Continuous glucose monitoring in patients with inherited metabolic disorders at risk for Hypoglycemia and Nutritional implications.

Managing Inherited Metabolic Disorders (IMDs) at risk for hypoglycemia, such as Glycogen Storage Diseases (GSDs), Hereditary Fructose Metabolism Disorders (HFMDs) and Congenital Hyperinsulinism (CH), poses challenges in dietary treatments and blood glucose monitoring. The effectiveness of Continuous Glucose Monitoring (CGM) remains a subject of ongoing debate, with IMD guidelines maintaining caution. Therefore, a systematic evaluation is needed to understand the potential benefits of CGM during dietary interventions. A systematic literature review was conducted in PubMed according to the PICOS model and PRISMA recommendations on studies published from January 01, 2003, up to October 15, 2023 (PROSPERO CRD42024497744). The risk of bias was assessed using NIH Quality Assessment Tools. Twenty-four studies in GSDs (n = 13), CH (n = 10), and HFMDs (n = 1) were analyzed. In GSDs, Real-time CGM (Rt-CGM) was associated with metabolic benefits during nutritional interventions, proving to be an accurate system for hypoglycemia detection although with some concerns about reliability. Rt-CGM in CH, primarily involving children, also showed potential benefits for glycemic control and metabolic stability with acceptable accuracy, although its use during dietary changes was limited. Few experiences on Flash Glucose Monitoring (FGM) were reported, with some concerns about reliability. Overall, the studies analyzed presented different designs, and their quality was predominantly fair or poor. Heterogeneity and limited consensus on reliability and glycemic targets underscore the need for prospective studies and future recommendations for the use of CGM in optimizing nutritional status and providing personalized dietary education in individuals with IMDs prone to hypoglycemia.

Triheptanoin in patients with long-chain fatty acid oxidation disorders: clinical experience in Italy.

BACKGROUND: Long-chain fatty acid oxidation disorders (LC-FAOD) are rare and potentially life-threatening diseases that cause deficient energy production and accumulation of toxic metabolites. Despite dietary management, adherence to maximum fasting guidelines, restricted long-chain triglyceride intake and supplementation with medium-chain triglyceride (MCT) oil (current standard of care), most patients experience recurrent decompensation episodes that can require hospitalisation. Herein, we analysed the effectiveness and safety of triheptanoin (a highly purified, synthetic medium odd-chain triglyceride) treatment in a cohort of Italian patients with LC-FAOD. METHODS: This retrospective, nationwide study included nine patients with LC-FAOD who switched from standard therapy with MCT oil to triheptanoin oral liquid. Data were collected between 2018 and 2022. Clinical outcome measures were the number and duration of intercurrent catabolic episodes and number and duration of metabolic decompensation episodes requiring hospitalisation. Creatine kinase (CK) levels and treatment-related adverse effects were also reported. RESULTS: Patients were provided a mean ± standard deviation (SD) triheptanoin dose of 1.5 ± 0.9 g/kg/day in four divided administrations, which accounted for 23.9 ± 8.9% of patients' total daily caloric intake. Triheptanoin treatment was started between 2.7 and 16 years of age and was continued for 2.2 ± 0.9 years. The number of intercurrent catabolic episodes during triheptanoin treatment was significantly lower than during MCT therapy (4.3 ± 5.3 vs 22.0 ± 22.2; p = 0.034), as were the number of metabolic decompensations requiring hospitalisation (mean ± SD: 2.0 ± 2.5 vs 18.3 ± 17.7; p = 0.014), and annualised hospitalisation rates and duration. Mean CK levels (outside metabolic decompensation episodes) were lower with triheptanoin treatment versus MCT oil for seven patients. No intensive care unit admissions were required during triheptanoin treatment. Epigastric pain and diarrhoea were recorded as adverse effects during both MCT and triheptanoin treatment. CONCLUSIONS: The significant improvement in clinical outcome measures after the administration of triheptanoin highlights that this treatment approach can be more effective than MCT supplementation in patients with LC-FAOD. Triheptanoin was well tolerated and decreased the number of intercurrent catabolic episodes, metabolic decompensation episodes requiring hospitalisation, and the annualised rate and duration of hospitalisations.

Determination of the Protein and Amino Acid Content of Fruit, Vegetables and Starchy Roots for Use in Inherited Metabolic Disorders.

Amino acid (AA)-related inherited metabolic disorders (IMDs) and urea cycle disorders (UCDs) require strict dietary management including foods low in protein such as fruits, vegetables and starchy roots. Despite this recommendation, there are limited data on the AA content of many of these foods. The aim of this study is to describe an analysis of the protein and AA content of a range of fruits, vegetables and starchy roots, specifically focusing on amino acids (AAs) relevant to AA-related IMDs such as phenylalanine (Phe), methionine (Met), leucine (Leu), lysine (Lys) and tyrosine (Tyr). AA analysis was performed using high-performance liquid chromatography (HPLC) on 165 food samples. Protein analysis was also carried out using the Dumas method. Foods were classified as either 'Fruits', 'Dried fruits', 'Cruciferous vegetables', 'Legumes', 'Other vegetables' or 'Starchy roots'. 'Dried fruits' and 'Legumes' had the highest median values of protein, while 'Fruits' and 'Cruciferous vegetables' contained the lowest median results. 'Legumes' contained the highest and 'Fruits' had the lowest median values for all five AAs. Variations were seen in AA content for individual foods. The results presented in this study provide useful data on the protein and AA content of fruits, vegetables and starchy roots which can be used in clinical practice. This further expansion of the current literature will help to improve diet quality and metabolic control among individuals with AA-related IMDs and UCDs.

Phenylketonuria - newborn screening as a health protection in society.

OBJECTIVE: Aim: Phenylketonuria is the most prevalent inherited metabolic disorder. Early detection and prompt treatment can prevent serious neurological consequences. This has become possible thanks to the implementation of newborn screening programmes. The objective of this review is to provide readers with a comprehensive understanding of the phenylketonuria and the role that neonatal screening plays in the protection of public health. PATIENTS AND METHODS: Materials and Methods: A review of the literature was conducted using the PubMed database, with the search period encompassing the most recently published scientific sources. Analysis of the literature. This article presents phenylketonuria as an example of an inherited metabolic disorder, outlines the treatment options, and discusses the potential implications of hyperphenylalaninemia. Furthermore, it also delineates the various aspects of health that are influenced by newborn screening. CONCLUSION: Conclusions: Phenylketonuria represents a significant health problem in the population. The development of screening tests has transformed healthcare, including improvements in quality of life, prognosis, and reductions in the number of comorbidities in patients. It is essential to disseminate knowledge among the society about the importance of newborn screening tests in order to enhance awareness and prevent refusal to participate.

Mapping the genetic landscape of treatable inherited metabolic disorders in a large Middle Eastern biobank.

BACKGROUND: To date, approximately 1,400 inherited metabolic disorders (IMDs) have been described, some of which are treatable. It is estimated that 2-3% of live births worldwide are affected by treatable IMDs. Roughly 80% of IMDs are autosomal recessive, leading to a potentially higher incidence in regions with high consanguinity. METHODOLOGY: The study utilized genome sequencing (GS) data from 14,060 adult Qatari participants who were recruited by the Qatar Biobank (QBB) and sequenced by the Qatar Genome Program (QGP). The GS data was analysed for 125 nuclear genes known to be associated with 115 treatable IMDs. RESULTS: Our study identified 253 pathogenic/likely pathogenic SNVs associated with 69 treatable IMDs, including 211 known and 42 novel predicted loss-of-function variants. We estimated that approximately 1 in 13 unrelated individuals (8%) carry a heterozygous pathogenic variant for at least one of 46 treatable IMDs. Notably, phenylketonuria/hyperphenylalaninemia and homocystinuria had among the highest carrier frequencies (1 in 68 and 1 in 85, respectively). CONCLUSION: Population-based studies of treatable IMDs, particularly in globally under-studied populations, can identify high-frequency alleles segregating in the community and inform public health policies, including carrier and newborn screening.

Standardized emergency protocols to improve the management of patients with suspected or confirmed inherited metabolic disorders (IMDs): An initiative of the French IMDs Healthcare Network for Rare Diseases.

OBJECTIVES: Patients with inherited metabolic disorders (IMDs) may require emergency hospital care to prevent life-threatening situations such as metabolic decompensation. To date, over one thousand different rare IMDs have been identified, which means that healthcare professionals (HCPs) initiating emergency treatment may not be familiar with these conditions. The objective of this initiative was to provide HCPs with practical guidance for the acute management of children and adults with IMDs who need emergency care, regardless of the underlying reason. METHODS: We outline how a multidisciplinary working group from the French IMDs Healthcare Network for Rare Diseases, known as G2M, has created concise and standardized protocols _each consisting of a single double-sided A4 sheet _ focused on a specific disease, a group of diseases, or a particular symptom. Prior to validation, these protocols were reviewed by all French reference and competence centres for IMDs, as well as by medical experts from other specialities when necessary, physicians from emergency and intensive care units, and representatives from patient associations. RESULTS AND CONCLUSION: In total, 51 emergency protocols containing essential information have been developed and provided to affected patients. All the emergency protocols are freely available in both French and English at https://www.filiere-g2m.fr/urgences. These standardized protocols aim to enhance the emergency care of patients without delay, while also assisting HCPs by increasing their confidence and efficiency, minimizing the risk of dosage errors when administering specialized treatments, saving time, and reducing the number of phone calls to metabolic medicine specialists on night duty. The protocols are scheduled for annual review to facilitate further improvements based on feedback from HCPs and patients, as well as to accommodate any changes in management practices as they evolve.

Disruption of Mitochondrial Quality Control in Inherited Metabolic Disorders.

Inherited metabolic disorders (IMDs) are genetic disorders often characterized by the accumulation of toxic metabolites in patient tissues and bodily fluids. Although the pathophysiologic effect of these metabolites and their direct effect on cellular function is not yet established for many of these disorders, animal and cellular studies have shown that mitochondrial bioenergetic dysfunction with impairment of citric acid cycle activity and respiratory chain, along with secondary damage induced by oxidative stress are prominent in some. Mitochondrial quality control, requiring the coordination of multiple mechanisms such as mitochondrial biogenesis, dynamics, and mitophagy, is responsible for the correction of such defects. For inborn errors of enzymes located in the mitochondria, secondary abnormalities in quality control this organelle could play a role in their pathophysiology. This review summarizes preclinical data (animal models and patient-derived cells) on mitochondrial quality control disturbances in selected IMDs.

Analysis of the causes of neonatal death and genetic variations in congenital anomalies: a multi-center study.

Background: Neonatal deaths often result from preventable conditions that can be addressed with appropriate interventions. This study aims to analyze the distribution of the causes of neonatal death and explore genetic variations that lead to congenital anomalies in Northwest China. Methods: This multi-center observational study was conducted across six medical centers in Shaanxi province, Northwest China. Clinical data were retrospectively collected from neonates admitted between 2016 and 2020. Kaplan-Meier analysis was utilized to estimate survival rates, while high-throughput sequencing platforms were employed to detect mutations causing congenital anomalies. Results: Among 73,967 neonates requiring hospital care, 424 neonatal deaths were recorded, leading to a neonatal mortality rate of 0.57%. The primary causes of death included neonatal respiratory distress syndrome (23.8%), birth asphyxia (19.8%), neonatal septicemia (19.3%), and congenital anomalies (13.6%). The leading causes of neonatal deaths due to congenital anomalies were congenital heart defects (38.6%), bronchopulmonary dysplasia (14.0%), and inherited metabolic disorders (10.5%). Genetic analysis identified 83 pathogenic or likely pathogenic variants in 23 genes among the neonates with congenital anomalies, including four novel mutations (c.4198+1G>T, c.1075delG, c.610-1G>A, c.7769C>T) in the ABCC8, CDKL5, PLA2G6, and NIPBL genes. Conclusion: Congenital anomalies represent a significant and preventable cause of neonatal deaths in Northwest China. Early detection of congenital anomalies through genetic testing and comprehensive prenatal care are crucial for reducing neonatal mortality rates and improving pregnancy outcomes.

Towards needed improvements in inherited metabolic medicine in adulthood: The SIMMESN adult metabolic working group and MetabERN Joint Position Statement.

Inherited metabolic disorders (IMDs), previously considered as a paediatric sub-specialisation are more and more prevalent in adults, thanks to improved survival, and the expansion of diagnostic tools detecting attenuated-late onset forms in adulthood. Italy is one of the countries with the highest number of IMDs screened by dry blood spots in neonates, allowing them to receive early treatments and to reach adult age. Despite this, awareness of IMDs is still low by the adult medical community, with difficulties in transition and transfer of patients to adult services and unmet patient needs. In 2022, a collaboration between the adult metabolic working group of the Italian Society for the Study of Inherited Metabolic Disorders and Neonatal Screening (SIMMESN) and the European Reference Network for Hereditary Metabolic Disorders (MetabERN) was established to face problems linked to IMDs in adulthood. "The Statement of Udine" was developed to guide further steps towards improvements in inherited metabolic medicine in adults, referencing the experience from the UK. The aim of this paper is to present "The Statement of Udine" explaining its background and its possible applications.

Clinicogenetic characterization of cerebrotendinous xanthomatosis in Brazil.

There are few cerebrotendineous xanthomatosis (CTX) case series and observational studies including a significant number of Latin American patients. We describe a multicenter Brazilian cohort of patients with CTX highlighting their clinical phenotype, recurrent variants and assessing possible genotype-phenotype correlations. We analyzed data from all patients with clinical and molecular or biochemical diagnosis of CTX regularly followed at six genetics reference centers in Brazil between March 2020 and August 2023. We evaluated 38 CTX patients from 26 families, originating from 4 different geographical regions in Brazil. Genetic analysis identified 13 variants in the CYP27A1 gene within our population, including 3 variants that had not been previously described. The most frequent initial symptom of CTX in Brazil was cataract (27%), followed by xanthomas (24%), chronic diarrhea (13.5%), and developmental delay (13.5%). We observed that the median age at loss of ambulation correlates with the age of onset of neurological symptoms, with an average interval of 10 years (interquartile range 6.9 to 11 years). This study represents the largest CTX case series ever reported in South America. We describe phenotypic characteristics and report three new pathogenic or likely pathogenic variants.

In vitro treatment with liposome-encapsulated Mannose-1-phosphate restores N-glycosylation in PMM2-CDG patient-derived fibroblasts.

PMM2-CDG is the most common congenital disorder of glycosylation (CDG). Patients with this disease often carry compound heterozygous mutations of the gene encoding the phosphomannomutase 2 (PMM2) enzyme. PMM2 converts mannose-6-phosphate (M6P) to mannose-1-phosphate (M1P), which is a critical upstream metabolite for proper protein N-glycosylation. Therapeutic options for PMM2-CDG patients are limited to management of the disease symptoms, as no drug is currently approved to treat this disease. GLM101 is a M1P-loaded liposomal formulation being developed as a candidate drug to treat PMM2-CDG. This report describes the effect of GLM101 treatment on protein N-glycosylation of PMM2-CDG patient-derived fibroblasts. This treatment normalized intracellular GDP-mannose, increased the relative glycoprotein mannosylation content and TNFα-induced ICAM-1 expression. Moreover, glycomics profiling revealed that GLM101 treatment of PMM2-CDG fibroblasts resulted in normalization of most high mannose glycans and partial correction of multiple complex and hybrid glycans. In vivo characterization of GLM101 revealed its favorable pharmacokinetics, liver-targeted biodistribution, and tolerability profile with achieved systemic concentrations significantly greater than its effective in vitro potency. Taken as a whole, the results described in this report support further exploration of GLM101's safety, tolerability, and efficacy in PMM2-CDG patients.

Liver gene transfer for metabolite detoxification in inherited metabolic diseases.

Inherited metabolic disorders (IMDs) are a growing group of genetic diseases caused by defects in enzymes that mediate cellular metabolism, often resulting in the accumulation of toxic substrates. The liver is a highly metabolically active organ that hosts several thousands of chemical reactions. As such, it is an organ frequently affected in IMDs. In this article, we review current approaches for liver-directed gene-based therapy aimed at metabolite detoxification in a variety of IMDs. Moreover, we discuss current unresolved challenges in gene-based therapies for IMDs.

Partial suppression of BCAA catabolism as a potential therapy for BCKDK deficiency.

Branched chain ketoacid dehydrogenase kinase (BCKDK) deficiency is a recently described inherited neurometabolic disorder of branched chain amino acid (BCAA) metabolism implying increased BCAA catabolism. It has been hypothesized that a severe reduction in systemic BCAA levels underlies the disease pathophysiology, and that BCAA supplementation may ameliorate disease phenotypes. To test this hypothesis, we characterized a recent mouse model of BCKDK deficiency and evaluated the efficacy of enteral BCAA supplementation in this model. Surprisingly, BCAA supplementation exacerbated neurodevelopmental deficits and did not correct biochemical abnormalities despite increasing systemic BCAA levels. These data suggest that aberrant flux through the BCAA catabolic pathway, not just BCAA insufficiency, may contribute to disease pathology. In support of this conclusion, genetic re-regulation of BCAA catabolism, through Dbt haploinsufficiency, partially rescued biochemical and behavioral phenotypes in BCKDK deficient mice. Collectively, these data raise into question assumptions widely made about the pathophysiology of BCKDK insufficiency and suggest a novel approach to develop potential therapies for this disease.

Inherited metabolic disorders in Cyprus.

Selective screening for inherited metabolic disorders (IMD) began in Cyprus in 1990. Over the last thirty-three years 7388 patients were investigated for IMD and 200 diagnoses were made (diagnostic yield 2.7%). The existence of a single laboratory of Biochemical Genetics for the whole island facilitated the creation of a national registry for IMD. The minimal prevalence of IMD in Cyprus is 53.3 cases per 100,000 live births. The most common group are disorders of amino acid metabolism (41.0%), followed by disorders of carbohydrate metabolism (16.5%), disorders of complex molecule degradation (16.5%), mitochondrial disorders (10.5%) and disorders of vitamin and co-factor metabolism (5.5%). Hyperphenylalaninaemia is the most common IMD (14.0%) followed by galactosaemia (7.0%), glutaric aciduria type I (5.5%) and MSUD (4.0%). Some disorders were found to have a relatively high incidence in specific communities, for example Sandhoff disease among the Cypriot Maronites and GM1 gangliosidosis in one particular area of the island. Other disorders were found to have a relatively higher overall incidence, compared to other Caucasian populations, for example galactosaemia, glutaric aciduria type I and MSUD, while fatty acid oxidation defects, Gaucher disease and classic PKU were found to have a relatively lower incidence. Molecular characterization of selected disorders revealed many novel genetic variants, specific to the Cypriot population.

Macrocephaly and Finger Changes: A Narrative Review.

Macrocephaly, characterized by an abnormally large head circumference, often co-occurs with distinctive finger changes, presenting a diagnostic challenge for clinicians. This review aims to provide a current synthetic overview of the main acquired and genetic etiologies associated with macrocephaly and finger changes. The genetic cause encompasses several categories of diseases, including bone marrow expansion disorders, skeletal dysplasias, ciliopathies, inherited metabolic diseases, RASopathies, and overgrowth syndromes. Furthermore, autoimmune and autoinflammatory diseases are also explored for their potential involvement in macrocephaly and finger changes. The intricate genetic mechanisms involved in the formation of cranial bones and extremities are multifaceted. An excess in growth may stem from disruptions in the intricate interplays among the genetic, epigenetic, and hormonal factors that regulate human growth. Understanding the underlying cellular and molecular mechanisms is important for elucidating the developmental pathways and biological processes that contribute to the observed clinical phenotypes. The review provides a practical approach to delineate causes of macrocephaly and finger changes, facilitate differential diagnosis and guide for the appropriate etiological framework. Early recognition contributes to timely intervention and improved outcomes for affected individuals.

Neurofilament light chain as a biomarker for acute hepatic porphyrias.

Background: Acute hepatic porphyrias (AHP) represent a rare group of inherited metabolic disorders of heme biosynthesis pathway. This study aims to determine the diagnostic and prognostic value of serum neurofilament light chain (NfL) as potential biomarker for AHP. Methods: We conducted a cross-sectional observational study to evaluate NfL levels in patients with AHP. They were divided in different groups: normal health individuals; patients with definitive diagnosis of AHP during acute episodes; patients with AHP and infrequent attacks; patients with AHP and recurrent attacks; asymptomatic individuals with positive genetic testing and urinary delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) levels elevated 4 or more times ("high excretors"); asymptomatic individuals with exclusive positive genetic test; control group with Hereditary Amyloidosis related to Transthyretin with Polyneuropathy (ATTRv-PN). Results: During acute attacks, serum NfL levels were 68 times higher compared to normal controls and disclosed a strong correlation with ALA and PBG levels; also exhibited elevated levels in patients with chronic symptoms regardless of the number of disease attacks compared to healthy controls, and at similar levels to patients with ATTRv-PN, which is a model of progressive neuropathy. Conclusion: This study represents the first to establish NfL as a biomarker for AHP, disclosing NfL as a sensitive biomarker for axonal damage and chronic symptom occurrence. This study not only underscores that neurological damage associated with the disease in any patient, irrespective of the number of attacks, but also reinforces the progressive and profoundly debilitating nature of acute and chronic symptoms observed in individuals with AHP.

Psychiatric Manifestations in Children and Adolescents with Inherited Metabolic Diseases.

Background: Inherited metabolic disorders (IEMs) can be represented in children and adolescents by psychiatric disorders. The early diagnosis of IEMs is crucial for clinical outcome and treatment. The aim of this review is to analyze the most recurrent and specific psychiatric features related to IEMs in pediatrics, based on the onset type and psychiatric phenotypes. Methods: Following the PRISMA Statement, a systematic literature review was performed using a predefined algorithm to find suitable publications in scientific databases of interest. After removing duplicates and screening titles and abstracts, suitable papers were analyzed and screened for inclusion and exclusion criteria. Finally, the data of interest were retrieved from the remaining articles. Results: The results of this study are reported by type of symptoms onset (acute and chronic) and by possible psychiatric features related to IEMs. Psychiatric phenomenology has been grouped into five main clinical manifestations: mood and anxiety disorders; schizophrenia-spectrum disorders; catatonia; eating disorders; and self-injurious behaviors. Conclusions: The inclusion of a variety of psychiatric manifestations in children and adolescents with different IEMs is a key strength of this study, which allowed us to explore the facets of seemingly different disorders in depth, avoiding possible misdiagnoses, with the related delay of early and appropriate treatments.

Broadening the Phenotype and Genotype Spectrum of Glycogen Storage Disease by Unraveling Novel Variants in an Iranian Patient Cohort.

Glycogen storage diseases (GSDs) are a group of rare inherited metabolic disorders characterized by clinical, locus, and allele heterogeneity. This study aims to investigate the phenotype and genotype spectrum of GSDs in a cohort of 14 families from Iran using whole-exome sequencing (WES) and variant analysis. WES was performed on 14 patients clinically suspected of GSDs. Variant analysis was performed to identify genetic variants associated with GSDs. A total of 13 variants were identified, including six novel variants, and seven previously reported pathogenic variants in genes such as AGL, G6PC, GAA, PYGL, PYGM, GBE1, SLC37A4, and PHKA2. Most types of GSDs observed in the cohort were associated with hepatomegaly, which was the most common clinical presentation. This study provides valuable insights into the phenotype and genotype spectrum of GSDs in a cohort of Iranian patients. The identification of novel variants adds to the growing body of knowledge regarding the genetic landscape of GSDs and has implications for genetic counseling and future therapeutic interventions. The diverse nature of GSDs underscores the need for comprehensive genetic testing methods to improve diagnostic accuracy. Continued research in this field will enhance our understanding of GSDs, ultimately leading to improved management and outcomes for individuals affected by these rare metabolic disorders.