Publications by authors named "Carlo Dionisi-Vici"

211 Publications

Organ donation from patients with a rare disease is often safe: the italian guidelines.

Clin Transplant 2022 Jul 29:e14769. Epub 2022 Jul 29.

Dipartimento di Scienze Mediche, Università di Torino - Centro Regionale Trapianti Regione Piemonte - SC Immunogenetica e Biologia dei Trapianti Az, Ospedaliera Universitaria Città della Salute e della Scienza, Torino, Italy.

Although a disease is defined as rare when it has a prevalence of less than 1:2000, the overall prevalence of rare diseases in the population is greater than 1%. Among potential organ donors, a similar frequency is observed. To date, guidelines have not been established, and operational decisions have been made empirically, case- by-case, based on the experience and expertise of clinicians. For this reason, the Italian Superior Health Council (CSS) has appointed a working Group to address "patients with a rare disease as potential organ donors," with the aim of devising recommendations for the management of transplant cases in which the donors have a rare disease. This group evaluated 493 diseases (10% of all rare diseases, including over 95% of patients with a rare disease) to deliver a technical report dealing with the suitability of organ donation and transplantation, with a focus on the organs most frequently used, including kidney, liver, heart, lung, and pancreas. This work has made it clear that a rare disease "per se" does not contraindicate organ donation at all. Indeed, in donors affected by a rare disease, almost 80% of the organs are suitable for transplantation, approximately 7% are unsuitable, and approximately 14% are suitable as non-standard with an acceptable risk.
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http://dx.doi.org/10.1111/ctr.14769DOI Listing
July 2022

Hepatic glycogen storage diseases type 0, VI and IX: description of an italian cohort.

Orphanet J Rare Dis 2022 07 19;17(1):285. Epub 2022 Jul 19.

Division of Metabolism, Department of Pediatric Subspecialties, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Background: Glycogen storage disease (GSD) type 0, VI and IX are inborn errors of metabolism involving hepatic glycogen synthesis and degradation. We performed a characterization of a large Italian cohort of 30 patients with GSD type 0a, VI, IXa, IXb and IXc. A retrospective evaluation of genetical, auxological and endocrinological data, biochemical tests, and nutritional intakes was assessed. Eventual findings of overweight/obesity and insulin-resistance were correlated with diet composition.

Results: Six GSD-0a, 1 GSD-VI, and 23 GSD-IX patients were enrolled, with an age of presentation from 0 to 72 months (median 14 months). Diagnosis was made at a median age of 30 months, with a median diagnostic delay of 11 months and a median follow-up of 66 months. From first to last visit, patients gained a median height of 0.6 SDS (from - 1.1 to 2.1 SDS) and a median weight of 0.5 SDS (from - 2.5 to 3.3 SDS); mean and minimal glucose values significant improved (p < 0.05). With respect to dietary intakes, protein intake (g/kg) and protein intake (g/kg)/RDA ratio directly correlated with the glucose/insulin ratio (p < 0.05) and inversely correlated with HOMA-IR (Homeostasis model assessment of insulin resistance, p < 0.05), BMI SDS (p < 0.05) and %ibw (ideal body weight percentage, p < 0.01).

Conclusion: A prompt establishment of specific nutritional therapy allowed to preserve growth, improve glycemic control and prevent liver complication, during childhood. Remarkably, the administration of a high protein diet appeared to have a protective effect against overweight/obesity and insulin-resistance.
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http://dx.doi.org/10.1186/s13023-022-02431-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9295101PMC
July 2022

High Incidence of Partial Biotinidase Deficiency in the First 3 Years of a Regional Newborn Screening Program in Italy.

Int J Environ Res Public Health 2022 07 2;19(13). Epub 2022 Jul 2.

Center for Advanced Studies and Technology (CAST), "G. d'Annunzio" University of Chieti-Pescara, 66100 Chieti, Italy.

Biotinidase deficiency (BD) is an autosomal recessive inherited disorder in which the enzyme biotinidase is totally or partially defective and the vitamin biotin is not recycled. BD meets the major criteria for a population screening program. Newborn bloodspot screening (NBS) allows early diagnosis of BD, thus preventing the high morbidity and mortality associated with untreated disease. Both profound and partial BD variant can be detected by NBS test, and serum enzyme activity and/or mutational analysis are required for definitive diagnosis. In Italy, BD is included in the screening panel for inborn errors of metabolism (IEMs) that has been declared mandatory in 2016. We analyzed the data of the first 3 years of the NBS for BD in our region (Abruzzo, Italy), with the aim to describe the outcomes of this recently introduced screening program. In over 26,393 newborns screened, we found 2 carriers and 16 cases with genotype associated with partial BD. Since the serum biotinidase assay has been recently introduced in our algorithm, only three of our newborns met the criteria of genetic and biochemical confirmation, with an incidence of 1:8797, which is in the high range of what has been reported in the literature. All affected infants carried the 1330G>C (D444H) variant in compound heterozygosis, with variants known to be associated with profound BD. A variant previously not described and likely pathogenic was found in one newborn. None of the infants had signs or symptoms. The study of the distribution of the enzyme activity in our population allowed us to validate the adopted cutoff with which the program has a positive predictive value of 18% and to analyze some preanalytical factors influencing biotinidase activity: A correlation of the enzyme activity with gestational age and time at specimen collection was found. Lower mean values of enzyme activity were found in infants born in the summer.
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http://dx.doi.org/10.3390/ijerph19138141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9265859PMC
July 2022

Glycogen storage diseases with liver involvement: a literature review of GSD type 0, IV, VI, IX and XI.

Orphanet J Rare Dis 2022 06 20;17(1):241. Epub 2022 Jun 20.

Division of Metabolism, Department of Pediatric Subspecialties, Ospedale Pediatrico Bambino Gesù, IRCCS, Piazza S. Onofrio 4, 00165, Rome, Italy.

Background: Glycogen storage diseases (GSDs) with liver involvement are classified into types 0, I, III, IV, VI, IX and XI, depending on the affected enzyme. Hypoglycemia and hepatomegaly are hallmarks of disease, but muscular and renal tubular involvement, dyslipidemia and osteopenia can develop. Considering the paucity of literature available, herein we provide a narrative review of these latter forms of GSDs.

Main Body: Diagnosis is based on clinical manifestations and laboratory test results, but molecular analysis is often necessary to distinguish the various forms, whose presentation can be similar. Compared to GSD type I and III, which are characterized by a more severe impact on metabolic and glycemic homeostasis, GSD type 0, VI, IX and XI are usually known to be responsive to the nutritional treatment for achieving a balanced metabolic homeostasis in the pediatric age. However, some patients can exhibit a more severe phenotype and an important progression of the liver and muscular disease. The effects of dietary adjustments in GSD type IV are encouraging, but data are limited.

Conclusions: Early diagnosis allows a good metabolic control, with improvement of quality of life and prognosis, therefore we underline the importance of building a proper knowledge among physicians about these rare conditions. Regular monitoring is necessary to restrain disease progression and complications.
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http://dx.doi.org/10.1186/s13023-022-02387-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9208159PMC
June 2022

Liver transplantation in an infant with cerebrotendinous xanthomatosis, cholestasis, and rapid evolution of liver failure.

Pediatr Transplant 2022 Sep 28;26(6):e14318. Epub 2022 May 28.

Institut für Pathologie, Medizinische Universität Graz, Österreich, Austria.

Background: Cerebrotendinous xanthomatosis (CTX) is a disorder of bile acid (BA) metabolism due to biallelic mutations in CYP27A1. The deposition of cholesterol and cholestanol in multiple tissues results, manifesting as neurologic disease in adults or older children. Neonatal cholestasis (NC) as a presentation of CTX is rare; it may self-resolve or persist, evolving to require liver transplantation (LT).

Methods: We present in the context of similar reports an instance of CTX manifest as NC and requiring LT.

Results: A girl aged 4mo was evaluated for NC with normal serum gamma-glutamyl transpeptidase activity. An extensive diagnostic work-up, including liver biopsy, identified no etiology. Rapid progression to end-stage liver disease required LT aged 5mo. The explanted liver showed hepatocyte loss and micronodular cirrhosis. Bile salt export pump (BSEP), encoded by ABCB11, was not demonstrable immunohistochemically. Both severe ABCB11 disease and NR1H4 disease-NR1H4 encodes farsenoid-X receptor, necessary for ABCB11 transcription-were considered. However, selected liver disorder panel sequencing and mass-spectrometry urinary BA profiling identified CTX, with homozygosity for the predictedly pathogenic CYP27A1 variant c.646G > C p.(Ala216Pro). Variation in other genes associated with intrahepatic cholestasis was not detected. Immunohistochemical study of the liver-biopsy specimen found marked deficiency of CYP27A1 expression; BSEP expression was unremarkable. Aged 2y, the girl is free from neurologic disease.

Conclusions: Bile acid synthesis disorders should be routinely included in the NC/"neonatal hepatitis" work-up. The mutually supportive triple approach of BA profiling, immunohistochemical study, and genetic analysis may optimally address diagnosis in CTX, a treatable disease with widely varying presentation.
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http://dx.doi.org/10.1111/petr.14318DOI Listing
September 2022

Therapeutic Drug Monitoring of Amphotericin-B in Plasma and Peritoneal Fluid of Pediatric Patients after Liver Transplantation: A Case Series.

Antibiotics (Basel) 2022 May 11;11(5). Epub 2022 May 11.

Department of Pediatric Specialties and Liver-kidney Transplantation, Division of Metabolic Diseases and Drug Biology, Bambino Gesù Children's Hospital, IRCCS, 00146 Rome, Italy.

Fungal infections represent a serious complication during the post-liver transplantation period. Abdominal infections can occur following pre-existing colonization, surgical procedures, and permanence of abdominal tubes. In our center, liposomal amphotericin-B is used as antifungal prophylaxis in pediatric patients undergoing liver transplantation. The aim of this study is to evaluate peritoneal levels of amphotericin-B following intravenous administration. Six liver recipients received liposomal amphotericin-B. Three of them were treated as prophylaxis; meanwhile, three patients received liposomal amphotericin-B to treat infection. Plasma and peritoneal amphotericin-B levels were measured by LC-MS/MS in two consecutive samplings. C (pre-dose) and C (2 h after the end of infusion) were evaluated as drug exposure parameters for both plasma and peritoneum. Our results showed that peritoneal amphotericin-B levels were significantly lower than plasma and that the correlation coefficient was 0.72 ( = 0.03) between plasma and peritoneal C. Moreover, although peritoneal levels were within the therapeutic range, they never reached the PK/PD target (Cmax/MIC > 4.5). In conclusion, PK exposure parameters could be differently used to analyze amphotericin-B concentrations in plasma and peritoneum. However, liposomal amphotericin-B should be preferred in these patients as prophylactic rather than therapeutic treatment for fungal infections.
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http://dx.doi.org/10.3390/antibiotics11050640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9137682PMC
May 2022

PET/CT in congenital hyperinsulinism: transforming patient's lives by molecular hybrid imaging.

Am J Nucl Med Mol Imaging 2022 15;12(2):44-53. Epub 2022 Apr 15.

Nuclear Medicine Unit/Imaging Department, IRCCS Bambino Gesù Children's Hospital Rome, Italy.

Congenital hyperinsulinism (HI) is a life-threatening condition characterized by severe and recurrent episodes of hypoglycaemia due to defects in key genes involved in regulating insulin secretion. The delay in diagnosis and inappropriate management of HI lead to high risk of permanent hypoglycemic brain injury. The management of HI is challenging as each form of HI (focal, diffuse, and atypical) requires its own therapeutic strategy. In HI diagnostic work-up, integrated PET/CT scan is currently the first-line imaging technique allowing to differentiate between diffuse and focal form and, in the latter case, to localize the focus within the pancreas with high precision. Only in focal HI partial pancreatectomy is the treatment of choice and a curative surgical treatment means a real chance of transforming patient's lives and HI patient's future. The aim of this review is to discuss the role of PET/CT imaging in HI scenario, its technical advantages and limitations and how successful surgery is strongly dependent on accurate preoperative assessment (genetic analysis and PET/CT scan). A multidisciplinary approach in HI diagnosis and treatment inside a single team (involving different expertise) allows to manage children safely and properly, supporting their families in an organized care network.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9077170PMC
April 2022

Hypoglycaemia Metabolic Gene Panel Testing.

Front Endocrinol (Lausanne) 2022 29;13:826167. Epub 2022 Mar 29.

Division of Metabolism, Department of Pediatrics Subspecialties, Ospedale Pediatrico Bambino Gesù, IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), Rome, Italy.

A large number of inborn errors of metabolism present with hypoglycemia. Impairment of glucose homeostasis may arise from different biochemical pathways involving insulin secretion, fatty acid oxidation, ketone bodies formation and degradation, glycogen metabolism, fructose and galactose metabolism, branched chain aminoacids and tyrosine metabolism, mitochondrial function and glycosylation proteins mechanisms. Historically, genetic analysis consisted of highly detailed molecular testing of nominated single genes. However, more recently, the genetic heterogeneity of these conditions imposed to perform extensive molecular testing within a useful timeframe new generation sequencing technology. Indeed, the establishment of a rapid diagnosis drives specific nutritional and medical therapies. The biochemical and clinical phenotypes are critical to guide the molecular analysis toward those clusters of genes involved in specific pathways, and address data interpretation regarding the finding of possible disease-causing variants at first reported as variants of uncertain significance in known genes or the discovery of new disease genes. Also, the trio's analysis allows genetic counseling for recurrence risk in further pregnancies. Besides, this approach is allowing to expand the phenotypic characterization of a disease when pathogenic variants give raise to unexpected clinical pictures. Multidisciplinary input and collaboration are increasingly key for addressing the analysis and interpreting the significance of the genetic results, allowing rapidly their translation from bench to bedside.
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http://dx.doi.org/10.3389/fendo.2022.826167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9001947PMC
April 2022

Genetic disorders of cellular trafficking.

Trends Genet 2022 Jul 31;38(7):724-751. Epub 2022 Mar 31.

Division of Metabolic Diseases, Bambino Gesù Children's Hospital IRCCS, Rome, Italy. Electronic address:

Cellular trafficking is essential to maintain critical biological functions. Mutations in 346 genes, most of them described in the last 5 years, are associated with disorders of cellular trafficking. Whereas initially restricted to membrane trafficking, the recent detection of many diseases has contributed to the discovery of new biological pathways. Accordingly, we propose to redesign this rapidly growing group of diseases combining biological mechanisms and clinical presentation into the following categories: (i) membrane trafficking (including organelle-related); (ii) membrane contact sites; (iii) autophagy; (iv) cytoskeleton-related. We present the most recently described pathophysiological findings, disorders and phenotypes. Although all tissues and organs are affected, the nervous system is especially vulnerable.
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http://dx.doi.org/10.1016/j.tig.2022.02.012DOI Listing
July 2022

Postauthorization safety study of betaine anhydrous.

J Inherit Metab Dis 2022 07 6;45(4):719-733. Epub 2022 Apr 6.

Division of Child Neurology and Metabolic Medicine, Centre for Child and Adolescent Medicine, University Hospital, Heidelberg, Germany.

Patient registries for rare diseases enable systematic data collection and can also be used to facilitate postauthorization safety studies (PASS) for orphan drugs. This study evaluates the PASS for betaine anhydrous (Cystadane), conducted as public private partnership (PPP) between the European network and registry for homocystinurias and methylation defects and the marketing authorization holder (MAH). Data were prospectively collected, 2013-2016, in a noninterventional, international, multicenter, registry study. Putative adverse and severe adverse events were reported to the MAH's pharmacovigilance. In total, 130 individuals with vitamin B nonresponsive (N = 54) and partially responsive (N = 7) cystathionine beta-synthase (CBS) deficiency, as well as 5,10-methylenetetrahydrofolate reductase (MTHFR; N = 21) deficiency and cobalamin C (N = 48) disease were included. Median (range) duration of treatment with betaine anhydrous was 6.8 (0-9.8) years. The prescribed betaine dose exceeded the recommended maximum (6 g/day) in 49% of individuals older than 10 years because of continued dose adaptation to weight; however, with disease-specific differences (minimum: 31% in B nonresponsive CBS deficiency, maximum: 67% in MTHFR deficiency). Despite dose escalation no new or potential risk was identified. Combined disease-specific treatment decreased mean ± SD total plasma homocysteine concentrations from 203 ± 116 to 81 ± 51 μmol/L (p < 0.0001), except in MTHFR deficiency. Recommendations for betaine anhydrous dosage were revised for individuals ≥ 10 years. PPPs between MAH and international scientific consortia can be considered a reliable model for implementing a PASS, reutilizing well-established structures and avoiding data duplication and fragmentation.
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http://dx.doi.org/10.1002/jimd.12499DOI Listing
July 2022

The diagnostic challenge of mild citrulline elevation at newborn screening.

Mol Genet Metab 2022 04 20;135(4):327-332. Epub 2022 Feb 20.

Division of Metabolism, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Citrulline is a target analyte measured at expanded newborn screening (NBS) and its elevation represents a biomarker for distal urea cycle disorders and citrin deficiency. Altered ratios of citrulline with other urea cycle-related amino acids are helpful for the differential diagnosis. However, the use of cut-off values in screening programmes has raised the issue about the interpretation of mild elevation of citrulline levels detected at NBS, below the usual range observed in the "classical/severe" forms of distal urea cycle disorders and in citrin deficiency. Herein, we report ten subjects with positive NBS for a mild elevation of citrulline (<100 μmol/L), in whom molecular investigations revealed carriers status for argininosuccinate synthase deficiency, a milder form of argininosuccinate lyase deficiency and two other diseases, lysinuric protein intolerance and dihydrolipoamide dehydrogenase deficiency, not primarily affecting the urea cycle. To guide the diagnostic process, we have designed an algorithm for mild citrulline elevation (<100 μmol/L) at NBS, which expands the list of disorders to be included in the differential diagnosis.
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http://dx.doi.org/10.1016/j.ymgme.2022.02.008DOI Listing
April 2022

A new phenotype of aldolase a deficiency in a 14 year-old boy with epilepsy and rhabdomyolysis - case report.

Ital J Pediatr 2022 Mar 4;48(1):39. Epub 2022 Mar 4.

Division of Metabolism, Department of Pediatric Subspecialties, Bambino Gesù Children's Hospital IRCCS, Rome, Italy.

Background: Glycogen storage disease type XII is a rare metabolic disease resulting from Aldolase A deficiency that causes muscle glycogen accumulation, with crisis of rhabdomyolysis and hemolytic anemia. In the very few cases described, rhabdomyolysis crises are caused by fever and/or exercise and can accompany acute hemolytic anemia. Although currently there is no therapy available for this disease, the guidelines for the management of other forms of glycogen storage diseases recommend a nutritional therapy in order to avoid hypoglycemia or prevent exercise-induced rhabdomyolysis.

Case Presentation: In this case report we describe a new phenotype of the disease in a 14-year-old boy, characterized by seizures and rhabdomyolysis. Beside an antiepileptic treatment, we propose a new therapeutic approach based on ketogenic diet in order to supply an energetic substrate for skeletal muscle and neurons.

Conclusions: The anti-epileptic therapy and the dietetic approach were well tolerated by the patient who showed good compliance. This led to a deceleration of the disease with no other acute episodes of seizures and rhabdomyolysis, without any side effects observed.
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http://dx.doi.org/10.1186/s13052-022-01228-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8895104PMC
March 2022

Diagnosis, treatment, and follow-up of a case of Wolman disease with hemophagocytic lymphohistiocytosis.

Mol Genet Metab Rep 2022 Mar 20;30:100833. Epub 2021 Dec 20.

Pediatric Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy.

Wolman Disease (WD) is a severe multi-system metabolic disease due to lysosomal acid lipase (LAL) deficiency. We report on a WD infant who developed an unusual hemophagocytic lymphohistiocytosis (HLH) phenotype related to WD treated with sebelipase alfa. A male baby came to our attention at six months of life for respiratory insufficiency and sepsis, abdominal distension, severe hepatosplenomegaly, diarrhea, and severe growth retardation. HLH was diagnosed and treated with intravenous immunoglobulin, steroids, cyclosporine, broad-spectrum antimicrobial therapy, and finally with the anti-IL-6 drug tocilizumab. WD was suspected for the presence of adrenal calcifications and it was confirmed by LAL enzyme activity and by molecular analysis of . Plasma oxysterols cholestan-3β,5α,6β-triol (C-triol), and 7-ketocholesterol (7-KC) were markedly increased. Sebelipase alfa was started with progressive amelioration of biochemical and clinical features. The child died from sepsis, 2 months after sebelipase discontinuation requested by parents. Our case shows the importance of an early diagnosis of WD and confirms the difficulty to reach a diagnosis in the HLH phenotype. Sebelipase alpha is an effective treatment for LAL deficiency, also in children affected by WD. Further data are necessary to confirm the utility of measuring plasma c-triol as a biochemical marker of the disease.
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http://dx.doi.org/10.1016/j.ymgmr.2021.100833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8856920PMC
March 2022

Cardiomyopathies in Children and Systemic Disorders When Is It Useful to Look beyond the Heart?

J Cardiovasc Dev Dis 2022 Jan 31;9(2). Epub 2022 Jan 31.

The European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart-ERN GUARD-Heart, Pediatric Cardiology and Arrhythmia/Syncope Units, Bambino Gesù Children Hospital and Research Institute, IRCCS, 00165 Rome, Italy.

Cardiomyopathy (CMP) is a rare disease in the pediatric population, with a high risk of morbidity and mortality. The genetic etiology of CMPs in children is extremely heterogenous. These two factors play a major role in the difficulties of establishing standard diagnostic and therapeutic protocols. Isolated CMP in children is a frequent finding, mainly caused by sarcomeric gene variants with a detection rate that can reach up to 50% of analyzed cohorts. Complex multisystemic forms of pediatric CMP are even more heterogenous. Few studies in literature take into consideration this topic as the main core since it represents a rarity (systemic CMP) within a rarity (pediatric population CMP). Identifying etiology in this cohort is essential for understanding prognosis, risk stratification, eligibility to heart transplantation and/or mechanical-assisted procedures, preventing multiorgan complications, and relatives' recurrence risk calculation. The previous points represent a cornerstone in patients' empowerment and personalized medical care approach. The aim of this work is to propose a new approach for an algorithm in the setting of the diagnostic framework of systemic pediatric CMP. On the other hand, during the literature review, we noticed a relatively common etiologic pattern in some forms of complex/multisystem CMP. In other words, certain syndromes such as Danon, Vici, Alström, Barth, and Myhre syndrome share a common pathway of directly or indirectly defective "autophagy" process, which appears to be a possible initiating/triggering factor for CMPs. This conjoint aspect could be important for possible prognostic/therapeutic implications in this category of patients. However, multicentric studies detailed functional and experimental models are needed prior to deriving conclusions.
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http://dx.doi.org/10.3390/jcdd9020047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8877723PMC
January 2022

Benefits and Toxicity of Disulfiram in Preclinical Models of Nephropathic Cystinosis.

Cells 2021 11 24;10(12). Epub 2021 Nov 24.

Renal Diseases Research Unit, Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy.

Nephropathic cystinosis is a rare disease caused by mutations of the CTNS gene that encodes for cystinosin, a lysosomal cystine/H+ symporter. The disease is characterized by early-onset chronic kidney failure and progressive development of extra-renal complications related to cystine accumulation in all tissues. At the cellular level, several alterations have been demonstrated, including enhanced apoptosis, altered autophagy, defective intracellular trafficking, and cell oxidation, among others. Current therapy with cysteamine only partially reverts some of these changes, highlighting the need to develop additional treatments. Among compounds that were identified in a previous drug-repositioning study, disulfiram (DSF) was selected for in vivo studies. The cystine depleting and anti-apoptotic properties of DSF were confirmed by secondary in vitro assays and after treating mice with 200 mg/kg/day of DSF for 3 months. However, at this dosage, growth impairment was observed. Long-term treatment with a lower dose (100 mg/kg/day) did not inhibit growth, but failed to reduce cystine accumulation, caused premature death, and did not prevent the development of renal lesions. In addition, DSF also caused adverse effects in cystinotic zebrafish larvae. DSF toxicity was significantly more pronounced in mice and zebrafish compared to wild-type animals, suggesting higher cell toxicity of DSF in cystinotic cells.
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http://dx.doi.org/10.3390/cells10123294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8699074PMC
November 2021

Pharmacokinetic Evaluation of Eltrombopag in ITP Pediatric Patients.

Front Pharmacol 2021 6;12:772873. Epub 2021 Dec 6.

Department of Pediatric Specialties and Liver-kidney Transplantation, Division of Metabolic Biochemistry, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Eltrombopag (EPAG) is an oral thrombopoietin receptor agonist, approved for refractory primary immune thrombocytopenia (ITP) in pediatric patients. In two pediatric RCTs, EPAG led to an improvement of platelet counts and a reduction in bleeding severity. However, a significant number of pediatric patients did not achieve the primary endpoints. We performed a pharmacokinetic evaluation of EPAG in pediatric patients with refractory ITP. Outpatients aged from 1 to 17 y, affected by refractory ITP to first-line treatment, were enrolled for a pharmacokinetic assessment. The analysis of drug plasma concentration was performed by the LC-MS/MS platform. Non-compartmental and statistical subgroup analyses were carried out using the R package ncappc. Among 36 patients eligible for PK analysis, the median dose of EPAG given once daily was 50 mg. The EPAG peak occurs between 2 and 4 h with a population Cmax and AUC 0-24 geo-mean of 23, 38 μg/ml, and 275, 4 µg*h/mL, respectively. The pharmacokinetic profile of EPAG did not show a dose proportionality. Female patients showed a statistically significant increase of dose-normalized exposure parameters, increasing by 110 and 123% for Cmax and AUC 0-24, respectively, when compared to male patients. Patients aged 1-5 y showed values increased by more than 100% considering both exposure parameters, compared to older children. Furthermore, patients presenting complete response (83%), showed augmented EPAG exposure parameters compared to subjects with partial or no response. These data highlight the need to further explore the variability of EPAG exposure and its pharmacokinetic/pharmacodynamic profile in pediatric patients also in a real-life setting.
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http://dx.doi.org/10.3389/fphar.2021.772873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8685423PMC
December 2021

Myocardial and Arrhythmic Spectrum of Neuromuscular Disorders in Children.

Biomolecules 2021 10 25;11(11). Epub 2021 Oct 25.

Division of Metabolism, Bambino Gesù Children Hospital and Research Institute, IRCCS, 00165 Rome, Italy.

Neuromuscular disorders (NMDs) are highly heterogenous from both an etiological and clinical point of view. Their signs and symptoms are often multisystemic, with frequent cardiac involvement. In fact, childhood onset forms can predispose a person to various progressive cardiac abnormalities including cardiomyopathies (CMPs), valvulopathies, atrioventricular conduction defects (AVCD), supraventricular tachycardia (SVT) and ventricular arrhythmias (VA). In this review, we selected and described five specific NMDs: Friedreich's Ataxia (FRDA), congenital and childhood forms of Myotonic Dystrophy type 1 (DM1), Kearns Sayre Syndrome (KSS), Ryanodine receptor type 1-related myopathies (-RM) and Laminopathies. These changes are widely investigated in adults but less researched in children. We focused on these specific topics due their relative frequency and their potential unexpected cardiac manifestations in children. Moreover these conditions present different inheritance patterns and mechanisms of action. We decided not to discuss Duchenne and Becker muscular dystrophies due to extensive work regarding the cardiac aspects in children. For each described NMD, we focused on the possible cardiac manifestations such as different types of CMPs (dilated-DCM, hypertrophic-HCM, restrictive-RCM or left ventricular non compaction-LVNC), structural heart abnormalities (including valvulopathies), and progressive heart rhythm changes (AVCD, SVT, VA). We describe the current management strategies for these conditions. We underline the importance, especially for children, of a serial multidisciplinary personalized approach and the need for periodic surveillance by a dedicated heart team. This is largely due to the fact that in children, the diagnosis of certain NMDs might be overlooked and the cardiac aspect can provide signs of their presence even prior to overt neurological diagnosis.
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http://dx.doi.org/10.3390/biom11111578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8615674PMC
October 2021

Comprehensive-targeted lipidomic analysis in Niemann-Pick C disease.

Mol Genet Metab 2021 12 16;134(4):337-343. Epub 2021 Nov 16.

Division of Metabolism, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Niemann-Pick C disease (NPC) is a lysosomal disease caused by mutations in NPC1 or NPC2 genes responsible for intracellular accumulation of free cholesterol and glycosphingolipids in a variety of tissues. We collected plasma samples from 15 NPC1 patients and 15 age-matched controls to analyze the impairment of lipid metabolism. Comprehensive-targeted quantitative lipidomic analysis was per-formed by Ion Mobility Mass Spectrometry, while oxysterols and lyso-sphingolipids, the classical NPC biomarkers, were analyzed by LC-MS/MS. Lipidomic analysis allowed the quantitation of ~1100 lipid species, belonging to 13 different classes. Statistical analysis of collected data showed a significant differentiation between NPC patients and controls. Lipid profiling showed an elevation of arachidonic acid and total diacylglycerols. Conversely, sphingomyelins, phosphatidylethano-lamines, phosphatidylcholines, cholesterylesters, and lactosylceramides were decreased. Indeed, the lipid imbalance was consistent with the increased concentrations of oxysterols and lyso-sphingolipids. Our study revealed a novel disease biosignature suggesting new potential diagnostic biomarkers. The alteration in key lipids molecules involved in inflammatory pathways and in oxidative stress regulation, provides new insights in the complex pathophysiology of the disease, still largely un-known.
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http://dx.doi.org/10.1016/j.ymgme.2021.11.005DOI Listing
December 2021

Diagnostic approach to neonatal and infantile cholestasis: A position paper by the SIGENP liver disease working group.

Dig Liver Dis 2022 Jan 20;54(1):40-53. Epub 2021 Oct 20.

Service of Paediatric Hepatology, Department of Paediatrics, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Neonatal and infantile cholestasis (NIC) can represent the onset of a surgically correctable disease and of a genetic or metabolic disorder worthy of medical treatment. Timely recognition of NIC and identification of the underlying etiology are paramount to improve outcomes. Upon invitation by the Italian National Institute of Health (ISS), an expert working grouped was formed to formulate evidence-based positions on current knowledge about the diagnosis of NIC. A systematic literature search was conducted to collect evidence about epidemiology, etiology, clinical aspects and accuracy of available diagnostic tests in NIC. Evidence was scored using the GRADE system. All recommendations were approved by a panel of experts upon agreement of at least 75% of the members. The final document was approved by all the panel components. This position document summarizes the collected statements and defines the best-evidence diagnostic approach to cholestasis in the first year of life.
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http://dx.doi.org/10.1016/j.dld.2021.09.011DOI Listing
January 2022

Ocular manifestations in patients with inborn errors of intracellular cobalamin metabolism: a systematic review.

Hum Genet 2022 Jul 15;141(7):1239-1251. Epub 2021 Oct 15.

UMR_S 1256, NGERE - Nutrition, Genetics, and Environmental Risk Exposure, INSERM, University of Lorraine, 54000, Nancy, France.

Inherited disorders of cobalamin (cbl) metabolism (cblA-J) result in accumulation of methylmalonic acid (MMA) and/or homocystinuria (HCU). Clinical presentation includes ophthalmological manifestations related to retina, optic nerve and posterior visual alterations, mainly reported in cblC and sporadically in other cbl inborn errors.We searched MEDLINE EMBASE and Cochrane Library, and analyzed articles reporting ocular manifestations in cbl inborn errors. Out of 166 studies a total of 52 studies reporting 163 cbl and 24 mut cases were included. Ocular manifestations were found in all cbl defects except for cblB and cblD-MMA; cblC was the most frequent disorder affecting 137 (84.0%) patients. The c.271dupA was the most common pathogenic variant, accounting for 70/105 (66.7%) cases. One hundred and thirty-seven out of 154 (88.9%) patients presented with early-onset disease (0-12 months). Nystagmus and strabismus were observed in all groups with the exception of MMA patients while maculopathy and peripheral retinal degeneration were almost exclusively found in MMA-HCU patients. Optic nerve damage ranging from mild temporal disc pallor to complete atrophy was prevalent in MMA-HCU.and MMA groups. Nystagmus was frequent in early-onset patients. Retinal and macular degeneration worsened despite early treatment and stabilized systemic function in these patients. The functional prognosis remains poor with final visual acuity < 20/200 in 55.6% (25/45) of cases. In conclusion, the spectrum of eye disease in Cbl patients depends on metabolic severity and age of onset. The development of visual manifestations over time despite early metabolic treatment point out the need for specific innovative therapies.
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http://dx.doi.org/10.1007/s00439-021-02350-8DOI Listing
July 2022

Ketogenic diet as elective treatment in patients with drug-unresponsive hyperinsulinemic hypoglycemia caused by glucokinase mutations.

Orphanet J Rare Dis 2021 10 11;16(1):424. Epub 2021 Oct 11.

Division of Metabolism, Department of Pediatric Subspecialties, Ospedale Pediatrico Bambino Gesù, IRCSS, Piazza S. Onofrio 4, 00165, Rome, Italy.

Background: Hyperinsulinemic hypoglycemia (HI) is the most frequent cause of recurrent hypoglycemia in children. Despite diagnostic and therapeutic advances, it remains an important cause of morbidity, leading to neurological complications, such as psychomotor retardation and epilepsy. Patients with diffuse drug-unresponsive HI manifest neurological impairment and neurobehavioral problems, even though surgically treated with a near-total pancreatectomy. Based on the analogies between HI and GLUT1 deficiency, both presenting with neuroglycopenia and lack of alternative cerebral energy sources, we administered a ketogenic diet (KD) in three drug-unresponsive GCK-HI patients with the aim of preserving neurodevelopment and avoiding the need of a near-total pancreatectomy. They presented recurrent symptomatic hypoglycemia, intellectual disability and refractory epilepsy. Patients were treated with classical KD for 79, 27 and 18 months, respectively.

Results: All patients became asymptomatic in a few days and showed an important improvement of the alert state. Epilepsy disappeared and no appearance of novel hypoglycemic lesions was detected with a brain MRI. Cognitive and adaptive abilities rapidly improved and normalized. IQ rose significantly from 81 to 111 (p = 0.04) in patient 1, from 82 vs 95 (p = 0.04) in patient 2, from 60 to 90 (p = 0.04) in patient 3.

Conclusions: We demonstrated the safety and efficacy of KD in the treatment of drug-unresponsive GCK-HI at a short and long-term. The neuroprotective effects of KD determined the recovery from epilepsy and intellectual disabilities and averted the need of a near-total pancreatectomy. All patients and their families reported an improvement of physical and psychosocial well-being, with a substantial improvement of their quality of life. These results might change the course and the quality of life of these patients and their families, having a relevant impact on human lives. Therefore, KD might be considered the elective treatment in unresponsive forms of GCK-HI.
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http://dx.doi.org/10.1186/s13023-021-02045-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8507241PMC
October 2021

Dysbiosis, Host Metabolism, and Non-communicable Diseases: Trialogue in the Inborn Errors of Metabolism.

Front Physiol 2021 6;12:716520. Epub 2021 Sep 6.

Department of Pediatrics, Vittore Buzzi Children's Hospital, University of Milan, Milan, Italy.

Inborn errors of metabolism (IEMs) represent a complex system model, in need of a shift of approach exploring the main factors mediating the regulation of the system, internal or external and overcoming the traditional concept of biochemical and genetic defects. In this context, among the established factors influencing the metabolic flux, i.e., diet, lifestyle, antibiotics, xenobiotics, infectious agents, also the individual gut microbiota should be considered. A healthy gut microbiota contributes in maintaining human health by providing unique metabolic functions to the human host. Many patients with IEMs are on special diets, the main treatment for these diseases. Hence, IEMs represent a good model to evaluate how specific dietary patterns, in terms of macronutrients composition and quality of nutrients, can be related to a characteristic microbiota associated with a specific clinical phenotype ("enterophenotype"). In the present review, we aim at reporting the possible links existing between dysbiosis, a condition reported in IEMs patients, and a pro-inflammatory status, through an altered "gut-liver" cross-talk network and a major oxidative stress, with a repercussion on the health status of the patient, increasing the risk of non-communicable diseases (NCDs). On this basis, more attention should be paid to the nutritional status assessment and the clinical and biochemical signs of possible onset of comorbidities, with the goal of improving the long-term wellbeing in IEMs. A balanced intestinal ecosystem has been shown to positively contribute to patient health and its perturbation may influence the clinical spectrum of individuals with IEMs. For this, reaching eubiosis through the improvement of the quality of dietary products and mixtures, the use of pre-, pro- and postbiotics, could represent both a preventive and therapeutic strategy in these complex diseases.
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http://dx.doi.org/10.3389/fphys.2021.716520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8475650PMC
September 2021

ASL expression in ALDH1A1 neurons in the substantia nigra metabolically contributes to neurodegenerative phenotype.

Hum Genet 2021 Oct 21;140(10):1471-1485. Epub 2021 Aug 21.

Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.

Argininosuccinate lyase (ASL) is essential for the NO-dependent regulation of tyrosine hydroxylase (TH) and thus for catecholamine production. Using a conditional mouse model with loss of ASL in catecholamine neurons, we demonstrate that ASL is expressed in dopaminergic neurons in the substantia nigra pars compacta, including the ALDH1A1 subpopulation that is pivotal for the pathogenesis of Parkinson disease (PD). Neuronal loss of ASL results in catecholamine deficiency, in accumulation and formation of tyrosine aggregates, in elevation of α-synuclein, and phenotypically in motor and cognitive deficits. NO supplementation rescues the formation of aggregates as well as the motor deficiencies. Our data point to a potential metabolic link between accumulations of tyrosine and seeding of pathological aggregates in neurons as initiators for the pathological processes involved in neurodegeneration. Hence, interventions in tyrosine metabolism via regulation of NO levels may be therapeutic beneficial for the treatment of catecholamine-related neurodegenerative disorders.
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http://dx.doi.org/10.1007/s00439-021-02345-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8460544PMC
October 2021

Long-term safety and outcomes in hereditary tyrosinaemia type 1 with nitisinone treatment: a 15-year non-interventional, multicentre study.

Lancet Diabetes Endocrinol 2021 07 21;9(7):427-435. Epub 2021 May 21.

Swedish Orphan Biovitrum (Sobi), Stockholm, Sweden. Electronic address:

Background: Since the EU approval of nitisinone in 2005, prognosis for patients with hereditary tyrosinaemia type 1 has changed dramatically, with patients living with the disease now reaching adulthood for the first time in history. This study aimed to assess the long-term safety and outcomes of nitisinone treatment in patients with hereditary tyrosinaemia type 1.

Methods: We did a non-interventional, non-comparative, multicentre study in 77 sites across 17 countries in Europe and collected retrospective and prospective longitudinal data in patients with hereditary tyrosinaemia type 1 who were treated with oral nitisinone during the study period (Feb 21, 2005, to Sept 30, 2019). There were no specific exclusion criteria. Patients were followed-up with an investigator at least annually for as long as they were treated, or until the end of the study. The primary endpoints, occurrence of adverse events related to hepatic, renal, ophthalmic, haematological, or cognitive or developmental function, were assessed in the complete set (all patients already receiving treatment at the index date [Feb 21, 2005] or starting treatment thereafter) and the index set (the subset of patients who had their first dose on the index date or later only).

Findings: 315 patients were enrolled during the study period (complete set). Additionally, data from 24 patients who had liver transplantation or died during the post-marketing surveillance programme were retrieved (extended analysis set; 339 patients). Median treatment duration was 11·2 years (range 0·7-28·4); cumulative nitisinone exposure was 3172·7 patient-years. Patients who were diagnosed by neonatal screening started nitisinone treatment at median age 0·8 months versus 8·5 months in those who presented clinically. Incidences of hepatic, renal, ophthalmic, haematological, or cognitive or developmental adverse events were low. Occurrence of liver transplantation or death was more frequent the later that treatment was initiated (none of 70 patients who started treatment at age <28 days vs 35 [13%] of 268 patients who started treatment at age ≥28 days). 279 (89%) of 315 patients were assessed as having either very good or good nitisinone treatment compliance. Treatment and diet compliance declined as patients aged. Suboptimal plasma phenylalanine and tyrosine levels were observed. The majority of patients were reported to have good overall clinical condition throughout treatment; 176 (87%) of 203 during the entire study, 98% following 1 year of treatment.

Interpretation: Long-term nitisinone treatment was well tolerated and no new safety signals were revealed. Life-limiting hepatic disease appears to have been prevented by early treatment start. Neonatal screening was the most effective way of ensuring early treatment. Standardised monitoring of blood tyrosine, phenylalanine, and nitisinone levels has potential to guide individualised therapy.

Funding: Swedish Orphan Biovitrum (Sobi).
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http://dx.doi.org/10.1016/S2213-8587(21)00092-9DOI Listing
July 2021

Ethylmalonic encephalopathy and liver transplantation: long-term outcome of the first treated patient.

Orphanet J Rare Dis 2021 05 19;16(1):229. Epub 2021 May 19.

Division of Metabolism, Bambino Gesù Children's Hospital, IRCCS, Piazza S. Onofrio 4, 00165, Rome, Italy.

Background: Ethylmalonic encephalopathy (EE) is a severe intoxication-type metabolic disorder with multisystem clinical features and leading to early death. In 2014, based on the promising results obtained by liver-targeted gene therapy in Ethe1 mouse model, we successfully attempted liver transplantation in a 9-month-old EE girl. Here we report her long-term follow-up, lasting over 6 years, with a comprehensive evaluation of clinical, instrumental and biochemical assessments.

Results: Neurological signs initially reverted, with a clinical stabilization during the entire follow-up course. Accordingly, gross motor functions improved and then stabilized. Psychomotor evaluations documented an increasing communicative intent, the acquisition of new social skills and the capability to carry out simple orders. Neurophysiological assessments, which included EEG, VEP/ERG and BAEPs, remained unchanged. Brain MRI also stabilized, showing no further lesions and cerebral atrophy improvement. Compared to pre-transplant assessments, urinary ethylmalonic acid strikingly reduced, and plasma thiosulphate fully normalized. The child maintained good clinical conditions and never experienced metabolic crises nor epileptic seizures.

Conclusions: The long-term follow-up of the first EE transplanted patient demonstrates that liver transplantation stabilizes, or even improves, disease course, therefore representing a potentially elective option especially in early-diagnosed patients, such as those detected by newborn screening, before irreversible neurological damage occurs.
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http://dx.doi.org/10.1186/s13023-021-01867-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136189PMC
May 2021

Novel NDUFA12 variants are associated with isolated complex I defect and variable clinical manifestation.

Hum Mutat 2021 06 25;42(6):699-710. Epub 2021 Mar 25.

Department of Neurosciences, Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Isolated biochemical deficiency of mitochondrial complex I is the most frequent signature among mitochondrial diseases and is associated with a wide variety of clinical symptoms. Leigh syndrome represents the most frequent neuroradiological finding in patients with complex I defect and more than 80 monogenic causes have been involved in the disease. In this report, we describe seven patients from four unrelated families harboring novel NDUFA12 variants, with six of them presenting with Leigh syndrome. Molecular genetic characterization was performed using next-generation sequencing combined with the Sanger method. Biochemical and protein studies were achieved by enzymatic activities, blue native gel electrophoresis, and western blot analysis. All patients displayed novel homozygous mutations in the NDUFA12 gene, leading to the virtual absence of the corresponding protein. Surprisingly, despite the fact that in none of the analyzed patients, NDUFA12 protein was detected, they present a different onset and clinical course of the disease. Our report expands the array of genetic alterations in NDUFA12 and underlines phenotype variability associated with NDUFA12 defect.
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http://dx.doi.org/10.1002/humu.24195DOI Listing
June 2021

U-IMD: the first Unified European registry for inherited metabolic diseases.

Orphanet J Rare Dis 2021 02 18;16(1):95. Epub 2021 Feb 18.

Division of Neuropediatrics and Metabolic Medicine, Department of General Pediatrics, Centre for Child and Adolescent Medicine, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany.

Background: Following the broad application of new analytical methods, more and more pathophysiological processes in previously unknown diseases have been elucidated. The spectrum of clinical presentation of rare inherited metabolic diseases (IMDs) is broad and ranges from single organ involvement to multisystemic diseases. With the aim of overcoming the limited knowledge about the natural course, current diagnostic and therapeutic approaches, the project has established the first unified patient registry for IMDs that fully meets the requirements of the European Infrastructure for Rare Diseases (ERDRI).

Results: In collaboration with the European Reference Network for Rare Hereditary Metabolic Disorders (MetabERN), the Unified European registry for Inherited Metabolic Diseases (U-IMD) was established to collect patient data as an observational, non-interventional natural history study. Following the recommendations of the ERDRI the U-IMD registry uses common data elements to define the IMDs, report the clinical phenotype, describe the biochemical markers and to capture the drug treatment. Until today, more than 1100 IMD patients have been registered.

Conclusion: The U-IMD registry is the first observational, non-interventional patient registry that encompasses all known IMDs. Full semantic interoperability for other registries has been achieved, as demonstrated by the use of a minimum common core data set for equivalent description of metabolic patients in U-IMD and in the patient registry of the European Rare Kidney Disease Reference Network (ERKNet). In conclusion, the U-IMD registry will contribute to a better understanding of the long-term course of IMDs and improved patients care by understanding the natural disease course and by enabling an optimization of diagnostic and therapeutic strategies.
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http://dx.doi.org/10.1186/s13023-021-01726-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893973PMC
February 2021

Guidelines for the diagnosis and management of methylmalonic acidaemia and propionic acidaemia: First revision.

J Inherit Metab Dis 2021 05 9;44(3):566-592. Epub 2021 Mar 9.

Division of Metabolism and Children's Research Center, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland.

Isolated methylmalonic acidaemia (MMA) and propionic acidaemia (PA) are rare inherited metabolic diseases. Six years ago, a detailed evaluation of the available evidence on diagnosis and management of these disorders has been published for the first time. The article received considerable attention, illustrating the importance of an expert panel to evaluate and compile recommendations to guide rare disease patient care. Since that time, a growing body of evidence on transplant outcomes in MMA and PA patients and use of precursor free amino acid mixtures allows for updates of the guidelines. In this article, we aim to incorporate this newly published knowledge and provide a revised version of the guidelines. The analysis was performed by a panel of multidisciplinary health care experts, who followed an updated guideline development methodology (GRADE). Hence, the full body of evidence up until autumn 2019 was re-evaluated, analysed and graded. As a result, 21 updated recommendations were compiled in a more concise paper with a focus on the existing evidence to enable well-informed decisions in the context of MMA and PA patient care.
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http://dx.doi.org/10.1002/jimd.12370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252715PMC
May 2021

Partial Biotinidase Deficiency Revealed Imbalances in Acylcarnitines Profile at Tandem Mass Spectrometry Newborn Screening.

Int J Environ Res Public Health 2021 02 9;18(4). Epub 2021 Feb 9.

Center for Advanced Studies and Technology (CAST), University "G. d'Annunzio" of Chieti-Pescara, 66100 Chieti, Italy.

Biotinidase (BTD) deficiency is an autosomal recessive inherited neurocutaneous disorder. BTD recycles the vitamin biotin, a coenzyme essential for the function of four biotin-dependent carboxylases, including propionyl-CoA carboxylase, 3-methylcrotonyl-CoA carboxylase, pyruvate carboxylase, and acetyl-CoA carboxylase. Due to deficient activities of the carboxylases, BTD deficiency is also recognized as late-onset multiple carboxylase deficiency and is associated with secondary alterations in the metabolism of amino acids, carbohydrates, and fatty acids. BTD deficiency can be classified as "profound", with less than 10% of mean normal activity, and as "partial" with 10-30% of mean normal activity. Newborn screening (NBS) of BTD deficiency is performed in most countries and is able to detect both variants. Moreover, mild metabolic alterations related to carboxylase deficiency in profound BTD deficiency could result and possibly be revealed in the metabolic profile by tandem mass spectrometry (MS/MS) NBS. Here, we report the case of a newborn female infant with an initial suspected BTD deficiency at the NBS test, finally confirmed as a partial variant by molecular testing. Although BTD deficiency was partial, interestingly her metabolic profile at birth and during the follow-up tests revealed, for the first time, alterations in specific acylcarnitines as a possible result of the deficient activity of biotin-dependent carboxylases.
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http://dx.doi.org/10.3390/ijerph18041659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916230PMC
February 2021
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