Karl Otfried Schwab

Efficacy and outcome of expanded newborn screening for metabolic diseases - Report of 10 years from South-West Germany *

BackgroundNational newborn screening programmes based on tandem-mass spectrometry (MS/MS) and other newborn screening (NBS) technologies show a substantial variation in number and types of disorders included in the screening panel. Once established, these methods offer the opportunity to extend newborn screening panels without significant investment and cost. However, systematic evaluations of newborn screening programmes are rare, most often only describing parts of the whole process from taking blood samples to long-term evaluation of outcome.MethodsIn a prospective single screening centre observational study 373 cases with confirmed diagnosis of a metabolic disorder from a total cohort of 1,084,195 neonates screened in one newborn screening laboratory between January 1, 1999, and June 30, 2009 and subsequently treated and monitored in five specialised centres for inborn errors of metabolism were examined. Process times for taking screening samples, obtaining results, initiating diagnostic confirmation and starting treatment as well as the outcome variables metabolic decompensations, clinical status, and intellectual development at a mean age of 3.3 years were evaluated.ResultsOptimal outcome is achieved especially for the large subgroup of patients with medium-chain acyl-CoA dehydrogenase deficiency. Kaplan-Meier-analysis revealed disorder related patterns of decompensation. Urea cycle disorders, organic acid disorders, and amino acid disorders show an early high and continuous risk, medium-chain acyl-CoA dehydrogenase deficiency a continuous but much lower risk for decompensation, other fatty acid oxidation disorders an intermediate risk increasing towards the end of the first year. Clinical symptoms seem inevitable in a small subgroup of patients with very early disease onset. Later decompensation can not be completely prevented despite pre-symptomatic start of treatment. Metabolic decompensation does not necessarily result in impairment of intellectual development, but there is a definite association between the two.ConclusionsPhysical and cognitive outcome in patients with presymptomatic diagnosis of metabolic disorders included in the current German screening panel is equally good as in phenylketonuria, used as a gold standard for NBS. Extended NBS entails many different interrelated variables which need to be carefully evaluated and optimized. More reports from different parts of the world are needed to allow a comprehensive assessment of the likely benefits, harms and costs in different populations.

Propionic acidemia: clinical course and outcome in 55 pediatric and adolescent patients

BackgroundPropionic acidemia is an inherited disorder caused by deficiency of propionyl-CoA carboxylase. Although it is one of the most frequent organic acidurias, information on the outcome of affected individuals is still limited.Study design/methodsClinical and outcome data of 55 patients with propionic acidemia from 16 European metabolic centers were evaluated retrospectively. 35 patients were diagnosed by selective metabolic screening while 20 patients were identified by newborn screening. Endocrine parameters and bone age were evaluated. In addition, IQ testing was performed and the patients’ and their families’ quality of life was assessed.ResultsThe vast majority of patients (>85%) presented with metabolic decompensation in the neonatal period. Asymptomatic individuals were the exception. About three quarters of the study population was mentally retarded, median IQ was 55. Apart from neurologic symptoms, complications comprised hematologic abnormalities, cardiac diseases, feeding problems and impaired growth. Most patients considered their quality of life high. However, according to the parents’ point of view psychic problems were four times more common in propionic acidemia patients than in healthy controls.ConclusionOur data show that the outcome of propionic acidemia is still unfavourable, in spite of improved clinical management. Many patients develop long-term complications affecting different organ systems. Impairment of neurocognitive development is of special concern. Nevertheless, self-assessment of quality of life of the patients and their parents yielded rather positive results.

Comorbidities Related to BMI Category in Children and Adolescents: German/Austrian/Swiss Obesity Register APV Compared to the German KiGGS Study

Purpose: To assess cardiovascular risk factors in overweight or obese children and adolescents in Germany, Austria and Switzerland and to investigate the relationship to BMI category. Methods: Data of 63,025 overweight or obese patients (APV population) were compared to normal-weight subjects from a representative study on health status of 14,298 children and adolescents in Germany (KiGGS survey). The weight status was assessed by BMI, and BMI-SDS values were cal-culated using national reference data. Results: In normal-weight KiGGS subjects, mean BMI was 17.3 ± 2.5 (BMI-SDS -0.1 ± 0.8). In the overweight or obese APV population, mean BMI was 30.2 ± 5.6 (BMI-SDS 2.5 ± 0.6). In normal-weight subjects blood pressure, total cholesterol, LDL-cholesterol, and triglycerides were elevated in 6.1, 8.6, 7.0 and 3.0%, respectively, and HDL-cholesterol was reduced in 3.0%, whereas in overweight/obese subjects the percentages of abnormal values were 35.3, 13.8, 14.5, 13.6, and 10.1%, respectively. Conclusions: Cardiovascular risk is increased in obese children and adolescents. There is a strong need to monitor blood pressure and serum lipids in this group of patients. Our results emphasize the importance of prevention of obesity in order to reduce cardiovascular risk.

Body Mass Index or Waist Circumference: Which Is the Better Predictor for Hypertension and Dyslipidemia in Overweight/Obese Children and Adolescents? Association of Cardiovascular Risk Related to Body Mass Index or Waist Circumference

Background: In order to assess the relationship between hypertension or dyslipidemia and obesity, the body mass index (BMI) is usually used. Unlike waist circumference (WC), BMI does not reflect body fat distribution. The aim of this study is to investigate whether BMI or WC is a better predictor of hypertension or dyslipidemia in overweight/obese children and adolescents. Methods: As of November 2012, the APV database contained data on 81,819 patients from 189 specialized pediatric obesity institutions in Germany, Austria and Switzerland. Logistic regression analysis was conducted using odds ratios (OR) with 95% CI. Results: The average age of the youths (n = 5.978) was 13.9 ± 1.8 years. Mean BMI-SDS was 2.0 ± 0.5, and mean WC-SDS was 2.2 ± 0.5. Both BMI-SDS and WC-SDS are significant predictors of hypertension and dyslipidemia: BMI-SDS is a better predictor (OR = 2.60) for hypertension than WC-SDS (OR = 1.85), while WC-SDS (OR = 1.90) was slightly superior to BMI-SDS (OR = 1.86) in predicting adverse lipid profiles. Compared to normal-weight patients, obese patients (BMI ≥97th percentile) exhibited increased systolic (+6.3 mm Hg) and diastolic blood pressure (+3.9 mm Hg). However, this difference was only +4.8 mm Hg (systolic) and +2.6 mm Hg (diastolic) if WC >97th percentile was used. Conclusion: BMI-SDS is more closely associated with hypertension, while WC-SDS is more closely associated with dyslipidemia. However, the additional measurement of WC has only a small benefit in obese youths.

Marked smoking-associated increase of cardiovascular risk in childhood type 1 diabetes.

Type 1 diabetes is a generally accepted atherogenic risk factor, and diabetic patients who smoke markedly accelerate the atherosclerotic process. The main intentions of our investigation were to ascertain differences between juvenile active/passive smokers and non-smokers with type 1 diabetes regarding the number and spectrum of cardiovascular risk factors and their associations with smoking. Ninety-two patients were enrolled comprising 19 active/passive smokers (median age 15.9 years) and 73 non-smokers (median age 12.3 years). To determine age-dependent influences we compared age- and gender-matched groups of 12 smokers with 12 non-smokers. Smokers had significantly higher HbA1c, fructosamine, total cholesterol, LDL cholesterol, apolipoprotein B, serum P-selectin, and lower serum L-selectin than non-smokers. However, L-selectin levels were not different between the age-matched smoker and non-smoker groups. A significant positive relation (Spearman rank correlation) was found between smoking and age, HbAlc, fructosamine, total cholesterol, apolipoprotein B, and P-selectin; a negative relationship between smoking and L-selectin. We conclude that smoking in children and adolescents with type 1 diabetes increases the cardiovascular risk through the deterioration of glucose metabolism, lipid profile, and endothelial function. Therefore, smoking diabetic juveniles may increase their number of cardiovascular risk factors from 1, diabetes, by another four factors, i.e. smoking, hyperglycemia, dyslipidemia, and endothelial perturbation.

Synergistic Effects of Elevated Systolic Blood Pressure and Hypercholesterolemia on Carotid Intima–Media Thickness in Children and Adolescents

This study aimed to investigate the synergistic effects of elevated systolic blood pressure (SBP) and hypercholesterolemia on carotid intima–media thickness (cIMT). For this study, 60 children with hypercholesterolemia and 40 healthy control children were divided into four subgroups: hypercholesterolemic children with normal (<90th percentile) or elevated (≥90th percentile) SBP and control children with normal or elevated SBP. The highest mean and maximal cIMT values were found in the hypercholesterolemic children with elevated SBP and were significantly different from those of all the other groups. The synergistic effects of elevated SBP and hypercholesterolemia lead to a significant increase in cIMT as a subclinical sign of early atherosclerosis.

Mutation analysis in 54 propionic acidemia patients

Deficiency of propionyl CoA carboxylase (PCC), a dodecamer of alpha and beta subunits, causes inherited propionic acidemia. We have studied, at the molecular level, PCC in 54 patients from 48 families comprised of 96 independent alleles. These patients of various ethnic backgrounds came from research centers and hospitals in Germany, Austria and Switzerland. The thorough clinical characterization of these patients was described in the accompanying paper (Grünert et al. 2012). In all 54 patients, many of whom originated from consanguineous families, the entire PCCB gene was examined by genomic DNA sequencing and in 39 individuals the PCCA gene was also studied. In three patients we found mutations in both PCC genes. In addition, in many patients RT-PCR analysis of lymphoblast RNA, lymphoblast enzyme assays, and expression of new mutations in E.coli were carried out. Eight new and eight previously detected mutations were identified in the PCCA gene while 15 new and 13 previously detected mutations were found in the PCCB gene. One missense mutation, p.V288I in the PCCB gene, when expressed in E.coli, yielded 134% of control activity and was consequently classified as a polymorphism in the coding region. Numerous new intronic polymorphisms in both PCC genes were identified. This study adds a considerable amount of new molecular data to the studies of this disease.

Fanconi–Bickel syndrome: GLUT2 mutations associated with a mild phenotype

Fanconi-Bickel syndrome (FBS, OMIM #227810), a congenital disorder of carbohydrate metabolism, is caused by mutations in GLUT2 (SLC2A2), the gene encoding the glucose transporter protein-2. The typical clinical picture is characterized by hepatorenal glycogen accumulation resulting in hepato- and nephromegaly, impaired utilization of glucose and galactose, proximal tubular nephropathy, rickets, and severe short stature. We report on two siblings with FBS and an unusually mild clinical course. A 9.5-year-old boy with failure to thrive was diagnosed at the age of 9 months, his younger sister (4.5 years) was investigated in the first months of life and also diagnosed with FBS. Both patients were found to be compound heterozygous for the novel GLUT2 (SLC2A2) mutations c.457_462delCTTATA (p.153_4delLI) and c.1250C>G (p.P417R). On a diet restricted in free glucose and galactose, both children showed normal growth. Hepatomegaly, nephromegaly and hypophosphatemic rickets have never been observed. Glucosuria and tubular proteinuria were only mild compared to previously reported patients with FBS. This report describes an unusually mild phenotype of FBS expanding the spectrum of this disease. Some clinical signs that have been considered hallmarks of FBS like hepatomegaly and short stature may be absent in this condition. As a consequence, clinicians will have to look for GLUT2 mutations even in patients with isolated glucosuria.

Difficulties in Diagnosis and Treatment of 5α-Reductase Type 2 Deficiency in a Newborn with 46,XY DSD

Background/Aims: Steroid 5α-reductase deficiency (MIM*607306) caused by mutations in the SRD5A2 gene is characterized by a predominantly female phenotype at birth and significant virilization at puberty. The undermasculinization at birth results from low dihydrotestosterone (DHT) levels during fetal development as the type 2 isoenzyme activity is reduced. In puberty, when the type 1 isoenzyme activity increases, significant virilization occurs. Most 46,XY individuals with 5α-reductase 2 deficiency develop a male gender identity. Case Report and Results: We present a case with a predominantly female phenotype and ambiguous external genitalia but a normal 46,XY karyotype. Plasma steroid analysis after β-hCG stimulation at 8 days of age revealed a steroid profile estimated as normal with a testosterone (T)/DHT ratio of 9.5 initially misleading to the exclusion of 5α-reductase deficiency. However, mutation analysis of the SRD5A2 gene revealed a homozygote point mutation (Leu55Gln) confirming the diagnosis of 5α-reductase deficiency. A male phenotype was successfully achieved by hormone treatment with T and DHT after diagnosing 5α-reductase deficiency and a masculinization operation. As a side effect skeletal age accelerated temporarily. Conclusion: In individuals with predominantly female phenotype and suspected 5α-reductase deficiency, a T/DHT ratio during the neonatal period >8.5 might point to 5α-reductase deficiency. After confirmation of the diagnosis by molecular analysis of the SRD5A2 gene, a satisfactory change to a male phenotype can be achieved by hormone treatment preceding surgery.

Against all odds: blended phenotypes of three single-gene defects

Whole-exome sequencing allows for an unbiased and comprehensive mutation screening. Although successfully used to facilitate the diagnosis of single-gene disorders, the genetic cause(s) of a substantial proportion of presumed monogenic diseases remain to be identified. We used whole-exome sequencing to examine offspring from a consanguineous marriage featuring a novel combination of congenital hypothyroidism, hypomagnesemia and hypercholesterolemia. Rather than identifying one causative variant, we report the first instance in which three independent autosomal-recessive single-gene disorders were identified in one patient. Together, the causal variants give rise to a blended and seemingly novel phenotype: we experimentally characterized a novel splice variant in the thyroglobulin gene (c.638+5G>A), resulting in skipping of exon 5, and detected a pathogenic splice variant in the magnesium transporter gene TRPM6 (c.2667+1G>A), causing familial hypomagnesemia. Based on the third variant, a stop variant in ABCG5 (p.(Arg446*)), we established a diagnosis of sitosterolemia, confirmed by elevated blood plant sterol levels and successfully initiated targeted lipid-lowering treatment. We propose that blended phenotypes resulting from several concomitant single-gene disorders in the same patient likely account for a proportion of presumed monogenic disorders of currently unknown cause and contribute to variable genotype-phenotype correlations.