The majority of patients with Hartnup disease are asymptomatic. The genetic defect is suspected in them only when a routine urinalysis shows the presence of aminoaciduria. Neutral hyper-aminoaciduria is the only consistent feature and so is the diagnostic marker for Hartnup disease . No intervention is indicated in asymptomatic individuals.
In symptomatic patients the initial sign is usually the distinctive pellagra-like skin rash. It occurs in late infancy or early childhood. The rash is identical to the rash in pellagra a disorder resulting from Vitamin B3 (niacin) deficiency . The rash is red and scaly, appearing on face, neck, hands, arms, and dorsal surface of the feet. The rash occurs after exposure to sunlight  .
Patients with Hartnup disease may experience some or all of the following symptoms :
- Pellagra-like skin rash
- Transient cerebellar ataxia
- Delayed motor development
- Psychiatric symptoms
- Visual disturbances: double vision, nystagmus, photophobia, and strabismus 
- Developmental retardation
The clinical manifestations are intermittent and inconsistent, and they usually improve spontaneously with age .
Exacerbations may occur after exposure to sunlight, usually in the spring or early summer . Symptoms may also be triggered by fever, drugs, and emotional or physical stress. These episodes develop over several days and last 1 to 4 weeks. Remission occurs spontaneous .
Entire Body System
Management and treatment Symptomatic subjects benefit from a high-protein diet, sunlight protection, and avoidance of photosensitizing drugs. Treatment includes nicotinamide supplements (40 to 200 mg per day). [orpha.net]
Patients also should avoid other aggravating factors, such as photosensitizing drugs, as much as possible. [en.wikipedia.org]
Advise patients to avoid other aggravating factors, such as photosensitizing drugs, as much as possible. [namrata.co]
Hartnup disease, first described by Baron, Dent, Harris, Hart, and Jepson (1956), is characterized by a photosensitive pellagra-like rash, cerebellar ataxia, generalized renal aminoaciduria, hyperindoluria, and hypertryptophanuria. [semanticscholar.org]
- Skin Rash
These include a pellagra-like skin rash and reversible episodes of neurologic dysfunction ( 1 ). The most dramatic expression of the neurological involvement is cerebellar ataxia. [ncbi.nlm.nih.gov]
Baron DN, Dent CE, Harris H, Hart EW, Jepson JB (1956) Hereditary pellagra-like skin rash with temporary cerebellar ataxia, constant renal amino-aciduria, and other bizarre biochemical features. [link.springer.com]
Hartnup disease - autosomal recessive metabolic disease characterized by skin rash, emotional lability, unsteady gait, and various neurological symptoms. [medical-dictionary.thefreedictionary.com]
[…] likely cause for the skin-rash. [flipper.diff.org]
- Scaly Skin Rash
If symptoms do occur, they most often appear in childhood and may include: Diarrhea Mood changes Nervous system (neurologic) problems, such as abnormal muscle tone and uncoordinated movements Red, scaly skin rash, usually when skin is exposed to sunlight [nlm.nih.gov]
If symptoms do occur, they usually appear in childhood and may include: Diarrhea Mood changes Nervous system (neurologic) problems, such as abnormal muscle tone Red, scaly skin rash, usually when skin is exposed to sunlight Sensitivity to light (photosensitivity [flipper.diff.org]
Additional symptoms included significant photosensitivity and severe scaly skin rash involving face, neck, lower and upper extremities (Figure 1 ). [bmcpediatr.biomedcentral.com]
- Photosensitive Skin Rash
Other symptoms reported in Hartnup disorder patients include a photosensitive skin rash, difficulties to control gait and psychotic behaviour. [sciencewise.anu.edu.au]
These include a photosensitive skin rash, intermittent ataxia, and psychotic behavior. Some affected individuals have also been mentally retarded or mentally subnormal to a mild degree. [ommbid.mhmedical.com]
- Cutaneous Manifestation
Google Scholar Collin P, Reunala T: Recognition and management of the cutaneous manifestations of celiac disease: a guide for dermatologists. Am J Clin Dermatol. 2003, 4: 13-20. 10.2165/00128071-200304010-00002. [bmcpediatr.biomedcentral.com]
Hartnup disease typically presents between 3-9 years of age, and most often with cutaneous manifestations. [ijdvl.com]
Blue diaper syndrome, ataxia-telangiectasia, hydroa vacciniforme, pityriasis alba, and xeroderma pigmentosum (see these terms) should be excluded. [orpha.net]
[…] aminoaciduria) Hart's E72.02 (pellagra-cerebellar ataxia-renal aminoaciduria) H E72.02 (Hartnup's) Hartnup's disease E72.02 Pellagra-cerebellar-ataxia-renal aminoaciduria syndrome E72.02 Syndrome - see also Disease pellagra-cerebellar ataxia-renal aminoaciduria [icd10data.com]
A 6-month-old girl developed intermittent dystonic posture of the legs and eczematous dermatitis without ataxia. Qualitative and quantitative urine amino acid testing confirmed the diagnosis of Hartnup disease. [ncbi.nlm.nih.gov]
Patients present with pellagra like skin eruptions, cerebellar ataxia, and gross aminoaciduria. [namrata.co]
- Cerebellar Ataxia
ataxia-renal aminoaciduria) Hart's E72.02 (pellagra-cerebellar ataxia-renal aminoaciduria) H E72.02 (Hartnup's) Hartnup's disease E72.02 Pellagra-cerebellar-ataxia-renal aminoaciduria syndrome E72.02 Syndrome - see also Disease pellagra-cerebellar ataxia-renal [icd10data.com]
Symptoms include transient manifestations of pellagra (rashes), cerebellar ataxia and psychosis. [ncbi.nlm.nih.gov]
ataxia and psychotic behavior. [link.springer.com]
A 6-year-old girl with Hartnup disease presented with recurrent attacks of intense, migraine-like, right-sided headache; a tender, pulsatile small mass was observed in the scalp. [ncbi.nlm.nih.gov]
Intellectual disability, short stature, headache, and collapsing or fainting are common. Urine testing for amino acids Diagnosis of Hartnup disease is made by showing the characteristic amino acid excretion pattern in the urine. [merckmanuals.com]
Symptomatic subjects usually present with skin photosensitivity (pellagra-like skin eruption), neurological symptoms (intermittent cerebellar ataxia, spasticity, delayed motor development, trembling, headaches, and hypotonia), and psychiatric symptoms [orpha.net]
Their symptoms may include skin rashes upon exposure to sunlight, mental retardation, short stature, fainting, and headaches. Occasionally psychiatric problems such as hallucinations and rapid mood changes occur as well (Kraut & Sachs, 2005). [pfond.cmmt.ubc.ca]
Ocular manifestations may occur (double vision, nystagmus, photophobia, and strabismus). Intellectual deficit and short stature have been described in a few patients. [orpha.net]
Intention tremor, nystagmus, diplopia, persistent headache, and psychiatric symptoms may be present ( 8 ). Patients have been reported with developmental retardation but no other symptoms ( 9 ). [ncbi.nlm.nih.gov]
In some instances, the eyes may be affected and individuals may experience double vision (diplopia), involuntary rhythmic movements of the eyes (nystagmus), and droopy upper eyelids (ptosis). [rarediseases.org]
Signs and symptoms Hartnup disease manifests during infancy with variable clinical presentation: failure to thrive, photosensitivity, intermittent ataxia, nystagmus, and tremor. [en.wikipedia.org]
- Neurologic Manifestation
Neurologic manifestations include cerebellar ataxia and mental abnormalities. Intellectual disability, short stature, headache, and collapsing or fainting are common. [merckmanuals.com]
Cutaneous signs usually precede the neurological manifestations. [namrata.co]
Abstract A 14-year-old boy of Arabic origin presented with a pellagra-like rash and neurological manifestations including ataxia, dysarthria, nystagmus, and coma. There was a striking response to oral nicotinamide. [ncbi.nlm.nih.gov]
Nicotinic acid or nicotinamide at 50 mg to 300 mg daily can provide remission from both the skin and neurological manifestations. [patient.info]
The physical examination of individuals with Hartnup disease should include particular attention to the skin. Skin findings may show :
- Photosensitivity, skin reddens with exposure
- Dry, scaly, rash, resembling chronic eczema
- Hypopigmentation and/or hyperpigmentation
- Urine chromatography , shows increased levels of neutral amino acids, while other amino acids remain normal. This differentiates Hartnup disease from other disorders with aminoaciduria .
- Blood concentrations of other amino acids are usually normal .
Imaging studies are not indicated in Hartnup disease.
- Skin biopsy may be indicated in some patients to differentiate the rash of Hartnup disease from other disorders with similar rashes .
Differential diagnoses  :
Patients with Hartnup disease who are symptomatic may benefit from:
- High-protein diet
- Protection from exposure to sunlight
- Avoiding photosensitizing drugs
Treatment for Hartnup disease should include  :
- Tryptophan-rich diet
- Nicotinic acid or nicotinamide (50-300 mg/d) for both the skin eruptions and the neurologic symptoms  .
- Tryptophan ethyl ester (20 mg/kg every 6 hours for children) increases serum and cerebrospinal fluid tryptophan to normal levels  .
Although Hartnup disease, as an inherited disorder, is always present, the symptoms are intermittent and vary from patient to patient. Many asymptomatic patients have only been diagnosed through routine screening, as aminoaciduria is always present .
Hartnup disease has a varied clinical picture. Most patients remain asymptomatic. The minority of patients with symptoms (skin rashes and photosensitivity, neurological and psychiatric disturbances) may be affected throughout their lives. These symptoms may interfere with their quality of life . Severe Central Nervous System involvement may occur rarely and may lead to death  . Mental retardation and delayed motor development, as well as growth retardation, have been seen in rare cases.
Recurrent exacerbations may occur when amino acid deficiency is increased due to other factors. These exacerbations become less frequent with age . Malnutrition and a low-protein diet are the primary factors causing clinical morbidity . The occurrence of symptoms in Hartnup disease is also affected by emotional stress, chronic illness, and severe diarrhea  .
Hartnup disease was first identified in members of the Hartnup family who had the symptoms of aminoaciduria, distinctive pellagra-like rash, and cerebellar ataxia. Hartnup disease is inherited as an autosomal recessive disorder requiring the defective gene from both parents. Carriers of the trait are asymptomatic .
The disease interferes with the absorption of neutral amino acids, particularly tryptophan, from the intestinal tract and it increases the excretion of them by the renal tubules   . All neutral amino acids are lost in urine and stool to varying degrees. Tryptophan is the most significant .
Individuals with Hartnup disease may be asymptomatic . Those who experience symptoms usually resolve over time. However symptoms may recur. Recurrent episodes most frequently are seen in the spring or early summer as a result of exposure to sunlight. The exacerbations can also be triggered by a febrile illness, poor nutrition, sulfonamides, emotional stress, and increased physical activity  .
The overall incidence of Hartnup disease is approximately 1 case per 30,000 births . Hartnup disease is considered one of the most common amino acid disorders . The disorder has been reported in all ethnic groups and equally in men and women .
The most common onset of symptoms in Hartnup disease is in early childhood (3-9 years of age). However, symptoms may occur as early as 10 days of age or as late as young adulthood  .
Hartnup disease is a metabolic disorder characterized by aminoaciduria due to abnormal renal and gastrointestinal transport of neutral amino acids (tryptophan, alanine, asparagine, glutamine, histidine, leucine, phenylalanine, tyrosine and valine)  . These compounds are necessary for optimal growth and bodyweight regulation and normal neurologic function .
Hartnup disease is an autosomal recessive abnormality . It has been determined that the gene responsible for the disorder is chromosome 5, band 5p15  . This gene mutation interferes with amino acid uptake by the epithelial cells of the intestinal mucosa and the permeability to them in the renal tubules . Approximately 10 separate mutations have been identified. The most common mutation, found in 43% of patients with Hartnup disorder, is c.517G→A, resulting in the amino acid substitution p.D173N  .
Neutral amino acid transport, primarily in the kidney and intestine, is dysfunctional in those who suffer from Hartnup disease. Amino acids from dietary sources, rather than being absorbed remain in the intestine. There they are converted by bacteria into compounds toxic to the central nervous system .
In the renal tubules they are excreted resulting in aminoaciduria  . The combined affect is the overall decrease in the availability of these necessary proteins. Tryptophan deficiency is the primary cause of symptoms. It is the precursor to many metabolites, serotonin in particular. Changes in serotonin metabolism may cause gastrointestinal dysfunction, mood abnormalities, and neurologic dysfunction. The action is not clearly understood  .
Tryptophan deficiency also leads to a decreased availability of this amino acid for the synthesis of niacin. It is believed that the main abnormalities associated with the disease result from niacin deficiency. They include the distinctive skin rash and reversible neurologic dysfunction .
Most patients are asymptomatic. Symptoms seem to occur when environmental, dietary, or constitutional factors further interfere with amino acid absorption . These factors are thought to include: acute diarrhea, malnutrition, and chronic illness .
Prevention of symptoms and exacerbation of Hartnup disease involves the following  :
- Sun exposure can exacerbate symptoms of Hartnup disease, avoidance of sun exposure is necessary.
- Avoid aggravating factors, such as sulfonamides, emotional stress, and extreme physical activity.
Hartnup disease is a metabolic, inherited disorder. It is an autosomal recessive disease , meaning that both parents must have the trait in order for an individual to have the disease. It is characterized by an inability to metabolize certain neutral amino acids. Aminoaciduria is the one consistent feature. The symptoms of Hartnup disease result from an irregularity in the neutral amino-acid transport system where these proteins cross the epithelium of the renal tubules and intestine .
Hartnup disease was named for the English family in which the disorder was identified in 1956 .
Individuals with the disease are generally asymptomatic. However, those who are symptomatic may experience a distinctive pellagra-like rash, nervous system abnormalities such as ataxia, and psychiatric symptoms . Symptoms may be transient with occasional exacerbations . Malnutrition and a low-protein diet are the primary factors that contribute to symptomatology  .
What is Hartnup disease?
Hartnup disease is a genetic disorder affecting the absorption of certain amino acids. Individuals with the disease have resulting deficiencies of these proteins necessary for normal growth and nervous system development.
The symptoms of Hartnup disease are usually transient and self-limited. However, reoccurrences may occur. These , too, are limited and usually resolve in 1 to 4 weeks.
What causes Hartnup disease?
Hartnup disease is an autosomal recessive disorder. This means that the defective gene is inherited from both parents, each having the disease or the trait for Hartnup Disorder.
What are the symptoms?
Though most often asymptomatic, individuals with Hartnup disease may experience:
- Pellagra-like skin rash, red and scaly
- Cerebellar ataxia, difficulty coordinating motor function
- Delayed motor development
- Psychiatric symptoms
- Visual disturbances: double vision, nystagmus, photophobia, and strabismus
- Developmental retardation
Who gets Hartnup disease?
Although the disease is inherited, not all individuals with the defective gene are symptomatic. Symptoms most commonly present in infancy or early childhood. However, those with the gene may become symptomatic at any age when exposed to certain risk factors. These include:
- Sun exposure
- Certain medications, such as sulfonamides
- Chronic illness
- Emotional or physical stress
How is it diagnosed?
Hartnup disease is suspected when the patient presents with the distinctive rash. The disorder may also be suspected when routine lab work shows aminoaciduria (the presence of certain proteins in the urine).
How is Hartnup disease treated?
Hartnup disease is treated symptomatically as there is no cure. Increasing the dietary intake of essential amino acids, avoiding sun exposure, and the replacement of nutritional deficiencies, are the primary treatments for those individuals who are experiencing symptoms.
- Sun screen 30 spf or greater
- High protein diet, especially tryptophan
- Medications include:
- Nicotinic acid – vitamin B
What are the complications?
The possible complications of Hartnup disease include the following:
- In infancy severe Central Nervous System symptoms may rarely lead to death.
- Psychotic episodes and delirium
- Mild mental retardation
- Hypopigmentation and/or hyperpigmentation of the skin may be long-lasting. It becomes worse with exposure to sunlight.
What can we do to prevent the complications of Hartnup disease?
Exacerbations of Hartnup disease can be prevented by the following:
- Kleta R, Romeo E, Ristic Z, Ohura T, Stuart C, Arcos-Burgos M, et al. . Koizumi A. Mutations in SLC6A19, encoding B0AT1, cause Hartnup disorder. Nat Genet 2004 36(9), 999-1002.
- Orbak Z, Ertekin V, Selimoglu A, Yilmaz N, Tan H, Konak M. Hartnup Disease Masked by Kwashiorkor. J Health Popul Nutr 2010 28(4): 413–415.
- Broer S. The Role of the Neutral Amino acid Transporter B0AT1 (SLC6A19) in Hartnup Disorder and protein nutrition. Life 2009 61(6): 591–599.
- Seow HF, Broer S, Broer A, Bailey CG, Potter SJ, Cavanaugh JA, Rasko JE. Hartnup disorder is caused by mutations in the gene encoding the neutral amino acid transporter SLC6A19. Nature Genetics 2004 36, 1003 – 1007.
- Nozaki J, Dakeishi M, Ohura T, Inoue K, Manabe M, Wada Y, Koizumi A. Homozygosity mapping to chromosome 5p15 of a gene responsible for Hartnup disorder. Biochem Biophys Res Commun 2001 284(2):255-60.
- Oakley A, Wallace J. Hartnup disease presenting in an adult. Clin Exp Dermatol 1994 19(5):407-8.
- Wilcken B, Yu JS, Brown DA. Natural history of Hartnup disease. Arch Dis Child 1977 52(1):38-40.
- Keszthelyi D, Troost FJ, Masclee AAM. Understanding the role of tryptophan and serotonin metabolism in gastrointestinal function. Neurogastroenterol Motil 2009 21, 1239–1249.
- Azmanov DN, Rodgers H, Auray-Blais C, Giguère R, Bailey C, Broer S, Rasko JE, Cavanaugh JA. Persistence of the common Hartnup Disease D173N allele in populations of European origin. Annals of Human Genetics 2007 71,755–761.