Excerpt from Hartnup Disease

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Background

Hartnup disease is an autosomal recessive disorder caused by defective transport of neutral (ie, monoaminomonocarboxylic) amino acids in the small intestine and the kidneys. Patients present with a pellagralike skin eruptions, cerebellar ataxia, and gross aminoaciduria.

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

Hartnup disease is inherited as an autosomal recessive trait. Heterozygotes are normal. Consanguinity is common. In 2004, a causative gene, SLC6A19, 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.

Pathophysiology

In 2001, homozygosity mapping by Nozaki et al in consanguineous Japanese pedigrees demonstrated linkage of Hartnup disorder to band 5p15. 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 B0AT1.

The human SLC6A19 gene was cloned independently by 3 groups of researchers in 2004 (Kleta et al and aSeow et al). 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.

Mutations in SLC6A19 gene, which encodes the B0AT1 neutral amino-acid transporter, causes a failure of the transport of neutral (ie, monoaminomonocarboxylic) amino acids in the small intestine and the renal tubules. The B0AT1 transporter is a Na⁺-dependent, Cl^--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.

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.

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.

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. Most of the 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.

Frequency

United States

Levy et al found that the incidence of Hartnup disease in Massachusetts is 1 case per 14,219 births, approximately the same incidence as that of phenylketonuria.

International

Hartnup defect, with an overall prevalence of 1 case per 24,000 population (range, 1 case per 18,000-42,000 population), ranks among the most common amino acid disorders in humans.

Mortality/Morbidity

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 their quality of life. Rarely, severe CNS involvement may lead to death. Mental retardation and short stature have been described in few patients. Malnutrition and a low-protein diet are the primary factors that contribute to morbidity.

Race

No racial predilection is recognized for Hartnup disease.

Sex

No sexual predilection has been reported for Hartnup disease.

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.

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