Two years of pegvaliase in Germany: Experiences and best practice recommendations.

BACKGROUND: In 2019, pegvaliase was approved in Europe for the treatment of phenylketonuria (PKU) in patients aged 16 years and older with blood phenylalanine (Phe) concentrations above 600 µmol/L despite prior management with available treatment options. Since its European approval, German metabolic centres have gained valuable experience, which may be of benefit to other treatment centres managing patients on pegvaliase. METHODS: After a virtual meeting that was attended by nine German physicians, three German dietitians and one American physician, a follow-up discussion was held via an online platform to develop a set of recommendations on the use of pegvaliase in Germany. Eight German physicians contributed to the follow-up discussion and subsequent consensus voting, using a modified Delphi technique. The recommendations were supported by literature and retrospectively collected patient data. RESULTS: Consensus (≥75% agreement) was achieved on 25 recommendations, covering seven topics deemed relevant by the expert panel when considering pegvaliase an option for the treatment of patients with PKU. In addition to the recommendations, a retrospective chart review was conducted in seven of the centres and included 71 patients who initiated treatment with pegvaliase. Twenty-seven patients had been treated for at least 24 months and 23 (85.2%) had achieved blood Phe ≤600 µmol/L with some degree of diet normalisation. Of these patients, 14 had physiological blood Phe on a normalised diet. CONCLUSION: The practical consensus recommendations provide guidance on the different steps along the pegvaliase journey from clinical site requirements to treatment goals and outcomes. The recommendations are intended to support less experienced European metabolic centres with the implementation of pegvaliase, emphasising that a core treatment team consisting of at least a dietitian and metabolic physician is sufficient to initiate pegvaliase and support patients during their treatment journey.

No association of SIDS with two polymorphisms in genes relevant for the noradrenergic system: COMT and DBH.

AIM: Recent research suggests that genetic variance determining the strength of noradrenergic transmitting might contribute to the aetiology of SIDS. We have typed 2 functional polymorphisms of relevance for both biosynthesis and catabolism of noradrenalin: The Val158Met single-nucleotide polymorphism (SNP) of the Catechol-O-methyl transferase gene (COMT) and the 1021C/T SNP of the dopamine dehydroxylase gene (DBH). METHODS: COMT and DBH were typed in 171 and 196 SIDS cases and 213 and 244 controls, respectively, using PCR followed by digestion with restriction enzymes. Typing was performed using a QIAxcel automatic electrophoresis unit. RESULTS: Both SNPs were in Hardy-Weinberg equilibrium, and for none of these polymorphisms, an association with SIDS could be demonstrated. The allelic frequencies of the DBH locus were C: 78.32% and T: 21.68% in SIDS and C: 77.66% and T: 22.34% in controls. For the COMT locus, the allelic frequencies were A: 51.17% and G: 48.83% in SIDS and A: 52.82% and G: 47.18% in controls. CONCLUSION: Despite these negative results, the noradrenergic system is still an attractive candidate as modulator of SIDS risk to our eyes. There are several genes involved in this system that have not been studied up to now.

Transfer of biological stains from different surfaces.

Highly sensitive short tandem repeat-based stain analysis of weak biological stains has been improved during the last years. The risk of transfer of cellular material from handled items contaminated with biological stains such as blood and saliva is of forensic relevance. Although the policemen working with crime scene items are very careful, there exists a potential risk of transfer contamination. To obtain estimates for the risk of stain transfer by handling, we have carried out an experimental study on 288 dried blood and saliva stains in two laboratories. DNA quantification showed only small amounts of DNA that could be transferred, especially from stains on paper and cotton. The saliva and especially the blood stains from plastic surface resulted in higher amounts of transferred DNA, depending on the relation of blood volume to included area: Of 192 direct transfers, 17% gave extracts above 10 pg DNA/µl, and only 3% of 96 secondary transfers resulted in amounts above 10 pg DNA/µl.

Association between a functional polymorphism in the MAOA gene and sudden infant death syndrome.

OBJECTIVES: Abnormalities in the serotonergic as well as the noradrenergic neuronal systems are believed to contribute to sudden infant death syndrome (SIDS). The X-chromosomal monoamine oxidase A (MAOA) gene is of importance for both systems and up to now no systematic study on a functional polymorphism in this gene has been performed in a sufficiently large group. METHODS: We investigated a functional MAOA promoter length polymorphism in 156 white SIDS cases and 260 gender- and age-matched control subjects by using capillary electrophoresis and fluorescence dye labeled primers. RESULTS: The pooled low-expressing alleles *2 and *3 were more frequent in the 99 male SIDS cases than in 161 male control subjects (44.4% vs 25.5%). However, there were no differences in female cases. The frequency of low expression alleles varied significantly with the age at death and were significantly more frequent in children who died between an age of 46 and 154 days than at an older age (54.9% vs 22.6%). CONCLUSIONS: Our results indicate a relationship between SIDS and the MAOA genotype in boys via influencing serotonergic and noradrenergic neurons in the brainstem. This locus is the first X-chromosomal locus associated with SIDS. Our results support the theory that abnormalities in the brainstem contribute to a subset of SIDS, at least in boys. Moreover, we argue that not only the serotonergic system but also other neuronal systems, among those the noradrenergic one, are involved.