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Case study – Hart Nup disease
A 12-year-old boy was admitted to the hospital with a red scaly rash and mild cerebellar ataxia. His mother thought that the boy is suffering from Pellagra because the same symptoms in her older daughter had been so diagnosed earlier. The boy did not have the usual dietary deficiency form of Pellagra, but large amounts of free amino acids were found in his urine. When the older daughter had a recurrent attack of ataxia, it was found that her urine also contained excessive amount of amino acids. Two other siblings had the sane aminoaciduria; however four others were normal. The parents were asymptomatic, but a family history revealed that they were first cousins.
Assuming that this defect is inherited, what abnormality could account for the unusual amount of amino acids in urine and what is its relationship with pellagra like rashes?
How can this defect be treated?
The boy is suffering from Hart Nup Disease.
Hartnup disease is an autosomal recessive disorder caused by impaired neutral (i.e., mono amino mono carboxylic) amino acid transport in the apical brush border membrane of the small intestine and the proximal tubule of the kidney. Patients present with pellagra like skin eruptions, cerebellar ataxia, and gross aminoaciduria.
The disorder was first observed in the Hartnup family of London; 4 of the 8 family members presented with aminoaciduria, a rash resembling pellagra, and cerebellar ataxia.
Hart Nup Disease
Hartnup disease is inherited as an autosomal recessive trait. Heterozygote are normal. Consanguinity is common. The causative gene, SLC6A19 is defective.Mutations in the SLC6A19 gene, which encodes the B0 AT1, sodium-dependent, chloride-independent, neutral amino acid transporter, cause a failure of the transport of neutral amino acids in the small intestine and the renal tubules (Figure-1)
A person with Hartnup disease cannot absorb amino acids properly from the intestine (Figure-1) and from tubules in the kidneys. Excessive amounts of amino acids, such as Tryptophan, are excreted in the urine. The body is thus left with inadequate amounts of amino acids, which are the building blocks of proteins.
Figure-1- Showing the mechanism of absorption of Tryptophan through a specific transporter.
With too little Tryptophan in the blood, the body is unable to make a sufficient amount of the B-complex vitamin niacinamide, (Figure-2 and 3) particularly under stress when more vitamins are needed. As a result, tryptophan and niacin deficiencies generate similar symptoms.
Figure-2- Showing tryptophan metabolism. Tryptophan is mainly metabolized through Kynurenine Anthranilate pathway(Major pathway), A fraction of tryptophan is also metabolized alternatively to produce niacin . 60 mg of tryptophan produces 1 mg of niacin.
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 (i.e., Indican uria).
Other Tryptophan degradation products, including kynurenine and serotonin,(Figure-3) 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.
Figure-3- showing the alternative pathways of tryptophan metabolism. Serotonin and niacin deficiencies are mainly responsible for symptoms of hartnup disease
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.
Hartnup disease manifest during infancy with variable clinical presentation: failure to thrive, photosensitivity, intermittent ataxia, nystagmus and tremors. Symptoms may be triggered by sunlight, fever, drugs, or emotional or physical stress. A period of poor nutrition nearly always precedes an attack. Most symptoms occur sporadically and are caused by a deficiency of niacinamide.
A rash develops on parts of the body exposed to the sun (Figure-4). Mental retardation, short stature, headaches, unsteady gait, and collapsing or fainting are common. Psychiatric problems (such as anxiety, rapid mood changes, delusions, and hallucinations) may also result. Cutaneous signs usually precede the neurological manifestations.
Figure-4- Pellagra like rash due to niacin deficiency
Urine Analysis – Neutral amino acids, Tryptophan, Indole derivatives and Tryptophan degradation products are present in urine.
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. Avoiding excessive exposure to sunlight, wearing protective clothing, and using physical and chemical sunscreens are mandatory. 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 both number and severity of attacks. Neurological and psychiatric treatment is needed in patients with severe CNS involvement.
Hartnup disease is manifested by a wide clinical spectrum. Most patients remain asymptomatic, but, in a minority of patients, skin photosensitivity and neurological and psychiatric symptoms may have a considerable influence on quality of life. Rarely, severe CNS involvement may lead to death.
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