Nephrology

Bernardo Boaventura Liberato, MD

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Hartnup Disease

Hartnup disease is a rare genetic disorder of amino acid transport, presenting intermittent and variable clinical abnormalities. Originally described in the Hartnup family in London in the late 50’s, this entity became increasingly more studied in the recent years. The original patients presented a pellagra-like rash but failed to provide any evidence of dietary tryptophan insufficiency. Upon chromatography of the urine from the original patients, more than 14 amino acids were found in excess, pointing out to the most likely pathogenic mechanism : failure of some amino acids transport system at the renal level.

Since the first description, numerous cases of the disease have been reported; and widespread screening of neonates points to an overall incidence of about 1 per 26,000 live births.

Clinical and Genetic Features

Hartnup disease is classified in the group of the Neutral Aminoacidurias, since the amino acids lost in the urine are the so called neutral amino acids : tryptophan, alanine, asparagine, glutamine, histidine,isoleucine, leucine, phenylalanine, serine, threonine, tyrosine and valine. Of importance is the fact that proline, hydroxyproline, methionine and arginin are always spared.

Careful genetic analysis of all affected individuals revealed that it consists of an autossomal recessive disease. Heterozygotes exhibit no abnormality of amino acid excretion, except for a delayed rise in plasma tryptophan concentration after an oral tryptophan loading dose. Usually first evident in children, Hartnup disease may have its first presentation in the 30’s or 40’s. Whether the age of presentation determines or not a worse prognosis is an unsettled issue.

The clinical features of Hartnup disease are virtually identical to those of pellagra, although being intermittent and slightly less severe than the latter . Patients present with a red, scaly rash that is exacerbated by exposure to sunlight. Although virtually universal, the dermal findings may be absent, as illustrated by a case description of one patient who presented the laboratory features of the disease but did not show any cutaneous anomaly; instead, the neuropsychiatric features dominated the clinical picture.

Cerebellar ataxia, psychiatric disturbances, and diarrhea are common. Intermittent dystonia without ataxia may occur, leading some authors to state that Hartnup disease should always be suspected in children with unexplained dystonia. Other neuropsychiatric findings include daytime bruxismus, hipertonicity, signs of frontal lobe hypofunction and stupor. Mental retardation and progressive encephalopathy have been associated with the disease.

Pathology

The pathologic hallmark of Hartnup disease is the defective transport of basic amino acids (excluding the ones previously mentioned) by the jejunal mucous membranes and proximal renal tubules. The vast majority of these patients have the same pattern of amino acid excretion. Based on this fact, it is reasonable to assume that the proximal tubule brush border contains at least one transport system for all 12 involved amino acids (further studies are still pending). It is generally agreed that the clinical features of Hartnup disease are due to the defective intestinal absorption of tryptophan, rather to the renal losses. This is based on the concept that with a normal absorption, the renal losses, even being important, would not be sufficient to establish such a florid clinical picture. This can be illustrated by the fact that, when tryptophan ethyl esther (a lipid-soluble form of tryptophan) is fed to children with Hartnup disease, serum tryptophan promptly increases, and the clinical signs of the disease are reversed.

It is noteworthy that tryptophan transportation mechanisms, other than the intestinal and renal ones, are normal in Hartnup disease.

Differential Diagnosis

Pellagra is the main differential diagnosis on clinical grounds; however, a negative history for dietary deficiency of tryptophan, in the presence of typical clinical findings should raise the suspicion of Hartnup disease, especially when present in siblings. Chromatographic analysis of the urine usually distinguishes the two processes, making the diagnosis straightforward.

The “blue diaper syndrome” should also be excluded. This entity is secondary to an isolated defective intestinal transport of tryptophan (with no renal abnormality). These patients present indicanuria, which is the urinary excretion of indigo, an oxidation product of the tryptophan breakdown product indican. Indoles and indicans are absorbed after their production by bacterial metabolism of excess tryptophan that is not absorbed in the intestinal tract. The history and chromatographic findings help exclude pellagra and Hartnup disease, respectively.

Diagnosis and Treatment

Once again the diagnosis of Hartnup disease is straightforward, provided that one can exclude dietary deficiencies as the primary abnormality. The use of urinary chromatography help establish the diagnosis with certainty. Since the clinical manifestations are due to the additive effects of a poor intestinal absorption coupled with a deficient renal conservation, it is expected that Hartnup disease responds well to treatment with supplemental nicotinamide (40 to 200 mg per day). Some patients may respond well to diets rich in tryptophan.

References

1) The Kidney 5th Edition - Barry M. Brenner

5) Oakley A; Wallace J “Hartnup disease presenting in an adult”- Clin Exp Dermatol, 19: 5, 1994 Sep, 407-8

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