Hartnup Disease 

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

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]

 

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]

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]

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]

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]

Patient Education

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

 

Presentation

History

Hartnup disease is manifested by a wide clinical spectrum and phenotypic heterogeneity (see Physical for a complete discussion of the clinical signs).[22, 23, 28]

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.[23]

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, but in rare patients, neurologic manifestations can precede skin changes.[24, 15]

Psychiatric symptoms (eg, anxiety, emotional instability, mood changes) are common in patients who are symptomatic. Psychotic episodes and delirium are rarely seen.

Physical Examination

Skin findings[1, 23, 26]

Photosensitivity occurs (see the image below).The skin reddens after exposure to sunlight (see the image below). 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.

Photosensitivity with erythema, desquamation, and Photosensitivity with erythema, desquamation, and hypopigmentation and hyperpigmentation on the face.
Erythema and desquamation on the sun-exposed area Erythema and desquamation on the sun-exposed area of the right arm.

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,[29] as well as a patient with manifestations of kwashiorkor and acrodermatitis enteropathica but with normal zinc levels, which led to the search for other metabolic disorders, and Hartnup disorder was confirmed.[30]

In two patients with celiac disease, Hartnup disease was found in treatment-refractory celiac disease. In both patients, exfoliative erythroderma of malnutrition developed and it resolved after a high-protein and gluten-free diet was instituted.[31, 32]

Central nervous system findings[33]

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.[34]

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.[23, 28, 35] . Late-onset seizures and adult-onset Hartnup disease with neurologic manifestations as the first signs have been described, with pellagralike skin lesions developing after the neurologic symptoms.[24, 15]

Other findings

Ocular manifestations include double vision, nystagmus, photophobia, and strabismus.[28]

Gingivitis, stomatitis, and glossitis suggest niacin deficiency.[3, 33]

Diarrhea occasionally precedes or follows attacks of the disease.[3, 33]

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.[23]

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.[24, 25]

Complications

Complications are as follows[3, 22, 35] :

  • Severe CNS involvement may rarely lead to death in the first years of life.

  • Psychotic episodes and delirium are described in a minority of patients.

  • Mild mental retardation is described in only a few patients.

  • Long-lasting hypopigmentation and/or hyperpigmentation of the skin are seen with repeated exposures to sunlight, which should be avoided by using proper photoprotection.

 

DDx

Diagnostic Considerations

Regarding rash, consider the following:

  • Infantile atopic eczema
  • Seborrheic eczema
  • Nutritional pellagra (Misdiagnosis can be prevented by performing urine chromatography.)
  • Congenital poikilodermas with photosensitivity (eg, Cockayne syndrome)
  • Malar rash of lupus erythematosus
  • Carcinoid syndrome (may lead to disturbance of tryptophan metabolism and pellagralike rash)
  • Indicanuria in inborn errors of amino acid metabolism (eg, phenylketonuria, blue diaper syndrome)

For the central nervous system, consider the following:

  • Ataxia-telangiectasia (can cause diagnostic difficulties, especially in patients with mild skin involvement)
  • Systemic lupus erythematosus (can be confused if photosensitivity with neuropsychiatric symptoms is present)
  • Other ataxias with biochemical and genetic defects

Differential Diagnoses

 

Workup

Laboratory Studies

With urine chromatography,[3, 21, 22, 25, 28] increased levels of neutral amino acids (eg, glutamine, valine, phenylalanine, leucine, asparagine, citrulline, isoleucine, threonine, alanine, serine, histidine, tyrosine, tryptophan) and indican are found in the urine. Urinary indoxyl derivatives (ie, 5-hydroxyindoleacetic acid) may be demonstrated following an oral tryptophan load. Urine excretion of proline, hydroxyproline, and arginine remains normal, which differentiates Hartnup disease from other causes of gross aminoaciduria. Perform urine chromatography to exclude nutritional pellagra.

Plasma concentrations of amino acids are usually normal.[3, 21, 22, 25, 28]

Procedures

Jejunal biopsy may be required in selected patients (transport defect may be identified in vitro). Skin biopsy may be required in selected patients.[22, 24, 25, 26]

Histologic Findings

Changes in the skin are similar to those seen in pellagra. Findings are not diagnostic and include hyperkeratosis, parakeratosis, epidermal atrophy, hyperpigmentation of the basal layer, and a mild superficial dermal lymphocytic infiltrate. Bullae may be either intraepidermal or subepidermal. Hyperplasia of the sebaceous glands with follicular dilatation and plugging may occur.[24, 25, 26]

 

Treatment

Medical Care

Medical care is discussed as follows[3, 22, 25, 26, 33] :

  • A high-protein diet can overcome the deficient transport of neutral amino acids in most patients. Poor nutrition leads to more frequent and more severe attacks of the disease, which is otherwise asymptomatic.

  • Advise all patients who are symptomatic to use physical and chemical protection from sunlight. Avoiding excessive exposure to sunlight, wearing protective clothing, and using physical and chemical sunscreens are mandatory. Recommend sunscreens with a skin protection factor of 15 or greater.

  • Advise patients to avoid other aggravating factors, such as photosensitizing drugs, as much as possible.

  • In patients with niacin deficiency and symptomatic disease, daily supplementation with nicotinic acid or nicotinamide reduces the number and the severity of attacks.

  • Neurologic and psychiatric treatment is needed in patients with severe CNS involvement.

Consultations

Helpful consultations are as follows[3, 26, 33, 35] :

  • Consult a dermatologist for diagnosis and treatment of photosensitivity and pellagralike rash.

  • Consult an experienced neurologist for thorough follow-up monitoring and treatment of CNS involvement.

  • Consult a psychiatrist to diagnose and treat psychiatric symptoms, which may vary considerably.

  • Consult an ophthalmologist if ocular manifestations, which are rare, occur.

Diet

Advise patients who are symptomatic to consume a high-protein diet because it decreases the number of attacks.[3, 25, 36]

Activity

Advise patients to protect themselves from sunlight. Protective clothing, hats and eyewear, and physical and chemical sunscreens provide photoprotection.[26]

Prevention

Deterrence and prevention are as follows[24, 25] :

  • Because sun exposure can exacerbate Hartnup disease, advise patients to protect themselves from sunlight.

  • Because aggravating factors, such as sulfonamides and possibly emotional stress, can exacerbate Hartnup disease, advise patients to avoid these factors.

Long-Term Monitoring

Advise patients to use protection from sunlight, to avoid other aggravating factors, to consume a high-protein diet, and to take daily supplements of nicotinic acid. In patients who are symptomatic, recommend regular follow-up examinations, depending on the severity of symptoms and the organ systems involved.

 

Medication

Medication Summary

Nicotinic acid or nicotinamide (50-300 mg/d) provides relief from both the skin manifestations and the neurologic manifestations.[3, 22, 36]

Administration of tryptophan ethyl ester (a lipid-soluble tryptophan metabolite) in a child with Hartnup disease at a dose of 20 mg/kg every 6 hours resulted in normalization of serum and cerebrospinal fluid tryptophan levels.[36]

Vitamins

Class Summary

Vitamins are necessary for normal growth and development. These agents are used to replace essential vitamins not obtained in sufficient quantities in the diet or to further supplement levels.

Vitamin B-3 (Niacin, Nicotinic acid, Nicotinamide)

Nicotinamide is more commonly recommended. It is a source of niacin used in tissue respiration, lipid metabolism, and glycogenolysis. It provides relief from skin and neurologic manifestations.