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Newborn screening for 5qSMA offers the potential for early, ideally pre-symptomatic, therapeutic intervention. However, limited data exist on the outcomes of individuals with 4 copies of SMN2, and there is no consensus within the SMA treatment community regarding early treatment initiation in this subgroup. To provide evidence-based insights into disease progression, we performed a retrospective analysis of 268 patients with 4 copies of SMN2 from the SMArtCARE registry in Germany, Austria and Switzerland. Inclusion criteria required comprehensive baseline data and diagnosis outside of newborn screening. Only data prior to initiation of disease-modifying treatment were included. The median age at disease onset was 3.0 years, with a mean of 6.4 years. Significantly, 55% of patients experienced symptoms before the age of 36 months. 3% never learned to sit unaided, a further 13% never gained the ability to walk independently and 33% of ambulatory patients lost this ability during the course of the disease. 43% developed scoliosis, 6.3% required non-invasive ventilation and 1.1% required tube feeding. In conclusion, our study, in line with previous observations, highlights the substantial phenotypic heterogeneity in SMA. Importantly, this study provides novel insights: the median age of disease onset in patients with 4 SMN2 copies typically occurs before school age, and in half of the patients even before the age of three years. These findings support a proactive approach, particularly early treatment initiation, in this subset of SMA patients diagnosed pre-symptomatically. However, it is important to recognize that the register will not include asymptomatic individuals. [ABSTRACT FROM AUTHOR]

The objective of this study was to investigate the relevance of routine assessment of c.−259C>T in the Austrian newborn screening program. Homozygous and compound heterozygous mutations in the coding region of the human gene encoding gap junction protein GJB2 (Connexin 26) cause up to 50 % of neonatal autosomal recessive non-syndromic hearing impairment identified in Caucasian newborn screening programs. More recently, a null mutation in the GC box of the GJB2 basal promoter c.−259C>T has been described which causes hearing impairment by completely suppressing GJB2 promoter activity. We determined the occurrence of c.−259C>T in cases of non-syndromic hearing impairment lacking known pathogenic alterations in GJB2 ( n = 43), a non-syndromic hearing impaired patient group ( n = 15) bearing the heterozygous GJB2 mutations c.35delG, c.[79G>A];[341A>G] (p. [V27I];[E114G]), c.109G>A (p.V37I), c.154G>C (p.V52L), c.262G>T (p.A88S), c.269T>C (p.L90P) and c.551G>C (p.R184P) and in a normal hearing group lacking alterations in GJB2 ( n = 50). In the analyzed groups, no occurrence of c.−259C>T was found. The c.−259C>T mutation, previously described as −3438C>T, is not a common cause of non-syndromic hearing impairment alone or together with heterozygous pathogenic GJB2 mutations that are statistically overrepresented in non-syndromic hearing impaired patient groups. Screening of newborns for c.−259C>T is therefore unlikely to be commonly found in Austrian NSHI patients but could make a significant contribution to non-syndromic hearing impairment in other populations. [ABSTRACT FROM AUTHOR]

This study aimed to estimate the number of infants who died of unrecognized congenital adrenal hyperplasia (CAH) in Austria and the Czech Republic within the past 13 years, before the introduction of adequate neonatal screening. The study was based on retrospective analysis of neonatal screening cards of 242 infants who died suddenly between 7 days and 12 months of age and whose cause of death could not be identified. 17-hydroxyprogesterone (17-OHP) was measured by fluoroimmunoassay and positive samples were subsequently genotyped. Three infants out of 242 may have had unrecognized CAH due to CYP21 (steroid 21-hydroxylase) gene defect. Their newborn 17-OHP levels and CYP21 genotypes were 706 nmol/l and del/conv//del/conv, 53 nmol/l and I2//I2, and 811 nmol/l and I2//Gln318stop, respectively. CAH due to CYP21 defect can lead to sudden unexpected death without prior symptoms typical for the condition. Hence, newborn screening would have prevented these deaths had it been available. In addition, we have shown that the I2 point mutation that is expected to lead to simple virilizing form may lead to a fatal outcome. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]