Three siblings with variable degrees of neuromuscular involvement and congenital sideroblastic anemia: A peculiar phenotype and a surprise genotypic explanation.

INTRODUCTION: Congenital sideroblastic anemias (CSAs) are a group of inherited bone-marrow disorders manifesting with erythroid hyperplasia and ineffective erythropoiesis. METHODS: We describe a detailed clinical and genetic characterization of three siblings with CSA. RESULTS: Two of them had limb-girdle myopathy and global developmental delay. The two elder siblings performed allogenic hematopoietic stem-cell transplantation 5 and 3 years prior with stabilization of the hematological features. Exome sequencing in the non-transplanted sibling revealed a novel homozygous nonsense variant in SLC25A38 gene NM_017875.2:c.559C > T; p.(Arg187*) causing autosomal-recessive sideroblastic anemia type-2, and a second homozygous pathogenic previously reported variant in GMPPB gene NM_013334.3:c.458C > T; p.(Thr153Ile) causing autosomal-recessive muscular dystrophy-dystroglycanopathy type B14. With the established diagnosis, hematopoietic stem cell transplantation is now being scheduled for the youngest sibling, and a trial therapy with acetylcholine esterase inhibitors was started for the two neurologically affected patients with partial clinical improvement. CONCLUSION: This family emphasizes the importance of whole-exome sequencing for familial cases with complex phenotypes and vague neurological manifestations.

Two consecutive large outbreaks of Salmonella Muenchen linked to pig farming in Germany, 2013 to 2014: Is something missing in our regulatory framework?

In 2013, raw pork was the suspected vehicle of a large outbreak (n = 203 cases) of Salmonella Muenchen in the German federal state of Saxony. In 2014, we investigated an outbreak (n = 247 cases) caused by the same serovar affecting Saxony and three further federal states in the eastern part of Germany. Evidence from epidemiological, microbiological and trace-back investigations strongly implicated different raw pork products as outbreak vehicles. Trace-back analysis of S. Muenchen-contaminated raw pork sausages narrowed the possible source down to 54 pig farms, and S. Muenchen was detected in three of them, which traded animals with each other. One of these farms had already been the suspected source of the 2013 outbreak. S. Muenchen isolates from stool of patients in 2013 and 2014 as well as from food and environmental surface swabs of the three pig farms shared indistinguishable pulsed-field gel electrophoresis patterns. Our results indicate a common source of both outbreaks in the primary production of pigs. Current European regulations do not make provisions for Salmonella control measures on pig farms that have been involved in human disease outbreaks. In order to prevent future outbreaks, legislators should consider tightening regulations for Salmonella control in causative primary production settings.

Clinical, biochemical, and molecular profiles of three Sri Lankan neonates with pyruvate carboxylase deficiency.

Objectives: Pyruvate carboxylase, a mitochondrial enzyme, catalyses the conversion of glycolytic end-product pyruvate to tricarboxylic acid cycle intermediate, oxaloacetate. Rare pyruvate carboxylase deficiency manifests in three clinical and biochemical phenotypes: neonatal onset type A, infantile onset type B and a benign C type. The objective of this case series is to expand the knowledge of overlapping clinical and biochemical phenotypes of pyruvate carboxylase deficiency. Case presentation: We report three Sri Lankan neonates including two siblings, of two unrelated families with pyruvate carboxylase deficiency. All three developed respiratory distress within the first few hours of birth. Two siblings displayed typical biochemical findings reported in type B. The other proband with normal citrulline, lysine, moderate lactate, paraventricular cystic lesions, bony deformities, and a novel missense, homozygous variant c.2746G>C [p.(Asp916His)] in the PC gene, biochemically favoured type A. Conclusions: Our findings indicate the necessity of prompt laboratory investigations in a tachypneic neonate with coexisting metabolic acidosis, as early recognition is essential for patient management and family counselling. Further case studies are required to identify overlapping symptoms and biochemical findings in different types of pyruvate carboxylase deficiency phenotypes.

At a glance: the largest Niemann-Pick type C1 cohort with 602 patients diagnosed over 15 years.

Niemann-Pick type C1 disease (NPC1 [OMIM 257220]) is a rare and severe autosomal recessive disorder, characterized by a multitude of neurovisceral clinical manifestations and a fatal outcome with no effective treatment to date. Aiming to gain insights into the genetic aspects of the disease, clinical, genetic, and biomarker PPCS data from 602 patients referred from 47 countries and diagnosed with NPC1 in our laboratory were analyzed. Patients' clinical data were dissected using Human Phenotype Ontology (HPO) terms, and genotype-phenotype analysis was performed. The median age at diagnosis was 10.6 years (range 0-64.5 years), with 287 unique pathogenic/likely pathogenic (P/LP) variants identified, expanding NPC1 allelic heterogeneity. Importantly, 73 P/LP variants were previously unpublished. The most frequent variants detected were: c.3019C > G, p.(P1007A), c.3104C > T, p.(A1035V), and c.2861C > T, p.(S954L). Loss of function (LoF) variants were significantly associated with earlier age at diagnosis, highly increased biomarker levels, and a visceral phenotype (abnormal abdomen and liver morphology). On the other hand, the variants p.(P1007A) and p.(S954L) were significantly associated with later age at diagnosis (p < 0.001) and mildly elevated biomarker levels (p ≤ 0.002), consistent with the juvenile/adult form of NPC1. In addition, p.(I1061T), p.(S954L), and p.(A1035V) were associated with abnormality of eye movements (vertical supranuclear gaze palsy, p ≤ 0.05). We describe the largest and most heterogenous cohort of NPC1 patients published to date. Our results suggest that besides its utility in variant classification, the biomarker PPCS might serve to indicate disease severity/progression. In addition, we establish new genotype-phenotype relationships for "frequent" NPC1 variants.

Incidence of notified Lyme borreliosis in Germany, 2013-2017.

Lyme borreliosis (LB) is the most commonly reported tick-borne disease in Germany. In 9/16 states, notification of erythema migrans (EM), acute neuroborreliosis (NB) and Lyme arthritis (LA) is mandatory. We describe incidence measures, time trends, geographical distribution and frequencies of manifestations to better understand LB epidemiology and target prevention measures. We used cases notified in the 9 states and confirmed by local health offices, 2013-2017, to calculate incidences by time, place and person. Altogether, we observed 56,446 cases. Disease onset peaked yearly in July. Incidence ranged from 26/100,000 (2015) to 41/100,000 (2013) with mean annual incidences 2013-2017 on district level between 0.5/100,000 and 138/100,000. Median age was 54 years with peaks in boys (5-9 years, mean incidence 36/100,000) and women (50-69 years, mean incidence 57/100,000). 95% experienced EM only, 2.7% NB and 2.1% LA. 54% were female, but more men had NB (56%) and LA (53%, p < 0.001). Hospitalisation was recorded for 10% of LA and 71% of NB cases. LB remains an important public health concern in Germany with marked regional variation. To facilitate early diagnosis and treatment, health authorities should raise awareness among physicians and promote prevention strategies among the general population: tick-bite-protection, prompt tick removal and medical consultation.

Quantification of neuroretinal rim loss using digital planimetry in long-term follow-up of normals and patients with ocular hypertension.

PURPOSE: The purpose of this study was to investigate if digital planimetry is appropriate for quantification of neuroretinal rim loss in patients with ocular hypertension (OHT) and if there is an age-related neuroretinal rim loss in normals. PATIENTS AND METHODS: Fifty-six patients with OHT without optic disc change, 13 patients with OHT and conversion to early glaucoma during follow-up and 42 age-matched controls were recruited from the Erlangen Glaucoma Registry. Annually, all patients underwent complete ophthalmologic examination including detailed diagnostic testing concerning glaucoma. Gold standard for morphologic evaluation of the optic nerve head was the semiquantitative 2-dimensional-method described by Jonas. Optic disc images from baseline and after 5 or 10 years follow-up were used for digital planimetry. Optic disc area and cup area were measured using commercial software: Soft Imaging System analysis. The investigator was masked for diagnosis and time point of examination. RESULTS: Mean neuroretinal rim loss was 0.36% per year in controls, 0.54% per year in patients with OHT without progressive disease, and 0.95% per year in OHT and conversion. CONCLUSIONS: Neuroretinal rim loss was highest in the group of OHT with conversion to early glaucoma during follow-up. In the control group we detected a very low mean neuroretinal rim loss during 10-year follow-up. In ocular hypertensive patients without progressive disease mean neuroretinal rim loss was approximately twice compared with normals.