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Carbamoyl phosphate synthetase 1 (CPS1) and ornithine transcarbamylase (OTC) deficiencies are rare urea cycle disorders, which can lead to life‐threatening hyperammonemia. Liver transplantation (LT) provides a cure and offers an alternative to medical treatment and life‐long dietary restrictions with permanent impending risk of hyperammonemia. Nevertheless, in most patients, metabolic aberrations persist after LT, especially low plasma citrulline levels, with questionable clinical impact. So far, little is known about these alterations and there is no consensus, whether l‐citrulline substitution after LT improves patients' symptoms and outcomes. In this multicentre, retrospective, observational study of 24 patients who underwent LT for CPS1 (n = 11) or OTC (n = 13) deficiency, 25% did not receive l‐citrulline or arginine substitution. Correlation analysis revealed no correlation between substitution dosage and citrulline levels (CPS1, p = 0.8 and OTC, p = 1). Arginine levels after liver transplantation were normal after LT independent of citrulline substitution. Native liver survival had no impact on mental impairment (p = 0.67). Regression analysis showed no correlation between l‐citrulline substitution and failure to thrive (p = 0.611) or neurological outcome (p = 0.701). Peak ammonia had a significant effect on mental impairment (p = 0.017). Peak plasma ammonia levels correlate with mental impairment after LT in CPS1 and OTC deficiency. Growth and intellectual impairment after LT are not significantly associated with l‐citrulline substitution. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Strict metabolic control with dietary treatment during pregnancy is essential for women with phenylketonuria (PKU), as elevated levels of phenylalanine (Phe) are toxic to the developing fetus. Maternal delay in achievement of the recommended Phe level during pregnancy is associated with delayed development of the child. However, the extent to which risk is changed by later or less stringently performed dietary treatment is unclear. The aim of this study was to investigate the impact of Phe levels and time of initiation of a Phe‐restricted diet in pregnant women with PKU on birth weight, head circumference and later development of their children. Birth data were obtained from the medical records of women with PKU giving birth in the period 1980–2020. Later development was investigated by interviewing the mothers about their children's development and health. We included 79 children of 41 women with PKU. The women showed good adherence with the diet and had mean blood Phe levels within target range (248 ± 62 μmol/L). The children's development was not affected by fluctuations in the women's Phe levels, that occurred especially in first trimester. Despite maternal Phe levels being within target range, 19 children (26.8%) had low birth weight below 10th percentile. This study indicates that with dietary treatment, the children are born with the same prospect for normal development and health as children born to non‐PKU mothers. This is despite maternal fluctuations in the Phe levels during first trimester. [ABSTRACT FROM AUTHOR]

Aim: Paediatric acute liver failure (P‐ALF) is a rare and devastating condition that leads to death or liver transplantation (LTx) in 40%–60% of cases. Determining the aetiology can enable disease‐specific treatment, aid in prognostication for hepatic recovery and guide the decision‐making for liver transplantation. This study aimed to retrospectively evaluate a systematic diagnostic approach to P‐ALF in Denmark and to collect epidemiological nationwide data. Methods: All Danish children aged 0–16 years with P‐ALF diagnosed between 2005 and 2018, and who were evaluated using a standardised diagnostic assessment programme, were eligible for retrospective analysis of clinical data. Results: A total of 102 children with P‐ALF were included (presentation at 0 days to 16.6 years of age, 57 females). Aetiological diagnosis was established in 82% of cases, the remainder were indeterminate. Fifty percent of children with P‐ALF of indeterminate aetiology died or underwent LTx within 6 months after their P‐ALF diagnosis, compared to 24% of children with an aetiological diagnosis, p = 0.04. Conclusion: Following a systematic diagnostic evaluation programme, made it possible to identify the aetiology of P‐ALF in 82% of cases which is associated with improved outcomes. The diagnostic workup should never be considered complete but rather adapt to ongoing diagnostic advances. [ABSTRACT FROM AUTHOR]

The SARS‐CoV‐2 pandemic challenges healthcare systems worldwide. Within inherited metabolic disorders (IMDs) the vulnerable subgroup of intoxication‐type IMDs such as organic acidurias (OA) and urea cycle disorders (UCD) show risk for infection‐induced morbidity and mortality. This study (observation period February 2020 to December 2021) evaluates impact on medical health care as well as disease course and outcome of SARS‐CoV‐2 infections in patients with intoxication‐type IMDs managed by participants of the European Registry and Network for intoxication type metabolic diseases Consortium (E‐IMD). Survey's respondents managing 792 patients (n = 479 pediatric; n = 313 adult) with intoxication‐type IMDs (n = 454 OA; n = 338 UCD) in 14 countries reported on 59 (OA: n = 36; UCD: n = 23), SARS‐CoV‐2 infections (7.4%). Medical services were increasingly requested (95%), mostly alleviated by remote technologies (86%). Problems with medical supply were scarce (5%). Regular follow‐up visits were reduced in 41% (range 10%–50%). Most infected individuals (49/59; 83%) showed mild clinical symptoms, while 10 patients (17%; n = 6 OA including four transplanted MMA patients; n = 4 UCD) were hospitalized (metabolic decompensation in 30%). ICU treatment was not reported. Hospitalization rate did not differ for diagnosis or age group (p = 0.778). Survival rate was 100%. Full recovery was reported for 100% in outpatient care and 90% of hospitalized individuals. SARS‐CoV‐2 impacts health care of individuals with intoxication‐type IMDs worldwide. Most infected individuals, however, showed mild symptoms and did not require hospitalization. SARS‐CoV‐2‐induced metabolic decompensations were usually mild without increased risk for ICU treatment. Overall prognosis of infected individuals is very promising and IMD‐specific or COVID‐19‐related complications have not been observed. [ABSTRACT FROM AUTHOR]

The lysosomal storage disorder Fabry disease is caused by deficient or absent activity of the GLA gene enzyme α-galactosidase A. In the present study we present the molecular and biochemical data of the Danish Fabry cohort and report 20 years' (2001–2020) experience in cascade genetic screening at the Danish National Fabry Disease Center. The Danish Fabry cohort consisted of 26 families, 18 index patients (9 males and 9 females, no available data for 8 index-patients) and 97 family members with a pathogenic GLA variant identified by cascade genetic testing (30 males and 67 females). Fourteen patients (5 males and 9 females; mean age of death 47.0 and 64.8 years respectively) died during follow-up. The completeness of the Fabry patient identification in the country has resulted in a cohort of balanced genotypes according to gender (twice number of females compared to males), indicating that the cohort was not biased by referral, and further resulted in earlier diagnosis of the disease by a lower age at diagnosis in family members compared to index-patients (mean age at diagnosis: index-patients 42.2 vs. family members 26.0 years). Six previously unreported disease-causing variants in the GLA gene were discovered. The nationwide screening and registration of Fabry disease families provide a unique possibility to establish a complete cohort of Fabry patients and to advance current knowledge of this inherited rare lysosomal storage disorder. [ABSTRACT FROM AUTHOR]

MTHFR deficiency is a severe inborn error of metabolism leading to impairment of the remethylation of homocysteine to methionine. Neonatal and early‐onset patients mostly exhibit a life‐threatening acute neurologic deterioration. Furthermore, data on early‐onset patients' long‐term outcomes are scarce. The aims of this study were (1) to study and describe the clinical and laboratory parameters of early‐onset MTHFR‐deficient patients (i.e., ≤3 months of age) and (2) to identify predictive factors for severe neurodevelopmental outcomes in a cohort with early and late onset MTHFR‐deficient patients. To this end, we conducted a retrospective, multicentric, international cohort study on 72 patients with MTHFR deficiency from 32 international metabolic centres. Characteristics of the 32 patients with early‐onset MTHFR deficiency were described at time of diagnosis and at the last follow‐up visit. Logistic regression analysis was used to identify predictive factors of severe neurodevelopmental outcome in a broader set of patients with early and non‐early‐onset MTHFR deficiency. The majority of early‐onset MTHFR‐deficient patients (n = 32) exhibited neurologic symptoms (76%) and feeding difficulties (70%) at time of diagnosis. At the last follow‐up visit (median follow‐up time of 8.1 years), 76% of treated early‐onset patients (n = 29) exhibited a severe neurodevelopmental outcome. Among the whole study population of 64 patients, pre‐symptomatic diagnosis was independently associated with a significantly better neurodevelopmental outcome (adjusted OR 0.004, [0.002–0.232]; p = 0.003). This study provides evidence for benefits of pre‐symptomatic diagnosis and appropriate therapeutic management, highlighting the need for systematic newborn screening for MTHFR deficiency and pre‐symptomatic treatment that may improve outcome. [ABSTRACT FROM AUTHOR]

Individuals with no significant seizure reduction (defined as >= 50 % reduction in seizure frequency after 3 months of treatment) with maximum daily dosage of pyridoxine were offered a switch from oral pyridoxine to oral P5P. Seizure types included bilateral tonic-clonic seizures ( I n i = 4), absence seizures ( I n i = 2), focal seizures with or without impaired awareness ( I n i = 3), focal to bilateral tonic-clonic seizures ( I n i = 2), myoclonic seizures ( I n i = 2), and tonic seizures ( I n i = 1). Although the treatment period was too short to observe any convincing changes in the first two seizure types, a drastic reduction in focal seizures (>90%) was seen during the last 8-10 weeks of pyridoxine treatment. ABBREVIATIONS ASM Antiseizure medication GPI Glycosylphosphatidylinositol P5P Pyridoxal 5-phosphate TNSALP Tissue non-specific alkaline phosphatase Introduction The glycolipid glycosylphosphatidylinositol (GPI) plays an important role in both embryonic development and neurogenesis.1,2 GPI is synthesized in the endoplasmic reticulum, transferred to proteins, and later modified in the Golgi apparatus.3 At least 31 genes are involved in this multistep pathway and, to date, pathogenic variants in 22 of these genes have been associated with human disease.4 The pattern of inheritance is autosomal recessive in all but one gene; I PIGA i is located on the X chromosome and inheritance is X-linked recessive. [Extracted from the article]

Background and aims: Alcoholic hepatitis (AH) is characterized by acute liver failure, neurocognitive impairment and renal failure. Severe inflammatory reactions are also known to occur in AH. Inflammation and bacterial translocation in the gut are thought to have major impact on disease development and progression. The mortality rate for AH is close to 50%. We aimed to assess the efficacy of rifaximin in treating AH and its impact on inflammation and metabolism. Methods: The trial was approved by relevant authorities (EudraCT no: 2014-02264-33, Scientific Ethics Committee, jr. no: H-1-2014-056). Primary outcomes were changes in metabolic and inflammatory markers. Secondary outcomes were portal hypertension, kidney and neurocognitive function. Results: Thirty-two patients were randomized to standard medical therapy (SMT) or SMT plus rifaximin, allocation was concealed. Four patients in the SMT group and five patients in the SMT + rifaximin group died due to AH and liver failure. No adverse events related to the study medication were observed. We found no significant differences in amino acids or inflammation markers (IL-2, IL-6, IL-8, IL-10, TNF-α, interferon-γ) between the groups after 28 and 90 days. Conclusion: Rifaximin does not alter inflammation or metabolism in patients with AH. [ABSTRACT FROM AUTHOR]

Introduction: Management of phenylketonuria (PKU) is mainly achieved through dietary control with limited intake of phenylalanine (Phe) from food, supplemented with low protein (LP) food and a mixture of free synthetic (FS) amino acids (AA) (FSAA). Casein glycomacropeptide (CGMP) is a natural peptide released in whey during cheese making by the action of the enzyme chymosin. Because CGMP in its pure form does not contain Phe, it is nutritionally suitable as a supplement in the diet for PKU when enriched with specific AAs. Lacprodan® CGMP-20 (= CGMP) used in this study contained only trace amounts of Phe due to minor presence of other proteins/peptides. Objective: The aims were to address the following questions in a classical PKU mouse model: Study 1, off diet: Can pure CGMP or CGMP supplemented with Large Neutral Amino Acids (LNAA) as a supplement to normal diet significantly lower the content of Phe in the brain compared to a control group on normal diet, and does supplementation of selected LNAA results in significant lower brain Phe level?. Study 2, on diet: Does a combination of CGMP, essential (non-Phe) EAAs and LP diet, provide similar plasma and brain Phe levels, growth and behavioral skills as a formula which alone consist of FSAA, with a similar composition?. Material and methods: 45 female mice homozygous for the Pahenu2 mutation were treated for 12 weeks in five different groups; G1(N-CGMP), fed on Normal (N) casein diet (75%) in combination with CGMP (25%); G2 (N-CGMP-LNAA), fed on Normal (N) casein diet (75%) in combination with CGMP (19,7%) and selected LNAA (5,3% Leu, Tyr and Trp); G3 (N), fed on normal casein diet (100%); G4 (CGMP-EAA-LP), fed on CGMP (70,4%) in combination with essential AA (19,6%) and LP diet; G5 (FSAA-LP), fed on FSAA (100%) and LP diet. The following parameters were measured during the treatment period: Plasma AA profiles including Phe and Tyr, growth, food and water intake and number of teeth cut. At the end of the treatment period, a body scan (fat and lean body mass) and a behavioral test (Barnes Maze) were performed. Finally, the brains were examined for content of Phe, Tyr, Trp, dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), serotonin (5-HT) and 5-hydroxyindole-acetic acid (5-HIAA), and the bone density and bone mineral content were determined by dual-energy x-ray absorptiometry. Results: Study 1: Mice off diet supplemented with CGMP (G1 (N-CGMP)) or supplemented with CGMP in combination with LNAA (G2 (N-CGMP-LNAA)) had significantly lower Phe in plasma and in the brain compared to mice fed only casein (G3 (N)). Extra LNAA (Tyr, Trp and Leu) to CGMP did not have any significant impact on Phe levels in the plasma and brain, but an increase in serotonin was measured in the brain of G2 mice compared to G1. Study 2: PKU mice fed with mixture of CGMP and EAA as supplement to LP diet (G4 (CGMP-EAA-LP)) demonstrated lower plasma-Phe levels but similar brain- Phe levels and growth as mice fed on an almost identical combination of FSAA (G5 (FSAA-LP)). Conclusion: CGMP can be a relevant supplement for the treatment of PKU. [ABSTRACT FROM AUTHOR]

Purpose: Bilateral childhood cataracts can be caused by a metabolic disease, constitute a part of a syndrome, run in families, be sporadic or iatrogenic. The amount of work-up needed to establish a cause is discussed and the aim of the present study was to evaluate causes of bilateral childhood cataract. Methods: Chart review of 211 Danish children with bilateral cataracts. Information on work-up was retrieved with special focus on general health, metabolic screening, evaluation for congenital infections and genetic testing. Results: Cataract was seen in combination with systemic disease in 40.8%, 29.4% had hereditary cataracts, 27.0% had isolated cataract, in 1.4% it was associated with ocular malformations and 1.4% had been born prematurely without any other sequelae than the cataract. A genetic cause could be demonstrated in 74 children. Conclusion: Systemic comorbidities are very common in children with cataract and are not always known prior to the diagnosis of cataract. Genetic evaluation, especially targeted analyses, provided a molecular genetic diagnosis in a large proportion of those tested but it also failed to provide a molecular genetic diagnosis in some patients with a family history suggesting autosomal dominant inheritance. Most importantly, in some patients, genetic work-up provided a diagnosis in patients where it had therapeutic consequences and where the systemic disease would have caused irreversible damage, had it not been treated timely. Given the high prevalence of systemic disease, it seems advisable to co-manage children with bilateral cataracts with a pediatrician and to include genetic evaluation as part of the work-up. [ABSTRACT FROM AUTHOR]

Primary carnitine deficiency (PCD) affects fatty acid oxidation and is associated with cardiomyopathy and cardiac arrhythmia, but the risk of sudden death in PCD is unknown. The Faroe Islands have a high prevalence of PCD, 1:300. This study systematically investigated a possible association between untreated PCD and sudden death in young Faroese subjects. We investigated all medico‐legal cases of sudden death between 1979 and 2012 among subjects below the age of 45. Stored biomaterial was examined with molecular genetic analysis to reveal PCD. We compared the prevalence of PCD among sudden death cases with that of the background population (0.23%) to calculate the odds ratio (OR) for sudden death with PCD. Biomaterial was available and genetically analyzed from 53 of 65 sudden death cases (82%) in the Faroe Islands. Six (one male and five females) of the 53 cases were homozygous for the PCD related c.95A>G mutation—a prevalence of 11.3% (95% CI 5%‐23%) and an OR of 54.3 (95% CI 21‐138, P <.0001) for the association between sudden death and untreated PCD. Only 11 of the 53 sudden death cases were women—of whom five were homozygous for the c.95A>G mutation (45.5%) yielding an OR of 348.8 (95% CI 94‐1287, P <.0001) for the association between sudden death and untreated PCD in females. This study showed a strong association between sudden death and untreated PCD, especially in females. [ABSTRACT FROM AUTHOR]

Organic acidurias (OAD) and urea‐cycle disorders (UCD) are rare inherited disorders affecting amino acid and protein metabolism. As dietary practice varies widely, we assessed their long‐term prescribed dietary treatment against published guideline and studied plasma amino acids levels. We analyzed data from the first visit recorded in the European registry and network for intoxication type metabolic diseases (E‐IMD, Chafea no. 2010 12 01). In total, 271 methylmalonic aciduria (MMA) and propionic aciduria (PA) and 361 UCD patients were included. Median natural protein prescription was consistent with the recommended daily allowance (RDA), plasma L‐valine (57%), and L‐isoleucine (55%) levels in MMA and PA lay below reference ranges. Plasma levels were particularly low in patients who received amino acid mixtures (AAMs‐OAD) and L‐isoleucine:L‐leucine:L‐valine (BCAA) ratio was 1.0:3.0:3.2. In UCD patients, plasma L‐valine, L‐isoleucine, and L‐leucine levels lay below reference ranges in 18%, 30%, and 31%, respectively. In symptomatic UCD patients who received AAM‐UCD, the median natural protein prescription lay below RDA, while their L‐valine and L‐isoleucine levels and plasma BCAA ratios were comparable to those in patients who did not receive AAM‐UCD. Notably, in patients with ornithine transcarbamylase syndrome (OTC‐D), carbamylphosphate synthetase 1 syndrome (CPS1‐D) and hyperammonemia‐hyperornithinemia‐homocitrullinemia (HHH) syndrome selective L‐citrulline supplementation resulted in higher plasma L‐arginine levels than selective L‐arginine supplementation. In conclusion, while MMA and PA patients who received AAMs‐OAD had very low BCAA levels and disturbed plasma BCAA ratios, AAMs‐UCD seemed to help UCD patients obtain normal BCAA levels. In patients with OTC‐D, CPS1‐D, and HHH syndrome, selective L‐citrulline seemed preferable to selective L‐arginine supplementation. [ABSTRACT FROM AUTHOR]

Background Nephropathy is common in Fabry disease (FD). Prior studies of renal function during enzyme replacement therapy (ERT) have primarily used estimated glomerular filtration rate (eGFR). We studied the attrition of renal function in FD by measured GFR (mGFR) and urine protein excretion, and explored the influence of age. Methods This was a long-term observational study of a nationwide, family-screened cohort of FD patients. All Danish genetically verified FD patients on ERT, without end-stage renal disease at baseline and with three or more mGFR values were included. Results In all, 52 patients with consecutive mGFR values (n  = 841) over median 7 years (range 1–13) were evaluated. Blood pressure remained normal and urine protein excretion was unchanged. Plasma globotriaosylceramide (Gb-3) levels normalized while plasma lyso-Gb-3 remained abnormal in 34% of patients. Baseline mGFR was 90 ± 3 mL/min/1.73 m2 and rate of renal function loss 0.9 ± 0.2 mL/min/1.73 m2/year. Baseline eGFR was 97 ± 5 mL/min/1.73 m2 and rate of renal function loss 0.8 ± 0.3 mL/min/1.73 m2/year. mGFR was age- adjusted to renal healthy non-FD subjects, giving a standard deviation score of −0.8 ± 0.2 with an annual slope of −0.03 ± 0.01 (P = 0.099), without differences between genders. Age grouping of age-adjusted data showed exaggerated renal function loss with age. Urine albumin–creatinine ratio (UACR) >300 mg/g was associated with faster renal function loss, independent of baseline mGFR, age and gender. Conclusions ERT-treated FD patients did not have a faster attrition of renal function than renal healthy non-FD subjects (background population). The rate of renal function loss with age was independent of gender and predicted by high UACR. We suggest cautious interpretation of non-age-adjusted FD renal data. [ABSTRACT FROM AUTHOR]

Introduction: Homozygous familial hypercholesterolaemia (HoFH) is a rare, autosomal disease affecting the clearance of low-density lipoprotein cholesterol (LDL-C) from circulation, and leading to early-onset atherosclerotic cardiovascular disease (ASCVD). Treatment consists mainly of statins, lipoprotein apheresis (LA) and, more recently, the microsomal triglyceride transfer protein inhibitor lomitapide. Lomitapide is not licensed for use in children, but has been made available through an expanded access programme or on a named patient basis.Methods: This case series includes 11 HoFH patients in 10 different centres in eight countries, less than 18 years of age (mean 11.6 ± 1.1 years, 64% male), with signs of ASCVD, and who have received treatment with lomitapide (mean dose 24.5 ± 4.3 mg/day; mean exposure 20.0 ± 2.9 months). Background lipid-lowering therapy was given according to local protocols. Lomitapide was commenced with a stepwise dose escalation from 2.5 mg or 5 mg/day; dietary advice and vitamin supplements were provided as per the product label for adults. Laboratory analysis was conducted as part of regular clinical care.Results: In the 11 cases, mean baseline LDL-C was 419 ± 74.6 mg/dL and was markedly reduced by lomitapide to a nadir of 176.7 ± 46.3 mg/dL (58.4 ± 6.8% decrease). Six patients achieved recommended target levels for children below 135 mg/dL, five of whom had LA frequency reduced. In one case, LDL-C levels were close to target when lomitapide was started but remained stable despite 75% reduction in LA frequency (from twice weekly to biweekly). Adverse events were mainly gastrointestinal in nature, occurred early in the treatment course and were well managed. Three patients with excursions in liver function tests were managed chiefly without intervention; two patients had decreases in lomitapide dose.Conclusions: Lomitapide demonstrated promising effectiveness in paediatric HoFH patients. Adverse events were manageable, and the clinical profile of the drug is apparently similar to that in adult patients.Funding: Amryt Pharma. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: This phase III, double‐blind, randomised, placebo‐controlled trial (and extension phase) was designed to assess the efficacy and safety of velmanase alfa (VA) in alpha‐mannosidosis (AM) patients. Methods: Twenty‐five patients were randomised to weekly 1 mg/kg VA or placebo for 52 weeks. At study conclusion, placebo patients switched to VA; 23 patients continued receiving VA in compassionate‐use/follow‐on studies and were evaluated in the extension phase [last observation (LO)]. Co‐primary endpoints were changes in serum oligosaccharide (S‐oligo) and in the 3‐min stair‐climb test (3MSCT). Results: Mean relative change in S‐oligo in the VA arm was −77.6% [95% confidence interval (CI) −81.6 to −72.8] at week 52 and −62.9% (95% CI −85.8 to −40.0) at LO; mean relative change in the placebo arm was −24.1% (95% CI −40.3 to −3.6) at week 52 and −55.7% (95% CI −76.4 to −34.9) at LO after switch to active treatment. Mean relative change in 3MSCT at week 52 was −1.1% (95% CI −9.0 to 7.6) and − % (95% CI −13.4 to 6.5) for VA and placebo, respectively. At LO, the mean relative change was 3.9% (95% CI −5.5 to 13.2) in the VA arm and 9.0% (95% CI −10.3 to 28.3) in placebo patients after switch to active treatment. Similar improvement pattern was observed in secondary parameters. A post hoc analysis investigated whether some factors at baseline could account for treatment outcome; none of those factors were predictive of the response to VA, besides age. Conclusions: These findings support the utility of VA for the treatment of AM, with more evident benefit over time and when treatment is started in the paediatric age. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Long‐term outcome data provide important insights into the clinical utility of enzyme replacement therapies. Such data are presented for velmanase alfa in the treatment of alpha‐mannosidosis (AM). Methods: Patient data (n = 33; 14 adults, 19 paediatric) from the clinical development programme for velmanase alfa were integrated in this prospectively‐designed analysis of long‐term efficacy and safety. Patients who participated in the phase I/II or phase III trials and were continuing to receive treatment after completion of the trials were invited to participate in a comprehensive evaluation visit to assess long‐term outcomes. Primary endpoints were changes in serum oligosaccharide and the 3‐minute stair climb test (3MSCT). Results: Mean (SD) treatment exposure was 29.3 (15.2) months. Serum oligosaccharide levels were significantly reduced in the overall population at 12 months (mean change: –72.7%, P < 0.001) and remained statistically significant at last observation (−62.8%, P < 0.001). A mean improvement of +9.3% in 3MSCT was observed at 12 months (P = 0.013), which also remained statistically significant at last observation (+13.8%, P = 0.004), with a more pronounced improvement detected in the paediatric subgroup. No treatment‐emergent adverse events were reported leading to permanent treatment discontinuation. Conclusions: Patients treated with velmanase alfa experienced improvements in biochemical and functional measures that were maintained for up to 4 years. Long term follow‐up is important and further supports the use of velmanase alfa as an effective and well‐tolerated treatment for AM. Based on the currently available data set, no baseline characteristic can be predictive of treatment outcome. Early treatment during paediatric age showed better outcome in functional endpoints. [ABSTRACT FROM AUTHOR]

Aim: Mucopolysaccharidosis type I is a lysosomal storage disorder that can result in significant disease burden, disability and premature death, if left untreated. The aim of this review was to elaborate on the diagnosis of mucopolysaccharidosis type I and the pros and cons of newborn screening.Methods: An international working group was established to discuss ways to improve the early diagnosis of mucopolysaccharidosis type I. It consisted of 13 experts in paediatrics, rare diseases and inherited metabolic diseases from Europe and the Middle East.Results: It is becoming increasingly clearer that the delay between symptom onset and clinical diagnosis is considerable for mucopolysaccharidosis type I and other rare lysosomal storage disorders, despite numerous awareness campaigns since therapies became available. Diagnosis currently depends on recognising the signs and symptoms of the disease. The practice of newborn screening, which is being explored by pilot programmes around the world, enables early diagnosis and consequently early treatment. However, these studies have highlighted numerous new problems and pitfalls that must be faced before newborn screening becomes generally available.Conclusion: Newborn screening for mucopolysaccharidosis type I offers the potential for early diagnosis and early pre-symptomatic treatment, but existing hurdles need to be overcome. [ABSTRACT FROM AUTHOR]

Introduction: Long-term outcome data provide important insights into the clinical utility of enzyme replacement therapies. Such data are presented for velmanase alfa in the treatment of alpha-mannosidosis (AM).Methods: Patient data (n = 33; 14 adults, 19 paediatric) from the clinical development programme for velmanase alfa were integrated in this prospectively-designed analysis of long-term efficacy and safety. Patients who participated in the phase I/II or phase III trials and were continuing to receive treatment after completion of the trials were invited to participate in a comprehensive evaluation visit to assess long-term outcomes. Primary endpoints were changes in serum oligosaccharide and the 3-minute stair climb test (3MSCT).Results: Mean (SD) treatment exposure was 29.3 (15.2) months. Serum oligosaccharide levels were significantly reduced in the overall population at 12 months (mean change: -72.7%, P < 0.001) and remained statistically significant at last observation (−62.8%, P < 0.001). A mean improvement of +9.3% in 3MSCT was observed at 12 months (P = 0.013), which also remained statistically significant at last observation (+13.8%, P = 0.004), with a more pronounced improvement detected in the paediatric subgroup. No treatment-emergent adverse events were reported leading to permanent treatment discontinuation.Conclusions: Patients treated with velmanase alfa experienced improvements in biochemical and functional measures that were maintained for up to 4 years. Long term follow-up is important and further supports the use of velmanase alfa as an effective and well-tolerated treatment for AM. Based on the currently available data set, no baseline characteristic can be predictive of treatment outcome. Early treatment during paediatric age showed better outcome in functional endpoints. [ABSTRACT FROM AUTHOR]

Introduction: This phase III, double-blind, randomised, placebo-controlled trial (and extension phase) was designed to assess the efficacy and safety of velmanase alfa (VA) in alpha-mannosidosis (AM) patients.Methods: Twenty-five patients were randomised to weekly 1 mg/kg VA or placebo for 52 weeks. At study conclusion, placebo patients switched to VA; 23 patients continued receiving VA in compassionate-use/follow-on studies and were evaluated in the extension phase [last observation (LO)]. Co-primary endpoints were changes in serum oligosaccharide (S-oligo) and in the 3-min stair-climb test (3MSCT).Results: Mean relative change in S-oligo in the VA arm was −77.6% [95% confidence interval (CI) −81.6 to −72.8] at week 52 and −62.9% (95% CI −85.8 to −40.0) at LO; mean relative change in the placebo arm was −24.1% (95% CI −40.3 to −3.6) at week 52 and −55.7% (95% CI −76.4 to −34.9) at LO after switch to active treatment. Mean relative change in 3MSCT at week 52 was −1.1% (95% CI −9.0 to 7.6) and − % (95% CI −13.4 to 6.5) for VA and placebo, respectively. At LO, the mean relative change was 3.9% (95% CI −5.5 to 13.2) in the VA arm and 9.0% (95% CI −10.3 to 28.3) in placebo patients after switch to active treatment. Similar improvement pattern was observed in secondary parameters. A post hoc analysis investigated whether some factors at baseline could account for treatment outcome; none of those factors were predictive of the response to VA, besides age.Conclusions: These findings support the utility of VA for the treatment of AM, with more evident benefit over time and when treatment is started in the paediatric age. [ABSTRACT FROM AUTHOR]

Mutations in ALDH18A1 can cause autosomal recessive and dominant hereditary spastic paraplegia and autosomal recessive and dominant cutis laxa. ALDH18A1 encodes delta-1-pyrroline-5-carboxylate synthetase (P5CS), which consists of two domains, the glutamate 5-kinase (G5K) and the gamma-glutamyl phosphate reductase (GR5P) domain. The location of the mutations in the gene has influence on whether the amino acid levels are affected. Mutations affecting the G5K domain have previously been found to cause reduced plasma levels of proline, citrulline and arginine, whereas such effect is not seen with mutations affecting the GR5P domain. We present a 19-year old male patient with autosomal recessive spastic paraplegia and compound heterozygosity for two ALDH18A1 mutations, one in each of the P5CS domains. This young man has spastic paraplegia with onset in childhood and temporal lobe epilepsy, but normal levels of proline, ornithine and arginine. To our knowledge, this is the first case with compound heterozygous mutations affecting both P5CS domains, where levels of plasma amino acids have been reported. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to develop an algorithm to prompt early clinical suspicion of mucopolysaccharidosis type I (MPS I).Methods: An international working group was established in 2016 that comprised 11 experts in paediatrics, rare diseases and inherited metabolic diseases. They reviewed real-world clinical cases, selected key signs or symptoms based on their prevalence and specificity and reached consensus about the algorithm. The algorithm was retrospectively tested.Results: An algorithm was developed. In patients under two years of age, kyphosis or gibbus deformity were the key symptoms that raised clinical suspicion of MPS I and in those over two years they were kyphosis or gibbus deformity, or joint stiffness or contractures without inflammation. The algorithm was tested on 35 cases, comprising 16 Hurler, 10 Hurler-Scheie, and nine Scheie patients. Of these 35 cases, 32 (91%) - 16 Hurler, nine Hurler-Scheie and seven Scheie patients - would have been referred earlier if the algorithm had been used.Conclusion: The expert panel developed and tested an algorithm that helps raise clinical suspicion of MPS I and would lead to a more prompt final diagnosis and allow earlier treatment. [ABSTRACT FROM AUTHOR]

Purpose: The aim was to describe the first experience with fertility preservation by cryopreservation of ovarian tissue (OTC) in pre-pubertal girls with galactosemia and further to characterize ovarian follicular morphology and expression of proteins important for ovarian function.Methods: Retrospectively, follicle density was estimated in ovarian cortical tissues from 6 pre-pubertal girls below the age of 12 years diagnosed with galactosemia and from 31 girls below the age of 18 years who had one ovary removed for fertility preservation for other reasons prior to gonadotoxic treatment. Additionally, expression of 4 glycoproteins important for follicle development were analyzed with immunohistochemistry in two galactosemic ovaries (aged 0.9 and 1.7 years) and compared to normal age-matched controls. The proteins included were: anti-Müllerian hormone (AMH) pro-mature and C-terminal, growth differentiation factor-9 (GDF-9), bone morphogenetic protein 15 (BMP-15), and pregnancy-associated plasma protein A (PAPP-A).Results: Girls with galactosemia below the age of 5 years presented with morphological normal follicles and follicle densities within the 95% confidence interval (CI) of controls. No follicles were detected in the ovary from an 11.7-year-old girl with galactosemia. Expression of AMH, GDF-9, BMP-15, and PAPP-A appeared similar in follicles from girls with galactosemia and controls.Conclusions: These findings suggest that young girls with galactosemia maintain follicles in early childhood and fertility cryopreservation may be considered an option in this patient group. The pathophysiology of galactosemia leading to an accelerated follicle loss is unknown and it is currently unknown to what extent transplanted ovarian tissue can sustain fertility in adult life. [ABSTRACT FROM AUTHOR]

Introduction. Management of phenylketonuria (PKU) is achieved through low-phenylalanine (Phe) diet, supplemented with low-protein food and mixture of free-synthetic (FS) amino acid (AA). Casein glycomacropeptide (CGMP) is a natural peptide released in whey during cheese-making and does not contain Phe. Lacprodan® CGMP-20 used in this study contained a small amount of Phe due to minor presence of other proteins/peptides. Objective. The purpose of this study was to compare absorption of CGMP-20 to FSAA with the aim of evaluating short-term effects on plasma AAs as well as biomarkers related to food intake. Methods. This study included 8 patients, who had four visits and tested four drink mixtures (DM1–4), consisting of CGMP, FSAA, or a combination. Plasma blood samples were collected at baseline, 15, 30, 60, 120, and 240 minutes (min) after the meal. AA profiles and ghrelin were determined 6 times, while surrogate biomarkers were determined at baseline and 240 min. A visual analogue scale (VAS) was used for evaluation of taste and satiety. Results. The surrogate biomarker concentrations and VAS scores for satiety and taste were nonsignificant between the four DMs, and there were only few significant results for AA profiles (not Phe). Conclusion. CGMP and FSAA had the overall same nonsignificant short-term effect on biomarkers, including Phe. This combination of FSAA and CGMP is a suitable supplement for PKU patients. [ABSTRACT FROM AUTHOR]

Patients with type 2 diabetes (T2D) and patients with nonalcoholic fatty liver disease (NAFLD) frequently exhibit elevated plasma concentrations of glucagon (hyperglucagonemia). Hyperglucagonemia and α-cell hyperplasia may result from elevated levels of plasma amino acids when glucagon’s action on hepatic amino acid metabolism is disrupted. We therefore measured plasma levels of glucagon and individual amino acids in patients with and without biopsy-verified NAFLD and with and without type T2D. Fasting levels of amino acids and glucagon in plasma were measured, using validated ELISAs and high-performance liquid chromatography, in obese, middle-aged individuals with I) normal glucose tolerance (NGT) and NAFLD, II) T2D and NAFLD, III) T2D without liver disease, and IV) NGT and no liver disease. Elevated levels of total amino acids were observed in participants with NAFLD and NGT compared with NGT controls (1,310 ± 235 µM vs. 937 ± 281 µM, P = 0.03) and in T2D and NAFLD compared with T2D without liver disease (1,354 ± 329 µM vs. 511 ± 235 µM, P < 0.0001). Particularly amino acids with known glucagonotropic effects (e.g., glutamine) were increased. Plasma levels of total amino acids correlated to plasma levels of glucagon also when adjusting for body mass index (BMI), glycated hemoglobin (HbA1c), and cholesterol levels (β = 0.013 ± 0.007, P = 0.024). Elevated plasma levels of total amino acids associate with hyperglucagonemia in NAFLD patients independently of glycemic control, BMI or cholesterol - supporting the potential importance of a “liver-α-cell axis” in which glucagon regulates hepatic amino acid metabolism. Fasting hyperglucagonemia as seen in T2D may therefore represent impaired hepatic glucagon action with increasing amino acids levels. NEW & NOTEWORTHY Hypersecretion of glucagon (hyperglucagonemia) has been suggested to be linked to type 2 diabetes. Here, we show that levels of amino acids correlate with levels of glucagon. Hyperglucagonemia may depend on hepatic steatosis rather than type 2 diabetes. [ABSTRACT FROM AUTHOR]

Fabry disease is an X- linked inherited lysosomal storage disease caused by mutations in the GLA gene encoding the lysosomal enzyme alpha-galactosidase A (α-Gal A). The possible pathological significance of the D313Y variant in the GLA gene has not been verified and it may be a Fabry variant. Our aim was to elucidate whether the presence of the D313Y variant influenced the α-Gal A activity or resulted in Fabry symptoms or Fabry organ involvement. In two Danish families the presence of the D313Y variant did not result in reduced α-Gal A activity or clinical Fabry manifestations in males, and the presence in Fabry females did not significantly enhance the phenotype of a known causative mutation in the GLA gene (G271S). Our findings indicate that the D313Y variant is not causative to nor enhancing Fabry disease phenotype. The D313Y variant in the GLA gene was not disease causative in 2 Danish families. Investigating male family members were crucial in excluding the Fabry phenotype, and thus very important for proper genetic counceling of all family members, as well as overdiagnosing a devastating genetic disease. [ABSTRACT FROM AUTHOR]

Reference 1 Effraimidis G, Rasmussen ÅK, Dunoe M, Hasholt LF, Wibrand F, Sorensen SS, et al. (2022) Systematic cascade screening in the Danish Fabry Disease Centre: 20 years of a national single-centre experience. The thirteenth author's initials are indexed incorrectly in PubMed. [Extracted from the article]

Purpose: Our aim was to assess the validity of the ICD-10 code for splenomegaly in the Danish National Registry of Patients (DNRP), as well as to investigate which underlying diseases explained the observed splenomegaly. Background: Splenomegaly is a common finding in patients referred to an internal medical department and can be caused by a large spectrum of diseases, including haematological diseases and liver cirrhosis. However, some patients remain without a causal diagnosis, despite extensive medical work-up. Patients and methods: We identified 129 patients through the DNRP, that had been given the ICD-10 splenomegaly diagnosis code in 1994–2013 at Odense University Hospital, Denmark, excluding patients with prior splenomegaly, malignant haematological neoplasia or liver cirrhosis. Medical records were reviewed for validity of the splenomegaly diagnosis, diagnostic work-up, and the underlying disease was determined. The positive predictive value (PPV) with 95% confidence interval (CI) was calculated for the splenomegaly diagnosis code. Patients with idiopathic splenomegaly in on-going follow-up were also invited to be investigated for Gaucher disease. Results: The overall PPV was 92% (95% CI: 85, 96). Haematological diseases were the underlying causal diagnosis in 39%; hepatic diseases in 18%, infectious disease in 10% and other diseases in 8%. 25% of patients with splenomegaly remained without a causal diagnosis. Lymphoma was the most common haematological causal diagnosis and liver cirrhosis the most common hepatic causal diagnosis. None of the investigated patients with idiopathic splenomegaly had Gaucher disease. Conclusion: Our findings show that the splenomegaly diagnosis in the DNRP is valid and can be used in registry-based studies. However, because of suspected significant under-coding, it should be considered if supplementary data sources should be used in addition, in order to attain a more representative population. Haematological diseases were the most common cause, however in a large fraction of patients no causal diagnosis was found. [ABSTRACT FROM AUTHOR]

Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is a rare X-linked recessive disease caused by deficiency of the lysosomal enzyme iduronate-2-sulphatase, leading to progressive accumulation of glycosaminoglycans in nearly all cell types, tissues and organs. Clinical manifestations include severe airway obstruction, skeletal deformities, cardiomyopathy and, in most patients, neurological decline. Death usually occurs in the second decade of life, although some patients with less severe disease have survived into their fifth or sixth decade. Until recently, there has been no effective therapy for MPS II, and care has been palliative. Enzyme replacement therapy (ERT) with recombinant human iduronate-2-sulphatase (idursulfase), however, has now been introduced. Weekly intravenous infusions of idursulfase have been shown to improve many of the signs and symptoms and overall wellbeing in patients with MPS II. This paper provides an overview of the clinical manifestations, diagnosis and symptomatic management of patients with MPS II and provides recommendations for the use of ERT. The issue of treating very young patients and those with CNS involvement is also discussed. ERT with idursulfase has the potential to benefit many patients with MPS II, especially if started early in the course of the disease. [ABSTRACT FROM AUTHOR]

Background: Patients with urea cycle disorders (UCDs) have an increased risk of neurological disease manifestation. Aims: Determining the effect of diagnostic and therapeutic interventions on the neurological outcome. Methods: Evaluation of baseline, regular follow-up and emergency visits of 456 UCD patients prospectively followed between 2011 and 2015 by the E-IMD patient registry. Results: About two-thirds of UCD patients remained asymptomatic until age 12 days [i.e. the median age at diagnosis of patients identified by newborn screening (NBS)] suggesting a potential benefit of NBS. In fact, NBS lowered the age at diagnosis in patients with late onset of symptoms (>28 days), and a trend towards improved long-term neurological outcome was found for patients with argininosuccinate synthetase and lyase deficiency as well as argininemia identified by NBS. Three to 17 different drug combinations were used for maintenance therapy, but superiority of any single drug or specific drug combination above other combinations was not demonstrated. Importantly, non-interventional variables of disease severity, such as age at disease onset and peak ammonium level of the initial hyperammonemic crisis (cut-off level: 500 μmol/L) best predicted the neurological outcome. Conclusions: Promising results of NBS for late onset UCD patients are reported and should be re-evaluated in a larger and more advanced age group. However, non-interventional variables affect the neurological outcome of UCD patients. Available evidence-based guideline recommendations are currently heterogeneously implemented into practice, leading to a high variability of drug combinations that hamper our understanding of optimised long-term and emergency treatment. [ABSTRACT FROM AUTHOR]

Background and aim: To describe current diagnostic and therapeutic strategies in organic acidurias (OADs) and to evaluate their impact on the disease course allowing harmonisation. Methods: Datasets of 567 OAD patients from the E-IMD registry were analysed. The sample includes patients with methylmalonic (MMA, n = 164), propionic (PA, n = 144) and isovaleric aciduria (IVA, n = 83), and glutaric aciduria type 1 (GA1, n = 176). Statistical analysis included description and recursive partitioning of diagnostic and therapeutic strategies, and odds ratios (OR) for health outcome parameters. For some analyses, symptomatic patients were divided into those presenting with first symptoms during (i.e. early onset, EO) or after the newborn period (i.e. late onset, LO). Results: Patients identified by newborn screening (NBS) had a significantly lower median age of diagnosis (8 days) compared to the LO group (363 days, p < 0.001], but not compared to the EO group. Of all OAD patients 71 % remained asymptomatic until day 8. Patients with cobalamin-nonresponsive MMA (MMA-Cbl) and GA1 identified by NBS were less likely to have movement disorders than those diagnosed by selective screening (MMA-Cbl: 10 % versus 39 %, p = 0.002; GA1: 26 % versus 73 %, p < 0.001). For other OADs, the clinical benefit of NBS was less clear. Reported age-adjusted intake of natural protein and calories was significantly higher in LO patients than in EO patients reflecting different disease severities. Variable drug combinations, ranging from 12 in MMA-Cbl to two in isovaleric aciduria, were used for maintenance treatment. The effects of specific metabolic treatment strategies on the health outcomes remain unclear because of the strong influences of age at onset (EO versus LO), diagnostic mode (NBS versus selective screening), and the various treatment combinations used. Conclusions: NBS is an effective intervention to reduce time until diagnosis especially for LO patients and to prevent irreversible cerebral damage in GA1 and MMA-Cbl. Huge diversity of therapeutic interventions hampers our understanding of optimal treatment. [ABSTRACT FROM AUTHOR]

Background: The clinical presentation of patients with organic acidurias (OAD) and urea cycle disorders (UCD) is variable; symptoms are often non-specific. Aims/methods: To improve the knowledge about OAD and UCD the E-IMD consortium established a web-based patient registry. Results: We registered 795 patients with OAD (n = 452) and UCD (n = 343), with ornithine transcarbamylase (OTC) deficiency (n = 196), glutaric aciduria type 1 (GA1; n = 150) and methylmalonic aciduria (MMA; n = 149) being the most frequent diseases. Overall, 548 patients (69 %) were symptomatic. The majority of them (n = 463) presented with acute metabolic crisis during (n = 220) or after the newborn period (n = 243) frequently demonstrating impaired consciousness, vomiting and/or muscular hypotonia. Neonatal onset of symptoms was most frequent in argininosuccinic synthetase and lyase deficiency and carbamylphosphate 1 synthetase deficiency, unexpectedly low in male OTC deficiency, and least frequently in GA1 and female OTC deficiency. For patients with MMA, propionic aciduria (PA) and OTC deficiency (male and female), hyperammonemia was more severe in metabolic crises during than after the newborn period, whereas metabolic acidosis tended to be more severe in MMA and PA patients with late onset of symptoms. Symptomatic patients without metabolic crises (n = 94) often presented with a movement disorder, mental retardation, epilepsy and psychiatric disorders (the latter in UCD only). Conclusions: The initial presentation varies widely in OAD and UCD patients. This is a challenge for rapid diagnosis and early start of treatment. Patients with a sepsis-like neonatal crisis and those with late-onset of symptoms are both at risk of delayed or missed diagnosis. [ABSTRACT FROM AUTHOR]

Background: Alpha-mannosidosis is caused by mutations in MAN2B1, leading to loss of lysosomal alpha-mannosidase activity. Symptoms include intellectual disabilities, hearing impairment, motor function disturbances, facial coarsening and musculoskeletal abnormalities. Methods: To study the genotype-phenotype relationship for alpha-mannosidosis 66 patients were included. Based on the predicted effect of the mutations and the subcellular localisation of mutant MAN2B1 in cultured cells, the patients were divided into three subgroups. Clinical and biochemical data were collected. Correlation analyses between each of the three subgroups of genotype/ subcellular localisation and the clinical and biochemical data were done to investigate the potential relationship between genotype and phenotype in alpha-mannosidosis. Statistical analyses were performed using the SPSS software. Analyses of covariance were performed to describe the genotype-phenotype correlations. The phenotype parameters were modelled by the mutation group and age as a covariate. P values of <0.05 were considered as statistically significant. Results: Complete MAN2B1 genotypes were established for all patients. We found significantly higher scores in the Leiter-R test, lower concentrations of CSF-oligosaccharides, higher point scores in the Bruininks-Oseretsky Test of Motor Proficiency subtests (BOT-2); Upper limb coordination and Balance, and a higher FVC% in patients in subgroup 3, harbouring at least one variant that allows localisation of the mutant MAN2B1 protein to the lysosomes compared to subgrou 2 and/or subgroup 1 with no lysosomal localization of the mutant MAN2B1 protein. Conclusion: Our results indicate a correlation between the MAN2B1 genotypes and the cognitive function, upper limb coordination, balance, FVC% and the storage of oligosaccharides in CSF. This correlation depends on the subcellular localisation of the mutant MAN2B1 protein. [ABSTRACT FROM AUTHOR]