This amino acid disorder, named after the family in which it was first observed, is probably transmitted in an autosomal recessive pattern. The babies are normal at birth. The onset of symptoms is in late infancy or early childhood. The clinical features consist of an intermittent red, scaly rash over the face, neck, hands, and legs, resembling that of pellagra. It is often combined with an episodic personality disorder in the form of emotional lability, uncontrolled temper, and confusional-hallucinatory psychosis; episodic cerebellar ataxia (unsteady gait, intention tremor, and dysarthria); and, occasionally, spasticity, vertigo, nystagmus, ptosis, and diplopia. Attacks of disease are triggered by exposure to sunlight, emotional stress, and sulfonamide drugs and last for about 2 weeks, followed by variable periods of relative normalcy. The frequency of attacks diminishes with maturation, but some children suffer retarded growth and development with a mild persistent mental retardation.
The metabolic faults are the result of a transport error of neutral amino acids across renal tubules, with excretion of greatly increased amounts of these amino acids in the urine and feces. In particular, there is the excretion of large amounts of indicans, mainly indoxyl sulfate, particularly after oral l-tryptophan loading, and an abnormally high excretion of nonhydroxylated indole metabolites. Impaired intestinal transport of tryptophan and loss in the urine reduce its availability for the synthesis of niacin and accounts for the pellagrous skin changes. The pathologic basis of the disease is undetermined. It must be differentiated from the large number of intermittent and progressive cerebellar ataxias of childhood, described below.
Treatment consists of avoiding exposure to sunlight and to sulfonamide drugs. Because of the similarities between pellagra and Hartnup disease, the usual practice is to give nicotinamide in doses of 50 to 300 mg daily. The skin lesions disappear and there are reports of subsidence of ataxia and psychotic behavior. However, the results of treatment are inconsistent. Possibly a better response is obtained by the administration of l-tryptophan ethyl ester in doses of 20 mg/kg tid.
Other Metabolic Diseases With Episodic or Persistent Ataxia, Seizures, and Developmental Delay
In addition to Hartnup disease, a number of other metabolic diseases give rise to intermittent episodes of ataxia during early childhood. These are (1) mild forms of maple syrup urine disease and the congenital hyperammonemias (type II hyperammonemia, citrullinemia, argininosuccinic aciduria, hyperornithinemia), described in an earlier part of the chapter; (2) subacute necrotizing encephalomyelopathy (Leigh disease), described further on; (3) hyperalaninemia and hyperpyruvic acidemia (Lonsdale et al; Blass et al); and (4) autosomal dominant, acetazolamide-responsive ataxia that may have its onset in childhood but usually appears later (see Griggs et al); and (5) familial hypobetalipoproteinemia—Bassen-Kornzweig disease.
In all of these conditions, the ataxia, which is of cerebellar type, is variable from time to time and may follow a burst of seizures (such as occur in argininosuccinic aciduria). The seizures are treated with antiepileptic drugs, which may at first be held responsible for the ataxia. In time, however, it becomes apparent that the ataxia lasts a week or two and bears no relation to the anticonvulsant therapy. Indeed, seizures and ataxia are both a result of the common biochemical abnormality. Between attacks, in all the intermittent ataxias, the patient’s movements are relatively normal, but most of the affected children have learning disabilities to a varying degree.
Progressive Cerebellar Ataxia of Early Childhood