Hartnup Disease

Etiology

Hartnup disease has a genetic etiology. SLC6A19 is a gene located on the short arm of chromosome 5 that encodes transport protein B0AT1 present at the apical cell surface of the small intestine and kidney. Immunohistochemical studies showed maximum expression of B0AT1 in the early proximal convoluted tubules in the kidney and jejunum in the small intestine.[5] Mutation in the SLC6A19 gene is responsible for Hartnup disease. The mutations noted to cause the disease are missense, splice site, frameshift, and nonsense.[5] The activation and trafficking of B0AT1 to the cell surface occurs via a specific type 1 membrane protein. These are collectrin at the kidneys and angiotensin-converting enzyme 2 at the intestines.[6][7] They activate it by catabolic reactions and transport B0AT1 to the apical cell surface. The human ACE 2 gene encodes angiotensin-converting enzyme 2, and the CLTRN gene encodes collectrin protein. Both genes are located at the X chromosome band Xp22.2. Mutations in these genes result in sequestration and reduced surface expression of the B0AT1 transporter, which presents with clinical symptoms of Hartnup disease. Hartnup disease has a wide range of clinical symptoms as it can result from a mutation in the transport protein B0AT1 or co-receptors collectrin and ACE2.

Epidemiology

The incidence of Hartnup disease is 1 in 15,000 live births.[1] Hartnup disease was first described by Baron et al in 1956 in a family in England where 4 siblings were affected.[8] The condition was first described in a boy in the Hartnup family who presented with photosensitive rash, ataxia, hand tremors, and gait disturbances. On investigation of further family members, his other 3 siblings were also found to have the same syndrome with varying clinical symptoms. Hartnup disease has an early age of onset, with most patients presenting in childhood. It is inherited in an autosomal recessive pattern and has no sexual predilection.

Pathophysiology

Protein digestion begins in the stomach by the action of pepsinogen. The proteins are then broken down into smaller peptides by the action of various enzymes secreted by the pancreas and enzymes present at the brush border of the small intestine. These enzymes break down proteins into tripeptides, dipeptides, and amino acids. Most amino acids are absorbed in jejunum through a special transport protein located at the apical surface of brush borders. B0AT1 is a sodium-dependent co-transport protein for absorbing neutral amino acids at the apical surface of the small intestine and renal tubular cells. The absorption of neutral amino acids is independent of chloride concentration. The absorbed neutral amino acids are transported via the blood to other organs. In the kidney, it is filtered through the glomerulus, where it is reabsorbed through B0AT1 membrane protein located in proximal tubular cells.[5]

In Hartnup disease, there is a defect in the B0AT1 protein, resulting in excessive excretion of neutral amino acids in urine and feces. A small amount of neutral amino acids is absorbed in the gut directly via paracellular transport and as oligopeptides from proton counter-transport proteins.[9] Excess tryptophan present in the gut is converted to indolic compounds by the action of colonic bacteria. These indolic compounds are conjugated in the liver and excreted as indican in urine.[10] Tryptophan is a neutral amino acid that is a precursor for niacin. Wasting of tryptophan results in niacin deficiency manifesting as pellagra-like skin eruptions and neurological symptoms.[10] An excess of leucine in the brain competes with other neutral amino acids, including tryptophan, for binding by transporters in the glial cell membranes. Tryptophan is needed for the production of serotonin.[11]

History and Physical

The patients present with intermittent and reversible episodes of cutaneous and neurological clinical symptoms aggravated by sunlight, hot weather, and nutritional deficiency. The skin eruptions that resemble pellagra are erythematous, scaly, and present in sun-exposed areas of skin. There have been reports of improvement of the skin rash with nicotinamide supplementation.[4] Neurological symptoms range from tremors, ataxia, mood disorders, depression, convulsions, and psychosis.[10] Developmental milestones are normal in children, but below-normal academic performance and short stature have been noted.[4] The clinical symptoms improve with age when protein demand decreases. Patients may remain asymptomatic throughout life if their niacin intake is adequate.

Evaluation

The diagnosis of Hartnup disease is determined by urine analysis, which shows neutral aminoaciduria except for proline. The neutral amino acids (valine, serine, phenylalanine, histidine, glutamine, leucine, asparagine, citrulline, isoleucine, threonine, alanine, tyrosine, tryptophan) undergo analysis by paper chromatography of urine. Indican is also present in the urine and is produced as a by-product of tryptophan degradation by colonic bacteria.

Treatment / Management

The main aim of treatment is to prevent the occurrence of clinical episodes. Hartnup disease is treatable by a high-protein diet. Patients should have a well-balanced diet, as episodes are more frequent in individuals who are malnourished and have maize as their staple diet. Nicotinamide supplements ameliorate skin eruptions and neurological symptoms in patients with niacin deficiency.[12] Patients with neurological symptoms require a complete neurological workup. Appropriate psychiatric and neurological treatments may be needed to resolve the neuropsychiatric symptoms.[4](B3)

Differential Diagnosis

Hartnup disease requires differentiation from other conditions that result in a photosensitive skin rash, such as:

• Nutritional pellagra
• Lupus erythematosus
• Congenital poikiloderma
• Carcinoid syndrome
• Seborrheic eczema   

Nutritional pellagra has normal urine analysis. Lupus has specific antinuclear (ANA), anti-Smith, and anti-double-stranded (anti-ds Ab) antibodies in plasma. Carcinoid syndrome is associated with flushing, diarrhea, and elevated levels of 5-hydroxy indoleacetic acid(5-HIAA) in urine. Seborrheic eczema has yellow crusting on skin lesions and a history of allergies.[13]

Prognosis

The severity of symptoms decreases with age.[10] There is a low incidence of recurrence of symptoms with a high protein diet and niacin supplement. The prognosis is good. The patients have a normal life expectancy with low morbidity.[14]

Complications

Complications for Hartnup disease include:

1. Severe neurodegenerative symptoms, including seizures, psychosis, and delirium.[15][16]
2. Skin hyperpigmentation and xerosis at the site of eruptive skin lesions.[17]
3. Developmental retardation and below-average school performance have been reported.[18][19]