Hartnup Disease

A rare metabolic disorder belonging to the neutral aminoacidurias, mainly characterized by skin photosensitivity, ocular and neuropsychiatric features, due to abnormal renal and gastrointestinal transport of neutral amino acids (tryptophan, alanine, asparagine, glutamine, histidine, isoleucine, leucine, phenylalanine, serine, threonine, tyrosine and valine).

Epidemiology

The estimated prevalence is approximately 1 in 30,000.

Clinical description

Most subjects who fulfil the biochemical diagnostic criteria (mostly detected by newborn screening programs) remain asymptomatic. In the few symptomatic subjects, clinical symptoms usually appear in childhood (3-9 years of age), but sometimes manifest as early as 10 days after birth, or as late as early adulthood. Symptomatic subjects usually present with skin photosensitivity (pellagra-like skin eruption), neurological symptoms (intermittent cerebellar ataxia, spasticity, delayed motor development, trembling, headaches, and hypotonia), and psychiatric symptoms (anxiety, emotional instability, delusions, and hallucinations). Ocular manifestations may occur (double vision, nystagmus, photophobia, and strabismus). Intellectual deficit and short stature have been described in a few patients. Exacerbations are seen most frequently in the spring or early summer after sunlight exposure. Symptoms may also be triggered by fever, drugs, and emotional or physical stress. They progress over several days and last for 1-4 weeks before spontaneous remission occurs.

Etiology

Hartnup disease is caused by mutations in SLC6A19 gene (5p15.33), encoding the sodium-dependent and chloride-independent neutral amino acid transporter B(0)AT1, expressed predominately in proximal renal tubules and intestinal epithelium.

Diagnostic methods

Neutral hyperaminoaciduria (determined by urine chromatography) is the diagnostic hallmark. Diagnostic confirmation relies upon the mutation analysis of the SLCA19 gene (broad allelic heterogeneity).

Differential diagnosis

Pellagra is the main differential diagnosis. Blue diaper syndrome, ataxia-telangiectasia, hydroa vacciniforme, pityriasis alba, and xeroderma pigmentosum should be excluded.

Genetic counseling

Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.

Management and treatment

Symptomatic subjects benefit from a high-protein diet, sunlight protection, and avoidance of photosensitizing drugs. Treatment includes nicotinamide supplements (40 to 200 mg per day). Some patients may respond to a tryptophan-rich diet. Patients with severe central nervous system involvement require neurologic and psychiatric treatment.

Prognosis

The presentation of the disorder is commonly benign. Hartnup disease probably does not adversely affect pregnancy and would be harmless to the fetus.