Inherited Metabolic Disorders Research Articles

Application of metabolite set enrichment analysis on untargeted metabolomics data prioritises relevant pathways and detects novel biomarkers for inherited metabolic disorders.

Untargeted metabolomics (UM) allows for the simultaneous measurement of hundreds of metabolites in a single analytical run. The sheer amount of data generated in UM hampers its use in patient diagnostics because manual interpretation of all features is not feasible. Here, we describe the application of a pathway‐based metabolite set enrichment analysis method to prioritise relevant biological pathways in UM data. We validate our method on a set of 55 patients with a diagnosed inherited metabolic disorder (IMD) and show that it complements feature‐based prioritisation of biomarkers by placing the features in a biological context. In addition, we find that by taking enriched pathways shared across different IMDs, we can identify common drugs and compounds that could otherwise obscure genuine disease biomarkers in an enrichment method. Finally, we demonstrate the potential of this method to identify novel candidate biomarkers for known IMDs. Our results show the added value of pathway‐based interpretation of UM data in IMD diagnostics context.

Allogeneic hematopoietic stem cell transplantation for inherited metabolic disorders.

Allogeneic hematopoietic stem cell transplantation (HSCT) has been used to treat patients with inherited metabolic disorders (IMDs) for more than 40years. In the first two decades, various IMDs were treated by HSCT with a wide variety of donor sources and conditioning regimens selected at the institutional level. However, HSCT was not always successful due to post-transplant complications such as graft failure. In the third decade, myeloablative conditioning with targeted busulfan-based pharmacokinetic monitoring was established as an optimal conditioning regimen, and unrelated cord blood was recognized as an excellent donor source. During the fourth decade, further improvements were made to transplant procedures, including modification of the conditioning regimen, and the survival rate after HSCT markedly improved. Simultaneously, several long-term observational studies for patients after HSCT clarified its therapeutic effects on growth and development of cognitive function, fine motor skills, and activities of daily living when compared with enzyme replacement therapy. Although immune-mediated cytopenia was newly highlighted as a problematic morbidity after HSCT for IMDs, especially in younger patients who received unrelated cord blood, a recent study with rituximab added to the conditioning raised expectations that this issue can be overcome.

The current state of adult metabolic medicine in the United States: Results of a nationwide survey

Patients with inherited metabolic disorders (IMDs) now have improved health outcomes and increased survival into adulthood. There is scant evidence on managing adults with IMDs. We present an analysis of current care practices for adults with IMDs in the United States. We created and distributed an online survey to US members of the Society of Inherited Metabolic Disorders. The survey addressed ambulatory care, acute management, and health care transition (HCT) practices of adults with IMDs. The survey was completed by 91 providers from 73 institutions. Most adult patients with IMDs receive lifelong care from a single metabolic clinician, predominantly in pediatric clinic settings. Adults receive comprehensive ambulatory metabolic care, but fewer trainees participate compared with pediatric visits. Most acute IMD management occurs in pediatric hospitals. Clinician comfort with HCT increased the frequency of HCT planning. Overall, all respondents felt that providing specialized care to adults with IMDs is high value. Our survey demonstrates the paucity of clinical resources dedicated to adult metabolic medicine. Care is fragmented and varies by medical system. Interest in HCT is robust but would benefit from standardized practices. Our findings reinforce the need for greater focus on adult metabolic medicine in the United States.

Targeting the Diagnosis in an Adolescent with Epilepsy and Intellectual Disability through Next-Generation Metabolic Screening.

A 16-year-old boy, born to consanguineous parents in Syria and living as a refugee in the Netherlands since the age of 14 years, was admitted to our tertiary pediatric intensive care unit with status epilepticus after discontinuation of valproic acid. He was treated with valproic acid since early infancy for seizures of unknown cause, but as he had been seizure-free for many years, discontinuation was attempted. Brain magnetic resonance imaging showed nonspecific white matter abnormalities and changes attributable to prolonged seizures or meningitis, such as brain fullness with mildly effaced ventricles and mild meningeal enhancement in the precentral gyri. Chromosomal microarray analysis showed a normal XY profile. Biochemical screening for inherited metabolic disorders (IMD) was performed through next-generation metabolic screening (NGMS) (1), an ultra-high performance liquid chromatography quadrupole time-of-flight mass spectrometry (Agilent 6545 QTOF) metabolomics approach, validated under ISO15189 accreditation as first-tier diagnostic screening for IMD in our laboratory. In short, a panel of known IMD-related metabolites is filtered from the untargeted metabolomics data for initial diagnostic interpretation. For each patient, significantly altered metabolites are identified, and a semiquantitative fold change compared to controls is evaluated. The NGMS IMD-metabolite panel is frequently updated to include novel diagnostic metabolites encountered in the untargeted metabolomics data in a research setting. For example, the metabolites 2S, 6S- and 2S; 6R-oxopropylpiperidine-2-carboxylic acid; 6-oxopiperidine-2-carboxylic acid; and 6-(carboxymethyl)piperidine-2-carboxylic acid were recently added to the panel as novel biomarkers for pyridoxine dependent epilepsy due to deficiency of α-aminoadipic semialdehyde dehydrogenase, encoded by ALDH7A1 (PDE-ALDH7A1) (2, 3). PDE-ALDH7A1 is a defect in lysine catabolism (Fig. 1), leading to secondary deficiency of pyridoxine (vitamin B6) through complexation with accumulating piperideine-6-carboxylic acid.

Breastfeeding practices for infants with inherited metabolic disorders: A survey of registered dietitians in the United States and Canada

BackgroundBreast milk is considered the optimal first food for infants. Breastfeeding infants with inherited metabolic disorders (IMDs) is complex due to the critical need to manage intake of specific macronutrients depending on the type of IMD. ObjectiveTo describe current practices of registered dietitians (RD) who treat patients with IMDs regarding the incorporation of breastmilk into disease management. DesignCross-sectional survey.Participants/setting:online survey conducted in December 2020 of 66 RDs who treat patients with IMDs in the United States and Canada.Main outcome measures:the survey focused on personal demographics, clinic characteristics, institutional feeding protocols for infants with IMDs, confidence in working with breastfeeding parents of infants with IMDs, and knowledge about breastfeeding with questions derived from the Iowa Infant Feeding Attitudes Scale.Statistical analysis performed:.Fisher's exact test was used for comparisons. ResultsMost RDs were confident or very confident in their ability to provide nutritional guidance for breastfeeding infants with IMDs. Half of the participants reported that they had received training on breastfeeding of infants of IMDs. For infants with phenylketonuria (PKU), most RDs include breastfeeding as part of nutritional management. Breastfeeding is less likely to be used in the management of infants with other aminoacidopathies and fatty acid oxidation disorders. Use of measured expressed breastmilk was preferred, including for aminoacidopathies other than PKU, organic acidemias, and fatty acid oxidation disorders. Knowledge about breastfeeding varied. Less than half of RDs referred mothers to a lactation specialist somewhat regularly or frequently. ConclusionsOur survey found variation in experience, training, and use of breastfeeding-related nutritional management protocols in IMDs. A lack of formal training programs for the nutritional management of IMDs may account for some of this variation. Future research, including the collection of more detailed disorder-specific data, could help contribute to the development of clinical practice guidelines.

What are the clues for an inherited metabolic disorder in Reye syndrome? A single Centre study of 58 children.

Reye Syndrome is an acute encephalopathy with increased liver enzymes and blood ammonia, without jaundice. The prevalence of an underlying inherited metabolic disorder (IMD) is unclear, nor the clinical or biological factors directing toward this diagnosis. Our aims were to define these clues in a large series of patients. We retrospectively studied all patients with Reye admitted in our institution from 1995. We defined 3 groups: Group 1 with a confirmed IMD, Group 2 considered as free of IMD, Group 3 unclassified. Statistical analysis compared patients in Groups 1 and 2, to find criteria for a diagnosis of IMD. Fifty-eight children were included; 41 (71%) had a confirmed IMD, 12 (20%) were free of IMD, and 5 remained unclassified. IMDs included Urea Cycle Disorders (51%), Fatty-Acid Oxidation Disorders (24%), ketogenesis defects (5%), other mitochondrial energy metabolism defects (10%), NBAS mutation (7%), Glycosylation Disorders (2%). In Group 2, the trigger was a viral infection, or a drug, deferasirox in three children. Univariate analysis showed that onset before 2 years-old, recurrent Reye and the association with rhabdomyolysis were significantly associated with IMD. Blood ammonia was a poor discriminating marker. All children were admitted into the intensive care unit, 23% needed continuous venovenous hemodialysis and one died from brain oedema. Metabolic tests should be performed early in all cases of Reye, regardless of triggers. As they can be inconclusive, we suggest to systematically go to Next-Generation Sequencing study. These children should be transferred early to a specialized unit.

Clinical and biochemical footprints of inherited metabolic disorders. VII. Ocular phenotypes.

Ocular manifestations are observed in approximately one third of all inherited metabolic disorders (IMDs). Although ocular involvement is not life-threatening, it can result in severe vision loss, thereby leading to an additional burden for the patient. Retinal degeneration with or without optic atrophy is the most frequent phenotype, followed by oculomotor problems, involvement of the cornea and lens, and refractive errors. These phenotypes can provide valuable clues that contribute to its diagnosis. In this issue we found 577 relevant IMDs leading to ophthalmologic manifestations. This article is the seventh of a series attempting to create and maintain a comprehensive list of clinical and metabolic differential diagnoses according to system involvement.

Pros and Cons of Telemedicine for Inherited Metabolic Disorders in a Developing Country During the COVID-19 Pandemic.

Introduction: The COVID-19 pandemic has led to considerable changes in the health care system. Experts suggested that individuals protect themselves through social isolation during the pandemic, and consequently, the importance of telemedicine came to be understood for patients with chronic diseases. Telemedicine started to be used in developing countries where the appropriate infrastructure was lacking earlier. The present study investigates the level of satisfaction of patients with inherited metabolic disorders (IMDs) with telemedicine. Methods: This prospective study was conducted by making use of a new video appointment program that ensures the privacy of the patients in video-based consultations. The sociodemographic characteristics of the patients, their clinical status, their views on the telemedicine system, and their levels of satisfaction were questioned. Results: Overall, 174 patients were included in the study. The most common diagnoses were aminoacidopathies, lipid metabolism disorders, biotinidase deficiency, and lysosomal/peroxisomal diseases. More than half of the parents (67.6%) who lived in another city reported accommodation issues when coming to the hospital, and most believed telemedicine would save them time (93.1%) and money for travel (81.6%). The lack of laboratory and radiological tests (83.9%) was stated as the main disadvantage by most parents. Almost all the parents (96.6%) stated that they would opt for telemedicine if it became available in daily practice. The overall satisfaction rate was 94.6 (±10.1)/100. Conclusions: The present research is the most extensive cohort study to date assessing telemedicine in patients with IMDs and it highlights the importance of telemedicine, especially in developing countries during the COVID-19 pandemic.

Application of a Novel Algorithm for Expanding Newborn Screening for Inherited Metabolic Disorders across Europe.

Inherited metabolic disorders (IMDs) are mostly rare, have overlapping symptoms, and can be devastating and progressive. However, in many disorders, early intervention can improve long-term outcomes, and newborn screening (NBS) programmes can reduce caregiver stress in the journey to diagnosis and allow patients to receive early, and potentially pre-symptomatic, treatment. Across Europe there are vast discrepancies in the number of IMDs that are screened for and there is an imminent opportunity to accelerate the expansion of evidence-based screening programmes and reduce the disparities in screening programmes across Europe. A comprehensive list of IMDs was created for analysis. A novel NBS evaluation algorithm, described by Burlina et al. in 2021, was used to assess and prioritise IMDs for inclusion on expanded NBS programmes across Europe. Forty-eight IMDs, of which twenty-one were lysosomal storage disorders (LSDs), were identified and assessed with the novel NBS evaluation algorithm. Thirty-five disorders most strongly fulfil the Wilson and Jungner classic screening principles and should be considered for inclusion in NBS programmes across Europe. The recommended disorders should be evaluated at the national level to assess the economic, societal, and political aspects of potential screening programmes.

OP033: An integrated multiomic panel as an excellent tool for the genetic diagnosis of metabolic diseases: Our first 3,720 patients

Inherited metabolic disorders (IMDs) constitute a vast, complex, and important group of rare diseases caused by disruption of metabolic pathway(s). Currently, over 1,400 IMDs are recognized. Although each disorder by itself is rare, they represent a common group of diseases with a prevalence of 1 in 784–2,555. The past decade has seen revolutionary changes in the diagnosis and discovery of IMDs, as well as in the development of new therapies. Early disease recognition and treatment are, in many cases, critical for preventing neurological impairment and/or death of the patient.

172 Ornithine transcarbamylase deficiency – life-threatening complications in pregnancy and postpartum period

Introduction: Inherited metabolic disorders (IMDs) are in most cases numbered among rare diseases. As the therapy has been improving during the past decades, numbers of pregnant women affected by these disorders are rising. Therefore, awareness of the diseases which may affect the mother or the fetus are becoming crucial. Among these disorders are urea cycle defects, the most common of them being ornithine transcarbamylase (OTC) deficiency. This X-linked IMD is typical by diverse symptoms varying from asymptomatic individuals to severe hyperammonemia leading to coma and death.

Dietetic Management of Adults with Phenylketonuria (PKU) in the UK: A Care Consensus Document.

There is an increasing number of adults and elderly patients with phenylketonuria (PKU) who are either early, late treated, or untreated. The principal treatment is a phenylalanine-restricted diet. There is no established UK training for dietitians who work with adults within the specialty of Inherited Metabolic Disorders (IMDs), including PKU. To address this, a group of experienced dietitians specializing in IMDs created a standard operating procedure (SOP) on the dietetic management of adults with PKU to promote equity of care in IMD dietetic services and to support service provision across the UK. The group met virtually over a period of 12 months until they reached 100% consensus on the SOP content. Areas of limited evidence included optimal blood phenylalanine reporting times to patients, protein requirements in older adults, management of weight and obesity, and management of disordered eating and eating disorders. The SOP does not include guidance on maternal PKU management. The SOP can be used as a tool for training dietitians new to the specialty and to raise the standard of education and care for patients with PKU in the UK.

Spectrum Analysis of Inherited Metabolic Disorders for Expanded Newborn Screening in a Central Chinese Population.

Neonatal inherited metabolic disorders (IMDs) are closely associated with early neonatal death and abnormal growth and development. Increasing attention has been paid to IMDs because of their high incidence and diversity. However, there are no reports about the incidence of IMDs in Changsha, China. Therefore, we retrospectively analyzed the screening results of neonates to evaluate the characteristics of IMDs in the area. From January 2016 to December 2020, 300,849 neonates were enrolled for expanded newborn screening by tandem mass spectrometry in the Neonatal Disease Screening Center of the Changsha Hospital for Maternal & Child Health Care. Newborns with mild initial results were recalled for repeated tests; if the second test was still positive, the patient was referred for confirmatory tests. A total of 71 confirmed cases were identified in our study, with an incidence rate of 1:4,237. There were 28 cases of amino acid metabolic disorders, representing 39.44% of the IMDs diagnosed, with an incidence rate of 1:10,745. Twelve newborns were diagnosed with organic acid metabolic disorders, accounting for 16.66% of IMDs, with an incidence rate of 1:25,071. There were 31 cases of fatty acid oxidation disorders, representing 43.05% of IMDs, with an incidence rate of 1:9,705. Overall, 14 types of IMDs were found in Changsha. The most common disorders in the region were primary carnitine deficiency, hyperphenylalaninemia and short-chain acyl-CoA dehydrogenase deficiency. Their incidence rate is respectively 1:13,675, 1:16,714 and 1:42,978. The mutations in PAH, SLC22A5, and ACADS are the leading causes of IMDs in this area. This study demonstrates the importance of utilizing MS/MS in IMD screening for early diagnosis and treatment. This strategy may be used for prenatal genetic counseling to avoid irreversible growth and intellectual development disorders in children.

Inherited metabolic disorders in the neonatal intensive care unit: Redflags to look out for.

We aimed to assess symptoms, laboratory findings, and radiological abnormalities in patients diagnosed with inherited metabolic disorders (IMDs) in the neonatal intensive care unit. A total of 6,150 newborns treated in a third-level neonatal intensive care unit between 2012 and 2020 in Turkey were screened, of which 195 consulted with a suspicion of metabolic disease based on their clinical, laboratory, or radiological findings were included in the present study. The prevalence of IMDs in the patients was 1:94.6. Those consulted in the department of pediatric metabolism were divided into two groups, with the 65 diagnosed with IMDs assigned as Group I, and the 130 patients who were not diagnosed with IMDs as Group II. The most common IMDs were organic acidemias (29.23%) and urea cycle disorders (UCDs) (26.15%). The rates of consanguinity marriage (75.3% vs 37.6%, P < 0.001), siblings diagnosed with an IMD (27.6% vs 3.8%, P < 0.001), and sibling death (56.9% vs 14.6%, P < 0.001) were higher in Group I than in Group II. Hyperammonemia (61.5% vs 18.4%, P < 0.001) was the most common laboratory finding in Group I, and anemia (Group I 60.0% vs 43.0% P = 0.033), metabolic acidosis (53.8% vs 36.9%, P = 0.028) and respiratory alkalosis (16.9% vs 1.5%, P < 0.001) were all higher in Group I. This retrospective study found that the results of clinical findings and basic laboratory tests could be strong indicators of IMDs, although extensive newborn screening tests and advanced biochemical and genetic tests should be carried out for the diagnosis of IMDs in newborns.

Lysosomal storage disorders with neurological manifestations

Lysosomal storage disorders (LSDs) constitute a large group of rare, multisystemic, progressive, inherited disorders of metabolism. The aberrant metabolic processes often lead to the cellular accumulation of incompletely metabolized macromolecules or their metabolic byproducts. Most of the patients affected by LSD can experience a variety of neurological presentations including, but not limited to, psychiatric complications, seizures, and/or developmental delays. The onset of symptoms can range from birth to adulthood, and disease severity can vary. Since there is significant overlap in the symptomatology of LSDs, diagnosis is typically confirmed through biochemical and molecular assays. There are currently no approved cures for any LSDs; however, in most cases, treatment of symptoms can lead to better outcomes and improvements in quality of life. The use of hematopoietic stem cell transplantation, enzyme replacement or substrate reduction therapy, and viral vector gene transfer is the subject of many ongoing and completed clinical trials. In this mini review, we provide an overview of LSDs with neurological manifestations, describe the current endeavors in alleviating peripheral symptoms and discuss effective therapeutics strategies.

Busulfan dose Recommendation in Inherited Metabolic Disorders: Population Pharmacokinetic Analysis

Busulfan is a commonly used alkylating agent in the conditioning regimens of hematopoietic cell transplantation (HCT). Population pharmacokinetic (popPK) models enable description of busulfan PK and optimization of exposure, which leads to improvement of event-free survival after HCT. Prior busulfan popPK analysis has been limited by small numbers in patients with inherited metabolic disorders (IMD). The primary objective was to characterize population PK of busulfan in a large cohort of children and young adults undergoing HCT for IMD. PopPK analysis of busulfan drug concentrations was performed using data from 78 patients with IMD who received intravenous busulfan (every 24 hours, 4 doses) as part of pretransplantation combination chemotherapy. The final model for busulfan drug clearance was used to estimate individual doses aimed to achieve a target cumulative area under the curve (cAUC) of 80 to 100 mg · h/L. We then compared the probability of cAUC within the range of 80 to 100 mg · h/L by the developed dosing regimen versus conventional regimen. A 1-compartment, linear elimination model best described the PK of busulfan. Significant covariates demonstrated to affect busulfan clearance included total body weight and the time (in days) from busulfan infusion start. The probability of target cAUC attainment by the developed dosing versus the conventional dosing were 47% versus 43% for body weight <12 kg, and 48% versus 36% for body weight ≥12 kg. We described population PK of intravenous busulfan in a large IMD cohort. The proposed dosing regimen based on the developed model can improve the target cAUC attainment of busulfan for IMD.

Nuclear Factor Erythroid-2-Related Factor 2 Signaling in the Neuropathophysiology of Inherited Metabolic Disorders.

Inherited metabolic disorders (IMDs) are rare genetic conditions that affect multiple organs, predominantly the central nervous system. Since treatment for a large number of IMDs is limited, there is an urgent need to find novel therapeutical targets. Nuclear factor erythroid-2-related factor 2 (Nrf2) is a transcription factor that has a key role in controlling the intracellular redox environment by regulating the expression of antioxidant enzymes and several important genes related to redox homeostasis. Considering that oxidative stress along with antioxidant system alterations is a mechanism involved in the neuropathophysiology of many IMDs, this review focuses on the current knowledge about Nrf2 signaling dysregulation observed in this group of disorders characterized by neurological dysfunction. We review here Nrf2 signaling alterations observed in X-linked adrenoleukodystrophy, glutaric acidemia type I, hyperhomocysteinemia, and Friedreich’s ataxia. Additionally, beneficial effects of different Nrf2 activators are shown, identifying a promising target for treatment of patients with these disorders. We expect that this article stimulates research into the investigation of Nrf2 pathway involvement in IMDs and the use of potential pharmacological modulators of this transcription factor to counteract oxidative stress and exert neuroprotection.

Special Low Protein Foods Prescribed in England for PKU Patients: An Analysis of Prescribing Patterns and Cost.

Patients with phenylketonuria (PKU) are reliant on special low protein foods (SLPFs) as part of their dietary treatment. In England, several issues regarding the accessibility of SLPFs through the national prescribing system have been highlighted. Therefore, prescribing patterns and expenditure on all SLPFs available on prescription in England (n = 142) were examined. Their costs in comparison to regular protein-containing (n = 182) and ‘free-from’ products (n = 135) were also analysed. Similar foods were grouped into subgroups (n = 40). The number of units and costs of SLPFs prescribed in total and per subgroup from January to December 2020 were calculated using National Health Service (NHS) Business Service Authority (NHSBSA) ePACT2 (electronic Prescribing Analysis and Cost Tool) for England. Monthly patient SLPF units prescribed were calculated using patient numbers with PKU and non-PKU inherited metabolic disorders (IMD) consuming SLPFs. This was compared to the National Society for PKU (NSPKU) prescribing guidance. Ninety-eight percent of SLPF subgroups (n = 39/40) were more expensive than regular and ‘free-from’ food subgroups. However, costs to prescribe SLPFs are significantly less than theoretical calculations. From January to December 2020, 208,932 units of SLPFs were prescribed (excluding milk replacers), costing the NHS £2,151,973 (including milk replacers). This equates to £962 per patient annually, and prescribed amounts are well below the upper limits suggested by the NSPKU, indicating under prescribing of SLPFs. It is recommended that a simpler and improved system should be implemented. Ideally, specialist metabolic dietitians should have responsibility for prescribing SLPFs. This would ensure that patients with PKU have the necessary access to their essential dietary treatment, which, in turn, should help promote dietary adherence and improve metabolic control.

Acute liver failure with hemolytic anemia in children with Wilson's disease: Genotype-phenotype correlations?

BACKGROUNDWilson’s disease (WD) is a rare autosomal recessive inherited disorder of copper metabolism. Acute liver failure (ALF) and hemolytic anemia represent the most severe presentation of WD in children. No clear genotype-phenotype correlations exist in WD. Protein-truncating nonsense, frame-shift, or splice-site variants may be associated with more severe disease. In contrast, missense variants may be associated with late-onset, less severe disease, and more neurological manifestations. Recently, a gene variant (HSD17B13:TA, rs72613567) with a possible hepatic protective role against toxins was associated with a less severe hepatic phenotype in WD.AIMTo analyze the possible genotype-phenotype correlations in children with WD presented with ALF and non-immune hemolytic anemia.METHODSThe medical records of children with WD diagnosed and treated in our hospital from January 2006 to December 2020 were retrospectively analyzed. The clinical manifestations (ALF with non-immune hemolytic anemia or other less severe forms), laboratory parameters, copper metabolism, ATP7B variants, and the HSD17B13:TA (rs72613567) variant were reviewed to analyze the possible genotype-phenotype correlations.RESULTSWe analyzed the data of 51 patients with WD, 26 females (50.98%), with the mean age at the diagnosis of 12.36 ± 3.74 years. ALF and Coombs-negative hemolytic anemia was present in 8 children (15.67%), all adolescent girls. The Kayser-Fleisher ring was present in 9 children (17.65%). The most frequent variants of the ATP7B gene were p.His1069Gln (c.3207A>G) in 38.24% of all alleles, p.Gly1341Asp (c.4021G>A) in 26.47%, p.Trp939Cys (c.2817G>T) in 9.80%, and p.Lys844Ter (c.2530A>T) in 4.90%. In ALF with hemolytic anemia, p.Trp939Cys (c.2817G>T) and p.Lys844Ter (c.2530A>T) variants were more frequent than in other less severe forms, in which p.His1069Gln (c.3207A>G) was more frequent. p.Gly1341Asp (c.4021G>A) has a similar frequency in all hepatic forms. For 33 of the patients, the HSD17B13 genotype was evaluated. The overall HSD17B13:TA allele frequency was 24.24%. Its frequency was higher in patients with less severe liver disease (26.92%) than those with ALF and hemolytic anemia (14.28%).CONCLUSIONIt remains challenging to prove a genotype-phenotype correlation in WD patients. In children with ALF and hemolytic anemia, the missense variants other than p.His1069Gln (c.3207A>G) and frame-shift variants were the most frequently present in homozygous status or compound heterozygous status with site splice variants. As genetic analysis is usually time-consuming and the results are late, the importance at the onset of the ALF is questionable. If variants proved to be associated with severe forms are found in the pre-symptomatic phase of the disease, this could be essential to predict a possible severe evolution.

COVID-19 Pandemic and Patients with Rare Inherited Metabolic Disorders and Rare Autoinflammatory Diseases-Organizational Challenges from the Point of View of Healthcare Providers.

COVID-19 pandemic is an organisational challenge for both healthcare providers and patients. People with rare inherited metabolic disorders (IMD) and rare autoinflammatory diseases (AD) are vulnerable patients whose well-being is deeply connected with regular follow-ups. This study aimed to assess how e one year of coronavirus pandemic has impacted the treatment of patients with IMD and AD in Poland. Surveys were distributed to all healthcare providers that coordinate the treatment of IMD and AD patients. Thirty-two responders (55%) answered the survey. They provide care to 1726 patients with IMD/AD, including 246 patients on dedicated treatment. In 35% of units, the regular appointments were disrupted, primarily because of patient infection. In 18 hospitals, remote visits were implemented, but only 66.6% of patients used this form of consultation. In 14/32 hospitals, administration of the therapy was delayed (median: 17.4 days). Forty-four patients suffered from SARS-COV-2 infection, in majority with mild symptoms. However, four adult patients developed complications, and one died following a SARS-COV-2 infection. Although most hospitals managed to maintain regular visits during the pandemic, more comprehensive implementation of telemedicine and switch to oral therapy or home infusions would be a reasonable solution for the current epidemic situation.