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Frontiers in Molecular Biosciences 2022Tryptophan is an essential amino acid, which is not only a building block for protein synthesis, but also a precursor for the biosynthesis of co-enzymes and... (Review)
Review
Tryptophan is an essential amino acid, which is not only a building block for protein synthesis, but also a precursor for the biosynthesis of co-enzymes and neuromodulators, such as NAD/NADP(H), kynurenic acid, melatonin and serotonin. It also plays a role in immune homeostasis, as local tryptophan catabolism impairs T-lymphocyte mediated immunity. Therefore, tryptophan plasmatic concentration needs to be stable, in spite of large variations in dietary supply. Here, we review the main checkpoints accounting for tryptophan homeostasis, including absorption, transport, metabolism and elimination, and we discuss the physiopathology of disorders associated with their dysfunction. Tryptophan is catabolized along the kynurenine pathway through the action of two enzymes that mediate the first and rate-limiting step of the pathway: indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO). While IDO1 expression is restricted to peripheral sites of immune modulation, TDO is massively expressed in the liver and accounts for 90% of tryptophan catabolism. Recent data indicated that the stability of the TDO protein is regulated by tryptophan and that this regulation allows a tight control of tryptophanemia. TDO is stabilized when tryptophan is abundant in the plasma, resulting in rapid degradation of dietary tryptophan. In contrast, when tryptophan is scarce, TDO is degraded by the proteasome to avoid excessive tryptophan catabolism. This is triggered by the unmasking of a degron in a non-catalytic tryptophan-binding site, resulting in TDO ubiquitination by E3 ligase SKP1-CUL1-F-box. Deficiency in TDO or in the hepatic aromatic transporter SLC16A10 leads to severe hypertryptophanemia, which can disturb immune and neurological homeostasis.
PubMed: 36188218
DOI: 10.3389/fmolb.2022.897929 -
Tremor and Other Hyperkinetic Movements... 2023Episodic ataxia (EA), characterized by recurrent attacks of cerebellar dysfunction, is the manifestation of a group of rare autosomal dominant inherited disorders. EA1... (Review)
Review
BACKGROUND
Episodic ataxia (EA), characterized by recurrent attacks of cerebellar dysfunction, is the manifestation of a group of rare autosomal dominant inherited disorders. EA1 and EA2 are most frequently encountered, caused by mutations in and . EA3-8 are reported in rare families. Advances in genetic testing have broadened the and phenotypes, and detected EA as an unusual presentation of several other genetic disorders. Additionally, there are various secondary causes of EA and mimicking disorders. Together, these can pose diagnostic challenges for neurologists.
METHODS
A systematic literature review was performed in October 2022 for 'episodic ataxia' and 'paroxysmal ataxia', restricted to publications in the last 10 years to focus on recent clinical advances. Clinical, genetic, and treatment characteristics were summarized.
RESULTS
EA1 and EA2 phenotypes have further broadened. In particular, EA2 may be accompanied by other paroxysmal disorders of childhood with chronic neuropsychiatric features. New treatments for EA2 include dalfampridine and fampridine, in addition to 4-aminopyridine and acetazolamide. There are recent proposals for EA9-10. EA may also be caused by gene mutations associated with chronic ataxias (), epilepsy syndromes (), GLUT-1, mitochondrial disorders (), metabolic disorders (Maple syrup urine disease, Hartnup disease, type I citrullinemia, thiamine and biotin metabolism defects), and others. Secondary causes of EA are more commonly encountered than primary EA (vascular, inflammatory, toxic-metabolic). EA can be misdiagnosed as migraine, peripheral vestibular disorders, anxiety, and functional symptoms. Primary and secondary EA are frequently treatable which should prompt a search for the cause.
DISCUSSION
EA may be overlooked or misdiagnosed for a variety of reasons, including phenotype-genotype variability and clinical overlap between primary and secondary causes. EA is highly treatable, so it is important to consider in the differential diagnosis of paroxysmal disorders. Classical EA1 and EA2 phenotypes prompt single gene test and treatment pathways. For atypical phenotypes, next generation genetic testing can aid diagnosis and guide treatment. Updated classification systems for EA are discussed which may assist diagnosis and management.
Topics: Humans; Ataxia; Cerebellar Ataxia; Acetazolamide; Mutation
PubMed: 37008993
DOI: 10.5334/tohm.747 -
Indian Journal of Dermatology Jan 2008A 10 year old girl presented with clinical signs and symptoms of the triad of niacin deficiency namely skin eruptions, ataxia, mental changes and diarrhea. Although this...
A 10 year old girl presented with clinical signs and symptoms of the triad of niacin deficiency namely skin eruptions, ataxia, mental changes and diarrhea. Although this deficiency could be nutritional where maize is a staple diet, this patient had neutral aminoaciduria which indicated a defective transport of neutral amino acid transporter in the kidneys and intestine resulting in failure of transport of tryptophan and other neutral (ie, monoaminomonocarboxylic) alpha-amino acids in the small intestine and the renal tubules.
PubMed: 19967017
DOI: 10.4103/0019-5154.39740 -
Canadian Medical Association Journal Oct 1976Pellagra due to malnutrition occurred in an Ottawa women in 1973. She was given a normal diet with supplements of riboflavin, thiamine, niacin and ascorbic acid. The...
Pellagra due to malnutrition occurred in an Ottawa women in 1973. She was given a normal diet with supplements of riboflavin, thiamine, niacin and ascorbic acid. The clinical response was striking. Although pellagra is still common in some parts of the world, it is now rare in North America. The disease may occur secondary to malnutrition or malabsorption; inborn errors of metabolism or transport, as in Hartnup disease; deviation of precursors of niacin, as in carcinoid syndrome; or competitive inhibition of niacin incorporation into nicotinamide-adenine dinucleotide, as with administration of isoniazid.
Topics: Adult; Canada; Diagnosis, Differential; Female; Humans; Pellagra; Recurrence; Vitamins
PubMed: 974966
DOI: No ID Found -
Eating and Weight Disorders : EWD Jun 2021Since the outbreak of COVID-19, clinicians have tried every effort to fight the disease, and multiple drugs have been proposed. However, no proven effective therapies...
Since the outbreak of COVID-19, clinicians have tried every effort to fight the disease, and multiple drugs have been proposed. However, no proven effective therapies currently exist, and different clinical phenotypes complicate the situation. In clinical practice, many severe or critically ill COVID-19 patients developed gastrointestinal (GI) disturbances, including vomiting, diarrhoea, or abdominal pain, even in the absence of cough and dyspnea. Understanding the mechanism of GI disturbances is warranted for exploring better clinical care for COVID-19 patients. With evidence collected from clinical studies on COVID-19 and basic research on a rare genetic disease (i.e., Hartnup disorder), we put forward a novel hypothesis to elaborate an effective nutritional therapy. We hypothesize that SARS-CoV-2 spike protein, binding to intestinal angiotensin-converting enzyme 2, negatively regulates the absorption of neutral amino acids, and this could explain not only the GI, but also systemic disturbances in COVID-19. Amino acid supplements could be recommended.Level of evidence No level of evidence: Hypothesis article.
Topics: Amino Acids; Angiotensin-Converting Enzyme 2; COVID-19; Gastrointestinal Absorption; Gastrointestinal Diseases; Hartnup Disease; Humans; Intestine, Small; Pandemics; SARS-CoV-2; Spike Glycoprotein, Coronavirus
PubMed: 32691334
DOI: 10.1007/s40519-020-00963-y -
IBRO Neuroscience Reports Jun 2023Hartnup disease is an autosomal recessive, metabolic disorder caused by mutations of the neutral amino acid transporter, SLC6A19/B0AT1. Reduced absorption in the... (Review)
Review
Hartnup disease is an autosomal recessive, metabolic disorder caused by mutations of the neutral amino acid transporter, SLC6A19/B0AT1. Reduced absorption in the intestine and kidney results in deficiencies in neutral amino acids and their down-stream metabolites, including niacin, associated with skin lesions and neurological symptoms. The effects on the nervous system such as ataxia have been related to systemic deficiencies of tryptophan (and other neutral amino acids) as no expression of the B0AT1 transporter was found in the brain. In the intestine, SLC6A19 cooperates with ACE2 which has received major attention as the cellular receptor for SARS-CoV-2. When transcriptomics data for ACE2 and its partner proteins were examined, a previously unrecognized expression of Slc6a19 mRNA in the ependymal cells of the mouse brain was encountered that is set into the context of neurological manifestations of Hartnup disease with this communication. A novel role for SLC6A19/B0AT1 in amino acid transport from CSF into ependymal cells is proposed and a role of niacin in ependymal cells highlighted.
PubMed: 37101820
DOI: 10.1016/j.ibneur.2023.03.010 -
The Biochemical Journal Feb 1969
Topics: Child; Child, Preschool; Female; Hartnup Disease; Humans; Infant; Infant, Newborn; Male; Nervous System Diseases; Niacinamide; Renal Tubular Transport, Inborn Errors; Tryptophan; Vitamin B Deficiency
PubMed: 4237364
DOI: 10.1042/bj1110003p -
The Tohoku Journal of Experimental... Apr 1967
Topics: Adult; Amino Acids; Chromatography, Paper; Female; Hartnup Disease; Humans; Liver; Male; Niacinamide; Pedigree; Tryptophan
PubMed: 4228120
DOI: 10.1620/tjem.91.383 -
Proceedings of the Royal Society of... Mar 1962
Topics: Amino Acids; Ataxia; Hartnup Disease; Humans; Indoles; Medical Records; Skin Diseases
PubMed: 13871450
DOI: No ID Found