entered the extension; 9 patients reached 39 months of extension. No drug-related serious adverse events or withdrawals, and no antibodies were observed. Home therapy was successfully implemented during the extension. Statistically significant improvements (P < .004) were noted in mean percentage change from baseline to 9 months and baseline to 48 months for hemoglobin (؉19.2%, ؉21.7%, respectively), platelet counts (؉67.6%, ؉157.8%, respectively), normalized liver volume (؊18.2%, ؊42.8%, respectively), and normalized spleen volume (؊49.5%, ؊79.3%, respectively).
Hypertrophic cardiomyopathy (HCM) is an important cause of sudden death in apparently healthy young individuals. In less than half of kindreds with HCM, the disease is linked to the ,B-myosin heavy-chain gene locus (MYH7). We have recently described two missense MYH7 gene mutations [Arg-403 to Gin (R403Q) and Leu-908 to Val (L908V)J and found that the mutant message is present in skeletal muscle (soleus) and that the mutant 8-myosin obtained from soleus muscle has abnormal in vitro motility activity. Having identified a second kindred with the R403Q mutation, and 3 other kindreds with two additional mutations (G741R and G256E), we performed histochemical analysis of soleus muscle biopsies from 25 HCM patients with one of these four mutations. Light microscopic examination of the NADH-stained biopsies revealed the presence of central core disease (CCD) of skeletal muscle, a rare autosomal dominant nonprogressive myopathy characterized by a predominance of type I "slow" fibers and an absence of mitochondria in the center of many type I fibers. CCD was present in 10 of 13 patients with the L908V mutation, 5 of 8 patients with the R403Q mutation, 1 of 3 patients with the G741R mutation, and 1 patient with the G256E mutation. Mild-to-moderate myopathic changes with muscle fiber hypertrophy were present in 16 patients. Notably, CCD was present in 2 adults and 3 children with the L908V mutation who did not have cardiac hypertrophy. In contrast, soleus muscle samples from 5 patients from 4 kindreds in which HCM was not linked to the MYH7 locus showed no myopathy or CCD. Soleus muscle biopsies from 5 control subjects also showed normal histology. This work demonstrates that (i) MYH7-associated HCM is often a disease of striated muscle but with predominant cardiac involvement and (ii) a subset of HCM patients with MYH7 gene missense mutations have CCD.
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