HARTNUP DISEASE
Key features
An autosomal recessive disorder associated with defective renal and intestinal neutral amino acid transport
Marked aminoaciduria and tryptophan deficiency
Typically presents with a pellagra-like dermatosis associated with photosensitivity
Systemic manifestations include ataxia and tremors
Hartnup disease is an autosomal recessive disorder caused by pathogenic variants in SLC6A19, which encodes a transporter that mediates epithelial uptake of neutral amino acids in the kidneys and intestines. The hallmark of the disorder is a specific hyperaminoaciduria due to diminished renal and intestinal reabsorption of neutral amino acids. Hartnup disease is one of the most common amino acid disorders, occurring in about 1 in 30 000 births. Most affected individuals, particularly those in high-income countries, remain asymptomatic throughout life, although symptoms can occur when exacerbating factors such as poor nutrition, celiac disease, or other causes of persistent diarrhea are present.
When clinical features develop, the most common finding is a recurrent photosensitive “pellagra-like” dermatosis. This eruption is thought to be related to a relative niacin deficiency, as tryptophan is a precursor in niacin synthesis. It typically develops in children on exposed areas of the body and may initially resemble a sunburn or acute cutaneous lupus erythematosus. After the development of erythema following sun exposure, the affected skin becomes dry and scaly with well-defined margins; later findings include desquamation and hypoor hyperpigmentation. The dermatosis is occasionally pruritic and blistering may occur; acrodermatitis enteropathica- and hydroa vacciniforme-like presentations have been described. The second major manifestation of symptomatic Hartnup disease is intermittent ataxia, which may be accompanied by nystagmus and tremors. Psychiatric disturbances, developmental delay, and other neurologic abnormalities have been reported in some patients.
The diagnosis of Hartnup disease is established by urine amino acid analysis, which reveals markedly elevated levels of neutral amino acids. In contrast, plasma levels of amino acids and niacin are typically normal, despite the clinical resemblance to pellagra. A high-protein diet or protein supplementation can help to prevent symptoms of Hartnup disease, and oral nicotinamide administration (50–300 mg/ day) improves dermatologic and neurologic manifestations.