Hartnup Disease

Hartnup disease or disorder is an autosomal recessive metabolic disorder effecting the transport of neutral amino-acids in the kidney and gut. It was first described in London in 1956,¹ afflicting 4 of 8 Hartnup family members.

Tryptophan and other neutral amino-acids are not absorbed in the small intestine² and are converted by gut bacteria convert to indolic compounds that are toxic to the CNS. Renal tubular transport is defective and causes gross aminoaciduria. The renal loss of amino-acids plus poor absorption from the gut causes protein malnutrition. Abnormal tryptophan transport leads to niacin deficiency or pellagra.

The mutated gene (SLC6A19) is located on chromosome locus 5p.15.33 and is known to encode an abnormal neutral amino-acid transporter.³ Heterozygotes have no abnormality.

It is a rare 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.

• There is a wide clinical spectrum but most patients are asymptomatic.⁵
• Symptoms are often intermittent. Exacerbations may be provoked by:
  • Change of season - northern hemisphere spring/summer with increasing sunlight
  • Febrile illness
  • Poor nutrition
  • Increased physical activity
  • Sulfonamides
• One study found that over 40% unrelated cases in North America and Australia shared the same mutation, which is thought to have derived from a common ancestor over 1,000 years ago.⁶ It is postulated that the persistence of this allele may be due to its failure to completely inactivate the amino-acid transporter.
• Other mutations have been described and this may explain, at least in part, the clinical heterogenicity.⁷
• Additional phenotypic variability may also have environmental causes e.g. the amount of protein in the diet (increasing dietary protein is protective).

Symptoms

• Symptoms tend to arise between 3-9 years, although sometimes in infancy. It occasionally presents in adults.⁸
• 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. Psychosis and delirium are rare.

Signs

• Photosensitivity occurs and the skin becomes red after exposure to sunlight. Continuing exposure leads to dry, scaly, well-delineated 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, made worse by further exposure to sunlight.
• Mental development is usually normal, but mild learning difficulties (IQ 50-70) is described in a few patients.
• Neurological symptoms may vary and are fully reversible. They include:
  • Intermittent cerebellar ataxia
  • Wide-based gait
  • Spasticity
  • Delayed motor development
  • Tremor
  • Headaches
  • Hypotonia
• 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 (e.g. Cockayne syndrome)
• Butterfly rash of discoid lupus erythematosus or systemic lupus erythematosus (SLE)
• Carcinoid syndrome (disturbs tryptophan metabolism and may cause a pellagra-like rash)

Nervous system

• Ataxia-telangiectasia
• SLE
• Other ataxias with biochemical and genetic defect

• 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,⁹ 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

• High protein diet
• Avoidance of sunlight and use of sun protection
• Neurological and psychiatric treatment where CNS involvement

Drugs

Nicotinic acid or nicotinamide at 50 to 300 mg daily can provide remission 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.¹⁰

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.