Serial Number Karall
Kym Cavrak
Study design: Twenty PA patients diagnosed through NBS were compared to 35 patients diagnosed by selective metabolic screening (SMS) prompted by clinical findings, family history, or routine laboratory test results. Clinical and biochemical data of patients from 16 metabolic centers in Germany, Austria, and Switzerland were evaluated retrospectively. Additionally, assessment of the intelligent quotient (IQ) was performed. In a second step, the number of PA patients who have died within the past 20 years was estimated based on information provided by the participating metabolic centers.
Results: Patients diagnosed through NBS had neither a milder clinical course regarding the number of metabolic crises nor a better neurological outcome. Among NBS patients, 63% were already symptomatic at the time of diagnosis, and
Conclusion: Early diagnosis of PA through NBS seems to be associated with a lower mortality rate. However, no significant benefit could be shown for surviving patients with regard to their clinical course, including the number of metabolic crises, physical and neurocognitive development, and long-term complications.
Ketogenic diets (KDs) were initially introduced to clinical practices as alimentary approaches with the aim to control drug-resistant epilepsies. Over the decades, a large and growing body of research has addressed the antiseizure effect of various KDs, and worked out KD-based dietary regimens, including their acting factors and modes of action. KDs have also appeared in weight loss therapies. Therapy control, particularly at initiation, happens through regular blood analysis and control of urine ketone levels. However, there is a lack of fast, reliable, and preferably non-invasive methods to accomplish this. The detection of exhaled breath constituents may offer a solution. The exhaled breath contains hundreds of volatile organic compounds (VOCs), which can be modified by diet. VOC detection technology has resulted in low-cost sensors that can facilitate the self-monitoring of patients in the future if reliable breath markers are available. Therefore, it is of interest to investigate the composition of exhaled breath in children on KDs. Twenty-two pediatric patients between 4 and 18 years of age were recruited in this study. Eleven of them received a KD and suffered from epilepsy, with the exception of one child, who was admitted to a weight-reduction therapy. The control group involved 11 patients with neurological disorders but not on KD. Breath volatiles were analyzed using gas chromatography mass spectrometry (GC-MS) after preconcentration of the analytes on needle traps (NTs). We found that the breath concentrations of a number of VOCs, namely acetaldehyde, acetone, 2-methylfuran, methyl-vinyl-ketone, and 2-pentanone were significantly elevated in the breath of children on a KD in comparison to their control counterparts. Interestingly, breath ethanol was lower in patients on a KD than in non-KD patients. Association studies revealed an interrelationship among (i) lipid parameters and ketone bodies, (ii) methacrolein, methyl-vinyl-ketone, and high-density lipoprotein, as well as (iii) methyl-vinyl-ketone, acetone, and 2-pentanone, thus raising the possibility of a common metabolic source. The duration of diet was positively and negatively associated with breath acetone and breath ethanol, respectively. Some of the changes were linked to β-oxidation, but there are uncertainties in regard to metabolic sources of other metabolites. Lipid peroxidation and alteration of intestinal microbial composition may also be involved in the changes of VOC profiles during KD. Since lipids used for metabolism during KD originate from external sources, the processes occurring cannot simply be compared to and deduced from changes appearing in starvation; however, lipid mobilization is also evident in starvation. To find reliable and sensitive VOC markers that are linked to the respective ketogenic regimen, further investigations are needed to reveal the metabolic background.
My research focuses in understanding secondary energy deficiency in individuals with the propionate organic acidemias such as Methylmalonic Acidemia and Propionic Acidemia. People with these disorders have a number of long term complication including myopathy, arrhythmias, diabetes, metabolic strokes and cardiomyopathies which we think is related to long term energy deficiencies. They also do poorly when they need to increase their cellular energy levels during illness or other stressful situations with metabolic decompensations. My basic science laboratory has examined cell lines from patients with propionate organic acidemias and controls and has identified a different responses to low and normal glucose conditions on a RNA level. However, as a population, this change in RNA expression does not pinpoint a particular biochemical pathway beyond a general implication of mitochondrial systems. Clinically individuals appear to have long term complications in high energy organs. As a result, I am now focusing my molecular biology and biochemical studies on examining the intersection of the propionate pathway with the Krebs cycle by looking for sites of interaction and potential moving towards understanding why these patients have such energy deficiency complications. In addition, I am working presently working with our collaborators at HemoShear to design and utilize a liver model system which allows validation and identification of possible therapeutics to treat these disorders with high mortality and morbidity. I also have established relationships with collaborators around the world through my work on guidelines treatment of propionate pathway disorders with whom we can obtain additional tissue if necessary.
Like our recently published results on phospholipid and acylcarnitine metabolomic examinations, this work is a subwork of the main study protocol (Trial registration number: ClinicalTrials.gov Identifier NCT03886935)9.
A lecture with 500 students is accompanied by a training session. Teachers publish the assignment names and the number of achievable points per assignment. Each week the students work on the assignments and use the checkmark module to inform the teacher in advance about the assignments that they managed to complete.
In the classroom session where individual students present their solutions, teachers can use a printed copy of the tabular overview to verify the indicated performance. After the training session there is the option of automatic grading on the basis of the assignments checked.
Between July 2012 and June 2015, fifty patients (Germany: 39, Austria: 7, Switzerland: 4) with newly diagnosed UCDs were reported and later confirmed resulting in an estimated cumulative incidence of 1 in 51,946 live births. At diagnosis, thirty-nine patients were symptomatic and 11 asymptomatic [10 identified by newborn screening (NBS), 1 by high-risk-family screening (HRF)]. The majority of symptomatic patients (30 of 39 patients) developed HE with (n = 25) or without coma (n = 5), 28 of them with neonatal onset. Despite emergency treatment 15 of 30 patients with HE already died during the newborn period. Noteworthy, 10 of 11 patients diagnosed by NBS or HRF remained asymptomatic. Comparison with the European registry and network for intoxication type metabolic diseases (E-IMD) demonstrated that cross-national surveillance identified a higher number of clinically severe UCD patients characterized by earlier onset of symptoms, higher peak ammonium concentrations in plasma and higher mortality.
Incidence of definite cases with UCDs were estimated from the number of live births in Germany (n = 2,102,583), Austria (n = 242,351) and Switzerland (n = 252,380) during the study period. Cases reported could be born before the start of the common study period (1st July 2012) and could therefore belong to earlier birth cohorts, whereas affected individuals born between 1st July 2012 to 30th June 2015 could have remained asymptomatic during the surveillance period. Furthermore, capture-recapture analysis was used as previously described [26, 27]. This methodology was designed to estimate population sizes on the basis of the proportion of individuals (re)captured by two or more sources. The Chapman estimate of the true number of cases has been calculated as
The major results of this cross-border study from Germany, Austria and Switzerland are that (1) the estimated cumulative incidence of UCD patients under 16 years of age is about 1 in 52,000 live births, (2) registries and observational studies focusing on the follow-up of surviving patients are likely to underestimate the number of UCD patients with a severe phenotype, (3) despite increased awareness for UCDs, improved NICU care, and evidence-based guidelines, the mortality rate of EO patients is still high, in particular for CPS1-D and mOTC-D, and (4) UCD patients identified by NBS had a favourable short-term outcome.
This study places the estimated incidence or UCDs below 16 years of age at about 1 in 52,000 live births in Germany, Austria and Switzerland ranging from about 1 in 63,000 (Switzerland) to 1 in 35,000 live births (Austria). Assuming that the same cumulative incidence is found in the 28 EU Member States, at least 100 new UCD patients are to be expected each year (2015: 5,091,295 live births, Similar estimated incidences have been reported in three previous publications from the US (1 in 35,000 live births; [13]), Japan (1 in 50,000 live births; [11]) and Finland (1 in 39,000 live births; [31]). A previous report from the US with a cumulative incidence of 1 in 8000 live births [12], however, is likely to over-estimate the total incidence of UCD patients. Although our study provides the first robust estimation of incidence for UCDs in Germany, Austria and Switzerland, we assume that the true incidence is under-estimated for the following reasons: First, the number of UCD patients who have not been reported or in whom the diagnosis has been missed is unknown. Second, this study has excluded UCD patients diagnosed after age 16 years, probably around 20%. The risk of missing UCD patients is still a relevant source of bias since patients with a fulminant phenotype might die early and undiagnosed and later manifestations can be unspecific. This notion is supported by the fact that 15 of 30 patients with HE in our study died shortly after the manifestation of symptoms. A recent meta-analysis evaluating 29 studies published between 1978 and 2014 with 1542 participants in the US, Japan and Europe confirms the overall high risk of neonatal death in UCD patients with EO disease manifestation, except for ASL deficiency [7].
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