Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism caused by deficiency in the enzyme phenylalanine hydroxylase that converts phenylalanine into tyrosine. If left untreated, PKU results in increased phenylalanine concentrations in blood and brain, which cause severe intellectual disability, epilepsy and behavioural problems. PKU management differs widely across Europe and therefore these guidelines have been developed aiming to optimize and standardize PKU care. Professionals from 10 different European countries developed the guidelines according to the AGREE (Appraisal of Guidelines for Research and Evaluation) method. Literature search, critical appraisal and evidence grading were conducted according to the SIGN (Scottish Intercollegiate Guidelines Network) method. The Delphi-method was used when there was no or little evidence available. External consultants reviewed the guidelines. Using these methods 70 statements were formulated based on the highest quality evidence available. The level of evidence of most recommendations is C or D. Although study designs and patient numbers are sub-optimal, many statements are convincing, important and relevant. In addition, knowledge gaps are identified which require further research in order to direct better care for the future.

Listeriosis is a severe foodborne infection and a notifiable disease in France. We did a nationwide prospective study to characterise its clinical features and prognostic factors. MONALISA was a national prospective observational cohort study. We enrolled eligible cases declared to the National Reference Center for Listeria (all microbiologically proven) between Nov 3, 2009, and July 31, 2013, in the context of mandatory reporting. The outcomes were analysis of clinical features, characterisation of Listeria isolates, and determination of predictors of 3-month mortality or persisting impairment using logistic regression. A hierarchical clustering on principal components was also done for neurological and bacteraemic cases. The study is registered at ClinicalTrials.gov, number NCT01520597. We enrolled 818 cases from 372 centres, including 107 maternal-neonatal infections, 427 cases of bacteraemia, and 252 cases of neurolisteriosis. Only five (5%) of 107 pregnant women had an uneventful outcome. 26 (24%) of 107 mothers experienced fetal loss, but never after 29 weeks of gestation or beyond 2 days of admission to hospital. Neurolisteriosis presented as meningoencephalitis in 212 (84%) of 252 patients; brainstem involvement was only reported in 42 (17%) of 252 patients. 3-month mortality was higher for bacteraemia than neurolisteriosis (hazard ratio [HR] 0·54 [95% CI 0·41-0·69], p<0·0001). For both bacteraemia and neurolisteriosis, the strongest mortality predictors were ongoing cancer (odds ratio [OR] 5·19 [95% CI 3·01-8·95], p<0·0001), multi-organ failure (OR 7·98 [4·32-14·72], p<0·0001), aggravation of any pre-existing organ dysfunction (OR 4·35 [2·79-6·81], p<0·0001), and monocytopenia (OR 3·70 [1·82-7·49], p=0·0003). Neurolisteriosis mortality was higher in blood-culture positive patients (OR 3·67 [1·60-8·40], p=0·002) or those receiving adjunctive dexamethasone (OR 4·58 [1·50-13·98], p=0·008). The severity of listeriosis is higher than reported elsewhere. We found evidence of a significantly reduced survival in patients with neurolisteriosis treated with adjunctive dexamethasone, and also determined the time window for fetal losses. MONALISA provides important new data to improve management and predict outcome in listeriosis. Programme Hospitalier Recherche Clinique, Institut Pasteur, Inserm, French Public Health Agency.

Cystathionine beta‐synthase (CBS) deficiency is a rare inherited disorder in the methionine catabolic pathway, in which the impaired synthesis of cystathionine leads to accumulation of homocysteine. Patients can present to many different specialists and diagnosis is often delayed. Severely affected patients usually present in childhood with ectopia lentis, learning difficulties and skeletal abnormalities. These patients generally require treatment with a low‐methionine diet and/or betaine. In contrast, mildly affected patients are likely to present as adults with thromboembolism and to respond to treatment with pyridoxine. In this article, we present recommendations for the diagnosis and management of CBS deficiency, based on a systematic review of the literature. Unfortunately, the quality of the evidence is poor, as it often is for rare diseases. We strongly recommend measuring the plasma total homocysteine concentrations in any patient whose clinical features suggest the diagnosis. Our recommendations may help to standardise testing for pyridoxine responsiveness. Current evidence suggests that patients are unlikely to develop complications if the plasma total homocysteine concentration is maintained below 120 μmol/L. Nevertheless, we recommend keeping the concentration below 100 μmol/L because levels fluctuate and the complications associated with high levels are so serious.

Phenylketonuria (PKU) is an autosomal recessive inherited disorder of phenylalanine metabolism caused by deficiency of the enzyme phenylalanine hydroxylase that converts phenylalanine into tyrosine. Untreated, PKU results in elevated phenylalanine levels in blood and brain, which cause severe intellectual disability, epilepsy and behavioural problems. For this first revision of the European PKU Guidelines previous recommendations were re-evaluated and updated according to new research findings. Twenty-one professionals were divided across four working groups and supported by a coordinator and chair. In addition to an update of the previous 70 recommendations, 20 new topics were included, resulting in a total of 87 statements in this first revision of the guidelines. Research publications were reviewed up until September 2022. Evidence was graded as high, moderate, low, very low or expert opinion and the recommendations were graded conditional or strong according to GRADE methodology. All recommendations were discussed during 14 plenary online or in person meetings. Recommendations were accepted if more than 75 % of the professionals were in agreement. When recommendations were not amended, the text reported in the European guidelines of 2017 remains valid.