Hartnup disease is an autosomal recessive

Recessive

In genetics, the term "recessive gene" refers to an allele that causes a phenotype that is only seen in a homozygous genotype and never in a heterozygous genotype. Every person has two copies of every gene on autosomal chromosomes, one from mother and one from father...

 metabolic disorder affecting the absorption of nonpolar amino acids (particularly tryptophan

Tryptophan

Tryptophan is one of the 20 standard amino acids, as well as an essential amino acid in the human diet. It is encoded in the standard genetic code as the codon UGG...

 that can be, in turn, converted into Serotonin

Serotonin

Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...

, Melatonin

Melatonin

Melatonin , also known chemically as N-acetyl-5-methoxytryptamine, is a naturally occurring compound found in animals, plants, and microbes...

 and Niacin

Niacin

"Niacin" redirects here. For the neo-fusion band, see Niacin .Niacin is an organic compound with the formula and, depending on the definition used, one of the forty to eighty essential human nutrients.Niacin is one of five vitamins associated with a pandemic deficiency disease: niacin deficiency...

). Niacin is a precursor to nicotinamide

Nicotinamide

Nicotinamide, also known as niacinamide and nicotinic acid amide, is the amide of nicotinic acid . Nicotinamide is a water-soluble vitamin and is part of the vitamin B group...

, a necessary component of NAD+.

The causative gene, SLC6A19

SLC6A19

Solute carrier family 6 member 19 also known as the sodium-dependent neutral amino acid transporter BAT1 or system B neutral amino acid transporter AT1 is a protein that in humans is encoded by the SLC6A19 gene.- Function :...

, is located on chromosome 5.

Diagnosis

The defective gene controls the absorption of certain amino acids from the
intestine and the reabsorption of those amino acids in the kidneys.
Consequently, a person with Hartnup disease cannot absorb amino acids properly
from the intestine and cannot reabsorb them properly 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. With too little tryptophan in the
blood, the body is unable to make a sufficient amount of the B-complex vitamin
niacinamide, particularly under stress when more vitamins are needed.

Causes

Hartnup disease is inherited as an autosomal recessive trait. Heterozygotes
are normal. Consanguinity is common. In 2004, a causative gene, SLC6A19, 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.

Symptoms

Hartnup disease manifests during infancy with variable clinical presentation: failure to thrive, photosensitivity, intermittent ataxia, nystagmus

Nystagmus

Nystagmus is a condition of involuntary eye movement, acquired in infancy or later in life, that may result in reduced or limited vision.There are two key forms of Nystagmus: pathological and physiological, with variations within each type. Nystagmus may be caused by congenital disorders,...

 and tremor.

Nicotinamide is necessary for neutral amino acid transporter production in the proximal renal tubules found in the kidney

Kidney

The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...

, and intestinal mucosal cells found in the small intestine

Small intestine

The small intestine is the part of the gastrointestinal tract following the stomach and followed by the large intestine, and is where much of the digestion and absorption of food takes place. In invertebrates such as worms, the terms "gastrointestinal tract" and "large intestine" are often used to...

. Therefore, a symptom stemming from this disorder results in increased amounts of amino acids in the urine.

Pellagra

Pellagra

Pellagra is a vitamin deficiency disease most commonly caused by a chronic lack of niacin in the diet. It can be caused by decreased intake of niacin or tryptophan, and possibly by excessive intake of leucine. It may also result from alterations in protein metabolism in disorders such as carcinoid...

, a similar condition, is also caused by low nicotinamide; this disorder results in dermatitis

Dermatitis

-Etymology:Dermatitis derives from Greek derma "skin" + -itis "inflammation" and genetic disorder.-Terminology:There are several different types of dermatitis. The different kinds usually have in common an allergic reaction to specific allergens. The term may describe eczema, which is also called...

, diarrhea

Diarrhea

Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...

 and dementia

Dementia

Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...

.

Hartnup disease is a disorder of amino acid transport in the intestine and
kidneys; otherwise, the intestine and kidneys function normally, and the
effects of the disease occur mainly in the brain and skin. Symptoms may
begin in infancy or early childhood, but sometimes they begin as late as early
adulthood. Symptoms may be triggered by sunlight, fever, drugs, or emotional or
physical stress. A period of poor nutrition nearly always precedes an attack.
The attacks usually become progressively less frequent with age. Most
symptoms occur sporadically and are caused by a deficiency of niacinamide. A
rash develops on parts of the body exposed to the sun. 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.

Treatment

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 both number and severity of attacks. Neurologic and psychiatric treatment is needed in
patients with severe CNS involvement.

External links

• University of Maryland