High-Dose ERT, Rituximab, and Early HSCT in an Infant with Wolman's Disease.

Wolman's disease, a severe form of lysosomal acid lipase deficiency, leads to pathologic lipid accumulation in the liver and gut that, without treatment, is fatal in infancy. Although continued enzyme-replacement therapy (ERT) in combination with dietary fat restriction prolongs life, its therapeutic effect may wane over time. Allogeneic hematopoietic stem-cell transplantation (HSCT) offers a more definitive solution but carries a high risk of death. Here we describe an infant with Wolman's disease who received high-dose ERT, together with dietary fat restriction and rituximab-based B-cell depletion, as a bridge to early HSCT. At 32 months, the infant was independent of ERT and disease-free, with 100% donor chimerism in the peripheral blood.

Consensus guidelines for the diagnosis and management of isolated sulfite oxidase deficiency and molybdenum cofactor deficiencies.

Sulfite intoxication is the hallmark of four ultrarare disorders that are caused by impaired sulfite oxidase activity due to genetic defects in the synthesis of the molybdenum cofactor or of the apoenzyme sulfite oxidase. Delays on the diagnosis of these disorders are common and have been caused by their unspecific presentation of acute neonatal encephalopathy with high early mortality, followed by the evolution of dystonic cerebral palsy and also by the lack of easily available and reliable diagnostic tests. There is significant variation in survival and in the quality of symptomatic management of affected children. One of the four disorders, molybdenum cofactor deficiency type A (MoCD-A) has recently become amenable to causal treatment with synthetic cPMP (fosdenopterin). The evidence base for the rational use of cPMP is very limited. This prompted the formulation of these clinical guidelines to facilitate diagnosis and support the management of patients. The guidelines were developed by experts in diagnosis and treatment of sulfite intoxication disorders. It reflects expert consensus opinion and evidence from a systematic literature search.

Expanding the clinical spectrum of primary coenzyme Q10 deficiency type 6: The first case with cardiomyopathy.

We report a 19-month-old patient with cardiomyopathy as the first presenting feature of primary COQ10 deficiency-6. This case expands the phenotypic spectrum of this disorder. Furthermore, it shows that genetic testing for primary COQ10 deficiency should be considered in patients with pediatric-onset cardiomyopathy as it can guide treatment options.

A generic emergency protocol for patients with inborn errors of metabolism causing fasting intolerance: A retrospective, single-center study and the generation of www.emergencyprotocol.net.

Patients with inborn errors of metabolism causing fasting intolerance can experience acute metabolic decompensations. Long-term data on outcomes using emergency letters are lacking. This is a retrospective, observational, single-center study of the use of emergency letters based on a generic emergency protocol in patients with hepatic glycogen storage diseases (GSD) or fatty acid oxidation disorders (FAOD). Data on hospital admissions, initial laboratory results, and serious adverse events were collected. Subsequently, the website www.emergencyprotocol.net was generated in the context of the CONNECT MetabERN eHealth project following multiple meetings, protocol revisions, and translations. Representing 470 emergency protocol years, 127 hospital admissions were documented in 54/128 (42%) patients who made use of emergency letters generated based on the generic emergency protocol. Hypoglycemia (here defined as glucose concentration < 3.9 mmol/L) was reported in only 15% of hospital admissions and was uncommon in patients with ketotic GSD and patients with FAOD aged >5 years. Convulsions, coma, or death was not documented. By providing basic information, emergency letters for individual patients with hepatic GSD or the main FAOD can be generated at www.emergencyprotocol.net, in nine different languages. Generic emergency protocols are safe and easy for home management by the caregivers and the first hour in-hospital management to prevent metabolic emergencies in patients with hepatic GSD and medium-chain Acyl CoA dehydrogenase deficiency. The website www.emergencyprotocol.net is designed to support families and healthcare providers to generate personalized emergency letters for patients with hepatic GSD and the main FAOD.

The first European guidelines on phenylketonuria: Usefulness and implications for BH4 responsiveness testing.

OBJECTIVE: This study aimed to investigate and improve the usefulness of the 48-hour BH4 loading test and to assess genotype for BH4 responsiveness prediction, using the new definition of BH4 responsiveness from the European guidelines, as well as an amended definition. METHOD: Applying the definition of the European guidelines (≥100% increase in natural protein tolerance) and an amended definition (≥100% increase in natural protein tolerance or tolerating a safe natural protein intake) to a previous dataset, we first assessed the positive predictive value (PPV) of the 48-hour BH4 loading test using a cutoff value of 30%. Then, we tried to improve this PPV by using different cutoff values and separate time points. Last, using the BIOPKU database, we compared predicted BH4 responsiveness (according to genotype) and genotypic phenotype values (GPVs) in BH4 -responsive and BH4 -unresponsive patients. RESULTS: The PPV of the 48-hour loading test was 50.0% using the definition of the European guidelines, and 69.4% when applying the amended definition of BH4 responsiveness. Higher cutoff values led to a higher PPV, but resulted in an increase in false-negative tests. Parameters for genotype overlapped between BH4 -responsive and BH4 -unresponsive patients, although BH4 responsiveness was not observed in patients with a GPV below 2.4. CONCLUSION: The 48-hour BH4 loading test is not as useful as previously considered and cannot be improved easily, whereas genotype seems mainly helpful in excluding BH4 responsiveness. Overall, the definition of BH4 responsiveness and BH4 responsiveness testing require further attention.

Bone mineral density is within normal range in most adult phenylketonuria patients.

Low bone mineral density (BMD) as a risk factor for fractures has been a long-standing concern in phenylketonuria (PKU). It is hypothesised that the disease itself or the dietary treatment might lead to a low BMD. Previous studies show conflicting results of BMD in PKU due to differences in age, techniques to assess BMD and criteria used. To assess the prevalence of low BMD and define possible risk factors in a large number of adult, early treated PKU (ETPKU) patients. European centres were invited for a survey, collecting retrospective data including results of dual-energy X-ray absorptiometry (DXA) scans of adult ETPKU patients. BMD of 183 adult ETPKU patients aged 18-46 (median age 28, all females premenopausal) years was lower than in the general population at most skeletal sites but the frequency of low BMD (Z-score <-2) was at maximum 5.5%. No risk factors for low BMD in PKU patients could be identified. Low BMD occurs only in a small subset of PKU patients. DXA scans should be considered for well controlled patients from age 35-40 years and up and on indication in those PKU patients considered to be at increased risk for fractures.

Safety issues associated with dietary management in patients with hepatic glycogen storage disease.

INTRODUCTION: Hepatic glycogen storage diseases (GSDs) are a group of inherited disorders of carbohydrate metabolism for which dietary management is the cornerstone. Safety and acute complications associated with dietary management have been poorly documented. We hypothesized that safety issues and complications associated with dietary management are prevalent amongst patients with these ultra-rare disorders. METHODS: A questionnaire was developed consisting of 40 questions and was distributed via eight GSD patient organizations from multiple countries. Respondents were (caregivers of) patients with self-reported hepatic GSD. RESULTS: 249 GSD patients from 26 countries responded with a median age of 14.8 years (range: 0.5-66.1). Although management was considered safe by 71% of patients, 51% reported at least one acute complication associated with dietary management, with a total number of 425 reported complications. Most frequently reported causes were: not waking up by an alarm clock (n = 70), forgetting a meal (n = 57) and infections (n = 43). Most frequently reported complications were: hypoglycemia (n = 112), hospital admissions (n = 79) and drowsiness (n = 74). Most complications occurred before the age of 12 years (82%; 637/774 total number of reported events) and during night time (63%; 340/536). Only 61% (152/249) of the GSD patients reported using a written emergency protocol. CONCLUSIONS: Safety issues and complications associated with dietary management are prevalently reported by (caregivers of) 249 GSD patients. A discrepancy has been observed between the patient's perspective on safety of dietary management and occurrence of complications as a result of dietary management.

A preliminary study of telemedicine for patients with hepatic glycogen storage disease and their healthcare providers: from bedside to home site monitoring.

BACKGROUND: The purpose of this project was to develop a telemedicine platform that supports home site monitoring and integrates biochemical, physiological, and dietary parameters for individual patients with hepatic glycogen storage disease (GSD). METHODS AND RESULTS: The GSD communication platform (GCP) was designed with input from software developers, GSD patients, researchers, and healthcare providers. In phase 1, prototyping and software design of the GCP has occurred. The GCP was composed of a GSD App for patients and a GSD clinical dashboard for healthcare providers. In phase 2, the GCP was tested by retrospective patient data entry. The following software functionalities were included (a) dietary registration and prescription module, (b) emergency protocol module, and (c) data import functions for continuous glucose monitor devices and activity wearables. In phase 3, the GSD App was implemented in a pilot study of eight patients with GSD Ia (n = 3), GSD IIIa (n = 1), and GSD IX (n = 4). Usability was measured by the system usability scale (SUS). The mean SUS score was 64/100 [range: 38-93]. CONCLUSIONS: This report describes the design, development, and validation process of a telemedicine platform for patients with hepatic GSD. The GCP can facilitate home site monitoring and data exchange between patients with hepatic GSD and healthcare providers under varying circumstances. In the future, the GCP may support cross-border healthcare, second opinion processes and clinical trials, and could possibly also be adapted for other diseases for which a medical diet is the cornerstone.

A False-Negative Newborn Screen for Tyrosinemia Type 1-Need for Re-Evaluation of Newborn Screening with Succinylacetone.

Undiagnosed and untreated tyrosinemia type 1 (TT1) individuals carry a significant risk for developing liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Elevated succinylacetone (SA) is pathognomonic for TT1 and therefore often used as marker for TT1 newborn screening (NBS). While SA was long considered to be elevated in every TT1 patient, here we present a recent false-negative SA TT1 screen. A nine-year-old boy presented with HCC in a cirrhotic liver. Additional tests for the underlying cause unexpectedly revealed TT1. Nine years prior, the patient was screened for TT1 via SA NBS with a negative result: SA 1.08 µmol/L, NBS cut-off 1.20 µmol/L. To our knowledge, this report is the first to describe a false-negative result from the TT1 NBS using SA. False-negative TT1 NBS results may be caused by milder TT1 variants with lower SA excretion. Such patients are more likely to be missed in NBS programs and can be asymptomatic for years. Based on our case, we advise TT1 to be considered in patients with otherwise unexplained liver pathology, including fibrosis, cirrhosis and HCC, despite a previous negative TT1 NBS status. Moreover, because the NBS SA concentration of this patient fell below the Dutch cut-off value (1.20 µmol/L at that time), as well as below the range of cut-off values used in other countries (1.29-10 µmol/L), it is likely that false-negative screening results for TT1 may also be occurring internationally. This underscores the need to re-evaluate TT1 SA NBS programs.

A Delphi Survey Study to Formulate Statements on the Treatability of Inherited Metabolic Disorders to Decide on Eligibility for Newborn Screening.

The Wilson and Jungner (W&J) and Andermann criteria are meant to help select diseases eligible for population-based screening. With the introduction of next-generation sequencing (NGS) methods for newborn screening (NBS), more inherited metabolic diseases (IMDs) can technically be included, and a revision of the criteria was attempted. This study aimed to formulate statements and investigate whether those statements could elaborate on the criterion of treatability for IMDs to decide on eligibility for NBS. An online Delphi study was started among a panel of Dutch IMD experts (EPs). EPs evaluated, amended, and approved statements on treatability that were subsequently applied to 10 IMDs. After two rounds of Delphi, consensus was reached on 10 statements. Application of these statements selected 5 out of 10 IMDs proposed for this study as eligible for NBS, including 3 IMDs in the current Dutch NBS. The statement: 'The expected benefit/burden ratio of early treatment is positive and results in a significant health outcome' contributed most to decision-making. Our Delphi study resulted in 10 statements that can help to decide on eligibility for inclusion in NBS based on treatability, also showing that other criteria could be handled in a comparable way. Validation of the statements is required before these can be applied as guidance to authorities.

Cervical high-intensity intramedullary lesions in achondroplasia: aetiology, prevalence and clinical relevance.

OBJECTIVES: In achondroplastic patients with slight complaints of medullary compression the cervical spinal cord regularly exhibits an intramedullary (CHII) lesion just below the craniocervical junction with no signs of focal compression on the cord. Currently, the prevalence of the lesion in the general achondroplastic population is studied and its origin is explored. METHODS: Eighteen achondroplastic volunteers with merely no clinical signs of medullary compression were subjected to dynamic magnetic resonance imaging (MRI). The presence of a CHII lesion and craniocervical medullary compression in flexed and retroflexed craniocervical positions was explored. Several morphological characteristics of the craniocervical junction, possibly related to compression on the cord, were assessed. RESULTS: A CHII lesion was observed in 39% of the subjects and in only one of these was compression at the craniocervical junction present. Consequently, no correlation between the CHII lesion and compression could be established. None of the morphological characteristics demonstrated a correlation with the CHII lesion, except thinning of the cord at the site of the CHII lesion. CONCLUSIONS: CHII lesions are a frequent finding in achondroplasia, and are generally unaccompanied by clinical symptoms or compression on the cord. Further research focusing on the origin of CHII lesions and their clinical implications is warranted. KEY POINTS : • MRI now reveals exquisite detail of the cervical spinal cord. • Cervical cord lesions are observed in one third of the achondroplastic population. • These lesions yield high signal intensity on T2 weighted MRI. • They are generally unaccompanied by clinical symptoms or cord compression. • Their aetiology is unclear and seems to be unrelated to mechanical causes.

Communication of an Abnormal Metabolic New-Born Screening Result in The Netherlands: The Parental Perspective.

In the Netherlands, abnormal New-Born Screening (NBS) results are communicated to parents by the general practitioner (GP). Good communication and consequential trust in professionals is of the utmost importance in the treatment of phenylketonuria (PKU). The aim of this study was to assess parental satisfaction regarding the communication of an abnormal NBS result for PKU in the Netherlands. An email containing the link to a web-based questionnaire was sent by the Dutch PKU Association to their members. Responses to open questions were categorized, data of both open and closed questions were analysed with descriptive statistics and the Chi-Square test using SPSS. Out of 113 parents of a child with PKU (born between 1979 and 2020), 68 stated they were overall unsatisfied with the first communication of the NBS result. Seventy-five parents indicated that wrong or no information about PKU was given. A significant decrease was found in the number of parents being contact by their own GP over the course of 40 years (p < 0.05). More than half of all parents were overall unsatisfied with the first communication of the abnormal NBS result for PKU. Further research on how to optimize communication of an abnormal NBS results is necessary.

Dietary treatment in Dutch children with phenylketonuria: An inventory of associated social restrictions and eating problems.

OBJECTIVES: Dietary treatment in phenylketonuria (PKU) is known to cause eating problems, but knowledge of both prevalence and magnitude, especially for social restrictions, is scarce. Our aim was to evaluate the social restrictions and eating problems that children with PKU and their caregivers experience with dietary treatment. METHODS: A web-based questionnaire, based on the Behavioral Pediatrics Feeding Assessment Scale with additional PKU-specific questions, was developed in close collaboration with and distributed by the Dutch PKU Association, which sent an e-mail to its members containing a link to the questionnaire. The questionnaire was completed by caregivers of children with PKU in the Netherlands and caregivers of age-matched children without PKU. Data were analyzed with the Kruskal-Wallis and Mann-Whitney U test using SPSS. RESULTS: Compared with caregivers of children in the control group (ages 1-16 y; n = 50), caregivers of children with PKU (ages 1-16 y; n = 57) reported more difficulty in offering food variety, experienced more stress when eating an evening meal outside the home and during vacation, and were stricter about (accidental) spilling of food during dinner by the child (P < 0.05). They also reported to being angrier, more frustrated, and more anxious when feeding their child, and they more often felt that their child's eating pattern had a negative influence on the child's general health (P < 0.05). CONCLUSION: This pilot study provides further evidence that restriction of social activities and eating problems associated with dietary restrictions is more common in children with PKU, and warrants awareness on this topic among professionals working with these children.

A retrospective study of eating and psychosocial problems in patients with hepatic glycogen storage diseases and idiopathic ketotic hypoglycemia: Towards a standard set of patient-reported outcome measures.

There is a paucity in literature on eating and psychosocial problems in patients with hepatic glycogen storage disease (GSD) and idiopathic ketotic hypoglycemia (IKH), problems that can greatly affect quality of life. This is a monocentre, retrospective, observational mixed method study of patients with hepatic GSD or IKH treated at the Beatrix Children's Hospital Groningen, who had been referred to SeysCentra, a specialist centre for the treatment of eating problems. Additionally, a systematic literature review has been performed to identify instruments to quantify patient-reported outcome measures of psychosocial problems in hepatic GSD patients. Sixteen patients from 12 families were included with ages ranging between 3 and 24 years. Five out of sixteen patients were diagnosed with Avoidant/Restrictive Food Intake Disorder and six patients showed characteristics of this disorder. Fourteen patients experienced sleeping problems, and 11 out of 12 parent couples experienced stress about the illness of their child. We subsequently identified 26 instruments to quantify patient-reported outcome measures for GSD patients. This study demonstrates that GSD patients can develop Avoidant/Restrictive Food Intake Disorder influencing quality of life at multiple domains. The identification of instruments to assess psychosocial wellbeing is an important step towards a standard set of patient-reported outcome measures.

Ketogenic diet as a glycine lowering therapy in nonketotic hyperglycinemia and impact on brain glycine levels.

BACKGROUND: Nonketotic hyperglycinemia (NKH) is a severe neurometabolic disorder characterized by increased glycine levels. Current glycine reduction therapy uses high doses of sodium benzoate. The ketogenic diet (KD) may represent an alternative method of glycine reduction. AIM: We aimed to assess clinical and biochemical effects of two glycine reduction strategies: high dose benzoate versus KD with low dose benzoate. METHODS: Six infants with NKH were first treated with high dose benzoate therapy to achieve target plasma glycine levels, and then switched to KD with low dose benzoate. They were evaluated as clinically indicated by physical examination, electroencephalogram, plasma and cerebral spinal fluid amino acid levels. Brain glycine levels were monitored by magnetic resonance spectroscopy (MRS). RESULTS: Average plasma glycine levels were significantly lower with KD compared to benzoate monotherapy by on average 28%. Two infants underwent comparative assessments of brain glycine levels via serial MRS. A 30% reduction of brain glycine levels was observed in the basal ganglia and a 50% reduction in the white matter, which remained elevated above normal, and was equivalent between the KD and high dose benzoate therapies. CSF analysis obtained while participants remained on the KD showed a decrease in glycine, serine and threonine levels, reflecting their gluconeogenetic usage. Clinically, half the patients had seizure reduction on KD, otherwise the clinical impact was variable. CONCLUSION: KD is an effective glycine reduction method in NKH, and may provide a more consistent reduction in plasma glycine levels than high-dose benzoate therapy. Both high-dose benzoate therapy and KD equally reduced but did not normalize brain glycine levels even in the setting of low-normal plasma glycine.

Successful Treatment of Hereditary Folate Malabsorption With Intramuscular Folinic Acid.

BACKGROUND: Hereditary folate malabsorption is a multisystem disease owing to biallelic variants in the gene encoding the proton-coupled folate transporter. Hereditary folate malabsorption is treated with folinic acid, aimed to restore blood and cerebrospinal fluid folate levels. Little is known as to whether oral or intramuscular supplementation of folinic acid is most effective. METHODS: Here we describe a one-year-old boy with hereditary folate malabsorption presenting with the typical features including failure to thrive, aphthous stomatitis, macrocytic anemia along with severe developmental impairment and epilepsy, as well as a magnetic resonance imaging of the brain showing bilateral occipital, cortical calcifications characteristic of hereditary folate malabsorption. We compared the effect of treatment with oral folinic acid versus intramuscular folinic acid supplementation by measuring plasma and cerebrospinal fluid folate levels. RESULTS: Compared with oral administration, intramuscular treatment resulted in higher folate levels in blood and, most importantly, normalization of folate levels in cerebrospinal fluid. Clinically, nearly all systemic and neurological symptoms resolved. CONCLUSION: Normal cerebrospinal fluid folate levels can be achieved in individuals with hereditary folate malabsorption with intramuscular (but not with oral) administration of folinic acid.

Biomarkers of Micronutrients in Regular Follow-Up for Tyrosinemia Type 1 and Phenylketonuria Patients.

Phenylketonuria (PKU) is treated with dietary restrictions and sometimes tetrahydrobiopterin (BH4). PKU patients are at risk for developing micronutrient deficiencies, such as vitamin B12 and folic acid, likely due to their diet. Tyrosinemia type 1 (TT1) is similar to PKU in both pathogenesis and treatment. TT1 patients follow a similar diet, but nutritional deficiencies have not been investigated yet. In this retrospective study, biomarkers of micronutrients in TT1 and PKU patients were investigated and outcomes were correlated to dietary intake and anthropometric measurements from regular follow-up measurements from patients attending the outpatient clinic. Data was analyzed using Kruskal-Wallis, Fisher's exact and Spearman correlation tests. Furthermore, descriptive data were used. Overall, similar results for TT1 and PKU patients (with and without BH4) were observed. In all groups high vitamin B12 concentrations were seen rather than B12 deficiencies. Furthermore, all groups showed biochemical evidence of vitamin D deficiency. This study shows that micronutrients in TT1 and PKU patients are similar and often within the normal ranges and that vitamin D concentrations could be optimized.

Hereditary folate malabsorption due to a mutation in the external gate of the proton-coupled folate transporter SLC46A1.

Hereditary folate malabsorption (HFM) is an autosomal recessive disorder characterized by impaired intestinal folate absorption and impaired folate transport across the choroid plexus due to loss of function of the proton-coupled folate transporter (PCFT-SLC46A1). We report a novel mutation, causing HFM, affecting a residue located in the 11th transmembrane helix within the external gate. The mutant N411K-PCFT was stable, trafficked to the cell membrane, and had sufficient residual activity to characterize the transport defect and the structural requirements at this site for gate function. The influx Vmax of the N411K mutant was markedly decreased, as was the affinity for most, but not all, folate/antifolate substrates. The greatest loss of activity was for 5-methyltetrahydrofolate. Substitutions with positive charged residues resulted in a loss of activity (arginine > lysine > histidine). Function was retained for the negative charged aspartate, but not the larger glutamate substitutions, whereas the bulky hydrophobic (leucine), or polar (glutamine) substitutions, were tolerated. Homology models of PCFT, in the inward and outward open conformations, based upon the mammalian Glut5 fructose transporter structures, localize Asn411 protruding into the aqueous pathway. This is most prominent when the carrier is in the inward open conformation when the external gate is closed. Mutations at this site likely result in highly specific steric and electrostatic interactions between the Asn411-substituted, and other, residues in the gate region that impede carrier function. The substrate specificity of the N411K mutant may be due to alterations of substrate flows through the external gate, downstream allosteric alterations in the folate-binding pocket, or both.

Molybdenum cofactor deficiency type A: Prenatal monitoring using MRI.

Molybdenum cofactor deficiency type A (MoCD-A) is an inborn error of metabolism presenting early after birth with severe seizures. Recently, experimental substitution treatment with cyclic pyranopterin monophosphate (cPMP) has become available. Because prenatal data is scarce, we report data of prenatal Magnetic Resonance Imaging (MRI) in two cases with MoCD-A demonstrating signs of possible early brain injury. Prenatal MRI can be used for monitoring in MoCD-A to guide decision-making in timing of delivery.