Hartnup Disease

Updated: Feb 06, 2017
  • Author: Lidija Kandolf Sekulovic, MD, PhD; Chief Editor: William D James, MD  more...
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Overview

Practice Essentials

Hartnup disease is an autosomal recessive disorder caused by impaired neutral (ie, monoaminomonocarboxylic) amino acid transport in the apical brush border membrane of the small intestine and the proximal tubule of the kidney. Patients present with pellagralike skin eruptions, cerebellar ataxia, and gross aminoaciduria. [1, 2, 3, 4]

 

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Background

In 1956, Baron et al described the disorder in the Hartnup family of London; 4 of the 8 family members presented with aminoaciduria, a rash resembling pellagra, and cerebellar ataxia. [1]

Hartnup disease is inherited as an autosomal recessive trait. Heterozygotes are normal. Consanguinity is common. In 2004, a causative gene, SLC6A19 (MIM#608893, Genbank accession NM 001003841) , was located on band 5p15.33. SLC6A19 is a sodium-dependent and chloride-independent neutral amino acid transporter, expressed predominately in the kidneys and intestine. [5, 6, 7, 8]

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Pathophysiology

In 2001, homozygosity mapping by Nozaki et al. in consanguineous Japanese pedigrees demonstrated linkage of Hartnup disorder to band 5p15. [8] A gene survey of 5p15 revealed several members of the SLC6 family comprising transporters for neurotransmitters, osmolytes, and amino acids, and linkage analysis in 7 Australian families narrowed the region to 7cM on 5p15.33 containing SLC6A18 and SLC6A19. Cloning and expression of the mouse SLC6A19 gene demonstrated that this transporter has all the properties of the amino acid transport system B0 AT1 [9, 10] . In an animal model of Hartnup disorder, mice lacking SLC6A19 (B0 AT1) transporter general neutral aminoaciduria were observed, as well as the decreased body weight, demonstrating the essential role of epithelial amino acid uptake in optimal growth and bodyweight regulation. [11]

The human SLC6A19 gene was cloned independently by 2 groups of researchers in 2004. [6, 12] It has the same transporter properties and expression pattern as the mouse transporter. Both studies demonstrated that mutations in SLC6A19 are associated with Hartnup disorder. The requirement for 2 transport-impairing mutations for disease expression confirmed a recessive mode of inheritance [5, 6] .

Currently, 17 mutations in SLC6A19 have been described in patients with Hartnup disorder. In all investigated individuals with Hartnup disorder, 2 mutant SLC6A19 alleles were found, confirming recessive mode of inheritance. Reanalysis of families in whom mutations in SLC6A19 were not found in the first study revealed the existence of mutations in different allelles. [5, 6, 13] Thus, in all families studied to date, allelic heterogeneity at SLC6A19 has been found, without the evidence for genetic heterogeneity of the disorder. [13] The most common mutation in Hartnup disorder is c.517G→A, resulting in the amino acid substitution p.D173N, and it can be found in 43% of patients. [13] .

A novel mutation, c.850G→A, in exon 6 of the SLC6A19 gene was described in a Chinese family with typical clinical characteristics of Hartnup disorder. [14] Also, a mutation in the SLC6A19 gene was described in a 6-year-old patient with late-onset seizures in whom pellagralike skin lesions developed after the diagnosis of Hartnup disease at age 9 years, confirming the allelic, as well as phenotypic, heterogeneity of the disease. [15]

Investigation of the origins of the D173N allele revealed an allele frequency estimate in the population of 0.004 and a heterozygote frequency of 1 in 122 healthy individuals of European descent. A single core haplotype surrounding the D173N alleles was found, which suggests that the mutation is identical by descent in all observed cases; therefore, it is not a result of a recurrent mutation. [16] Estimates of the allele age indicate that this allele arose more than 1000 years ago. [16]

Mutations in the SLC6A19 gene, which encodes the SLC6A19 (B0 AT1) neutral amino acid transporter, causes a failure of the transport of neutral (ie, monoaminomonocarboxylic) amino acids in the small intestine and the renal tubules. [2, 4, 17] The B0 AT1 transporter is a sodium-dependent, chloride-independent system and transports all neutral amino acids in the following order: Leu=Val=Ile=Met –> Gln=Phe=Ala=Ser=Cys=Thr –> His=Trp=Tyr=Pro=Gly. [2, 18] B0 AT1 appears to be largely restricted to the kidneys and intestine; however, expressed sequence tags have been reported in skin. [17, 18] .

SLC6A19 (B0 AT1) expression and function is controlled by the brush-border angiotensin-converting enzyme 2 (ACE2), as well as the serum and glucocorticoid inducible kinases SGK1-3, which were shown recently to be potent stimulators of SLC6A19. [19] Other mechanisms of SLC6A19 regulation are unknown. In patients with Hartnup disease and in cystinuria, intestinal peptid transporter (PEPT1) appears to be essential to compensate for the reduced amino acid delivery through intestinal epithelium. [20]

Although tryptophan is transported by this transporter rather inefficiently, it is thought to be one of the key substrates in the development of the nonrenal symptoms of Hartnup disorder. Tryptophan is converted in the liver to niacin, and approximately half of the nicotinamide adenine dinucleotide phosphate (NADPH) synthesis in humans is generated through tryptophan. As a result, tryptophan and niacin deficiencies generate similar symptoms. In addition, symptoms in persons with Hartnup disorder quickly respond to nicotinic acid supplementation. [2, 4, 17, 18]

Amino acids are retained within the intestinal lumen, where they are converted by bacteria to indolic compounds that can be toxic to the CNS. Tryptophan is converted to indole in the intestine. Following absorption, indole is converted to 3-hydroxyindole (ie, indoxyl, indican) in the liver, where it is conjugated with potassium sulfate or glucuronic acid. Subsequently, it is transported to the kidneys for excretion (ie, indicanuria). Other tryptophan degradation products, including kynurenine and serotonin, are also excreted in the urine. Tubular renal transport is also defective, contributing to gross aminoaciduria. Neutral amino acids are also found in the feces. [2, 4, 7, 17, 21]

Resorption of the peptides may partially compensate for the lack of amino acid transport in persons with Hartnup disorder, and thus phenotypic variability is wide, which may result from a number of factors: differential resorption, allelic and genetic heterogeneity, modifier genes, and dietary intake. [22, 23] Most patients remain asymptomatic, and it has been suggested that Hartnup phenotype becomes apparent when environmental or genetic factors predispose individuals to a lack of amino acid uptake. Oakley and Wallace reported a case of Hartnup disease in an adult, with the first appearance of symptoms after prolonged lactation and increased physical activity. [24]

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Epidemiology

Frequency

United States

Newborn screening programs in Australia and North America have identified an overall incidence of 1 case per 30,000 births; in Massachusetts, it was 1 case per 23,000 births. [25] With an overall prevalence of 1 case per 24,000 population (range, 1 case per 18,000-42,000 population), Hartnup disease ranks among the most common amino acid disorders in humans. [25]

International

Newborn screening programs in Australia and North America have identified an overall incidence 1 case per 25,000 births in New South Wales and 1 case per 54,000 births in Quebec. [25] The disorder has been reported to occur in all ethnic groups studied to date, including those from Israel, Japan, West Africa, and India.

Race

No racial predilection is recognized for Hartnup disease. [25]

Sex

No sexual predilection has been reported for Hartnup disease. [25]

Age

The onset of Hartnup disease is in childhood, usually in children aged 3-9 years, but it may present as early as 10 days after birth. In addition, a case of Hartnup disease presenting for the first time in an adult female, after prolonged lactation and increased physical activity, is described. [3, 24, 25]

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Prognosis

Hartnup disease is manifested by a wide clinical spectrum. Most patients remain asymptomatic, but, in a minority of patients, skin photosensitivity and neurologic and psychiatric symptoms may have a considerable influence on quality of life. Rarely, severe CNS involvement may lead to death. Mental retardation and short stature have been described in a few patients. Malnutrition and a low-protein diet are the primary factors that contribute to morbidity. [3, 22, 23, 25, 26]

Attacks become less frequent with increasing age. [23]

Maternal Hartnup disease does not influence the outcome of pregnancy. Placental transport of free amino acids may not be reduced in maternal Hartnup disorder. [27]

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Patient Education

Educate patients to protect themselves from sunlight, to avoid other aggravating factors, and to consume a high-protein diet.

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