Clinical aspects of short-chain acyl-CoA dehydrogenase deficiency

Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is an autosomal recessive inborn error of mitochondrial fatty acid oxidation. SCADD is biochemically characterized by increased C4-carnitine in plasma and ethylmalonic acid in urine. The diagnosis of SCADD is confirmed by DNA analysis showing SCAD gene mutations and/or variants. SCAD gene variants are present in homozygous form in approximately 6% of the general population and considered to confer susceptibility to development of clinical disease. Clinically, SCADD generally appears to present early in life and to be most frequently associated with developmental delay, hypotonia, epilepsy, behavioral disorders, and hypoglycemia. However, these symptoms often ameliorate and even disappear spontaneously during follow-up and were found to be unrelated to the SCAD genotype. In addition, in some cases, symptoms initially attributed to SCADD could later be explained by other causes. Finally, SCADD relatives of SCADD patients as well as almost all SCADD individuals diagnosed by neonatal screening remained asymptomatic during follow-up. This potential lack of clinical consequences of SCADD has several implications. First, the diagnosis of SCADD should never preclude extension of the diagnostic workup for other potential causes of the observed symptoms. Second, patients and parents should be clearly informed about the potential lack of relevance of the disorder to avoid unfounded anxiety. Furthermore, to date, SCADD is not an optimal candidate for inclusion in newborn screening programs. More studies are needed to fully establish the relevance of SCADD and solve the question as to whether SCADD is involved in a multifactorial disease or represents a nondisease

The natural history of classic galactosemia: lessons from the GalNet registry.

BACKGROUND Classic galactosemia is a rare inborn error of carbohydrate metabolism, caused by a severe deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT). A galactose-restricted diet has proven to be very effective to treat the neonatal life-threatening manifestations and has been the cornerstone of treatment for this severe disease. However, burdensome complications occur despite a lifelong diet. For rare diseases, a patient disease specific registry is fundamental to monitor the lifespan pathology and to evaluate the safety and efficacy of potential therapies. In 2014, the international Galactosemias Network (GalNet) developed a web-based patient registry for this disease, the GalNet Registry. The aim was to delineate the natural history of classic galactosemia based on a large dataset of patients. METHODS Observational data derived from 15 countries and 32 centers including 509 patients were acquired between December 2014 and July 2018. RESULTS Most affected patients experienced neonatal manifestations (79.8%) and despite following a diet developed brain impairments (85.0%), primary ovarian insufficiency (79.7%) and a diminished bone mineral density (26.5%). Newborn screening, age at onset of dietary treatment, strictness of the galactose-restricted diet, p.Gln188Arg mutation and GALT enzyme activity influenced the clinical picture. Detection by newborn screening and commencement of diet in the first week of life were associated with a more favorable outcome. A homozygous p.Gln188Arg mutation, GALT enzyme activity of ≤ 1% and strict galactose restriction were associated with a less favorable outcome. CONCLUSION This study describes the natural history of classic galactosemia based on the hitherto largest data set

Transatlantic combined and comparative data analysis of 1095 patients with urea cycle disorders?A successful strategy for clinical research of rare diseases

BACKGROUND: To improve our understanding of urea cycle disorders (UCDs) prospectively followed by two North American (NA) and European (EU) patient cohorts. AIMS: Description of the NA and EU patient samples and investigation of the prospects of combined and comparative analyses for individuals with UCDs. METHODS: Retrieval and comparison of the data from 1095 individuals (NA: 620, EU: 475) from two electronic databases. RESULTS: The proportion of females with ornithine transcarbamylase deficiency (fOTC-D), particularly those being asymptomatic (asfOTC-D), was higher in the NA than in the EU sample. Exclusion of asfOTC-D resulted in similar distributions in both samples. The mean age at first symptoms was higher in NA than in EU patients with late onset (LO), but similar for those with early (</= 28 days) onset (EO) of symptoms. Also, the mean age at diagnosis and diagnostic delay for EO and LO patients were similar in the NA and EU cohorts. In most patients (including fOTC-D), diagnosis was made after the onset of symptoms (59.9%) or by high-risk family screening (24.7%), and less often by newborn screening (8.9%) and prenatal testing (3.7%). Analysis of clinical phenotypes revealed that EO patients presented with more symptoms than LO individuals, but that numbers of symptoms correlated with plasma ammonium concentrations in EO patients only. Liver transplantation was reported for 90 NA and 25 EU patients. CONCLUSIONS: Combined analysis of databases drawn from distinct populations opens the possibility to increase sample sizes for natural history questions, while comparative analysis utilizing differences in approach to treatment can evaluate therapeutic options and enhance long-term outcome studies

The positive impact of a facilitated peer mentoring program on academic skills of women faculty

<p>Abstract</p> <p>Background</p> <p>In academic medicine, women physicians lag behind their male counterparts in advancement and promotion to leadership positions. Lack of mentoring, among other factors, has been reported to contribute to this disparity. Peer mentoring has been reported as a successful alternative to the dyadic mentoring model for women interested in improving their academic productivity. We describe a facilitated peer mentoring program in our institution's department of medicine.</p> <p>Methods</p> <p>Nineteen women enrolled in the program were divided into 5 groups. Each group had an assigned facilitator. Members of the respective groups met together with their facilitators at regular intervals during the 12 months of the project. A pre- and post-program evaluation consisting of a 25-item self-assessment of academic skills, self-efficacy, and academic career satisfaction was administered to each participant.</p> <p>Results</p> <p>At the end of 12 months, a total of 9 manuscripts were submitted to peer-reviewed journals, 6 of which are in press or have been published, and another 2 of which have been invited to be revised and resubmitted. At the end of the program, participants reported an increase in their satisfaction with academic achievement (mean score increase, 2.32 to 3.63; <it>P </it>= 0.0001), improvement in skills necessary to effectively search the medical literature (mean score increase, 3.32 to 4.05; <it>P </it>= 0.0009), an improvement in their ability to write a comprehensive review article (mean score increase, 2.89 to 3.63; <it>P </it>= 0.0017), and an improvement in their ability to critically evaluate the medical literature (mean score increased from 3.11 to 3.89; <it>P </it>= 0.0008).</p> <p>Conclusions</p> <p>This facilitated peer mentoring program demonstrated a positive impact on the academic skills and manuscript writing for junior women faculty. This 1-year program required minimal institutional resources, and suggests a need for further study of this and other mentoring programs for women faculty.</p

Adult cognitive outcomes in phenylketonuria:explaining causes of variability beyond average Phe levels

OBJECTIVE: The objective was to deepen the understanding of the causes of individual variability in phenylketonuria (PKU) by investigating which metabolic variables are most important for predicting cognitive outcomes (Phe average vs Phe variation) and by assessing the risk of cognitive impairment associated with adopting a more relaxed approach to the diet than is currently recommended. METHOD: We analysed associations between metabolic and cognitive measures in a mixed sample of English and Italian early-treated adults with PKU (N = 56). Metabolic measures were collected through childhood, adolescence and adulthood; cognitive measures were collected in adulthood. Metabolic measures included average Phe levels (average of median values for each year in a given period) and average Phe variations (average yearly standard deviations). Cognition was measured with IQ and a battery of cognitive tasks. RESULTS: Phe variation was as important, if not more important, than Phe average in predicting adult outcomes and contributed independently. Phe variation was particularly detrimental in childhood. Together, childhood Phe variation and adult Phe average predicted around 40% of the variation in cognitive scores. Poor cognitive scores (> 1 SD from controls) occurred almost exclusively in individuals with poor metabolic control and the risk of poor scores was about 30% higher in individuals with Phe values exceeding recommended thresholds. CONCLUSIONS: Our results provide support for current European guidelines (average Phe value = < 360 μmol/l in childhood; = < 600 μmo/l from 12 years onwards), but they suggest an additional recommendation to maintain stable levels (possibly Phe SD = < 180 μmol/l throughout life). PUBLIC SIGNIFICANCE STATEMENTS: We investigated the relationship between how well people with phenylketonuria control blood Phe throughout their life and their ability to carry out cognitive tasks in adulthood. We found that avoiding blood Phe peaks was as important if not more important that maintaining average low Phe levels. This was particularly essential in childhood. We also found that blood Phe levels above recommended European guidelines was associated with around 30% increase in the risk of poor cognitive outcomes

Effect of the Size of Clods Contained Covering Soil on the Seedling Emergence of Rice Plant Sown under Upland Field Condition

水稲農林23号を用いて, 覆土の土塊の大きさが, 乾田に深播き(覆土7cm)された個体の出芽ならびに幼苗諸器官の長さに及ぼす影響について, 覆土が3cmの場合と比較しながら検討した。乾田に播種された種子が大きい土塊で覆土されると, 覆土が3cmの場合には鞘葉の伸長が抑制される。しかし, 不完全葉はほとんどの個体で3cm以上に伸長する。また大土塊の間隙が小土塊で充足された場合は, 鞘葉および不完全葉ともに, 大土塊だけの場合よりも長くなる。その結果, すべての区の出芽率は, 播種後12日目には90%以上に達する。覆土が7cmの場合には, 覆土の土塊が大きくても, 鞘葉および不完全葉は覆土が3cmの場合よりも著しく長くなる。その結果, 第1本葉が不完全葉から抽出する位置が高められる。しかし, 鞘葉および不完全葉の伸長のみによっては出芽することはできず, 出芽するためには, 第2節間および第1本葉が伸長しなければならない。覆土の土塊が大きい場合には, 第2節間の伸長が抑制される。と同時に, 出芽までの間に幼芽の伸長を妨げる土塊の数も多くなるので, 出芽率は著しく低下する。しかし, 大土塊の間隙が小さい土塊によって充足されると, 第2節間が著しく長くなり, 第1本葉をおしあげる。その結果, 出芽率は単一土塊の場合に比べて著しく高まる。以上の結果と土壌中への光の侵入量との関係について, 若干考察した。 / This experiment was carried out to clarify the effects of size of clods in covering soil on the emergence and the elongation of rice seedling sown under upland field condition in pot (10cm×10cm×12cm) culture. Variety used was Norin No. 23. Seeds were covered with 3cm and 7cm depth of soil. In the case of 3cm in depth of seeding, if seeds were covered with larger clods, the elongation of coleoptile was inhibited, but the profile elongated longer than 3cm. When gaps between larger clods were filled with smaller clods, the length of coleoptile and profile became longer. Consequently, the emergence percentage of all plots reached more than 90% the 12th day after seeding. In the case of 7cm in depth of seeding, if seeds were covered with larger clods, coleoptile or profile elongated to 3 to 4cm in length, but the elongation of second internode was inhibited. As a result, the emergence percentage decreased significantly. When gaps between larger clods were filled with smaller clods, however, the length of second internode increased and first leaf was pushed up through the soil by second internode. Consequently, the emergence percentage increased significantly