Hartnup disease

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Classification according to ICD-10
E72.0 Disorders of the amino acid transport
ICD-10 online (WHO version 2019)
Classification
Hartnup disease
L-Tryptophan - L-Tryptophan.svg
Tryptophan

The Hartnup disease (Hartnup syndrome) is an inherited disorder of the transport of most amino acids by the body's cells. The deficiency of the amino acid tryptophan, which is essential for humans, is most pronounced in the organism .

Epidemiology

The disease is autosomal - recessive inherited. Several authors, e.g. B. Tahmoush, Kimmig, but also report on milder diseases such as photodermatoses and amino acid uria in close relatives with probably only one defective gene. The first manifestation is in childhood between three and nine years. It can also occur earlier or only in adults.

Hartnup's disease is comparatively rare and has a prevalence of 1 in 24,000. By no means all carriers of the corresponding genetic defect develop this disease. What is striking is the extreme difference in the course in people who were tested using urine series tests and those who were only found through an acute outbreak of the disease. In the former, only minor illnesses were observed, many did not become ill at all. In the latter, the death rate is high.

So far, 21 mutations of SLC6A19 have been identified in chromosome 5 gene locus p15.33, which impair the transport of amino acids in different ways. Most people affected have two different mutations. The D173N allele is found in 42% of the gene carriers found by urine screening in newborns in America, Australia and Canada. Similarities between the D173N carriers suggest a common ancestor more than a thousand years ago. The authors postulate that the long survival of this allele is due to its inability to completely deactivate transport. With some mutations, such as the D173N and P265L alleles, the number of transport channels depends on ACE2 in the intestine or collectrin (Tmem27) in the kidneys.

The great variability of Hartnup's disease can be explained by the involvement of up to six genetic variants: 1–2 alleles each of SLC6A19 and 2–4 alleles each for the complementary expression by ACE2 and collectrin. This enables everything from a single and total blockage of transport in the kidneys and many intermediate stages to a single and total blockage of transport in the intestine. Even the harmless allele D173N has a lethal potential without the complementary expression by ACE2 and collectrin.

Naturally, with the first group, it is easier to obtain data on a relatively large number of people affected than to collect data on the “wild” cases. However, these data relate to people in whom an increased need for vitamins and proteins was taken into account throughout their life, which, in addition to the D173N allele, offers a possible explanation for the mild courses. This also led to the presentation of Hartnup's disease as “ benign ” in specialist books and publications worldwide .

Pathogenesis

It is a disruption of the transport of amino acids through the membranes of the body cells. This is due to the lack of a certain channel-like membrane protein (neutral amino acid transporter), which is responsible for the passage of aromatic and neutral amino acids through the cells. The defect is omnipresent, but is more evident in tissues that are designed to be more absorbent (uptake) of amino acids. The disorder mainly affects the upper section of the small intestine ( jejunum ) and the proximal tubular cells of the kidneys that make up the proximal tubule .

The inability of the kidneys to keep certain amino acids in the blood (decreased reabsorption) causes them to accumulate in the urine and are consequently lost in the body. The urine contains alanine , serine , threonine , valine , leucine , isoleucine , phenylalanine , tyrosine , tryptophan , glutamic acid , asparagine and histidine . Provided the protein intake is satisfactory, the amount excreted in the urine is nutritionally insignificant. If the abnormality were confined to the kidneys, it would not cause symptoms and would have been barely recognized.

A disturbance in the absorption of these amino acids in the small intestine has serious consequences. A deficiency of these substances in the body is a consequence of this absorption disorder. Most of the essential amino acids necessary for life support are obtained through amino acid recycling in the intestine.

A large number of cells are continually being broken down in the body. These cells are broken down and the components - including amino acids - excreted in the intestine. In Hartnup's disease, the amino acids that are valuable for the body are largely lost due to the reduced reabsorption. As a result, the need for an external supply of the amino acids affected by the transport defect can increase sharply and reach a level that cannot be satisfied by mere ingestion of food. Amino acids that are normally not essential for humans can also become essential as a result. The human metabolism can often produce missing substances itself and thus largely compensate for the deficit. However, the lack of tryptophan, an essential amino acid, proves to be problematic . There is no possibility of synthesis for this molecule in the human metabolism . A deficiency in tryptophan can, to a limited extent, be eliminated by substituting its secondary products niacin and nicotinamide . Depending on the individual, 1/80 to 1/40 of the tryptophan is converted into nicotinamide. By increasing the intake of nicotinamide, the body has to convert less tryptophan, which means that more is available for other purposes. Unabsorbed tryptophan is metabolized in the intestine by bacteria to various indole compounds . In contrast to tryptophan, these are absorbed by the intestine. They can also cross the blood-brain barrier . Many central nervous symptoms are attributed to it.

Symptoms

The clinical picture is essentially the same as that of Pellagra (niacin deficiency). If there is a lack of essential amino acids, the symptoms of kwashiorkor can also occur. Factors that trigger a disease flare-up are fever or some antipyretic drugs, excessive sun exposure, stress and certain drugs ( sulfonamides ), inhibitors of the vitamin B complex, especially ( niacin ), ( riboflavin ) and ( pyridoxine ). Pellagra can also lead to disorders in porphyrin metabolism. Drugs that trigger porphyria can aggravate these disorders and ultimately trigger a Hartnup flare-up. Some mutations can also be activated by drugs that affect blood pressure (ACE2).

  • Skin : This syndrome is characterized by skin lesions in the form of erythematous eczema .
  • Intestine : It comes to recurrent diarrhea ( diarrhea ).
  • CNS : Intermittent neurological or psychiatric symptoms. It can lead to impaired movement coordination ( ataxia ), ( Parkinsonoid ), paralysis ( paresis ) or mood swings. Conditions similar to dementia , strabismus and seizures ( convulsions ) are also rarely described.
  • Immune system : Malnutrition damages the immune system, the frequency and severity of infections increase. L-cystine and L-cysteine ​​are of particular importance for the immune system and are therefore targets of attack by HIV. L-cystine can become essential for Hartnup.
  • Liver, adrenal glands and pancreas : Pellage patients show hypersensitivity to insulin with remarkable regularity. Two organs, the adrenal glands and the liver, involved (with others) in the regulation of carbohydrate metabolism, show severe anatomical damage in most pelagic patients. Damage to these organs has also been reported at Hartnup.

diagnosis

Every patient who suffers from pellagra-like symptoms and in whom the diet-related niacin deficiency typical of this disease cannot be understood should be examined for the presence of the genetic defect for Hartnup disease. With the relatively high number of mutations found, this is very difficult. One study did not identify all causative alleles in all affected individuals, increasing the possibility that genes other than SLC6A19 could contribute to Hartnup's disease.

Diagnosis of Hartnup's disease can usually be made using urinalysis . A neutral amino aciduria (presence of amino acids in the urine) is often found . However, due to a non-existent amino aciduria, Hartnup's disease cannot be ruled out if adequate nutrition can be assumed. Two cases of hypoaminoaciduria have also been reported.

Due to the transport defect, there may be a deficiency in the cells even with normal blood values. Paradoxically, due to the restricted absorption capacity of the cells, the blood values ​​of the amino acids concerned can even be increased, even if not as much as z. B. in hypertryptophanemia .

In the absence of amino aciduria and apparently normal blood values, a simple test for porphyrogens ( indolylacrylic acid and close relatives, absorption maximum of 509 µm) can provide further information. A little hydrochloric acid (pH = 2 to 2.5) is added to the morning urine and the sample is heated. Existing porphyrogens then form a red pigment, which can turn the urine almost black. This test can also be positive for porphyria and some other diseases, as well as after taking phenothiazine derivatives.

Reference range tryptophan in plasma or serum:

  • Infants: 25 µmol / l to 69 µmol / l (0.5 mg / dl to 1.3 mg / dl)
  • Children: 32 µmol / l to 79 µmol / l (0.6 mg / dl to 1.6 mg / dl)
  • Adults: 34 µmol / L to 90 µmol / L (0.7 mg / dL to 1.7 mg / dL)

Some laboratories erroneously state extremely low lower limit values, down to 10 µmol / l, which under certain circumstances can be lethal.

therapy

Treatment consists in administering the missing substances (substitution therapy). A daily food supplement of 50 to 250 mg nicotinamide usually improves the situation significantly, sometimes it has little effect or is ineffective. However, due to the liver toxicity of nicotinamide, it is better to take niacin . Daily doses of up to 3 grams of niacin in an initial phase and then 500 mg per day in the maintenance phase are ideal. The flushing that occurs with niacin is often found unpleasant, but goes away after a few weeks.

A high-protein diet high in tryptophan is usually recommended. Tryptophan is found primarily in milk and dairy products, as well as poultry, beef, nuts, and potatoes.

In severe cases it is not possible to significantly increase the blood level of the amino acids affected by the transport defect by a diet enriched with proteins. The deficiency must then be eliminated by circumventing the transport defect by means of intravenous substitution or oral substitution with chemically modified amino acids. If this does not happen, the deficiency will lead to serious damage in the medium term and death in the long term.

Photodermatoses can be treated well with an ointment containing urea (10 to 15%), even if blistering occurs.

Historical

This disease was first described in 1956 in London in children of the Hartnup family. It is possible that the Julius -Claudian imperial family from Julius Caesar to Emperor Nero also suffered from this disease.

literature

  • Dennis L. Kasper (Ed.), Eugene Braunwald (Ed.), Anthony Fauci: Harrison's Principles of Internal Medicine. 16th Edition Volume II ISBN 0-07-139142-8

Individual evidence

  1. ↑ a b K. Schmidtke, W. Endres u. a .: Hartnup syndrome, progressive encephalopathy and allo-albuminaemia. A clinico-pathological case study. In: European Journal of Pediatrics. Volume 151, Number 12, December 1992, pp. 899-903, ISSN  0340-6199 . PMID 1473543 .
  2. ↑ a b E. Mori, A. Yamadori and a .: [Adult-onset Hartnup disease presenting with neuropsychiatric symptoms but without skin lesions]. In: Rinsho shinkeigaku = Clinical neurology. Volume 29, Number 6, June 1989, pp. 687-692, ISSN  0009-918X . PMID 2582682 . (Article in Japanese)
  3. ↑ A. Oakley, J. Wallace: Hartnup disease presenting in an adult. In: Clinical and Experimental Dermatology . Volume 19, Number 5, September 1994, pp. 407-408, ISSN  0307-6938 . PMID 7955499 .
  4. ^ KH Daute, K. Dietel, W. Ebert: Das Hartnupsyndrom - Report on a fatal course of the disease. In: Journal of Pediatrics. Volume 95, Number 2, January 1966, pp. 103-113, ISSN  0044-2917 . PMID 5983075 .
  5. ↑ a b A. J. Tahmoush, DH Alpers u. a .: Hartnup disease. Clinical, pathological, and biochemical observations. In: Archives of Neurology . Volume 33, Number 12, December 1976, pp. 797-807, ISSN  0003-9942 . PMID 999542 .
  6. ↑ D. Milovanović, A. Djukić u. a .: [Hartnup disease (report of 2 cases in one family)]. In: Srpski arhiv za celokupno lekarstvo. Volume 128, Numbers 3-4, 2000 Mar-Apr, pp 97-103, ISSN  0370-8179 . PMID 10932618 . (Article in Serbian)
  7. ↑ OMIM, Hartnup Disorder
  8. ↑ Kazuhiko Oyanagi, Masayo Takagi, Michiyuki Kitabatake and Tooru Nakao. Hartnup Disease, Tohoku J. exp. Mod., 1967, 91, 383-395
  9. ↑ Examples of autopsy reports - Non coroner, Michael Fishbein, MD (March 08)
  10. ↑ a b Hartnup disease, By MD MILNE. Medical Unit, Westminster, Medical School, London, SW 1
  11. ↑ DN Azmanov, H. Rodgers et al. a .: Persistence of the common Hartnup disease D173N alleles in populations of European origin. In: Annals of Human Genetics. Volume 71, Pt 6 November 2007, pp. 755-761, ISSN  0003-4800 . doi: 10.1111 / j.1469-1809.2007.00375.x . PMID 17555458 .
  12. ↑ SM Camargo, D. Singer et al. a .: Tissue-specific amino acid transporter partners ACE2 and collectrin differentially interact with hartnup mutations. In: Gastroenterology . Volume 136, Number 3, March 2009, pp. 872-882, ISSN  1528-0012 . doi: 10.1053 / j.gastro.2008.10.055 . PMID 19185582 .
  13. ↑ Critical Review: The role of the neutral amino acid transporter B0AT1 (SLC6A19) in Hartnup disorder and protein nutrition. http://onlinelibrary.wiley.com/doi/10.1002/iub.210/full#sec1-6
  14. ↑ Br Med J. 1964 February 8; 1 (5379): 327-336. Disorders of Amino-Acid Transport * MD Milne
  15. ^ Vitamin lexicon: Bässler, Grühn, Loew, Pietrzik
  16. ↑ Pschyrembel® Clinical Dictionary Edition 253
  17. ↑ Z. Orbak, V. Ertekin et al. a .: Hartnup disease masked by kwashiorkor. In: Journal of health, population, and nutrition. Volume 28, Number 4, August 2010, pp. 413-415, ISSN  1606-0997 . PMID 20824986 . PMC 2965334 (free full text).
  18. ↑ HIV-induced cysteine ​​deficiency and T-cell dysfunction - a rationale for treatment with N-acetylcysteine. W. Dröge, H.-P. Eck, S. Mihm
  19. ↑ insulin hypersensitivity in Pella Grins and its significance, Fr. Mainz, Anglo-Swiss Hospital, Alexandria, Egypt.
  20. ↑ omim.org entry 234500
  21. ↑ HF Seow, S. Bröer u. a .: Hartnup disorder is caused by mutations in the gene encoding the neutral amino acid transporter SLC6A19. In: Nature genetics. Volume 36, Number 9, September 2004, pp. 1003-1007, ISSN  1061-4036 . doi: 10.1038 / ng1406 . PMID 15286788 .
  22. ↑ E. Freundlich, M. Statter, S. Yatziv: Familial pellagra-like skin rash with neurological manifestations. In: Archives of Disease in Childhood . Volume 56, Number 2, February 1981, pp. 146-148, ISSN  1468-2044 . PMID 6451201 . PMC 1627116 (free full text).
  23. ^ ER Da Gloria, JG Assunção, MA Costa: [Clinical picture of Hartnup disease. Without urine amino acids or any other identified metabolic disorder (a new entity)]. In: Medicina cutánea ibero-latino-americana. Volume 18, Number 4, 1990, pp. 227-231, ISSN  0210-5187 . PMID 2077308 . (Article in Portuguese)
  24. ↑ a b P.F. Borrie, CA Lewis: Hartnup disease. In: Proceedings of the Royal Society of Medicine. Volume 55, March 1962, pp. 231-232, ISSN  0035-9157 . PMID 13871450 . PMC 1896568 (free full text).
  25. ↑ M. Goulon, R. Escourolle et al. a .: Pellagre endogène, sans hyperaminoaciduria. In: Revue neurologique. Volume 120, Number 3, March 1969, pp. 149-158, ISSN  0035-3787 . PMID 5343986 . (Article in French)
  26. ^ Voiculescu V. Luca N. Hategan D. Biochemical Research in Two Cases of Endogenous Pellagra. Eur Neurol 1973; 10: 205-214 ( doi: 10.1159 / 000114277 )
  27. ↑ J. Kimmig-Hamburg: Metabolic disorders in polymorphic light dermatoses and recent research results in connection with Hartnup syndrome. In: Archives for Clinical and Experimental Dermatology . Volume 219, Number 1, 1964, pp. 753-762. ISSN  1432-069X doi: 10.1007 / BF00522954
  28. ↑ Textbook of Clinical Chemistry and Pathobiochemistry, Schattauer 3rd Edition
  29. ↑ a b c A. J. Jonas, IJ Butler: Circumvention of defective neutral amino acid transport in Hartnup disease using tryptophan ethyl ester. In: The Journal of clinical investigation. Volume 84, Number 1, July 1989, pp. 200-204, ISSN  0021-9738 . doi: 10.1172 / JCI114141 . PMID 2472426 . PMC 303970 (free full text).
  30. ↑ DN Baron, CE Dent u. a .: Hereditary pellagra-like skin rash with temporary cerebellar ataxia, constant renal amino-aciduria, and other bizarre biochemical features. In: Lancet. Volume 271, Number 6940, September 1956, pp. 421-428, ISSN  0140-6736 . PMID 13358233 .
  31. ↑ JH Dirckx: Julius Caesar and the Julian emperors. A family cluster with Hartnup disease? In: The American Journal of Dermatopathology . Volume 8, Number 4, August 1986, pp. 351-357, ISSN  0193-1091 . PMID 3532855 .

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