eMedicine Specialties > Dermatology > Pediatric Diseases

Hartnup Disease

Author: Lidija Kandolf Sekulovic, MD, PhD, Associate Professor, Head of the First Division, Department of Dermatology and Venereology, Military Medical Academy, Serbia
Coauthor(s): Djordjije Karadaglic, MD, DSc, Professor, School of Medicine, University of Podgorica, Podgorica, Montenegro; Ljubomir Stojanov, MD, PhD, Professor, University of Belgrade School of Medicine, Serbia
Contributor Information and Disclosures

Updated: Feb 6, 2009

Introduction

Background

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

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

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

The human SLC6A19 gene was cloned independently by 2 groups of researchers in 2004.^6,11 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.^5,6,12 Thus, in all families studied to date, allelic heterogeneity at SLC6A19 has been found, without the evidence for genetic heterogeneity of the disorder.¹² 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.¹²

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.¹³ Estimates of the allele age indicate that this allele arose more than 1000 years ago.¹³

Mutations in the SLC6A19 gene, which encodes the 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.^2,4,14 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.^2,15 B⁰ AT1 appears to be largely restricted to the kidneys and intestine; however, expressed sequence tags have been reported in skin.^14,15

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.^2,4,14,15

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.^2,4,7,14,16

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.^17,18 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.¹⁹

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.²⁰ 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.²⁰

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.²⁰ The disorder has been reported to occur in all ethnic groups studied to date, including those from Israel, Japan, West Africa, and India.

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 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.^{3,17,18,20,21}

Race

No racial predilection is recognized for Hartnup disease.²⁰

Sex

No sexual predilection has been reported for Hartnup disease.²⁰

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.^3,19,20

Clinical

History

Hartnup disease is manifested by a wide clinical spectrum (see Physical for a complete discussion of the clinical signs).^17,18,22

• Most children with the Hartnup defect remain asymptomatic.
• In Australia, an 8-year follow-up study of 12 patients found only 2 clinical episodes that may be ascribed to Hartnup disease; mental development of all of the children was normal. In the United States, a full-blown picture of the disorder is rarely seen, probably because the diet of US residents is adequate.¹⁸
• Patients who are symptomatic present with episodic deterioration of neurologic and dermatologic manifestations. Symptoms progress over several days and last for 1-4 weeks before spontaneous remission occurs.
• Cutaneous signs usually precede the neurologic manifestations.
• Psychiatric symptoms (eg, anxiety, emotional instability, mood changes) are common in patients who are symptomatic. Psychotic episodes and delirium are rarely seen.

Physical

• Skin^1,18,21
  • Photosensitivity occurs (see Media File 1).The skin reddens after exposure to sunlight (see Media File 2). Further exposures lead to the development of dry, scaly, well-marginated eruptions, sometimes resembling chronic eczema. This eruption preferentially affects the forehead, the cheeks, the periorbital regions, the dorsal surfaces of the hands, and other light-exposed areas.
  • Lesions on the face may resemble the malar rash of lupus erythematosus.
  • A vesiculobullous eruption with exudation may occur.
  • Skin changes leave long-lasting hypopigmentation and/or hyperpigmentation, which are intensified with further sunlight exposure.
  • One case with widespread cutaneous eruption resembling acrodermatitis enteropathica was described.²³
• Central nervous system²⁴
  • Mental development is normal in most patients, but mental retardation (intelligence quotient of 50-70) is described in a few patients. Of 1087 patients screened for the detection of inherited metabolic diseases from the Alexandra Institute for persons with mental retardation in Cape Town, Hartnup disease was found in only 1 patient.²⁵
  • Neurologic symptoms may vary and are fully reversible. Intermittent cerebellar ataxia, a wide-based gait, spasticity, delayed motor development, and tremulousness are the most frequent findings. Headaches and hypotonia may also occur.^18,22,26
  • Ocular manifestations include double vision, nystagmus, photophobia, and strabismus.²²
• Gingivitis, stomatitis, and glossitis suggest niacin deficiency.^3,24
• Diarrhea occasionally precedes or follows attacks of the disease.^3,24
• Short stature has been described. Wilcken et al found that of 14 patients with Hartnup disorder who were observed for 8 years, 10 had height percentiles less than the midparent height percentiles, while 4 had percentiles equal to or above the midparent percentiles.¹⁸

Causes

Exacerbations are seen most frequently in the spring or early summer after exposure to sunlight. The attacks may be provoked by a febrile illness, poor nutrition, sulfonamides, and possibly emotional stress and increased physical activity.^19,20

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