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 Boricua Founder Variant in FRRS1L Causes Epileptic Encephalopathy With Hyperkinetic Movements

2020 ◽  
Vol 36 (2) ◽  
pp. 93-98
Author(s):  
Imane Abdelmoumen ◽  
Sandra Jimenez ◽  
Ignacio Valencia ◽  
Joseph Melvin ◽  
Agustin Legido ◽  
...  
Keyword(s):  
Movement Disorder ◽  
Puerto Rican ◽  
Cerebellar Atrophy ◽  
Intractable Epilepsy ◽  
Brain Magnetic Resonance Imaging ◽  
Epileptic Encephalopathy ◽  
Pathogenic Variant ◽  
Global Developmental Delay ◽  
Neurodevelopmental Outcomes ◽  
Developmental Regression

Objective: To describe a founder mutation effect and the clinical phenotype of homozygous FRRS1L c.737_739delGAG (p.Gly246del) variant in 15 children of Puerto Rican (Boricua) ancestry presenting with early infantile epileptic encephalopathy (EIEE-37) with prominent movement disorder. Background: EIEE-37 is caused by biallelic loss of function variants in the FRRS1L gene, which is critical for AMPA-receptor function, resulting in intractable epilepsy and dyskinesia. Methods: A retrospective, multicenter chart review of patients sharing the same homozygous FRRS1L (p.Gly246del) pathogenic variant identified by clinical genetic testing. Clinical information was collected regarding neurodevelopmental outcomes, neuroimaging, electrographic features and clinical response to antiseizure medications. Results: Fifteen patients from 12 different families of Puerto Rican ancestry were homozygous for the FRRS1L (p.Gly246del) pathogenic variant, with ages ranging from 1 to 25 years. The onset of seizures was from 6 to 24 months. All had hypotonia, severe global developmental delay, and most had hyperkinetic involuntary movements. Developmental regression during the first year of life was common (86%). Electroencephalogram showed hypsarrhythmia in 66% (10/15), with many older children evolving into Lennox-Gastaut syndrome. Six patients demonstrated progressive volume loss and/or cerebellar atrophy on brain magnetic resonance imaging (MRI). Conclusions: We describe the largest cohort to date of patients with epileptic encephalopathy. We estimate that 0.76% of unaffected individuals of Puerto Rican ancestry carry this pathogenic variant due to a founder effect. Children homozygous for the FRRS1L (p.Gly246del) Boricua variant exhibit a very homogenous phenotype of early developmental regression and epilepsy, starting with infantile spasms and evolving into Lennox-Gastaut syndrome with hyperkinetic movement disorder.

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 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 Eye involvement in inherited metabolic disorders

2020 ◽  
Vol 12 ◽  
pp. 251584142097910
Author(s):  
James E. Davison
Keyword(s):  
Metabolic Disorder ◽  
Metabolic Disorders ◽  
Holistic Approach ◽  
Optic Pathway ◽  
Rare Disorders ◽  
Biochemical Pathways ◽  
Eye Disorders ◽  
Inherited Metabolic Disorders ◽  
History Of ◽  
Eye Involvement

Inherited metabolic disorders are a large group of rare disorders affecting normal biochemical pathways. Many metabolic disorders can present with symptoms affecting the eye, and eye disorders can evolve later in the natural history of an already diagnosed metabolic disorder. The ophthalmic involvement can be very varied affecting any part of the eye, including abnormalities of cornea, lens dislocation and cataracts, retina and the distal optic pathway, and extraocular muscles. Awareness of inherited metabolic disorders is important to facilitate early diagnosis and in some cases instigate early treatment if a patient presents with eye involvement suggestive of a metabolic disorder. Ophthalmological interventions are also an important component of the multisystem holistic approach to treating patients with metabolic disorders.

Report of rapid diagnosis and precise management of MMADHC-related intracellular cobalamin defect

2021 ◽  
Vol 14 (6) ◽  
pp. e239755
Author(s):  
Vivekananda Bhat ◽  
Dhanya Lakshmi Narayanan ◽  
Anju Shukla
Keyword(s):  
Metabolic Disorders ◽  
Clinical Presentation ◽  
Male Infant ◽  
Rapid Diagnosis ◽  
Genomic Testing ◽  
Macrocytic Anaemia ◽  
Developmental Regression ◽  
Inherited Metabolic Disorders ◽  
Significant Clinical Improvement ◽  
Cobalamin Metabolism

Disorders of intracellular cobalamin metabolism are a group of metabolic disorders that lead to varied clinical presentation from intrauterine life to adulthood. We report a male infant with developmental regression, macrocytic anaemia and hyperpigmentation. Exome sequencing identified a homozygous pathogenic variant in the MMADHC gene, known to cause homocystinuria, cblD type (MIM #277410). We describe significant clinical improvement with targeted therapy and emphasise the relevance of genomic testing in accurate management of inherited metabolic disorders.

Gut Microbiota Patterns in Obese and Type 2 Diabetes (T2D) Patients from Romanian Black Sea Coast Region

2018 ◽  
Vol 69 (8) ◽  
pp. 2260-2267 ◽  
Author(s):  
Andra Iulia Suceveanu ◽  
Anca Pantea Stoian ◽  
Irinel Parepa ◽  
Claudia Voinea ◽  
Razvan Hainarosie ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Organic Acid ◽  
Black Sea ◽  
Metabolic Disorders ◽  
Obese Patients ◽  
Bacterial Counts ◽  
Black Sea Coast ◽  
History Of ◽  
Coast Region ◽  
Sea Coast

Gut microbiota plays a major role in the process of food absorption and low grade inflammation, two key steps in obesity and diabetes mellitus occurrence. Gut microbiota metabolites, such as short chain fatty acids (SCFA), have an important impact over the metabolic pathways like insulin signalling, incretin production and inflammation. [1-3] We aimed to study the microbiota patterns in obese and T2D patients from Black Sea Coast region, considering the ethnic mixture, environmental and geographical particularities, involving diet or various habits in this area. 100 patients and 100 controls matched by age, gender and ethnicity were studied regarding feaces predominance of Lactobacillus and Bifidobacterium species. We compared the results of microbiota patterns from patients to those obtained in a similar control group of healthy subjects. The standard pour plate 0.05% L-cystine enriched method was used to obtain the bacterial cultures and anaerobic conditions. Morphological and biochemical tests were used to identify the Lactobacillus and Bifidobacterium spp. Fecal organic acid concentrations were explored in frozen samples. The association between bacterial counts/organic acid concentrations and independent variables, including age, diet, ethnicity and other risk factors were calculated using multivariable linear regression analysis. Pearson�s correlation coefficients were calculated to detect associations between fecal bacteria counts/organic acid concentrations and laboratory variables (serum biomarkers, body mass index, age, and severity of obesity/T2D according to international scales). Junk and sweet diets, lack of physical activity and familial aggregation of hypercholesterolemia and diabetes were significantly more often present in our T2D/obese patients than in controls. The bacterial counts of the L. acidophilus, L plantarum and L. reuteri subgroups of Lactobacillus sp were significantly lower among patients with T2D and obesity than in controls. The counting of Bifidobacterium spp revealed a higher presence of B. bifidum in controls than in obese or T2D patients. Diet type (junk food and sweets), BMI (]25) and personal history of metabolic disorders were associated with decreased counts of L acidophilus and increased counts of L. fermentum and B. adolescentis in T2D patients. Ethnicity, metabolic disorders history and junk and sweet diet were associated with low counts of L. acidophilus and L. reuteri and low counts of B. longum. Junk and sweet diet was associated with low counts of B. bifidum. Romanian ethnicity and metabolic disorders were associated with low counts of B. choerinum at obese patients, independent of age or previous antidiabetic treatments. The concentrations of acetic and butyric acids were significantly lower in all patients groups, while the concentrations of valeric acid were significantly higher in patients with untreated T2D and obese patients compared to the controls. Low counts of L. acidophilus and L. reuteri were positively correlated with the increased levels of HbA1c, LDL cholesterol, TG and inflammatory markers such as CRP, ESR and IL-6, no matter of diet, age, ethnicity or metabolic disorders history. Also, low counts of B. bifidum and B. infantis were positively correlated with high levels of CRP, IL-6 and TG. In obese patients, statistic analysis results showed that low counts of L. acidophilus, L. plantarum, L. johnsonii and L. reuteri were positively associated with increased levels of CPR, IL-6 and TG, while low counts of B. bifidum, B infantis and B. breve were positively correlated with higher counts of CPR, LDL cholesterol and TG. Low counts of B. bifidum and B choerinum were positively correlated with low counts of HDL cholesterol in Romanian ethnicity patients and in those with previous metabolic disorders. Low bacterial counts of some particular strains of Lactobacillus spp and Bifidobacterium spp were positively correlated with diet type, BMI, Romanian ethnicity and personal history of metabolic disorders obese and T2D patients from Romanian Black Sea Coast Region.

John von Neumann and the Evolutionary Growth of Complexity: Looking Backward, Looking Forward

2000 ◽  
Vol 6 (4) ◽  
pp. 347-361 ◽  
Author(s):  
Barry McMullin
Keyword(s):  
Subsequent Development ◽  
Early Death ◽  
Problem Situation ◽  
John Von Neumann ◽  
Von Neumann ◽  
Comprehensive Theory ◽  
History Of ◽  
The Subject ◽  
To Come ◽  
Evolutionary Growth

In the late 1940s John von Neumann began to work on what he intended as a comprehensive “theory of [complex] automata.” He started to develop a book length manuscript on the subject in 1952. However, he put it aside in 1953, apparently due to pressure of other work. Due to his tragically early death in 1957, he was never to return to it. The draft manuscript was eventually edited, and combined for publication with some related lecture transcripts, by Burks in 1966. It is clear from the time and effort that von Neumann invested in it that he considered this to be a very significant and substantial piece of work. However, subsequent commentators (beginning even with Burks) have found it surprisingly difficult to articulate this substance. Indeed, it has since been suggested that von Neumann's results in this area either are trivial, or, at the very least, could have been achieved by much simpler means. It is an enigma. In this paper I review the history of this debate (briefly) and then present my own attempt at resolving the issue by focusing on an analysis of von Neumann's problem situation. I claim that this reveals the true depth of von Neumann's achievement and influence on the subsequent development of this field, and further that it generates a whole family of new consequent problems, which can still serve to inform—if not actually define—the field of artificial life for many years to come.

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