scholarly journals Treatable inherited metabolic disorders causing intellectual disability: 2021 review and digital app

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Eva M. M. Hoytema van Konijnenburg ◽  
Saskia B. Wortmann ◽  
Marina J. Koelewijn ◽  
Laura A. Tseng ◽  
Roderick Houben ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Metabolic Disorders ◽  
Clinical Symptoms ◽  
Early Recognition ◽  
Diagnostic Algorithm ◽  
Global Developmental Delay ◽  
Digital Tool ◽  
Enzyme Replacement ◽  
Published Evidence ◽  
Inherited Metabolic Disorders

Abstract Background The Treatable ID App was created in 2012 as digital tool to improve early recognition and intervention for treatable inherited metabolic disorders (IMDs) presenting with global developmental delay and intellectual disability (collectively ‘treatable IDs’). Our aim is to update the 2012 review on treatable IDs and App to capture the advances made in the identification of new IMDs along with increased pathophysiological insights catalyzing therapeutic development and implementation. Methods Two independent reviewers queried PubMed, OMIM and Orphanet databases to reassess all previously included disorders and therapies and to identify all reports on Treatable IDs published between 2012 and 2021. These were included if listed in the International Classification of IMDs (ICIMD) and presenting with ID as a major feature, and if published evidence for a therapeutic intervention improving ID primary and/or secondary outcomes is available. Data on clinical symptoms, diagnostic testing, treatment strategies, effects on outcomes, and evidence levels were extracted and evaluated by the reviewers and external experts. The generated knowledge was translated into a diagnostic algorithm and updated version of the App with novel features. Results Our review identified 116 treatable IDs (139 genes), of which 44 newly identified, belonging to 17 ICIMD categories. The most frequent therapeutic interventions were nutritional, pharmacological and vitamin and trace element supplementation. Evidence level varied from 1 to 3 (trials, cohort studies, case–control studies) for 19% and 4–5 (case-report, expert opinion) for 81% of treatments. Reported effects included improvement of clinical deterioration in 62%, neurological manifestations in 47% and development in 37%. Conclusion The number of treatable IDs identified by our literature review increased by more than one-third in eight years. Although there has been much attention to gene-based and enzyme replacement therapy, the majority of effective treatments are nutritional, which are relatively affordable, widely available and (often) surprisingly effective. We present a diagnostic algorithm (adjustable to local resources and expertise) and the updated App to facilitate a swift and accurate workup, prioritizing treatable IDs. Our digital tool is freely available as Native and Web App (www.treatable-id.org) with several novel features. Our Treatable ID endeavor contributes to the Treatabolome and International Rare Diseases Research Consortium goals, enabling clinicians to deliver rapid evidence-based interventions to our rare disease patients.

scholarly journals Intellectual Disability and Brain Creatine Deficit: Phenotyping of the Genetic Mouse Model for GAMT Deficiency

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1201
Author(s):  
Luigia Rossi ◽  
Francesca Nardecchia ◽  
Francesca Pierigè ◽  
Rossella Ventura ◽  
Claudia Carducci ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Mouse Model ◽  
Clinical Symptoms ◽  
Global Developmental Delay ◽  
Behavioral Alterations ◽  
Biochemical Alterations ◽  
Bodily Fluids ◽  
Genetic Mouse Model ◽  
Gamt Deficiency ◽  
Pathogenic Variants

Guanidinoacetate methyltransferase deficiency (GAMT-D) is one of three cerebral creatine (Cr) deficiency syndromes due to pathogenic variants in the GAMT gene (19p13.3). GAMT-D is characterized by the accumulation of guanidinoacetic acid (GAA) and the depletion of Cr, which result in severe global developmental delay (and intellectual disability), movement disorder, and epilepsy. The GAMT knockout (KO) mouse model presents biochemical alterations in bodily fluids, the brain, and muscles, including increased GAA and decreased Cr and creatinine (Crn) levels, which are similar to those observed in humans. At the behavioral level, only limited and mild alterations have been reported, with a large part of analyzed behaviors being unaffected in GAMT KO as compared with wild-type mice. At the cerebral level, decreased Cr and Crn and increased GAA and other guanidine compound levels have been observed. Nevertheless, the effects of Cr deficiency and GAA accumulation on many neurochemical, morphological, and molecular processes have not yet been explored. In this review, we summarize data regarding behavioral and cerebral GAMT KO phenotypes, and focus on uncharted behavioral alterations that are comparable with the clinical symptoms reported in GAMT-D patients, including intellectual disability, poor speech, and autistic-like behaviors, as well as unexplored Cr-induced cerebral alterations.

scholarly journals Status Epilepticus in Neonates

2018 ◽  
Vol 05 (01) ◽  
pp. 002-008 ◽  
Author(s):  
Arushi Saini ◽  
Kollencheri Vinayan
Keyword(s):  
Status Epilepticus ◽  
Metabolic Disorders ◽  
Neonatal Period ◽  
Total Duration ◽  
Global Developmental Delay ◽  
Management Guidelines ◽  
Inherited Metabolic Disorders ◽  
Infantile Seizures ◽  
Ischemic Encephalopathy

AbstractSeizures are a reflection of acute brain injury in the neonatal period, and status epilepticus reflects a state of high seizure burden. Neonatal status epilepticus has been reported in 8 to 43% of newborns with seizures. There is no separate definition for neonatal status epilepticus, and it has been commonly defined as a continuous seizure lasting at least 30 minutes and/or a series of seizures whose total duration exceeds 50% of a given epoch. The causes of status epilepticus in the neonatal period mirror the causes of neonatal seizures. It is symptomatic, usually associated with hypoxic–ischemic encephalopathy, inherited metabolic disorders, infections, and cerebral hemorrhage. Management guidelines are not separately outlined for neonatal status epilepticus and are commonly derived from the recommendations for neonatal and infantile seizures. The presence of neonatal status epilepticus significantly increases the odds for development of cerebral palsy, global developmental delay, and epilepsy later in life. Further research is needed into the role of current antiepileptic drugs in causing neuronal injury and use of neuroprotective agents during neonatal status epilepticus.

scholarly journals Inherited Metabolic Disorders Presenting with Ataxia

2020 ◽  
Vol 21 (15) ◽  
pp. 5519 ◽  
Author(s):  
Grace Silver ◽  
Saadet Mercimek-Andrews
Keyword(s):  
Metabolic Disorders ◽  
Early Death ◽  
Clinical Feature ◽  
Global Developmental Delay ◽  
Facial Features ◽  
Neurodevelopmental Outcomes ◽  
Inherited Metabolic Disorder ◽  
Developmental Regression ◽  
Inherited Metabolic Disorders ◽  
History Of

Ataxia is a common clinical feature in inherited metabolic disorders. There are more than 150 inherited metabolic disorders in patients presenting with ataxia in addition to global developmental delay, encephalopathy episodes, a history of developmental regression, coarse facial features, seizures, and other types of movement disorders. Seizures and a history of developmental regression especially are important clinical denominators to consider an underlying inherited metabolic disorder in a patient with ataxia. Some of the inherited metabolic disorders have disease specific treatments to improve outcomes or prevent early death. Early diagnosis and treatment affect positive neurodevelopmental outcomes, so it is important to think of inherited metabolic disorders in the differential diagnosis of ataxia.

scholarly journals Acute Pancreatitis as a Complication of Antiepileptic Treatment: Case Series and Review of the Literature

2021 ◽  
Vol 13 (1) ◽  
pp. 98-103
Author(s):  
Agnieszka Pawłowska-Kamieniak ◽  
Paulina Krawiec ◽  
Elżbieta Pac-Kożuchowska
Keyword(s):  
Valproic Acid ◽  
Acute Pancreatitis ◽  
Metabolic Disorders ◽  
Genetic Factors ◽  
Clinical Symptoms ◽  
Gallstone Disease ◽  
Young Patients ◽  
Case Series ◽  
Review Of The Literature ◽  
Acid Therapy

Acute pancreatitis (AP) appears to be rare disease in childhood. In children, it has a different aetiology and course, and requires different management than in adult patients. The diagnosis of AP is based on at least two of the three criteria, which include typical clinical symptoms, abnormalities in laboratory tests and/or imaging studies of the pancreas. There are many known causes leading to AP in children including infections, blunt abdominal trauma, genetic factors, gallstone disease, metabolic disorders, anatomical defects of the pancreas, systemic diseases, as well as drugs, including antiepileptic drugs, and especially preparations of valproic acid. In our study, we present four cases of young patients diagnosed with acute pancreatitis as a complication of valproic acid therapy and we present a review of the literature. We believe that the activity of pancreatic enzymes should be monitored in children treated with valproate preparations in the case of clinical symptoms suggesting AP.

scholarly journals Targeted Therapies for Metabolic Myopathies Related to Glycogen Storage and Lipid Metabolism: a Systematic Review and Steps Towards a ‘Treatabolome’

2021 ◽  
pp. 1-18
Author(s):  
A. Manta ◽  
S. Spendiff ◽  
H. Lochmüller ◽  
R. Thompson
Keyword(s):  
Systematic Review ◽  
Lipid Metabolism ◽  
Genetic Defect ◽  
Genetic Mutation ◽  
Glycogen Storage ◽  
Carnitine Deficiency ◽  
Exercise Intolerance ◽  
Enzyme Replacement ◽  
Metabolic Myopathies ◽  
Published Evidence

Background: Metabolic myopathies are a heterogenous group of muscle diseases typically characterized by exercise intolerance, myalgia and progressive muscle weakness. Effective treatments for some of these diseases are available, but while our understanding of the pathogenesis of metabolic myopathies related to glycogen storage, lipid metabolism and β-oxidation is well established, evidence linking treatments with the precise causative genetic defect is lacking. Objective: The objective of this study was to collate all published evidence on pharmacological therapies for the aforementioned metabolic myopathies and link this to the genetic mutation in a format amenable to databasing for further computational use in line with the principles of the “treatabolome” project. Methods: A systematic literature review was conducted to retrieve all levels of evidence examining the therapeutic efficacy of pharmacological treatments on metabolic myopathies related to glycogen storage and lipid metabolism. A key inclusion criterion was the availability of the genetic variant of the treated patients in order to link treatment outcome with the genetic defect. Results: Of the 1,085 articles initially identified, 268 full-text articles were assessed for eligibility, of which 87 were carried over into the final data extraction. The most studied metabolic myopathies were Pompe disease (45 articles), multiple acyl-CoA dehydrogenase deficiency related to mutations in the ETFDH gene (15 articles) and systemic primary carnitine deficiency (8 articles). The most studied therapeutic management strategies for these diseases were enzyme replacement therapy, riboflavin, and carnitine supplementation, respectively. Conclusions: This systematic review provides evidence for treatments of metabolic myopathies linked with the genetic defect in a computationally accessible format suitable for databasing in the treatabolome system, which will enable clinicians to acquire evidence on appropriate therapeutic options for their patient at the time of diagnosis.

scholarly journals Rare Variants in Autophagy and Non-Autophagy Genes in Late-Onset Pompe Disease: Suggestions of Their Disease-Modifying Role in Two Italian Families

2021 ◽  
Vol 22 (7) ◽  
pp. 3625
Author(s):  
Filomena Napolitano ◽  
Giorgia Bruno ◽  
Chiara Terracciano ◽  
Giuseppina Franzese ◽  
Nicole Piera Palomba ◽  
...  
Keyword(s):  
Pompe Disease ◽  
Rare Variants ◽  
Clinical Symptoms ◽  
Late Onset ◽  
Respiratory Muscles ◽  
Autosomal Recessive Disorder ◽  
Compound Heterozygous ◽  
Enzyme Replacement ◽  
Whole Exome ◽  
Clinical Pictures

Pompe disease is an autosomal recessive disorder caused by a deficiency in the enzyme acid alpha-glucosidase. The late-onset form of Pompe disease (LOPD) is characterized by a slowly progressing proximal muscle weakness, often involving respiratory muscles. In LOPD, the levels of GAA enzyme activity and the severity of the clinical pictures may be highly variable among individuals, even in those who harbour the same combination of GAA mutations. The result is an unpredictable genotype–phenotype correlation. The purpose of this study was to identify the genetic factors responsible for the progression, severity and drug response in LOPD. We report here on a detailed clinical, morphological and genetic study, including a whole exome sequencing (WES) analysis of 11 adult LOPD siblings belonging to two Italian families carrying compound heterozygous GAA mutations. We disclosed a heterogeneous pattern of myopathic impairment, associated, among others, with cardiac defects, intracranial vessels abnormality, osteoporosis, vitamin D deficiency, obesity and adverse response to enzyme replacement therapy (ERT). We identified deleterious variants in the genes involved in autophagy, immunity and bone metabolism, which contributed to the severity of the clinical symptoms observed in the LOPD patients. This study emphasizes the multisystem nature of LOPD and highlights the polygenic nature of the complex phenotype disclosed in these patients.

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