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Objective: De novo variants in cullin-3 ubiquitin ligase (CUL3) have been strongly associated with neurodevelopmental disorders (NDDs), but no large case series have been reported so far. Here, we aimed to collect sporadic cases carrying rare variants in CUL3, describe the genotype-phenotype correlation, and investigate the underlying pathogenic mechanism., Methods: Genetic data and detailed clinical records were collected via multicenter collaboration. Dysmorphic facial features were analyzed using GestaltMatcher. Variant effects on CUL3 protein stability were assessed using patient-derived T-cells., Results: We assembled a cohort of 37 individuals with heterozygous CUL3 variants presenting a syndromic NDD characterized by intellectual disability with or without autistic features. Of these, 35 have loss-of-function (LoF) and 2 have missense variants. CUL3 LoF variants in patients may affect protein stability leading to perturbations in protein homeostasis, as evidenced by decreased ubiquitin-protein conjugates in vitro. Notably, we show that 4E-BP1 (EIF4EBP1), a prominent substrate of CUL3, fails to be targeted for proteasomal degradation in patient-derived cells., Interpretation: Our study further refines the clinical and mutational spectrum of CUL3-associated NDDs, expands the spectrum of cullin RING E3 ligase-associated neuropsychiatric disorders, and suggests haploinsufficiency via LoF variants is the predominant pathogenic mechanism. ANN NEUROL 2024., (© 2024 American Neurological Association.)

Vitamin B12 (B12) deficiency (B12D) can have detrimental effects on early growth and development. The Austrian newborn screening (NBS) program targets inborn errors of cobalamin metabolism and also detects B12D. Of 59 included neonates with B12D suspected by NBS, B12D was not further investigated in 16 (27%) retrospectively identified cases, not confirmed in 28 (48%), and confirmed in 15 (25%) cases. NBS and recall biomarkers were recorded. Age at sampling of the dried blood spots for NBS and the 1st-tier methionine/phenylalanine ratio were the strongest parameters to predict B12D (67.4% correct allocations). No differences between cases with confirmed, unconfirmed, or unknown B12D or differences to norms were observed for growth and psychomotor development (Vineland III scales, phone interviews with parents of children between months 10 and 14 of life). B12 intake was below recommendations in most mothers. NBS can detect reduced intracellular B12 activity. No advantage of NBS detection and treatment regarding infant cognitive development or growth could be proven. Since conspicuous NBS findings cannot be ignored, and to prevent exposing newborns to invasive diagnostics, assessment of maternal B12 status during pregnancy seems advisable.

Purpose: A high rate of lost to follow-up (LTFU) in patients with phenylketonuria (PKU) represents a main challenge. In this study, we investigated potential risk factors for becoming LTFU related to adolescence as a critical period of life., Methods: We retrospectively analyzed longitudinal data collected from 1993 to 2019 of patients diagnosed with classic PKU that were followed at our center during adolescence (14-18 y) and at least once in adulthood (>18 y). Patients who interrupted their contact with our center after the 18th birthday for at least 2 years were classified as LTFU. We performed a multivariate regression analysis to investigate following potential risk factors for becoming LTFU in adult life: sex, dietary compliance during adolescence assessed through the mean of the annual medians of phenylalanine plasma values, average number of contacts with the center during adolescence and age at first visit after the 18th birthday., Results: 93 patients (52 males, 41 females) were included in the study. 58% became LTFU during adulthood. The mean age at the last visit before becoming LTFU was 26.2 ± 5.1 years. In the multivariate Cox regression analysis we found that poor dietary compliance during adolescence was significantly associated with a higher risk of becoming LTFU during adulthood ( p -value = 0.028)., Discussion: Adult patients who displayed poor treatment adherence during adolescence should be identified and carefully monitored to prevent loss of contact., Competing Interests: All authors declare no conflict of interest., (© 2024 Published by Elsevier Inc.)

Background and Aims: Pediatric acute liver failure (PALF) is a life-threatening condition. In Europe, the main causes are viral infections (12%-16%) and inherited metabolic diseases (14%-28%). Yet, in up to 50% of cases the underlying etiology remains elusive, challenging clinical management, including liver transplantation. We systematically studied indeterminate PALF cases referred for genetic evaluation by whole-exome sequencing (WES), and analyzed phenotypic and biochemical markers, and the diagnostic yield of WES in this condition., Approach and Results: With this international, multicenter observational study, patients (0-18 y) with indeterminate PALF were analyzed by WES. Data on the clinical and biochemical phenotype were retrieved and systematically analyzed., Results: In total, 260 indeterminate PALF patients from 19 countries were recruited between 2011 and 2022, of whom 59 had recurrent PALF. WES established a genetic diagnosis in 37% of cases (97/260). Diagnostic yield was highest in children with PALF in the first year of life (41%), and in children with recurrent acute liver failure (64%). Thirty-six distinct disease genes were identified. Defects in NBAS (n=20), MPV17 (n=8), and DGUOK (n=7) were the most frequent findings. When categorizing, the most frequent were mitochondrial diseases (45%), disorders of vesicular trafficking (28%), and cytosolic aminoacyl-tRNA synthetase deficiencies (10%). One-third of patients had a fatal outcome. Fifty-six patients received liver transplantation., Conclusions: This study elucidates a large contribution of genetic causes in PALF of indeterminate origin with an increasing spectrum of disease entities. The high proportion of diagnosed cases and potential treatment implications argue for exome or in future rapid genome sequencing in PALF diagnostics., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Two siblings showed increased galactose and galactose-related metabolites in neonatal screening. Diagnostic workup did not reveal abnormalities in any of the known disease-causing enzymes involved in galactose metabolism. Using whole-exome sequencing, we identified a homozygous missense variant in PPA1 encoding the cytosolic pyrophosphatase 1 (PPA1), c.557C>T (p.Thr186Ile). The enzyme activity of PPA1 was determined using a colorimetric assay, and the protein content was visualized via western blotting in skin fibroblasts from one of the affected individuals. The galactolytic activity of the affected fibroblasts was determined by measuring extracellular acidification with a Seahorse XFe96 analyzer. PPA1 activity decreased to 22% of that of controls in the cytosolic fraction of homogenates from patient fibroblasts. PPA1 protein content decreased by 50% according to western blot analysis, indicating a reduced stability of the variant protein. The extracellular acidification rate was reduced in patient fibroblasts when galactose was used as a substrate. Untargeted metabolomics of blood samples revealed an elevation of other metabolites related to pyrophosphate metabolism. Besides hyperbilirubinemia in the neonatal period in one child, both children were clinically unremarkable at the ages of 3 and 14 years, respectively. We hypothesize that the observed metabolic derangement is a possible mild manifestation of PPA1 deficiency. Unresolved abnormalities in galactosemia screening might result in the identification of more individuals with PPA1 deficiency, a newly discovered inborn metabolic disorder (IMD).

Alpha-mannosidosis (AM) is a rare, autosomal recessive, lysosomal storage disorder caused by alpha-mannosidase deficiency that leads to the accumulation of mannose-rich oligosaccharides. AM symptoms and severity vary among individuals; consequently, AM is often not diagnosed until late childhood. Velmanase alfa (VA), a recombinant human lysosomal alpha-mannosidase product, is the first enzyme replacement therapy indicated to treat non-neurological symptoms of AM in Europe. Previous studies suggested that early VA treatment in children may produce greater clinical benefit over the disease course than starting treatment in adolescents or adults; however, long-term studies in children are limited, and very few studies include children under 6 years of age. The present phase 2, multicenter, open-label study evaluated the safety and efficacy of long-term VA treatment in children under 6 years of age with AM. Five children (three males) received VA weekly for ≥24 months, and all children completed the study. Four children experienced adverse drug reactions (16 events) and two experienced infusion-related reactions (12 events). Most (99.5%) adverse events were mild or moderate, and none caused study discontinuation. Four children developed antidrug antibodies (three were neutralizing). After VA treatment, all children improved in one or more efficacy assessments of serum oligosaccharide concentrations (decreases), hearing, immunological profile, and quality of life, suggesting a beneficial effect of early treatment. Although the small study size limits conclusions, these results suggest that long-term VA treatment has an acceptable safety profile, is well tolerated, and may provide potential benefits to patients with AM under 6 years of age., (© 2023 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

The mitochondrial malate aspartate shuttle system (MAS) maintains the cytosolic NAD+/NADH redox balance, thereby sustaining cytosolic redox-dependent pathways, such as glycolysis and serine biosynthesis. Human disease has been associated with defects in four MAS-proteins (encoded by MDH1 , MDH2 , GOT2 , SLC25A12 ) sharing a neurological/epileptic phenotype, as well as citrin deficiency ( SLC25A13 ) with a complex hepatopathic-neuropsychiatric phenotype. Ketogenic diets (KD) are high-fat/low-carbohydrate diets, which decrease glycolysis thus bypassing the mentioned defects. The same holds for mitochondrial pyruvate carrier (MPC) 1 deficiency, which also presents neurological deficits. We here describe 40 (18 previously unreported) subjects with MAS-/MPC1-defects (32 neurological phenotypes, eight citrin deficiency), describe and discuss their phenotypes and genotypes (presenting 12 novel variants), and the efficacy of KD. Of 13 MAS/MPC1-individuals with a neurological phenotype treated with KD, 11 experienced benefits-mainly a striking effect against seizures. Two individuals with citrin deficiency deceased before the correct diagnosis was established, presumably due to high-carbohydrate treatment. Six citrin-deficient individuals received a carbohydrate-restricted/fat-enriched diet and showed normalisation of laboratory values/hepatopathy as well as age-adequate thriving. We conclude that patients with MAS-/MPC1-defects are amenable to dietary intervention and that early (genetic) diagnosis is key for initiation of proper treatment and can even be lifesaving.

In the last decade, health-related quality of life (HrQoL) has become an increasingly important outcome parameter in children and adolescents with chronic health conditions; among them are pediatric patients with inborn metabolic diseases (IMDs). Hence, knowledge on this topic is increasing, but findings on non-medical influences on the HrQoL of IMD patients are still scarce. In the present study, we retrospectively evaluated the self-reported generic HrQoL of a cohort of pediatric patients (ages 7 to 17 years) with diverse IMDs (n = 204) and explored associations between HrQoL and psychosocial and medical characteristics of the patients. We aimed to identify risk factors for impaired HrQoL to improve and tailor support for the patients and economize resources. Generic HrQoL was assessed with the KINDL-R questionnaire. We compared the HrQoL scores to published German normative data and analyzed the impact of demographic variables and intellectual and psychosocial functioning on the HrQoL. Moreover, we examined the influence of the diagnostic category and the health impairment (as judged by the physicians) on our patients' HrQoL. Overall, the HrQoL of the adolescent patients was comparable to the HrQoL of the norm group. Disorders of intellectual development, impaired psychosocial functioning, and a severe health impairment were associated with lower HrQoL scores.Conclusion: We recommend evaluating these factors in children and adolescents with IMDs to identify patients at risk for impaired HrQoL. What is Known: • Studies on HrQoL in pediatric patients with IMDs mainly focused on subgroups with specific diagnoses and found normal HrQoL in some of those subgroups. • In healthy children and adolescents as well as in pediatric patients with various chronic diseases, associations between psychosocial factors and HrQoL are well known. What is New: • Impaired psychosocial functioning, disorders of intellectual development, and a significant disease and/or treatment burden are risk factors for impaired HrQoL in pediatric patients with IMDs. • Evaluating these factors in children and adolescents with IMDs can help identify patients and families in need of enhanced psychological support., (© 2021. The Author(s).)

Inherited metabolic disorders (IMDs) are a heterogeneous group of rare disorders characterized by disruption of metabolic pathways. To date, data on incidence and prevalence of IMDs are limited. Taking advantage of a functioning network within the Austrian metabolic group, our registry research aimed to update the data of the "Registry for Inherited Metabolic Disorders" started between 1985 and 1995 with retrospectively retrieved data on patients with IMDs according to the Society for the Study of Inborn Errors of Metabolism International Classification of Diseases 11 (SSIEM ICD11) catalogue. Included in this retrospective register were 2631 patients with an IMD according to the SSIEM ICD11 Classification, who were treated in Austria. Thus, a prevalence of 1.8/10 000 for 2020 and a median minimal birth prevalence of 16.9/100 000 (range 0.7/100 000-113/100 000) were calculated for the period 1921 to February 2021. We detected a male predominance (m:f = 1.2:1) and a mean age of currently alive patients of 17.6 years (range 5.16 months-100 years). Most common diagnoses were phenylketonuria (17.7%), classical galactosaemia (6.6%), and biotinidase deficiency (4.2%). The most common diagnosis categories were disorders of amino acid and peptide metabolism (819/2631; 31.1%), disorders of energy metabolism (396/2631; 15.1%), and lysosomal disorders (395/2631; 15.0%). In addition to its epidemiological relevance, the "Registry for Inherited Metabolic Disorders" is an important tool for enhancing an exchange between care providers. Moreover, by pooling expertise it prospectively improves patient treatment, similar to pediatric oncology protocols. A substantial requirement for ful filling this goal is to regularly update the registry and provide nationwide coverage with inclusion of all medical specialties., (© 2021 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Background: High rates of lost to follow-up (LTFU) adult patients are a major concern in the long-term management of phenylketonuria (PKU). To address this issue, we designed the project "Backtoclinic" with the purpose of identifying LTFU adult PKU patients in Austria as a first step to reestablish appropriate treatment., Subjects and Methods: Individuals born between 1966 and 1999 and diagnosed with PKU through the National Austrian Newborn Screening Program (NANSP) were identified using the NANSP's database. Follow-up data were collected in the Austrian metabolic centers (Medical University of Vienna, Graz, Innsbruck and Salzburg). Patients with no contact to any of these centers within the previous two years were classified as LTFU. Epidemiological characteristics of the whole study population as well as of LTFU- and currently in follow-up patients were analyzed., Results: Between 1966 and 1999, 281 individuals were diagnosed with PKU through the NANSP. Two patients died in their first year of life and were excluded from the analysis. Of the remaining 279 patients (mean age ± SD: 36.7 ± 9.1 y, 42.7% females), 177 (63.4%) are currently LTFU. The rate of LTFU patients is higher in men than in women (68.1% vs 57.5%), and markedly increases with age in both sexes. The gender gap is greatest in young adults (52.6% vs. 25.0% in the age range 20.0-24.9 y) and declines with age (94.4% vs. 80.0% in the age range > 45.0 y)., Conclusions: We found an alarming rate of 63.4% of LTFU adult PKU patients in Austria, and observed a gender gap in the PKU state of care. Our findings illustrate the urgent need for the metabolic community to identify LTFU adult PKU patients and to develop strategies to reestablish appropriate treatment for men and women with PKU., Competing Interests: Declaration of Competing Interest All authors declare no conflict of interest., (Copyright © 2021. Published by Elsevier Inc.)

Glutaric aciduria type I (GA-1) is a rare autosomal-recessive disorder of the degradation of the amino acids lysine and tryptophan caused by mutations of the GCDH gene encoding glutaryl-CoA-dehydrogenase. Newborn screening (NBS) for this condition is based on elevated levels of glutarylcarnitine (C5DC) in dried blood spots (DBS). Here we report four cases from three families in whom a correctly performed NBS did not detect the condition. Glutarylcarnitine concentrations were either normal (slightly below) or slightly above the cut-off. Ratios to other acylcarnitines were also not persistently elevated. Therefore, three cases were defined as screen negative, and one case was defined as normal, after a normal control DBS sample. One patient was diagnosed after an acute encephalopathic crisis, and the other three patients had an insidious onset of the disease. GA-1 was genetically confirmed in all cases. Despite extensive efforts to increase sensitivity and specificity of NBS for GA-1, by adjusting cut-offs and introducing various ratios, the biological diversity still leads to false-negative NBS results for GA-1.

Background: Long-chain fatty acid oxidation disorders (LC-FAOD) are a group of rare inborn errors of metabolism with autosomal recessive inheritance that may cause life-threatening events. Treatment with triheptanoin, a synthetic seven-carbon fatty acid triglyceride compound with an anaplerotic effect, seems beneficial, but clinical experience is limited. We report our long-term experience in an Austrian cohort of LC-FAOD patients., Methods: We retrospectively assessed clinical outcome and total hospitalization days per year before and after start with triheptanoin by reviewing medical records of 12 Austrian LC-FAOD patients RESULTS: For 12 Austrian LC-FAOD patients at three metabolic centers, triheptanoin was started shortly after birth in 3/12, and between 7.34 and 353.3 (median 44.5; mean 81.1) months of age in 9/12 patients. For 11 pediatric patients, mean duration of triheptanoin intake was 5.3 (median 3.9, range 1.2-15.7) years, 10/11 pediatric patients have an ongoing intake of triheptanoin. One patient quit therapy due to reported side effects. Total hospitalization days per year compared to before triheptanoin treatment decreased by 82.3% from 27.1 (range 11-65) days per year to 4.8 (range 0-13) days per year, and hospitalization days in the one year pre- compared to the one year post-triheptanoin decreased by 69.8% from 27.1 (range 4-75) days to 8.2 (range 0-25) days. All patients are in good clinical condition, show normal psychomotor development and no impairment in daily life activities., Conclusion: In this retrospective observational study in an Austrian LC-FAOD cohort, triheptanoin data show improvement in disease course. Triheptanoin appears to be a safe and beneficial treatment option in LC-FAOD. For further clarification, additional prospective randomized controlled trials are needed.

Early diagnostics and treatment of vitamin B12 deficiency (B12D) in infants, mainly maternally conditioned, is crucial in preventing possible developmental delay and neurological deficits. Currently, B12D is rarely listed in regular newborn screening panels and mostly regarded as an incidental finding. The aim of this study was to evaluate a targeted newborn screening strategy for detection of suspected B12D. A decision strategy based on the primary parameters propionylcarnitine and methionine for selection of samples to be analyzed for total homocysteine by mass spectrometry was established. Therefore, 93,116 newborns were initially screened. Concentrations of vitamin B12 and holotranscobalamin in serum were obtained from clinical follow-up analyses of recalled newborns. Moreover, an extremely sensitive mass spectrometric method to quantify methylmalonic acid from the dried blood spots was developed. Overall, 0.15% of newborns were screened positive for suspected B12D, of which 64% had vitamin B12 concentrations below 148 pM. We also determined a cutoff value for methylmalonic acid in dried blood spots indicative for B12D in infants. Overall, we calculated a prevalence of 92/100,000 for suspected B12D in the Austrian newborns. In conclusion, we present a screening algorithm including second-tier measurement of total homocysteine that allows detection of low B12 serum concentrations with a high detection rate and low false-positive rate.

The ectonucleotidase CD39 on human regulatory T-cells (Treg) is an important immune regulator which is dysregulated in autoimmune diseases and cancer immunosuppression. We here define that CD39 expression on Treg is independent of the Treg-specific transcription factors FOXP3 and HELIOS and promoted by canonical TGF-b- and mTOR-signaling. Furthermore, the TGF-b mediated upregulation of CD39 is counteracted by reactive oxygen species (ROS)-driven autophagy. In line, CD39 + peripheral blood Treg constitute a distinct lineage with low autophagic flux and absent ROS production. Patients with rare genetic defects in autophagy show supraphysiological levels of CD39 + Treg, validating our observations in vivo. These biological processes rely on a distinct transcriptional program with CD39 + Treg expressing low levels of two genes with putative involvement in autophagy, NEFL and PLAC8. Furthermore, the TGF-b downstream transcription factor SOX4 is selectively upregulated in CD39 + Treg. Overexpression of SOX4 in Treg strongly increases CD39 expression, while Crispr/Cas9-mediated knockout of SOX4 in Treg has the opposing effect. Thus, we identify a crucial role of SOX4 in immune regulation and provide new insights involving the interplay of tolerogenic cues and autophagy in Treg., (© 2020 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

The importance of protein glycosylation in regulating lipid metabolism is becoming increasingly apparent. We set out to further investigate this by studying the effects of defective glycosylation on plasma lipids in patients with B4GALT1-CDG, caused by a mutation in B4GALT1 with defective N-linked glycosylation. We studied plasma lipids, cholesteryl ester transfer protein (CETP) glyco-isoforms with isoelectric focusing followed by a western blot and CETP activity in three known B4GALT1-CDG patients and compared them with 11 age- and gender-matched, healthy controls. B4GALT1-CDG patients have significantly lowered non-high density lipoprotein cholesterol (HDL-c) and total cholesterol to HDL-c ratio compared with controls and larger HDL particles. Plasma CETP was hypoglycosylated and less active in B4GALT1-CDG patients compared to matched controls. Our study provides insight into the role of protein glycosylation in human lipoprotein homeostasis. The hypogalactosylated, hypo-active CETP found in patients with B4GALT1-CDG indicates a role of protein galactosylation in regulating plasma HDL and LDL. Patients with B4GALT1-CDG have large HDL particles probably due to hypogalactosylated, hypo-active CETP., (© 2019 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Purpose: Pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause an autosomal recessive disorder with a wide range of symptoms affecting liver, skeletal system, and brain, among others. There is a continuously growing number of patients but a lack of systematic and quantitative analysis., Methods: Individuals with biallelic variants in NBAS were recruited within an international, multicenter study, including novel and previously published patients. Clinical variables were analyzed with log-linear models and visualized by mosaic plots; facial profiles were investigated via DeepGestalt. The structure of the NBAS protein was predicted using computational methods., Results: One hundred ten individuals from 97 families with biallelic pathogenic NBAS variants were identified, including 26 novel patients with 19 previously unreported variants, giving a total number of 86 variants. Protein modeling redefined the β-propeller domain of NBAS. Based on the localization of missense variants and in-frame deletions, three clinical subgroups arise that differ significantly regarding main clinical features and are directly related to the affected region of the NBAS protein: β-propeller (combined phenotype), Sec39 (infantile liver failure syndrome type 2/ILFS2), and C-terminal (short stature, optic atrophy, and Pelger-Huët anomaly/SOPH)., Conclusion: We define clinical subgroups of NBAS-associated disease that can guide patient management and point to domain-specific functions of NBAS.

Complex I (CI) is the first enzyme of the mitochondrial respiratory chain and couples the electron transfer with proton pumping. Mutations in genes encoding CI subunits can frequently cause inborn metabolic errors. We applied proteome and metabolome profiling of patient-derived cells harboring pathogenic mutations in two distinct CI genes to elucidate underlying pathomechanisms on the molecular level. Our results indicated that the electron transfer within CI was interrupted in both patients by different mechanisms. We showed that the biallelic mutations in NDUFS1 led to a decreased stability of the entire N-module of CI and disrupted the electron transfer between two iron-sulfur clusters. Strikingly interesting and in contrast to the proteome, metabolome profiling illustrated that the pattern of dysregulated metabolites was almost identical in both patients, such as the inhibitory feedback on the TCA cycle and altered glutathione levels, indicative for reactive oxygen species (ROS) stress. Our findings deciphered pathological mechanisms of CI deficiency to better understand inborn metabolic errors., Competing Interests: The authors declare no conflict of interest.

By using exome sequencing and a gene matching approach, we identified de novo and inherited pathogenic variants in KDM3B in 14 unrelated individuals and three affected parents with varying degrees of intellectual disability (ID) or developmental delay (DD) and short stature. The individuals share additional phenotypic features that include feeding difficulties in infancy, joint hypermobility, and characteristic facial features such as a wide mouth, a pointed chin, long ears, and a low columella. Notably, two individuals developed cancer, acute myeloid leukemia and Hodgkin lymphoma, in childhood. KDM3B encodes for a histone demethylase and is involved in H3K9 demethylation, a crucial part of chromatin modification required for transcriptional regulation. We identified missense and truncating variants, suggesting that KDM3B haploinsufficiency is the underlying mechanism for this syndrome. By using a hybrid facial-recognition model, we show that individuals with a pathogenic variant in KDM3B have a facial gestalt, and that they show significant facial similarity compared to control individuals with ID. In conclusion, pathogenic variants in KDM3B cause a syndrome characterized by ID, short stature, and facial dysmorphism., (Copyright © 2019 American Society of Human Genetics. All rights reserved.)

Aim: To explore the clinical presentation, course, treatment and impact of early treatment in patients with remethylation disorders from the European Network and Registry for Homocystinurias and Methylation Defects (E-HOD) international web-based registry., Results: This review comprises 238 patients (cobalamin C defect n = 161; methylenetetrahydrofolate reductase deficiency n = 50; cobalamin G defect n = 11; cobalamin E defect n = 10; cobalamin D defect n = 5; and cobalamin J defect n = 1) from 47 centres for whom the E-HOD registry includes, as a minimum, data on medical history and enrolment visit. The duration of observation was 127 patient years. In 181 clinically diagnosed patients, the median age at presentation was 30 days (range 1 day to 42 years) and the median age at diagnosis was 3.7 months (range 3 days to 56 years). Seventy-five percent of pre-clinically diagnosed patients with cobalamin C disease became symptomatic within the first 15 days of life. Total homocysteine (tHcy), amino acids and urinary methylmalonic acid (MMA) were the most frequently assessed disease markers; confirmatory diagnostics were mainly molecular genetic studies. Remethylation disorders are multisystem diseases dominated by neurological and eye disease and failure to thrive. In this cohort, mortality, thromboembolic, psychiatric and renal disease were rarer than reported elsewhere. Early treatment correlates with lower overall morbidity but is less effective in preventing eye disease and cognitive impairment. The wide variation in treatment hampers the evaluation of particular therapeutic modalities., Conclusion: Treatment improves the clinical course of remethylation disorders and reduces morbidity, especially if started early, but neurocognitive and eye symptoms are less responsive. Current treatment is highly variable. This study has the inevitable limitations of a retrospective, registry-based design., (© 2018 SSIEM.)

Purpose: To assess how the current practice of newborn screening (NBS) for homocystinurias compares with published recommendations., Methods: Twenty-two of 32 NBS programmes from 18 countries screened for at least one form of homocystinuria. Centres provided pseudonymised NBS data from patients with cystathionine beta-synthase deficiency (CBSD, n = 19), methionine adenosyltransferase I/III deficiency (MATI/IIID, n = 28), combined remethylation disorder (cRMD, n = 56) and isolated remethylation disorder (iRMD), including methylenetetrahydrofolate reductase deficiency (MTHFRD) (n = 8). Markers and decision limits were converted to multiples of the median (MoM) to allow comparison between centres., Results: NBS programmes, algorithms and decision limits varied considerably. Only nine centres used the recommended second-tier marker total homocysteine (tHcy). The median decision limits of all centres were ≥ 2.35 for high and ≤ 0.44 MoM for low methionine, ≥ 1.95 for high and ≤ 0.47 MoM for low methionine/phenylalanine, ≥ 2.54 for high propionylcarnitine and ≥ 2.78 MoM for propionylcarnitine/acetylcarnitine. These decision limits alone had a 100%, 100%, 86% and 84% sensitivity for the detection of CBSD, MATI/IIID, iRMD and cRMD, respectively, but failed to detect six individuals with cRMD. To enhance sensitivity and decrease second-tier testing costs, we further adapted these decision limits using the data of 15 000 healthy newborns., Conclusions: Due to the favorable outcome of early treated patients, NBS for homocystinurias is recommended. To improve NBS, decision limits should be revised considering the population median. Relevant markers should be combined; use of the postanalytical tools offered by the CLIR project (Collaborative Laboratory Integrated Reports, which considers, for example, birth weight and gestational age) is recommended. tHcy and methylmalonic acid should be implemented as second-tier markers., (© 2018 SSIEM.)