Hartnup Disease

The disease was first described in London in 1956,¹ affecting 4 of 8 members of the Hartnup family.

It is caused by a failure of the transport of tryptophan and other amino-acids in the small intestine² and the renal tubules. Amino-acids remain in the gut where bacteria convert them to indolic compounds that are toxic to the CNS. Tryptophan is converted to indole.

Renal tubular transport is defective and causes gross aminoaciduria. This loss of amino-acids plus poor absorption from the gut causes protein malnutrition. Abnormal tryptophan transport leads to niacin deficiency.

The mutation is on chromosome locus 5p.15.33. Heterozygotes have no abnormality.

It is an autosomal recessive condition that occurs in about 1 in 24,000 with no difference between sexes or races. It is one the commonest disorders of aminoaciduria. Many are asymptomatic.

There is a wide clinical spectrum but most patients are asymptomatic.³ There are a number of mutations that have been described and this may explain, at least in part, the clinical heterogenicity. The amount of protein in the diet is probably important too. Rarely, severe CNS involvement causes death. Mental retardation and short stature have been described occasionally.

It usually presents between 3 and 9 years old but can present a few weeks after birth.

Symptoms

• Most children are asymptomatic.
• Episodes of neurological and dermatological problems progress for several days and last from a week to a month before spontaneous remission.
• Skin problems usually precede neurological features.
• Psychiatric symptoms including anxiety, emotional instability and changes of mood are common in patients with other symptoms. Psychotic episodes and delirium are rare.

Signs

• Photosensitivity occurs and the skin becomes red after exposure to sunlight. Further exposure leads to dry, scaly, well-marginated eruptions, sometimes resembling chronic eczema. These eruptions tend to affect the forehead, cheeks, periorbital regions, the dorsum of the hands, and other light-exposed areas.
• Lesions on the face may be similar to the butterfly rash of lupus erythematosus.
• Skin changes cause permanent hypopigmentation and/or hyperpigmentation, being intensified with further exposure to sunlight.
• Mental development is usually normal, but mild learning difficulties (IQ 50 to 70) is described in a few patients.
• Neurological symptoms may vary and are fully reversible. Intermittent cerebellar ataxia, a wide-based gait, spasticity, delayed motor development, and tremulousness are the most frequent findings. Headaches and hypotonia may also occur.
• Ocular manifestations include diplopia, nystagmus, photophobia, and strabismus.
• Gingivitis, stomatitis, and glossitis suggest niacin deficiency.
• Diarrhoea occasionally precedes or follows attacks of the disease.
• Short stature has been described but is not marked.

Skin

• Xeroderma Pigmentosum.
• Infantile atopic eczema or seborrheic eczema.
• Nutritional pellagra (Urine chromatography will not show amino-acids).
• Congenital poikiloderma with photosensitivity (eg, Cockayne syndrome).
• Butterfly rash of discoid lupus erythematosus or systemic lupus erythematosus.
• Carcinoid syndrome can disturb tryptophan metabolism and pellagra-like rash.

Nervous system

• Ataxia-telangiectasia can be difficult to distinguish, especially if skin involvement is mild.
• Systemic lupus erythematosus can be confused if there is photosensitivity and neuropsychiatric symptoms.
• Other ataxias with biochemical and genetic defects.

A study in Cape Town looked for biochemical disorders in those in an institution for the mentally retarded.⁴ Of the 1087 tested, the results were positive in only 0.6%. There were 3 cases of phenylketonuria, 2 of cystinuria and 1 of Hartnup disease.

• Urine chromatography shows increased levels of neutral amino acids.
• Urinary 5-hydroxyindoleacetic acid may be found after an oral tryptophan load.
• Urine excretion of proline, hydroxyproline, and arginine is normal,⁵ unlike other causes of gross aminoaciduria.
• Jejunal biopsy may be required in a few patients to detect the transport defect in vitro.
• Skin biopsy may rarely be required.

Non-Drug

• A high-protein diet is beneficial. Poor nutrition leads to more frequent and more severe attacks. Otherwise the condition is usually asymptomatic.
• Especially if there are dermatological symptoms, patients should cover up in sunlight and use sun protection cream of SPF15 or more.
• Neurological and psychiatric treatment is needed if there is severe CNS involvement.

Drugs

Nicotinic acid or nicotinamide at 50 to 300 mg daily provides relief from both the skin and neurological manifestations.

• Severe CNS involvement may rarely be fatal in the first years of life.
• Psychotic episodes and delirium occur in a few patients.
• Mild mental retardation is uncommon.
• Permanent hypopigmentation and/or hyperpigmentation of the skin occur with repeated exposure to sunlight.

Maternal Hartnup disease, unlike phenylketonuria, does not have an adverse effect on the fetus.⁶

Malnutrition and a low-protein diet increase morbidity. Attacks become less frequent with increasing age.

Educate patients to protect themselves from sunlight, to avoid other aggravating factors, and to consume a high-protein diet.