Dilemma in diagnosing Metabolic Disorder: A case of Galactokinase Deficiency with an unusual presentation

An infant with metabolic disorder can have vague presentations like repeated chest infections, feeding intolerance and failure to thrive. This may lead to a diagnostic dilemma. Detailed clinical history together with biochemical investigations are must to reach a diagnosis. Galactokinase Deficiency (GKD) has a varied presentation with some features like microcephaly, juvenile cataracts and failure to thrive. We encountered a case of GKD in an infant in which there was an absence of cataracts. Raised Immunoreactive Trypsinogen (IRT) in Newborn Screening was strongly suggestive of Cystic Fibrosis (CF), however Genetic Analysis revealed a heterozygous missense variation in EXON4 of the GALK1 GENE, confirming the diagnosis of GKD. Hence, this case highlights the importance of considering different metabolic disorders as differential diagnoses of one another even in absence of a typical feature of a particular disorder.

Immunoreactive Trypsinogen and Free Carnitine Changes on Newborn Screening after Birth in Patients Who Develop Type 1 Diabetes

Are free carnitine concentrations on newborn screening (NBS) 48–72 h after birth lower in patients who develop type 1 diabetes than in controls? A retrospective case-control study of patients with type 1 diabetes was conducted. NBS results of patients from a Sydney hospital were compared against matched controls from the same hospital (1:5). Multiple imputation was performed for estimating missing data (gestational age) using gender and birthweight. Conditional logistic regression was used to control for confounding and to generate parameter estimates (α = 0.05). The Hommel approach was used for post-hoc analyses. Results are reported as medians and interquartile ranges. A total of 159 patients were eligible (80 females). Antibodies were detectable in 86. Median age at diagnosis was 8 years. Free carnitine concentrations were lower in patients than controls (25.50 µmol/L;18.98–33.61 vs. 27.26; 21.22–34.86 respectively) (p = 0.018). Immunoreactive trypsinogen was higher in this group (20.24 µg/L;16.15–29–52 vs. 18.71; 13.96–26.92) (p = 0.045), which did not persist in the post-hoc analysis. Carnitine levels are lower and immunoreactive trypsinogen might be higher, within 2–3 days of birth and years before development of type 1 diabetes as compared to controls, although the differences were well within reference ranges and provide insight into the pathogenesis into neonatal onset of type 1 diabetes development rather than use as a diagnostic tool. Given trypsinogen’s use for evaluation of new-onset type 1 diabetes, larger studies are warranted.

Predictors for the quantity not sufficient sweat collection for ionic conductivity in newborns and young infants

Background: Sweat conductivity (SC) is a semi-automated method widely used as a screening test for Cystic Fibrosis. Quantity not sufficient (QNS) is defined when collecting a volume lower than 15 μl of sweat during 30 minutes. Objective: To verify the rate and factors related to QNS for SC in newborns and young infants. Methods: Newborns and infants aged less than three months that had undergone sweat conductivity after two abnormal immunoreactive trypsinogen results, were recruited prospectively and consecutively. Statistical analysis included descriptive statistics, univariate and multivariate logistic regression. Results: A total of 1020 individuals were included. Among them, the rate of QNS was 8.9%. Subjects with gestational age <37 weeks (OR=5.0), birth weight <2.000g (OR=3.5), and daily weight gain <25g/day (OR=3.4) were more likely to produce an insufficient quantity of sweat. Conclusion: Our results suggest that QNS rates for SC could successfully fulfill the Cystic Fibrosis Foundation standards in newborns and young infants. In cases of QNS, SC should be scheduled as early as possible when the infant is older than 37 weeks (corrected age).

Cystic Fibrosis Newborn Screening in Austria Using PAP and the Numeric Product of PAP and IRT Concentrations as Second-Tier Parameters

In Austria, newborns have been screened for cystic fibrosis (CF) by analyzing immunoreactive trypsinogen (IRT) from dried blood spots (DBS)s for nearly 20 years. Recently, pancreatitis-associated protein (PAP) analysis was introduced as a second-tier test with the aim of reducing recalls for second DBS cards while keeping sensitivity high. For 28 months, when IRT was elevated (65–130 ng/mL), PAP was measured from the first DBS (n = 198,927) with a two-step cut-off applied. For the last 12 months of the observation period (n = 85,421), an additional IRT×PAP cut-off was introduced. If PAP or IRT×PAP were above cut-off, a second card was analyzed for IRT and in case of elevated values identified as screen-positive. Above 130 ng/mL IRT in the first DBS, newborns were classified as screen-positive. IRT analysis of first DBS resulted in 1961 (1%) tests for PAP. In the first 16 months, 26 of 93 screen-positive were confirmed to have CF. Two false-negatives have been reported (sensitivity = 92.8%). Importantly, less than 30% of families compared to the previous IRT-IRT screening scheme had to be contacted causing distress. Adding IRT×PAP caused a marginally increased number of second cards and sweat tests to be requested during this period (15 and 3, respectively) compared to the initial IRT-PAP scheme. One case of confirmed CF was found due to IRT×PAP, demonstrating an increase in sensitivity. Thus, the relatively simple and economical algorithm presented here performs effectively and may be a useful model for inclusion of CF into NBS panels or modification of existing schemes.