Hypertryptophanemia

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Hypertryptophanemia
Other namesFamilial hypertryptophanemia [1]
L-tryptophan-skeletal.png
Tryptophan
Specialty Endocrinology   OOjs UI icon edit-ltr-progressive.svg

Hypertryptophanemia is a rare autosomal recessive [2] metabolic disorder that results in a massive buildup of the amino acid tryptophan in the blood, with associated symptoms and tryptophanuria (-uria denotes 'in the urine'). [3] [4]

Contents

Elevated levels of tryptophan are also seen in Hartnup disease, [5] a disorder of amino acid transport. [6] However, the increase of tryptophan in that disorder is negligible when compared to that of hypertryptophanemia. [1] [5]

Symptoms and signs

A number of abnormalities and symptoms have been observed with hypertryptophanemia.[ citation needed ]

Musculoskeletal effects include: joint contractures of the elbows and interphalangeal joints of the fingers and thumbs (specifically the distal phalanges), pes planus (fallen arches), an ulnar drift affecting the fingers of both hands (an unusual, yet correctible feature where the fingers slant toward the ulnar side of the forearm), joint pain and laxity, and adduction of the thumbs (where the thumb appears drawn into the palm, related to contracture of the adductor pollicis). [1] [2]

Behavioral, developmental and other anomalies often include: hypersexuality, perceptual hypersensitivity, emotional lability (mood swings), [3] hyperaggressive behavior; [2] hypertelorism (widely-set eyes), optical strabismus (misalignment) and myopia. [1] [2]

Metabolically, hypertryptophanemia results in tryptophanuria and exhibits significantly elevated serum levels of tryptophan, exceeding 650% of maximum (normal range: 25–73 micromole/l) in some instances. [2] [3]

A product of the bacterial biosynthesis of tryptophan is indole. [7] [8] The excess of tryptophan in hypertryptophanemia also results in substantial excretion of indoleic acids. These findings suggest a possible congenital defect in the metabolic pathway where tryptophan is converted to kynurenine. [3]

Kynurenine, a metabolite of tryptophan Kynurenine.svg
Kynurenine, a metabolite of tryptophan

Genetics

Familial hypertryptophanemia has an autosomal recessive pattern of inheritance. Autorecessive.svg
Familial hypertryptophanemia has an autosomal recessive pattern of inheritance.

Hypertryptophanemia is believed to be inherited in an autosomal recessive manner. [2] This means a defective gene responsible for the disorder is located on an autosome, and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder.[ citation needed ]

Pathophysiology

At present, no specific enzyme deficiency nor genetic mutation has been implicated as the cause of hypertryptophanemia. [1] [2] Several known factors regarding tryptophan metabolism and kynurenines, however, may explain the presence of behavioral abnormalities seen with the disorder.[ citation needed ]

Tryptophan is an essential amino acid, and is required for protein synthesis. [9] Aside from this crucial role, the remainder of tryptophan is primarily metabolized along the kynurenine pathway in most tissues, including those of the brain and central nervous system. [10] [11] [12] [13]

As the main defect behind hypertryptophanemia is suspected to alter and disrupt the metabolic pathway from tryptophan to kynurenine, [2] a possible correlation between hypertryptophanemia and the known effects of kynurenines on neuronal function, physiology and behavior may be of interest. [14] [15]

One of these kynurenines, aptly named kynurenic acid, serves as a neuroprotectant through its function as an antagonist at both nicotinic and glutamate receptors (responsive to the neurotransmitters nicotine and glutamate, respectively). [11] [12] This action is in opposition to the agonist quinolinic acid, another kynurenine, noted for its potential as a neurotoxin. [10] [13] Quinolinic acid activity has been associated with neurodegenerative disorders such as Huntington's disease, the neuroprective abilities of kynurenic acid forming a counterbalance against this process, and the related excitotoxicity and similar damaging effects on neurons. [13] [14]

Indoleic acid excretion is another indicator of hypertryptophanemia. [2] [3] Indirectly related to kynurenine metabolism, indole modifies neural function and human behavior by interacting with voltage-dependent sodium channels (integral membrane proteins that form ion channels, allowing vital synaptic action potentials). [15]

Diagnosis

Management

See also

Related Research Articles

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Tryptophan is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an α-amino group, an α-carboxylic acid group, and a side chain indole, making it a polar molecule with a non-polar aromatic beta carbon substituent. Tryptophan is also a precursor to the neurotransmitter serotonin, the hormone melatonin, and vitamin B3. It is encoded by the codon UGG.

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Isovaleric acidemia is a rare autosomal recessive metabolic disorder which disrupts or prevents normal metabolism of the branched-chain amino acid leucine. It is a classical type of organic acidemia.

<span class="mw-page-title-main">Hartnup disease</span> Metabolic disorder

Hartnup disease is an autosomal recessive metabolic disorder affecting the absorption of nonpolar amino acids. Niacin is a precursor to nicotinamide, a necessary component of NAD+.

<span class="mw-page-title-main">Tetrahydrobiopterin deficiency</span> Medical condition

Tetrahydrobiopterin deficiency (THBD, BH4D) is a rare metabolic disorder that increases the blood levels of phenylalanine. Phenylalanine is an amino acid obtained normally through the diet, but can be harmful if excess levels build up, causing intellectual disability and other serious health problems. In healthy individuals, it is metabolised (hydroxylated) into tyrosine, another amino acid, by phenylalanine hydroxylase. However, this enzyme requires tetrahydrobiopterin as a cofactor and thus its deficiency slows phenylalanine metabolism.

<span class="mw-page-title-main">Blue diaper syndrome</span> Medical condition

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<span class="mw-page-title-main">Glycine encephalopathy</span> Medical condition

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<span class="mw-page-title-main">Kynurenine</span> Chemical compound

l-Kynurenine is a metabolite of the amino acid l-tryptophan used in the production of niacin.

<span class="mw-page-title-main">Hawkinsinuria</span> Medical condition

Hawkinsinuria is an autosomal dominant metabolic disorder affecting the metabolism of tyrosine.

<span class="mw-page-title-main">Kynurenic acid</span> Chemical compound

Kynurenic acid is a product of the normal metabolism of amino acid L-tryptophan. It has been shown that kynurenic acid possesses neuroactive activity. It acts as an antiexcitotoxic and anticonvulsant, most likely through acting as an antagonist at excitatory amino acid receptors. Because of this activity, it may influence important neurophysiological and neuropathological processes. As a result, kynurenic acid has been considered for use in therapy in certain neurobiological disorders. Conversely, increased levels of kynurenic acid have also been linked to certain pathological conditions.

<span class="mw-page-title-main">Aromatic amino acid</span> Amino acid having an aromatic ring

An aromatic amino acid is an amino acid that includes an aromatic ring.

<span class="mw-page-title-main">Kynurenine 3-monooxygenase</span> Enzyme

In enzymology, a kynurenine 3-monooxygenase (EC 1.14.13.9) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Tryptophan 2,3-dioxygenase</span> Mammalian protein found in Homo sapiens

In enzymology, tryptophan 2,3-dioxygenase (EC 1.13.11.11) is a heme enzyme that catalyzes the oxidation of L-tryptophan (L-Trp) to N-formyl-L-kynurenine, as the first and rate-limiting step of the kynurenine pathway.

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<span class="mw-page-title-main">Quinolinic acid</span> Dicarboxylic acid with pyridine backbone

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<span class="mw-page-title-main">Urocanic aciduria</span> Medical condition

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<span class="mw-page-title-main">Carnosinemia</span> Disease

Carnosinemia is a rare autosomal recessive metabolic disorder caused by a deficiency of carnosinase, a dipeptidase.

<span class="mw-page-title-main">Iminoglycinuria</span> Medical condition

Iminoglycinuria is an autosomal recessive disorder of renal tubular transport affecting reabsorption of the amino acid glycine, and the imino acids proline and hydroxyproline. This results in excess urinary excretion of all three acids.

<span class="mw-page-title-main">Kynurenine pathway</span> Metabolic pathway that produces the NAD coenzyme

The kynurenine pathway is a metabolic pathway leading to the production of nicotinamide adenine dinucleotide (NAD+). Metabolites involved in the kynurenine pathway include tryptophan, kynurenine, kynurenic acid, xanthurenic acid, quinolinic acid, and 3-hydroxykynurenine. The kynurenine pathway is responsible for total catabolization of tryptophan about 95%. Disruption in the pathway is associated with certain genetic and psychiatric disorders.

Immuno-psychiatry, according to Pariante, is a discipline that studies the connection between the brain and the immune system. It differs from psychoneuroimmunology by postulating that behaviors and emotions are governed by peripheral immune mechanisms. Depression, for instance, is seen as malfunctioning of the immune system.

References

  1. 1 2 3 4 5 Online Mendelian Inheritance in Man (OMIM): 600627
  2. 1 2 3 4 5 6 7 8 9 Martin JR, Mellor CS, Fraser FC (April 1995). "Familial hypertryptophanemia in two siblings". Clin. Genet. 47 (4): 180–183. doi:10.1111/j.1399-0004.1995.tb03956.x. PMID   7628119. S2CID   27203561.
  3. 1 2 3 4 5 Snedden W, Mellor CS, Martin JR (July 1983). "Familial hypertryptophanemia, tryptophanuria and indoleketonuria". Clinica Chimica Acta. 131 (3): 247–256. doi:10.1016/0009-8981(83)90094-3. ISSN   0009-8981. PMID   6883719.
  4. ↑ Snedden W, Mellor CS, Martin JR (November 1982). "Hypertryptophanemia and indoleketonuria in two mentally subnormal siblings" (Free full text). The New England Journal of Medicine. 307 (22): 1405. doi:10.1056/NEJM198211253072219. ISSN   0028-4793. PMID   7133092.
  5. 1 2 Online Mendelian Inheritance in Man (OMIM): 234500
  6. ↑ Seow HF, Bröer S, Bröer A, Bailey CG, Potter SJ, Cavanaugh JA, Rasko JE (September 2004). "Hartnup disorder is caused by mutations in the gene encoding the neutral amino acid transporter SLC6A19". Nature Genetics. 36 (9): 1003–1007. doi: 10.1038/ng1406 . PMID   15286788.
  7. ↑ Dunn MF, Niks D, Ngo H, Barends TR, Schlichting I (June 2008). "Tryptophan synthase: the workings of a channeling nanomachine". Trends in Biochemical Sciences. 33 (6): 254–264. doi:10.1016/j.tibs.2008.04.008. PMID   18486479.
  8. ↑ Houben KF, Dunn MF (March 1990). "Allosteric effects acting over a distance of 20-25 A in the Escherichia coli tryptophan synthase bienzyme complex increase ligand affinity and cause redistribution of covalent intermediates". Biochemistry. 29 (9): 2421–2429. doi:10.1021/bi00461a028. ISSN   0006-2960. PMID   2186812.
  9. ↑ Reeds PJ (1 July 2000). "Dispensable and indispensable amino acids for humans" (Free full text). The Journal of Nutrition. 130 (7): 1835S–1840S. doi: 10.1093/jn/130.7.1835S . ISSN   0022-3166. PMID   10867060.
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  13. 1 2 3 Stone TW (April 2001). "Kynurenic acid antagonists and kynurenine pathway inhibitors". Expert Opin Investig Drugs. 10 (4): 633–645. doi:10.1517/13543784.10.4.633. PMID   11281814. S2CID   30077788.
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