In Hartnup disorder (MIM 234500), pellagra-like dermatitis and
neurological symptoms associated with a characteristic pattern
of hyperaminoaciduria can be present. These symptoms were first
reported in several members of the Hartnup family in 1956.80Since
then, newborn screening programs have picked up several mostly asymptomatic
subjects with the diagnostic urinary amino acid profile (estimated
incidence 1 in 20,000).81 Due to a renal transport
defect of neutral monoamino-monocarboxylic amino acids, the patients
excrete alanine, serine, threonine, valine, leucine, isoleucine,
phenylalanine, tyrosine, tryptophan, histidine and citrulline, and
the monoamino-dicarboxylic amidesasparagine and glutamine into the
urine in five- to twentyfold excess. Their stools contain increased
amounts of the same free amino acids,82 while the
plasma concentrations are decreased or low normal. Bacterial degradation
of unabsorbed tryptophan in the intestine produces large amounts
of indole compounds excreted in the urine.The autosomal recessive disorder
is caused by at least 10 mutations in the gene encoding the neutral
amino acid transporter SLC6A19 at the luminal border of the epithelial cells
in the renal tubuli and intestinal epithelium.81,83-86Recent
data suggest that defects in other amino acid transporters may also
result in the Hartnup phenotype.3The phenotypic heterogeneity
of Hartnup disorder is puzzling: The monogenic transport defect
probably develops into symptomatic disease only in association with
certain polygenic and/or environmental factors. The clinical
manifestations resembling niacin deficiency probably reflect deficient
production of nicotinamide, a tryptophan metabolite. It has also
been suggested that bacterial degradation products of tryptophan
may be toxic to the central nervous system.87 On
a protein-rich diet, most patients remain asymptomatic, most likely
due to sufficient amino acid supply in peptide form.87In
the few patients who develop clinical symptoms, the skin lesions
on light-exposed areas and neurological problems, including intermittent
cerebellar ataxia, headache, muscle pain, and weakness,88,89usually appear
in early childhood and often ameliorate with age. Exposure to sunlight,
infection, poor nutrition, or stress may precipitate the symptoms. Growth
and developmental outcome are generally normal. Maternal Hartnup
disorder seems to be harmless to the fetus.90 The
characteristic excess of neutral amino acids in the urine and reduced
or low-normal concentrations in plasma confirm the diagnosis. The
symptoms usually disappear rapidly with oral nicotinamide (50–300 mg/day).
Early recognition of the condition in newborn screening programs
permits adequate follow-up and treatment. Clinical and molecular aspects
of amino acid transport defects are summarized in Table
143-1.