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We report on a 4-year-old boy affected by Gaucher disease (GD) type 3, who presented with splenomegaly and a history of oculomotor apraxia. GD is a rare lysosomal storage disorder caused by glucocerebrosidase deficiency with multi-organ involvement. Besides common clinical features such as hepatosplenomegaly and skeletal involvement, less frequent neurological symptoms, such as oculomotor apraxia, are indicative of neuronopathic forms of the disease, namely GD type 3, to be confirmed both by enzyme activity and genetic testing. Overall, GD management requires a multidisciplinary approach involving metabolic pediatricians, neurologists, psychologists, and geneticists, and currently relies on early enzyme replacement therapy. Although enzyme replacement therapy has proved to be effective in improving systemic signs and symptoms, it is unable to alleviate neurological complications once these have occurred, as it does not pass across the blood–brain barrier. Neurological improvements may occur through indirect mechanisms. Thus, our case report aims to highlight the importance of considering GD in the differential diagnosis of pediatric patients presenting with splenomegaly associated with neurological manifestations, as early intervention may significantly modify the disease progression and prevent further irreversible complications. [ABSTRACT FROM AUTHOR]

Inherited metabolic diseases (IMDs) are a group of heterogeneous genetic disorders resulting in substrate accumulation, energy deficiency, or complex molecular defects due to the failure of specific molecules to act as enzymes, cofactors, transporters, or receptors in specific metabolic pathways. The pathophysiological changes seen in IMDs are sometimes associated with intellectual disability (ID) or neurocognitive decline, necessitating multidisciplinary input. We here describe our experience at one tertiary metabolic centre in the UK. We reviewed the case prevalence and existing service provision in one adult IMD service covering a multi-ethnic population of 10 million in North England. In our cohort of 2268 IMD patients, 1598 patients had general metabolic conditions (70.5%), and 670 had lysosomal storage disease/disorders (LSD)s (29.5%). The overall prevalence of ID and neurocognitive decline was found to be 15.7% (n = 357), with patients with LSDs accounting for 23.5% (n = 84) of affected patients. Given the prevalence of ID in adults with IMDs, access to multidisciplinary input from neuropsychology and neuropsychiatry services is important. Education of healthcare professionals to diagnose IMDs in patients with ID, in addition to neurocognitive and neuropsychiatric presentations, will avoid missed diagnoses of IMD and will have a positive effect on patient outcomes. [ABSTRACT FROM AUTHOR]

Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders characterized by impaired social interaction, limited communication skills, and restrictive and repetitive behaviours. The pathophysiology of ASD is multifactorial and includes genetic, epigenetic, and environmental factors, whereas a causal relationship has been described between ASD and inherited metabolic disorders (IMDs). This review describes biochemical, genetic, and clinical approaches to investigating IMDs associated with ASD. The biochemical work-up includes body fluid analysis to confirm general metabolic and/or lysosomal storage diseases, while the advances and applications of genomic testing technology would assist with identifying molecular defects. An IMD is considered likely underlying pathophysiology in ASD patients with suggestive clinical symptoms and multiorgan involvement, of which early recognition and treatment increase their likelihood of achieving optimal care and a better quality of life. [ABSTRACT FROM AUTHOR]

Diseases that affect the liver account for approximately 2 million deaths worldwide each year. The increasing prevalence of these diseases and the limited efficacy of current treatments are expected to stimulate substantial growth in the global market for therapeutics that target the liver. Currently, liver transplantation is the only curative option available for many liver diseases. Gene therapy represents a valuable approach to treatment. The liver plays a central role in a myriad of essential metabolic functions, making it an attractive organ for gene therapy; hepatocytes comprise the most relevant target. To date, viral vectors constitute the preferred approach to targeting hepatocytes with genes of therapeutic interest. Alternatively, mRNA-based therapy offers a number of comparative advantages. Clinical and preclinical studies undertaken to treat inherited metabolic diseases affecting the liver, cirrhosis and fibrosis, hepatocellular carcinoma, hepatitis B, and cytomegalovirus using lipid nanoparticle-encapsulated mRNAs that encode the therapeutic or antigenic protein of interest are discussed. [ABSTRACT FROM AUTHOR]

Inherited metabolic diseases (IMDs) are rare heterogenous genetic conditions. Advanced technology and novel therapeutic developments have led to the improved life expectancy of patients with IMDs. Long-term, they require close surveillance from specialist adult metabolic providers. Healthcare transition (HCT) is the planned, purposeful process of preparing adolescents for adult-centered medical care and has been recognized globally as a necessary component of care for IMDs. Two recent surveys outlined barriers to the HCT in the US and the UK. The limited knowledge of IMDs among adult physicians was one of the barriers. Some work on specialty curriculum has started and aims to improve the structured training and awareness of rare diseases. Other barriers included social and legal aspects of adulthood, social, vocational and educational support for young adults, care fragmentation and insurance coverage. Although various HCT tools are available, they cannot always be standardized for IMDs. Despite the remarkable differences in the healthcare systems and physicians' training, collaboration among metabolic centers is possible. International rare disease alliance may enhance the patients' management via guidelines development and standardized training for adult metabolic providers. [ABSTRACT FROM AUTHOR]

(1) Background: Phenotypic diversity and long-term health outcomes of individuals with urea cycle disorders (UCDs) have been described in detail. However, there is limited information on the burden on affected families. (2) Methods: To evaluate the family burden in parents with children suffering from UCDs, we used validated questionnaires. Socio-demographic characteristics were evaluated, and an adapted version of the Parental Need Scale for Rare Diseases questionnaire was used. The survey was conducted in families of UCD patients cared for at the University Children's Hospital Heidelberg. (3) Results: From April to November 2021, 59 participants were interviewed (mothers n = 34, fathers n = 25). The affected patients most frequently suffered from ornithine transcarbamylase deficiency (OTC-D) (female n = 12, male n = 12), followed by argininosuccinate synthetase deficiency (ASS-D, n = 13) and argininosuccinate lyase deficiency (ASL-D, n = 8). About one-third of the participants were "dissatisfied" or "extremely dissatisfied" with health professionals' disease knowledge. In addition, 30% of the participants reported a medium or high need for "additional information on the development of their children", and 44% reported a medium or high need "for information on available services". A majority of 68% reported a need for additional support regarding services such as support groups (42%) or psychological counseling (29%). (4) Conclusions: Our study indicates that there is an unmet need for sufficient information about the development of children with UCDs, as well as for information about available support services for families with UCD patients. Furthermore, the results highlight the importance of establishing or improving family-centered care approaches. This pilot study may serve as a template for the assessment of the family burden associated with other inherited metabolic diseases. [ABSTRACT FROM AUTHOR]

Understanding the genetic architecture of metabolic epilepsies is of paramount importance, both to current clinical practice and for the identification of further research directions. The main goals of our study were to identify the scope of metabolic epilepsies and to investigate their clinical presentation, diagnostic approaches and treatments. The International Classification of Inherited Metabolic Disorders and IEMbase were used as a basis for the identification and classification of metabolic epilepsies. Six hundred metabolic epilepsies have been identified, accounting for as much as 37% of all currently described inherited metabolic diseases (IMD). Epilepsy is a particularly common symptom in disorders of energy metabolism, congenital disorders of glycosylation, neurotransmitter disorders, disorders of the synaptic vesicle cycle and some other IMDs. Seizures in metabolic epilepsies may present variably, and most of these disorders are complex and multisystem. Abnormalities in routine laboratory tests and/or metabolic testing may be identified in 70% of all metabolic epilepsies, but in many cases they are non-specific. In total, 111 metabolic epilepsies (18% of all) have specific treatments that may significantly change health outcomes if diagnosed in time. Although metabolic epilepsies comprise an important and significant group of disorders, their real scope and frequency may have been underestimated. [ABSTRACT FROM AUTHOR]

Propionic Acidemia (PA) is a rare inherited metabolic disorder caused by the enzymatic block of propionyl-CoA carboxylase with the consequent accumulation of propionic acid, which is toxic for the brain and cardiac cells. Since a considerable amount of propionate is produced by intestinal bacteria, interest arose in the attempt to reduce propionate-producing bacteria through a monthly antibiotic treatment of metronidazole. In the present study, we investigated the gut microbiota structure of an infant diagnosed at 4 days of life through Expanded Newborn Screening (NBS) and treated the child following international guidelines with a special low-protein diet, specific medications and strict biochemical monitoring. Microbiota composition was assessed during the first month of life, and the presence of Bacteroides fragilis, known to be associated with propionate production, was effectively decreased by metronidazole treatment. After five antibiotic therapy cycles, at 4 months of age, the infant was supplemented with a daily mixture of three bifidobacterial strains, known not to be propionate producers. The supplementation increased the population of bifidobacteria, with Bifidobacterium breve as the dominating species; Ruminococcus gnavus, an acetate and formate producer, was also identified. Metabarcoding analysis, compared with low coverage whole metagenome sequencing, proved to capture all the microbial biodiversity and could be the elected tool for fast and cost-effective monitoring protocols to be implemented in the follow up of rare metabolic disorders such as PA. Data obtained could be a possible starting point to set up tailored microbiota modification treatment studies in the attempt to improve the quality of life of people affected by propionic acidemia. [ABSTRACT FROM AUTHOR]

3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) Lyase deficiency (HMGLD) (OMIM 246450) is an autosomal recessive genetic disorder caused by homozygous or compound heterozygous variants in the HMGCL gene located on 1p36.11. Clinically, this disorder is characterized by a life-threatening metabolic intoxication with a presentation including severe hypoglycemia without ketosis, metabolic acidosis, hyper-ammoniemia, hepatomegaly and a coma. HMGLD clinical onset is within the first few months of life after a symptomatic free period. In nonacute periods, the treatment is based on a protein- and fat-restricted diet. L-carnitine supplementation is recommended. A late onset presentation has been described in very few cases, and only two adult cases have been reported. The present work aims to describe an incidental discovery of an HMGLD case in a 54-year-old patient and reports a comprehensive review of clinical and biological features in adult patients to raise awareness about the late-onset presentation of this disease. [ABSTRACT FROM AUTHOR]

Inborn errors of metabolism (IEM) are inherited conditions caused by genetic defects in enzymes or cofactors. These defects result in a specific metabolic fingerprint in patient body fluids, showing accumulation of substrate or lack of an end-product of the defective enzymatic step. Untargeted metabolomics has evolved as a high throughput methodology offering a comprehensive readout of this metabolic fingerprint. This makes it a promising tool for diagnostic screening of IEM patients. However, the size and complexity of metabolomics data have posed a challenge in translating this avalanche of information into knowledge, particularly for clinical application. We have previously established next-generation metabolic screening (NGMS) as a metabolomics-based diagnostic tool for analyzing plasma of individual IEM-suspected patients. To fully exploit the clinical potential of NGMS, we present a computational pipeline to streamline the analysis of untargeted metabolomics data. This pipeline allows for time-efficient and reproducible data analysis, compatible with ISO:15189 accredited clinical diagnostics. The pipeline implements a combination of tools embedded in a workflow environment for large-scale clinical metabolomics data analysis. The accompanying graphical user interface aids end-users from a diagnostic laboratory for efficient data interpretation and reporting. We also demonstrate the application of this pipeline with a case study and discuss future prospects. [ABSTRACT FROM AUTHOR]

Low-protein diets (LPDs) are the main treatment for urea cycle disorders (UCDs) and organic acidemias (OAs). In most cases, LPDs start in childhood and must be continued into adulthood. The improved life expectancy of patients with UCDs and OAs raises the question of their consequences on nutritional status in adult subjects. As this topic has so far received little attention, we conducted a review of scientific studies that investigated the nutrient intake and nutritional status in adult patients with UCDs and branched chain organic acidemias (BCOAs) on LPD. Methods: The literature search was conducted in PubMed/MEDLINE, Scopus, EMBASE and Google Scholar from 1 January 2000 to 31 May 2020, focusing on nutrient intake and nutritional status in UCD and OA adult patients. Results: Despite protein restriction is recommended as the main treatment for UCDs and OAs, in these patients, protein intake ranges widely, with many patients who do not reach safety levels. When evaluated, micronutrient intake resulted below recommended values in some patients. Lean body mass resulted in most cases lower than normal range while fat body mass (FM) was often found normal or higher than the controls or reference values. Protein intake correlated inversely with FM both in adult and pediatric UCD patients. Conclusions: The clinical management of adult patients with UCDs and BCOAs should include an accurate assessment of the nutritional status and body composition. However, as little data is still available on this topic, further studies are needed to better clarify the effects of LPDs on nutritional status in adult UCD and BCOA patients. [ABSTRACT FROM AUTHOR]

Metabolic phenotyping is poised as a powerful and promising tool for biomarker discovery in inherited metabolic diseases. However, few studies applied this approach to mcopolysaccharidoses (MPS). Thus, this innovative functional approach may unveil comprehensive impairments in MPS biology. This study explores mcopolysaccharidosis VI (MPS VI) or Maroteaux–Lamy syndrome (OMIM #253200) which is an autosomal recessive lysosomal storage disease caused by the deficiency of arylsulfatase B enzyme. Urine samples were collected from 16 MPS VI patients and 66 healthy control individuals. Untargeted metabolomics analysis was applied using ultra-high-performance liquid chromatography combined with ion mobility and high-resolution mass spectrometry. Furthermore, dermatan sulfate, amino acids, carnitine, and acylcarnitine profiles were quantified using liquid chromatography coupled to tandem mass spectrometry. Univariate analysis and multivariate data modeling were used for integrative analysis and discriminant metabolites selection. Pathway analysis was done to unveil impaired metabolism. The study revealed significant differential biochemical patterns using multivariate data modeling. Pathway analysis revealed that several major amino acid pathways were dysregulated in MPS VI. Integrative analysis of targeted and untargeted metabolomics data with in silico results yielded arginine-proline, histidine, and glutathione metabolism being the most affected. This study is one of the first metabolic phenotyping studies of MPS VI. The findings might shed light on molecular understanding of MPS pathophysiology to develop further MPS studies to enhance diagnosis and treatments of this rare condition. [ABSTRACT FROM AUTHOR]