LZTR1 loss-of-function variants associated with café au lait macules with or without freckling.

Pathogenic variants in the leucine zipper-like transcriptional regulator 1 gene (LZTR1) have been identified in schwannomatosis and Noonan syndrome. Here, we expand the phenotype spectrum of LZTR1 variants. We identified four loss-of-function heterozygous LZTR1 variants in five children with multiple café au lait macules and one adult with multiple café au lait macules and axillar freckling, by applying gene panel analysis in four families. The three LZTR1 variants, namely, c.184del/p.Glu62Serfs*39, c.1927C < T/p.Gln643*, and c.857_858delinsT/p.Gly286Valfs*65, were novel, whereas the variant c.1018C > T/ p.Arg340* had been previously reported in a patient with schwannomatosis. Similar to what is known from other LZTR1-associated conditions, penetrance of the skin manifestations was reduced in two carriers of the familial variants. Our study expands the LZTR1 phenotype to the presence of isolated café au lait macules with or without freckling. Thus, variants in the LZTR1 gene should be considered in patients with multiple café au lait macules.

[Clinical acute and emergency medicine curriculum-focus on internal medicine : Recommendations for advanced training in internal medicine in the emergency department]. / Curriculum Klinische Akut- und Notfallmedizin ­ Schwerpunkt Innere Medizin : Empfehlung zu Weiterbildungsinhalten der Inneren Medizin in der Notaufnahme.

In Germany, physicians qualify for emergency medicine by combining a specialty medical training-e.g. internal medicine-with advanced training in emergency medicine according to the statutes of the State Chambers of Physicians largely based upon the Guideline Regulations on Specialty Training of the German Medical Association. Internal medicine and their associated subspecialities represent an important column of emergency medicine. For the internal medicine aspects of emergency medicine, this curriculum presents an overview of knowledge, skills (competence levels I-III) as well as behaviours and attitudes allowing for the best treatment of patients. These include general aspects (structure and process quality, primary diagnostics and therapy as well as indication for subsequent treatment; resuscitation room management; diagnostics and monitoring; general therapeutic measures; hygiene measures; and pharmacotherapy) and also specific aspects concerning angiology, endocrinology, diabetology and metabolism, gastroenterology, geriatric medicine, hematology and oncology, infectiology, cardiology, nephrology, palliative care, pneumology, rheumatology and toxicology. Publications focussing on contents of advanced training are quoted in order to support this concept. The curriculum has primarily been written for internists for their advanced emergency training, but it may generally show practising emergency physicians the broad spectrum of internal medicine diseases or comorbidities presented by patients attending the emergency department.

[Hypercholesterolemia - who, when, how to treat?] / Hypercholesterinämie ­ Wen, wann, wie behandeln?

In recent years, clinical scientific data on LDL cholesterol and atherosclerosis has led to lowering of LDL-C targets and the expansion of the indication for lipid drug therapy to larger populations or patients. The calculators SCORE2 and SCORE-OP were newly developed to calculate the cardiovascular risk in primary prevention. When assessing the cardiovascular risk of patients, in addition to e.g., pre-existing cardiovascular disease, familial hypercholesterolaemia and type II diabetes, type I diabetes, diabetic complications, renal insufficiency and subclinical arteriosclerosis are also considered. Statins are the basic therapy for hypercholesterolemia. Alternative medication are ACL inhibitors e.g., Bempedoic acid and Inclisiran which represent new drug therapy options for statin intolerance. Nevertheless, a dietary intervention belongs at the beginning of every lipid-lowering therapy.

The German CaRe high registry for familial hypercholesterolemia - Sex differences, treatment strategies, and target value attainment.

Background and aims: Familial hypercholesterolemia (FH) is among the most common genetic disorders in primary care. However, only 15% or less of patients are diagnosed, and few achieve the goals for low-density lipoprotein cholesterol (LDL-C). In this analysis of the German Cascade Screening and Registry for High Cholesterol (CaRe High), we examined the status of lipid management, treatment strategies, and LDL-C goal attainment according to the ESC/EAS dyslipidemia guidelines. Methods: We evaluated consolidated datasets from 1501 FH patients diagnosed clinically and seen either by lipid specialists or general practitioners and internists. We conducted a questionnaire survey of both the recruiting physicians and patients. Results: Among the 1501 patients, 86% regularly received lipid-lowering drugs. LDL-C goals were achieved by 26% and 10% of patients with atherosclerotic cardiovascular disease (ASCVD) according to the 2016 and 2019 ESC/EAS dyslipidemia guidelines, respectively. High intensity lipid-lowering was administered more often in men than in women, in patients with ASCVD, at higher LDL-C and in patients with a genetic diagnosis of FH. Conclusions: FH is under-treated in Germany compared to guideline recommendations. Male gender, genetic proof of FH, treatment by a specialist, and presence of ASCVD appear to be associated with increased treatment intensity. Achieving the LDL-C goals of the 2019 ESC/EAS dyslipidemia guidelines remains challenging if pre-treatment LDL-C is very high.

Characterisation and differential diagnosis of neurological complications in adults with phenylketonuria: literature review and expert opinion.

OBJECTIVE: Phenylketonuria (PKU) is a rare inherited metabolic disorder characterised by elevated phenylalanine (Phe) concentrations that can exert neurotoxic effects if untreated or upon treatment discontinuation. This systematic review supported by expert opinion aims to raise awareness among the neurological community on neurological complications experienced by adults with PKU (AwPKU). METHODS: The PubMed database was searched for articles on neurological signs and symptoms in AwPKU published before March 2022. In addition, two virtual advisory boards were held with a panel of seven neurologists and two metabolic physicians from Germany and Austria. Findings are supported by three illustrative patient cases. RESULTS: Thirty-nine articles were included. Despite early diagnosis and treatment, neurological signs and symptoms (e.g. ataxia, brisk tendon reflexes, tremor, visual impairment) can emerge in adulthood, especially if treatment has been discontinued after childhood. In PKU, late-onset neurological deficits often co-occur with cognitive impairment and psychiatric symptoms, all of which can be completely or partially reversed through resumption of treatment. CONCLUSION: Ideally, neurologists should be part of the PKU multidisciplinary team, either to bring lost to follow-up patients back to clinic or to manage symptoms in referred patients, considering that symptoms are often reversible upon regaining metabolic control. The current findings have been combined in a leaflet that will be disseminated among neurologists in Germany and Austria to create awareness.

Management, vaccination status and COVID-19 morbidity of patients with Gaucher disease in Germany during the COVID-19 pandemic.

BACKGROUND: Continuation of standard management of Gaucher disease (GD) has been challenging during the COVID-19 pandemic, resulting in infrequent/missed infusions and follow-up appointments. Little data are available on the consequences of these changes and on the SARS-CoV-2 vaccinations in German GD patients. METHODS: A survey with 22 questions about GD management during the pandemic was sent to 19 German Gaucher centres. It was answered by 11/19 centres caring for 257 GD patients (almost ¾ of the German GD population); 245 patients had type 1 and 12 had type 3 GD; 240 were ≥ 18 years old. RESULTS: Monitoring intervals were prolonged in 8/11 centres from a median of 9 to 12 months. Enzyme replacement therapy (ERT) was changed to home ERT in 4 patients and substituted by oral substrate reduction therapy (SRT) in 6 patients. From March 2020 to October 2021, no serious complications of GD were documented. Only 4 SARS-CoV-2 infections were reported (1.6%). Two infections were asymptomatic and two mild; all occurred in adult type 1, non-splenectomized patients on ERT. Vaccination rate in adult GD was 79.5% (95.3% mRNA vaccines). Serious vaccination complications were not reported. CONCLUSIONS: The COVID-19 pandemic has lowered the threshold for switching from practice- or hospital-based ERT to home therapy or to SRT. No major GD complication was documented during the pandemic. Infection rate with SARS-CoV-2 in GD may rather be lower than expected, and its severity is mild. Vaccination rates are high in GD patients and vaccination was well tolerated.

[Triglycerides - assessment as risk factor and therapeutic goals]. / Triglyzeride ­ Aktuelle Bewertung als Risikomarker und Therapieziele.

Elevated triglycerides and their lipidological consequences (small, dense LDL, residual particles (remnants), reduced HDL cholesterol) are an important and independent cardiovascular risk factor. Particularly in diabetes mellitus, hypertriglyceridemia is regarded as the main cause of high cardiovascular morbidity and mortality; very high triglyceride levels can cause acute pancreatitis. This article provides an overview of the current scientific status of the pathogenesis and clinical significance of hypertriglyceridemia.

Photosensitivity and cGAS-Dependent IFN-1 Activation in Patients with Lupus and TREX1 Deficiency.

The exonuclease TREX1 safeguards the cells against DNA accumulation in the cytosol and thereby prevents innate immune activation and autoimmunity. TREX1 mutations lead to chronic DNA damage and cell-intrinsic IFN-1 response. Associated disease phenotypes include Aicardi‒Goutières syndrome, familial chilblain lupus, and systemic lupus erythematosus. Given the role of UV light in lupus pathogenesis, we assessed sensitivity to UV light in patients with lupus and TREX1 mutation by phototesting, which revealed enhanced photosensitivity. TREX1-deficient fibroblasts and keratinocytes generated increased levels of ROS in response to UV irradiation as well as increased levels of 8-oxo-guanine lesions after oxidative stress. Likewise, the primary UV-induced DNA lesions cyclobutane pyrimidine dimers were induced more strongly in TREX1-deficient cells. Further analysis revealed that single-stranded DNA regions, frequently formed during DNA replication and repair, promote cyclobutane pyrimidine dimer formation. Together, this resulted in a strong UV-induced DNA damage response that was associated with a cGAS-dependent IFN-1 activation. In conclusion, these findings link chronic DNA damage to photosensitivity and IFN-1 production in TREX1 deficiency and explain the induction of disease flares on UV exposure in patients with lupus and TREX1 mutation.

[Pathophysiological principles of dyslipoproteinaemia]. / Pathophysiologische Prinzipien von Dyslipoproteinämien.

The effective reduction of atherogenic lipoproteins has contributed to the rate of atherosclerosis-related cardiovascular complications being approximately halved over the last 50 years. Nevertheless, cardiovascular disease will be the leading cause of death worldwide in the coming years. The focus of this review is on the clinical significance of the pathophysiology of changes in lipid and lipoprotein metabolism. Elevated levels of atherogenic lipoproteins are a causal risk factor for atherosclerotic cardiovascular disease. Primary forms of hypercholesterolaemia have a significantly higher ASCVD risk because of the already lifelong LDL elevation (higher cumulative LDL exposure for the vessel wall). Secondary changes in lipid and lipoprotein metabolism (e. g. in diabetes or hypothyroidism) must be excluded or treated. Regulatory key steps in the pathophysiology of lipid metabolism and atherosclerotic plaque are "drug targets" for existing and new lipid and lipoprotein modifying therapies.

[Diabetic Dyslipidemia]. / Dyslipidämie bei Diabetes.

Diabetic dyslipidemia is a major cause of the increased cardiovascular risk in diabetes. This lipid disorder is characterized by increased plasma triglycerides, increased remnant particles of triglyceride-rich lipoproteins, small dense LDL particles and reduced HDL cholesterol. The main pathogenetic triggers are obesity and insulin resistance. In addition to lifestyle measures, statins, ezetimibe and eventually PCSK9 inhibitors are available to treat diabetic dyslipidemia and to reduce the cardiovascular risk. Fibrates and omega-3 fatty acids currently do not play a significant therapeutic role. A consistent and target-oriented therapy of diabetic dyslipidemia is a prerequisite for a cardiovascular risk reduction in patients with diabetes, which has been well proven in clinical studies.

Deficient knowledge in adult Turner syndrome care as an incentive to found Turner centers in Germany.

OBJECTIVE: Turner syndrome (TS) is characterized by the complete or partial loss of the second sex chromosome and associated with a wide range of clinical manifestations. We aimed to assess the medical care of adult patients with TS in Germany. DESIGN: Retrospective multicenter observational study. METHODS: Data were collected from medical records of 258 women with TS treated between 2001 and 2017 in five non-university endocrinologic centers in Germany. RESULTS: Mean age was 29.8 ± 11.6 years, mean height 152 ± 7.7 cm, and mean BMI 26.6 ± 6.3 kg/m2. The karyotype was known in 50% of patients. Information on cholesterol state, liver enzymes, and thyroid status was available in 81-98% of women with TS; autoimmune thyroiditis was diagnosed in 37%. Echocardiography was performed in 42% and cardiac MRI in 8.5%, resulting in a diagnosis of cardiovascular disorder in 28%. Data on growth hormone therapy were available for 40 patients (15%) and data concerning menarche in 157 patients (61%). CONCLUSION: In 258 women with TS, retrospective analysis of healthcare data indicated that medical management was focused on endocrine manifestations. Further significant clinical features including cardiovascular disease, renal malformation, liver involvement, autoimmune diseases, hearing loss, and osteoporosis were only marginally if at all considered. Based on this evaluation and in accordance with recent guidelines, we compiled a documentation form facilitating the transition from pediatric to adult care and further medical management of TS patients. The foundation of Turner Centers in March 2019 will improve the treatment of TS women in Germany.

Survey to estimate the prevalence of type 2 diabetes mellitus in hospital patients in Germany by systematic HbA1c measurement upon admission.

OBJECTIVES: The objective of this survey was to estimate the prevalence of type 2 diabetes mellitus (T2DM) in hospitalised patients ≥55 years based on routine HbA1c measurement upon admission, using the diagnosis algorithm according to the German National Diabetes Care Guideline. DESIGN: Non-interventional survey. SETTING: Four German maximum care hospitals. POPULATION: Consecutive patients ≥55 years of age admitted to hospital. MAIN OUTCOME MEASURES: Participating hospitals measured HbA1c upon admission and applied the algorithm for diagnosing T2DM per the clinical recommendations of the American Diabetes Association (ADA) and the German National Diabetes Care Guideline as part of the clinical routine and allocated patients to three diagnostic categories: T2DM, increased risk for T2DM, no T2DM. RESULTS: Between Oct 2014 and May 2015, the survey documented data from 6092 patients; the analyses included 5820 patients fulfilling validity criteria (95.5%). Of these, 1906 (32.7%) had a known history of T2DM. Among the 3914 remaining patients, 2181 had no T2DM (55.8%), 1180 an increased risk for T2DM (30.1%) and 553 unrecognised T2DM (14.1%; 95% CI: 13.1%-15.3%). The overall prevalence of known and unrecognised T2DM was 42.3% (95% CI: 41.0%-43.5%). Patients with previously unrecognised T2DM were admitted to hospital predominantly for cardiac disorders (21.9%), nervous system disorders such as cerebral infarction (15.0%) and infections/infestations (13.4%). CONCLUSIONS: This survey revealed an overall prevalence of known and unrecognised T2DM of more than 40%. Among patients with unrecognised T2DM on admission, the prevalence of T2DM was 14%. These data indicate that systematic documentation of T2DM in in-patients is clinically useful. Hospitals should consider using the diagnostic algorithm and to streamline pathways of care to secure adequate care considering patients' diabetic risk profiles, and to manage related additional costs.

[Hyperlipidemia: What role do PCSK9 inhibitors play?] / Hyperlipidämie: Welche Rolle spielen PCSK9-Inhibitoren?

PCSK9 inhibitors are a new and safe option of lowering LDL cholesterol. This article summarizes current recommendations for the use of PCSK9 inhibitors. Statins and ezetimibe are still the basis of cholesterol-lowering therapy. Through their use, the largest proportion of patients can be adequately treated. PCSK9 inhibitors should be used in patients at very high cardiovascular risk if, despite the maximum tolerated statin/ezetimibe therapy, an LDL-C reduction of more than 50 % would be needed to achieve the recommended LDL-C target. The use in patients with familial hypercholesterolemia is usually carried out according to this scheme as well. For statin intolerance, PCSK9 inhibitors should be considered in patients at very high cardiovascular risk who have not tolerated low doses of at least two different statins/ezetimibe.

Cold-Induced Brown Adipose Tissue Activity Alters Plasma Fatty Acids and Improves Glucose Metabolism in Men.

Context: Mounting evidence suggests beneficial effects of brown adipose tissue (BAT) activation on glucose and lipid metabolism in humans. It is unclear whether cold-induced BAT activation affects not only insulin sensitivity but also insulin secretion. Likewise, the role in clearing circulating fatty acids (FAs) has not been fully explored. Objective: Exploring the effects of cold-induced BAT activation on insulin sensitivity and secretion, as well as on plasma FA profiles. Design: Fifteen healthy men participated in a cross-balanced repeated within-subject study with two experimental conditions. Subjects were exposed to thermoneutrality (22°C) and to moderate cold (18.06°C, shivering excluded) by use of a water-perfused whole body suit. Cold-induced BAT activation was quantified by [18F]-fluorodeoxyglucose positron emission tomography-computed tomography in a subset of volunteers. A Botnia clamp procedure was applied to determine pancreatic first phase insulin response (FPIR) and insulin sensitivity. Hormones and metabolites, including 26 specific plasma FAs, were sampled throughout the experiment. Results: Cold exposure induced BAT activity. Plasma noradrenaline and dopamine concentrations increased in response to cold. Peripheral glucose uptake and insulin sensitivity significantly improved by ∼20%, whereas FPIR remained stable. Lignoceric acid (C24:0) concentrations increased, whereas levels of eicosanoic acid (C20:1n9), nervonic acid (C24:1n9), and behenic acid (C22:0) decreased. Conclusions: Cold-exposure induces sympathetic nervous system activity and BAT metabolism in humans, resulting in improved glucose metabolism without affecting pancreatic insulin secretion. In addition, BAT activation is associated with altered circulating concentrations of distinct FAs. These data support the concept that human BAT metabolism significantly contributes to whole body glucose and lipid utilization in a coordinated manner.