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 [8]. 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 [2]. 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 [2] .

Patients with Hartnup disease may experience some or all of the following symptoms [2]:

• Pellagra-like skin rash
• Photosensitivity
• Transient cerebellar ataxia
• Delayed motor development
• Headaches
• Psychiatric symptoms
• Visual disturbances: double vision, nystagmus, photophobia, and strabismus [2]
• Developmental retardation

The clinical manifestations are intermittent and inconsistent, and they usually improve spontaneously with age [2].

Exacerbations may occur after exposure to sunlight, usually in the spring or early summer [2]. 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 [2].

• Disability

  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]

  Scalp AVFs may progress in size, causing significantly disabling symptoms, particularly in children. We recommend endovascular treatment at the earliest possible stage. [ncbi.nlm.nih.gov]

  Intellectual disability, short stature, headache, and collapsing or fainting are common. Psychiatric symptoms also occur, including emotional lability and psychosis. [msdmanuals.com]

• Epilepsy

  […] disorder 46,XX性分化異常症 46,XX disorder of sex development 46,XX精巣性性分化異常症 46,XX testicular disorder of sex development 46,XY性分化異常症 46,XY disorder of sex development 外転神経疾患 abducens nerve disease 欠神てんかん absence epilepsy 副神経疾患 accessory nerve disease 酸塩基平衡異常 [life-science-dictionary.com]

• Developmental Delay

  delay : pure renal, in urinary findings only. [ijdvl.com]

  Clinical features of Fanconi Syndrome Developmental delay Slow growth Polyuria Polydipsia Dehydration Osteomalacia in adults Hypophosphatemic rickets in children Acidosis Growth failure Hyperchloremia Hypokalemia Glycosuria Aminoaciduria Hyperuricosuria [lecturio.com]

• Abdominal Pain

  In clinical practice, many severe or critically ill COVID-19 patients developed gastrointestinal (GI) disturbances, including vomiting, diarrhoea, or abdominal pain, even in the absence of cough and dyspnea. [search.bvsalud.org]

  pain, nausea and vomiting are common It may be difficult to eat and drink, leading to further malnutrition Neurological Initially symptoms of apathy and slight depression may go unnoticed Other symptoms include headache, confusion, irritability, restlessness [dermnetnz.org]

• Photosensitivity

  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]

  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. [symptoma.com]

  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]

  Advise patients to avoid other aggravating factors, such as photosensitizing drugs, as much as possible. [namrata.co]

• Skin Rash

  Procedures Skin biopsy may be indicated in some patients to differentiate the rash of Hartnup disease from other disorders with similar rashes. [symptoma.com]

  Familial pellagra-like skin rash with neurological manifestations. Arch Dis Child. 1981 Feb;56(2):146-8. [PMC free article: PMC1627116] [PubMed: 6451201] 3. Seakins JW, Ersser RS. [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]

  […] reduced availability of trytohan is the most likely cause for the skin-rash%& • .he ataxia might also be related to trytohan metabolism and its conversion to serotonin ! [scribd.com]

• Skin Lesion

  Skin lesions in our case were of the acrodermatitis enteropathica-type, and these were different from the typical skin eruptions of Hartnup disease. Acrodermatitis enteropathica lesions as a result of zinc deficiency are frequent in kwashiorkor. [ncbi.nlm.nih.gov]

  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 [emedicine.medscape.com]

• Eruptions

  Here we report a girl who first presented with an acrodermatitis enteropathica-like eruption and eventually had the diagnosis of Hartnup disease with a normal isoleucine level. [ncbi.nlm.nih.gov]

  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]

• Hyperpigmentation

  The cutaneous lesions were classically pellagroid, being sharply demarcated erythematous plaques with peripheral scaling, crusting and hyperpigmentation. [ijdvl.com]

  Permanent hypopigmentation and/or hyperpigmentation of the skin occur with repeated exposure to sunlight. Prognosis Malnutrition and a low-protein diet increase morbidity. Attacks become less frequent with increasing age. [patient.info]

  Figure 1 Initial Presentation: significant photosensitivity with severe scaly desquamating skin rash and hyperpigmentation involving the face, neck, lower and upper extremities. [bmcpediatr.biomedcentral.com]

  The patients have a normal life expectancy with low morbidity.[13] Complications Complications include: Severe neurodegenerative symptoms, including seizures, psychosis, and delirium.[14][15] Skin hyperpigmentation and xerosis at the site of eruptive [ncbi.nlm.nih.gov]

• Psychiatric Symptoms

  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]

  However, individuals who are nutrient-deficient due to their diet, illness, stress, or a variety of other reasons, can develop serious signs and symptoms of this condition including rashes, cerebellar ataxia, and psychiatric symptoms. [medlineplus.gov]

  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. [symptoma.com]

  Psychiatric symptoms also occur, including emotional lability and psychosis. Urine testing for amino acids Diagnosis of Hartnup disease is made by showing the characteristic amino acid excretion pattern in the urine. [merckmanuals.com]

• Psychiatric Manifestation

  In the present case, therefore, absence of neurological and psychiatric manifestations does not in any way contradict the diagnosis of Hartnup disease; the abnormal EEG pattern noted may be an indicator of future such developments. [ijdvl.com]

• Ataxia

  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]

  Hartnup disease was first identified in members of the Hartnup family who had the symptoms of aminoaciduria, distinctive pellagra-like rash, and cerebellar ataxia. [symptoma.com]

  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]

  Symptoms include transient manifestations of pellagra (rashes), cerebellar ataxia and psychosis. [ncbi.nlm.nih.gov]

• 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]

  Neurologic manifestations include cerebellar ataxia and mental abnormalities. Intellectual disability, short stature, headache, and collapsing or fainting are common. [merckmanuals.com]

  Keywords Cerebellar Ataxia Emotional Instability Rare Autosomal Recessive Disorder Oral Load Indolacetic Acid These keywords were added by machine and not by the authors. [link.springer.com]

  관련질환명 에이취 병(H Disease),하트 병 또는 하아트 병(Hart Syndrome),하르트누프 병 또는 하아트누프 병(Hartnup Disorder),하르트누프 증후군 또는 하아트누프 증후군(Hartnup Syndrome),펠라그라-소뇌 운동실조-신장 아미노산뇨증 증후군(Pellagra-Cerebellar Ataxia-Renal Aminoaciduria Syndrome),트립토판 피롤라제 결핍(Tryptophan Pyrrolase Deficiency [carerare.kr]

• Headache

  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]

  Intellectual disability, short stature, headache, and collapsing or fainting are common. Psychiatric symptoms also occur, including emotional lability and psychosis. [msdmanuals.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]

  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]

• Nystagmus

  Ocular manifestations may occur (double vision, nystagmus, photophobia, and strabismus). Intellectual deficit and short stature have been described in a few patients. [orpha.net]

  Patients with Hartnup disease may experience some or all of the following symptoms: Pellagra-like skin rash Photosensitivity Transient cerebellar ataxia Delayed motor development Headaches Psychiatric symptoms Visual disturbances: double vision, nystagmus [symptoma.com]

  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]

• Neurologic Manifestation

  Neurologic manifestations include cerebellar ataxia and mental abnormalities. Intellectual disability, short stature, headache, and collapsing or fainting are common. [merckmanuals.com]

  Neurologic manifestations include cerebellar ataxia and mental abnormalities. Intellectual disability, short stature, headache, and collapsing or fainting are common. Psychiatric symptoms also occur, including emotional lability and psychosis. [msdmanuals.com]

  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]

  Cutaneous signs usually precede the neurological manifestations. [namrata.co]

Hartnup disease is usually suspected when the patient presents with the distinctive rash. Diagnosis is made by urine chromatography which shows increased neutral amino acid levels [3].

Physical examination

The physical examination of individuals with Hartnup disease should include particular attention to the skin. Skin findings may show [3]:

• Photosensitivity, skin reddens with exposure
• Dry, scaly, rash, resembling chronic eczema
• Hypopigmentation and/or hyperpigmentation

A complete neurological examination to determine central nervous system involvement: ataxia, tremor, nystagmus, or strabismus, should also be done.

Laboratory studies

• Urine chromatography [9], shows increased levels of neutral amino acids, while other amino acids remain normal. This differentiates Hartnup disease from other disorders with aminoaciduria [6].
• Blood concentrations of other amino acids are usually normal [6].

Imaging studies are not indicated in Hartnup disease.

Procedures

• Skin biopsy may be indicated in some patients to differentiate the rash of Hartnup disease from other disorders with similar rashes [6].

Differential diagnoses [3] [8]:

• Ataxia-Telangiectasia
• Hydroa Vacciniforme
• Pityriasis Alba
• Xeroderma Pigmentosum

• Hypouricemia

  Fanconi syndrome，ファンコニー症候群 95～99% 8. hereditary renal hypouricemia，遺伝性腎性低尿酸血症 Fanconi Syndrome E7（ファンコニー症候群）とXanthinuria M2（キサンチン尿症）を除外できるため、本疾患E8の診断指針の第3の必須項目を提供できる。 9. hypophosphatasia，低ホスファターゼ症 F. [jc-metabolomics.com]

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 [6] [8]:

• Tryptophan-rich diet
• Nicotinic acid or nicotinamide (50-300 mg/d) for both the skin eruptions and the neurologic symptoms [7] [8].
• Tryptophan ethyl ester (20 mg/kg every 6 hours for children) increases serum and cerebrospinal fluid tryptophan to normal levels [7] [8].

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 [2].

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 [6]. Severe Central Nervous System involvement may occur rarely and may lead to death [6] [7]. 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 [9]. Malnutrition and a low-protein diet are the primary factors causing clinical morbidity [7]. The occurrence of symptoms in Hartnup disease is also affected by emotional stress, chronic illness, and severe diarrhea [3] [6].

Hartnup disease was first identified in members of the Hartnup family who had the symptoms of aminoaciduria, distinctive pellagra-like  rash, and cerebellar ataxia[1][2]. Hartnup disease is inherited as an autosomal recessive disorder requiring the defective gene from both parents. Carriers of the trait are asymptomatic [2].

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 [3] [4] [5]. All neutral amino acids are lost in urine and stool to varying degrees. Tryptophan is the most significant [2].

Individuals with Hartnup disease may be asymptomatic [1]. 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 [2] [6].

The overall incidence of Hartnup disease is approximately 1 case per 30,000 births [3]. Hartnup disease is considered one of the most common amino acid disorders [3]. The disorder has been reported in all ethnic groups and equally in men and women [7].

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 [3] [7].  

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) [1] [8]. These compounds are necessary for optimal growth and bodyweight regulation and normal neurologic function [5].

Hartnup disease is an autosomal recessive abnormality [4]. It has been determined that the gene responsible for the disorder is chromosome 5, band 5p15 [1] [5]. 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 [5]. 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 [4] [5].  

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 [3].

In the renal tubules they are excreted resulting in aminoaciduria [3] [2]. 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 [2] [8].

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 [2].

Most patients are asymptomatic. Symptoms seem to occur when environmental, dietary, or constitutional factors further interfere with amino acid absorption [3]. These factors are thought to include: acute diarrhea, malnutrition, and chronic illness [3].

Prevention of symptoms and exacerbation of Hartnup disease involves the following [3] [7]:

• 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 [4], 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 [1].  

Hartnup disease was named for the English family in which the disorder was identified in 1956 [1].

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 [1]. Symptoms may be transient with occasional exacerbations [1]. Malnutrition and a low-protein diet are the primary factors that contribute to symptomatology [1] [2].

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.

Most individuals with the disorder are asymptomatic. The predominant symptoms are a distinctive, red, scaly rash and photosensitivity.

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
• Photosensitivity
• Cerebellar ataxia, difficulty coordinating motor function
• Delayed motor development
• Headaches
• 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
• Malnutrition
• 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.

Treatment includes:

• Sun screen 30 spf or greater
• High protein diet, especially tryptophan
• Medications include:
• Nicotinic acid – vitamin B
• Tryptophan

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:

• Consume a high-protein diet.
• Prevent exposure to sunlight with protective clothing, sunglasses, and sunscreen (30 spy or greater).
• Avoid aggravating factors such as sulphonomides, emotional and physical stress, and malnutrition.
• Take supplements as prescribed.

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2. 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.
3. Broer S. The Role of the Neutral Amino acid Transporter B0AT1 (SLC6A19) in Hartnup Disorder and protein nutrition. Life 2009 61(6): 591–599.
4. 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.
5. 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.
6. Oakley A, Wallace J. Hartnup disease presenting in an adult. Clin Exp Dermatol 1994 19(5):407-8.
7. Wilcken B, Yu JS, Brown DA. Natural history of Hartnup disease. Arch Dis Child 1977 52(1):38-40.
8. Keszthelyi D, Troost FJ, Masclee AAM. Understanding the role of tryptophan and serotonin metabolism in gastrointestinal function. Neurogastroenterol Motil 2009 21, 1239–1249.
9. 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.