Assessment of intellectual impairment, health-related quality of life, and behavioral phenotype in patients with neurotransmitter related disorders: Data from the iNTD registry.

Inherited disorders of neurotransmitter metabolism are a group of rare diseases, which are caused by impaired synthesis, transport, or degradation of neurotransmitters or cofactors and result in various degrees of delayed or impaired psychomotor development. To assess the effect of neurotransmitter deficiencies on intelligence, quality of life, and behavior, the data of 148 patients in the registry of the International Working Group on Neurotransmitter Related Disorders (iNTD) was evaluated using results from standardized age-adjusted tests and questionnaires. Patients with a primary disorder of monoamine metabolism had lower IQ scores (mean IQ 58, range 40-100) within the range of cognitive impairment (<70) compared to patients with a BH4 deficiency (mean IQ 84, range 40-129). Short attention span and distractibility were most frequently mentioned by parents, while patients reported most frequently anxiety and distractibility when asked for behavioral traits. In individuals with succinic semialdehyde dehydrogenase deficiency, self-stimulatory behaviors were commonly reported by parents, whereas in patients with dopamine transporter deficiency, DNAJC12 deficiency, and monoamine oxidase A deficiency, self-injurious or mutilating behaviors have commonly been observed. Phobic fears were increased in patients with 6-pyruvoyltetrahydropterin synthase deficiency, while individuals with sepiapterin reductase deficiency frequently experienced communication and sleep difficulties. Patients with BH4 deficiencies achieved significantly higher quality of life as compared to other groups. This analysis of the iNTD registry data highlights: (a) difference in IQ and subdomains of quality of life between BH4 deficiencies and primary neurotransmitter-related disorders and (b) previously underreported behavioral traits.

Health Outcomes of Infants with Vitamin B12 Deficiency Identified by Newborn Screening and Early Treated.

OBJECTIVE: To evaluate the clinical outcomes at age 1.5 ± 0.5 years of infants with vitamin B12 deficiency identified by newborn screening (NBS). STUDY DESIGN: Prospective multicenter observational study on health outcomes of 31 infants with vitamin B12 deficiency identified by NBS. Neurodevelopment was assessed by the Denver Developmental Screening Test. RESULTS: In 285 862 newborns screened between 2016 and 2019, the estimated birth prevalence of vitamin B12 deficiency was 26 in 100 000 newborns, with high seasonal variations (lowest in summer: 8 in 100 000). Infants participating in the outcome study (N = 31) were supplemented with vitamin B12 for a median (range) of 5.9 (1.1-16.2) months. All achieved age-appropriate test results in Denver Developmental Screening Test at age 15 (11-23) months and did not present with symptoms characteristic for vitamin B12 deficiency. Most (81%, n = 25) mothers of affected newborns had a hitherto undiagnosed (functional) vitamin B12 deficiency, and, subsequently, received specific therapy. CONCLUSIONS: Neonatal vitamin B12 deficiency can be screened by NBS, preventing the manifestation of irreversible neurologic symptoms and the recurrence of vitamin B12 deficiency in future pregnancies through adequate treatment of affected newborns and their mothers. The high frequency of mothers with migrant background having a newborn with vitamin B12 deficiency highlights the need for improved prenatal care.

Newborn screening and disease variants predict neurological outcome in isovaleric aciduria.

Isovaleric aciduria (IVA), a metabolic disease with severe (classic IVA) or attenuated phenotype (mild IVA), is included in newborn screening (NBS) programs worldwide. The long-term clinical benefit of screened individuals, however, is still rarely investigated. A national, prospective, observational, multi-center study of individuals with confirmed IVA identified by NBS between 1998 and 2018 was conducted. Long-term clinical outcomes of 94 individuals with IVA were evaluated, representing 73.4% (for classic IVA: 92.3%) of the German NBS cohort. In classic IVA (N = 24), NBS prevented untimely death except in one individual with lethal neonatal sepsis (3.8%) but did not completely prevent single (N = 10) or recurrent (N = 7) metabolic decompensations, 13 of them occurring already neonatally. IQ (mean ± SD, 90.7 ± 10.1) was mostly normal but below the reference population (P = .0022) and was even lower in individuals with severe neonatal decompensations (IQ 78.8 ± 7.1) compared to those without crises (IQ 94.7 ± 7.5; P = .01). Similar results were obtained for school placement. In contrast, individuals with mild IVA had excellent neurocognitive outcomes (IQ 105.5 ± 15.8; normal school placement) and a benign disease course (no metabolic decompensation, normal hospitalization rate), which did not appear to be impacted by metabolic maintenance therapy. In conclusion, NBS reduces mortality in classic IVA, but does not reliably protect against severe neonatal metabolic decompensations, crucial for favorable neurocognitive outcome. In contrast, individuals with mild IVA had excellent clinical outcomes regardless of metabolic maintenance therapy, questioning their benefit from NBS. Harmonized stratified therapeutic concepts are urgently needed.

Thawed solvent/detergent-treated plasma: too precious to be wasted after 6 hours?

BACKGROUND: Coagulopathy associated with trauma and bleeding requires early administration of haemostatic agents. Solvent/detergent-treated plasma (S/D-plasma) requires thawing and its availability for clinical use is, therefore, delayed. The long-term stability of clotting factors in thawed S/D-plasma has not been thoroughly investigated. The purpose of this study was to evaluate stability of clotting factors and inhibitors in thawed S/D-plasma stored at 4 °C for 6 days. MATERIALS AND METHODS: Clotting factor levels and bacterial contamination were investigated using 20 units of S/D-plasma. Fibrinogen, factor (F) II, FV, FVII, FVIII, FIX, FX, FXI, FXII, FXIII, antithrombin, von Willebrand antigen (VWF-Ag), plasmin inhibitor, protein C and free protein S were analysed over time. RESULTS: After 6 days of storage the results were as follows: fibrinogen 270 mg/dL (-10 mg/dL, p=0.0204), FII 75% (-5%, p<0.0001), FV 88% (-14%, p<0.0001), FVII 81% (-24%, p<0.0001), FVIII 70% (-16%, p<0.0001), FIX 96% (-8, p<0.0001), FX 92% (-1%, p<0.0001), FXI 119% (-4%, p=0.3666), FXII 94% (-2%, p=0.3602), FXIII 89% (-1%, p 0.0019), free protein S 76% (-4%, p<0.0001), protein C 96% (+1%, p=0.0371), antithrombin 92% (-3%, p<0.0001), plasmin inhibitor 29% (-4%, p<0.0299), VWF-Ag 137% (+2%, p=0.2205). FVII and FVIII showed a critical drop of more than 20% or approached the lower quality assurance threshold after storage for more than 24 hours. No S/D-plasma showed bacterial contamination. CONCLUSION: All clotting factors in thawed S/D plasma remained stable for up to 24 hours when stored at 4 °C. Storage of thawed S/D plasma may improve the availability of this product in emergency situations.

Clotting factor activity in thawed Octaplas® LG during storage at 2-6°C for 6 days from a quality assurance point of view.

INTRODUCTION: Octaplas® LG is a second-generation solvent/detergent-treated plasma that offers an additional safety benefit by prion elimination. The stability of clotting factors of the new S/D plasma after thawing has not been investigated yet. This study intended to measure the time course of fibrinogen, FII, FV, FVII, FVIII, FIX, PC, fPS and PI through storage at 2-6°C over 6 days. MATERIALS AND METHODS: We investigated 20 plasma bags (five bags per blood group) and measured fibrinogen, FII, FV, FVII, FVIII, FIX, PC, fPS and PI immediately after thawing and after 2, 4, 6, 24, 48, 72, 96, 120 and 144 h storage at 2-6°C. Five separate plasma bags were thawed and stored at 2-6°C for microbiological assessment. After 6 days samples were drawn for blood cultures that were incubated for six more days. RESULTS: After 6 days FII, FIX and PC showed no significant changes. FV (-16%, p<0.001), FVII (-19%, p<0.001), FVIII (-19%, p<0.001), FXI (-13%, p<0.0001) and fPS (-4%, p<0.0007) decreased significantly. PI levels were stable at 56%. The microbiological investigation showed no bacterial contamination. CONCLUSIONS: In Octaplas® LG plasma clotting factors decreased slightly through storage of 6 days. PI levels were remarkably higher and stable over time in the new Octaplas® LG. Stability of stored Octaplas® LG was limited by the decrease of FVIII to 53%, which may warrant storage up to 24h from a quality assurance point of view. This could result in reduced plasma wastage and costs for healthcare givers.

Lyophilised plasma: evaluation of clotting factor activity over 6 days after reconstitution for transfusion.

AIMS: Little is known about long-term stability of clotting factors in dissolved human lyophilised plasma. This study evaluated clotting factor and inhibitor activity in reconstituted lyophilised plasma after storage for up to 6 days at 4 degrees C. METHODS: Five samples from different lots of pooled lyophilised plasma (LyoPlas; German Red Cross Blood Transfusion Service West) were reconstituted. The activity of fibrinogen, factor II (FII), FV, FVII, FVIII, FIX, FX, FXI, FXII, FXIII, antithrombin, plasmin inhibitor, von Willebrand factor antigen, free protein S and protein C were determined immediately and at 2, 4, 6, 24, 48, 72, 96, 120 and 144 h after reconstitution. Tests for bacterial contamination were performed after 12, 72 and 144 h from each plasma bottle. RESULTS: Storage at 4 degrees C for 6 h led to a decrease in the activity of FVIII (Delta -14.9%), FIX (Delta -6.9%) and FXI (Delta -6.3%), and an increase in the activity of plasmin inhibitor (Delta +10.2%). Storage for up to 6 days resulted in a further decrease in activity of FVIII (Delta -24.3%), FIX (Delta -13.4%) and FXI (Delta -22.9%), and, additionally, a decrease in the activity of FV (Delta -15.0%), fibrinogen (Delta -6.9%) and plasmin inhibitor (Delta -17.5%). Other factors and inhibitors, with exception of protein C (Delta +8.2%), remained almost unchanged over time. Blood cultures were sterile and showed no bacterial growth. CONCLUSIONS: The activity of all measured coagulation factors and inhibitors in a time course of up to 6 days met required quality standards. Further in vivo testing is required to demonstrate safety and efficacy of extended clinical use of refrigerated reconstituted lyophilised plasma.

Activity of clotting factors in fresh-frozen plasma during storage at 4 degrees C over 6 days.

BACKGROUND: Fresh-frozen plasma (FFP) requires thawing, which delays availability. We investigated clotting factor activity and bacterial contamination of FFP when stored at 4 degrees C +/- 2 degrees C for 6 days. STUDY DESIGN AND METHODS: Plasma of 20 healthy plasma donors was sampled, frozen, and analyzed at baseline and repeatedly over a period of 6 days after thawing. The activity of fibrinogen, Factor (F)II, FV, FVII, FVIII, F IX, FX, XI, FXII, FXIII, antithrombin III (ATIII), von Willebrand factor antigen (VWF-Ag), protein C (PC), and free protein S (FPS) were determined and analyzed over time. RESULTS: Immediately after thawing there was a significant decrease of fibrinogen (-9%), FII (-7%), FV (-14%), FVII (-12%), FX (-11%), FXIII (-20%), PC (-7%), and ATIII (-4%), whereas FVIII (+8%), F IX (+1%), FXI (+11%), FXII (-1%), FPS (-1%), and VWF-Ag (-6%) remained stable without significant change. Over 6 days after thawing fibrinogen, ATIII (+2%) and VWF-Ag (+2%) remained stable whereas FXII (+2%), FXIII (+6%), and PC (+3%) changed significantly over time and increased at the end. FII (-8%), FV (-16%), FVII (-31%), FVIII (-47%), F IX (-12%), FX (-10%), FXI (-25%), and FPS (+/-0%) changed also significantly over time and decreased at the end. All clotting factors and inhibitors remained within the reference range requested by quality assurance regulations. No FFP bag showed bacterial contamination. CONCLUSION: This provides evidence for maintaining quality of thawed FFP and may improve rapid availability in emergency situations and reduce cost for health care givers.