Intermittent Dystonia in Hartnup Disease Basil T. Darras , MD*,

Mary G. A m p o l a , MD+,

W i l l i a m H. Dietz , MD, PhD§, and

He r b e r t E. G i lmore , M D *

A 6-month-old girl developed intermittent dystonic pos- ture of the legs and eczematous dermatitis without ataxia. Qualitative and quantitative urine amino acid testing confirmed the diagnosis of Hartnup disease. Cranial computed tomography, electroencephalogram, electromyogram/nerve conduction study, posterior tibial somatosensory evoked potentials, 24-hour electroencephalographic telemetry, and metrizamide myelogram were normal. Spinal fluid hydroxy-in- doleacetic acid concentration was _< 2 S.D. of normal; oral tryptophan loading (70 mg/kg) resulted in a two- fold rise in cerebrospinal fluid 5-hydroxy-indoleacetic acid concentration. Tryptophan administered alone or with nicotinic acid failed to improve the dystonia; how- ever, trihexyphenidyl (1-2 mg/kg/day) dramatically im- proved it. Hartnup disease should be considered in chil- dren with unexplained dystonia.

Darras BT, Ampola MG, Dietz WH, Gilmore HE. Inter- mittent dystonia in Hartnup disease. Pediatr Neurol 1989; 5:118-20.

Introduction

Hartnup disease (HD) is an autosomal recessive condi- tion characterized by a defect in renal and intestinal membrane transport of monoamino-monocarboxylic acids [1]. Decreased renal tubular reabsorption results in an in- crease in urine concentration of these amino acids and a characteristic urine amino acid chromatographic pattern which provides the only accurate diagnostic test for HD. As a result of both decreased intestinal absorption and renal tubular reabsorption, the serum concentration of many amino acids may be decreased. It appears that HD is main- ly an asymptomatic disorder unless there is inadequate nutrition in the patient [2]. The usual clinical manifestations of rare symptomatic HD are intermittent pellagra-like skin

rash, reversible attacks of cerebellar ataxia, and occasional- ly behavioral changes, ranging from emotional instabililv to psychosis and delirium. Some patients are mildly retarded [ 1 ].

We report a patient with HD presenting early in life with intermittent dystonia. To our knowledge, dystonia has not been previously described as a presenting manifestation of HD.

Case Report

A 17-month-old girl was referred for evaluation of frequent, brief episodes of leg "tightening" which had been occurring since 6 months of age. Her right leg would stiffen and flex at the knee and hip, her right foot would plantar-flex and invert, and her left leg would rotate inwardly and hyperextend. There was no change in mental status during the episodes which occurred only during wakefulness, mainly when in a recumbent position. The parents are of Polish descent and there is no consanguinity or family history of a movement disorder. The pregnancy and delivery were uncomplicated; psychomotor development was nor- mat. Physical examination disclosed a patchy eczematous dermatitis involving mainly areas exposed to sunlight. During the episodes of tightening, her right leg could not be straightened by the examiner.

At 18 months of age, the parents observed that she dragged her left leg while walking. Physical examination at that time revealed hyperreflexia of the lower extremities with normal muscle tone and mild leg weak- ness. Contrast-enhanced cranial computed tomography (CT) scan, electroencephalogram (EEG), nerve conduction studies, electromyo- gram, and metrizamide myelogram were normal. The diagnosis of idiopathic dystonia was made. By 20 months of age, the dystonic episodes occurred more frequently (20-30 per day) and lasted longer (up to a few minutes). Random-sample urine amino acid paper chromatog- raphy was diagnostic of HD. Measurement of 24-hour urine amino acid excretion revealed a marked increase in excretion of almost all neutral amino acids. Serum amino acid concentrations (i.e., threonine, gluta- mine, proline, alanine, methionine, and lysine) were either normal or slightly elevated. The urinary niacin metabolites 2-pyridone (2-PY) and N-l-methylnicotinamide (N-I-MN) both were decreased but their ratio (2-PY/N-1-MN) was normal (2-PY: 1.5 mg/24 hr: N-1-MN: 0.4 mg] 24 hr; 2-PY/N-I-MN: 3.8; normal: 6.0-51 mg/24 hr: 1.6-14.8 mg/24 hr; and 1.8-5.9, respectively). Urine organic acids and serum lysosomal en- zymes, including arylsulfatase A, galactocerebrosidase, [~-gatactosidase, and [~-N-acetylhexosaminidases A and B, were normal. Blood count and serum electrolytes were normal. Cerebrospinal fluid (CSF) concentra- tions of glucose and protein were 61 mg/dl and 12 mg/di, respectively.

At age 22 months, nicotinic acid was administered, the dosage of which was gradually increased to 300 mg daily with resolution of the ec- zema; however, no change occurred in the pattern or frequency of dys- tonia. Mild erythema, reported early in the course of nicotinic acid treat- ment, resolved spontaneously and did not recur at higher doses. Oral tryptophan 70 mg/kg was administered in 5 doses over 24 hours in an attempt to increa~ brain tryptophan concentrations. CSF 5-hydroxy- indoleacetic acid (5-HIAA) concentration, which was measured prior to tryptophan and 3 hours after the last dose (10 mg/kg), increased by al- most two-fold (pre-dose: 7. I ng/ml; post-dose: 13.8 ng/ml). Tryptophan given orally (60 mg/kg/day) for 2 months, alone or with nicotinic acid, failed to improve her neurologic symptoms or signs.

At age 30 months, she had normal contrast-enhanced Cq, EEG, posterior tibial somatosensory evoked potentials (SSEPs). and 24-hour

From the *Division of Pediatric Neurology, *Pediatric Amino Acid Laboratory, and §Division of Gastroenterology and Nutrition; Department of Pediatrics; Boston Floating Hospital; New England Medical Center Hospitals and Tufts University School of Medicine; Boston, Massachusetts.

Communications should be addressed to: Dr. Darras; Division of Pediatric Neurology; New England Medical Center Hospital; 750 Washington Street; Boston, MA 02111. Received December 29, 1988; accepted February 22, 1989.

118 PEDIATRIC NEUROLOGY Vol. 5 No. 2

EEG telemetry. Tryptophan was increased to 100 mg/kg/day, given with carbohydrate-rich meals without improvement. This treatment sub- sequently was di~ontinued and trihexyphenidyl (Artane ®) therapy 1 mg/kg/day begun. Dramatic improvement was observed 7 days after the initiation of this treatment (1 mg/kg/day). She currently is 6 years, 10 months of age and continues to have occasional dystonic posture of the left leg, but not as frequent or severe as prior to treatment. She has persistent hyperreflexia of the lower extremities and there is no ataxia. Serial psychometric evaluations have revealed slightly declining IQ scores over a 3-year period from high average (Full-Scale IQ [FSIQ]: 112 at age 3 years, 2 months) to values slightly below the midpoint of the average range (FSIQ: 99 at age 6 years, 3 months). She currently is treated with trihexyphenidyl 40 mg/day (2 mg/kg/day) and nicotinic acid 300 mg/day (15 mg/kg/day).

Discussion

Baron et al. described the first patient with Hartnup dis- ease and reported recurrent episodes of a pellagra-like skin rash, cerebellar ataxia, pyramidal tract signs, and progres- sive dementia [3]. This patient's sister had similar rash and ataxic episodes, but no permanent neurologic abnor- malities. The clinical courses of 3 patients reported by Tahmoush et al. differed from those of the index cases [4]. These patients had progressive cerebellar ataxia, early onset of dementia, spasticity, and choreoathetosis resulting in severe and permanent neurologic deficits. Two of these patients had dystonic posturing of the trunk late in the course of the disease. Our patient's clinical course is quite different. Dystonia was the first sign of disease; it has remained intermittent and focal, confined to the lower ex- tremities with normal muscle tone between episodes of im- pairment. Pyramidal tract findings in our patient, first ob- served 12 months after the onset of dystonia, have been mild and nonprogressive. Cerebellar ataxia has not been ob- served and her cognitive development has declined only slightly.

The central nervous system (CNS) has been examined pathologically in only 2 patients with severe HD [4,5]. Among other findings, there was generalized brain atrophy, most marked in the cerebellum, with loss of Purkinje cells and thinning of the granular cell layer. Although both patients had prominent extrapyramidal signs, no structural abnormalities were found in the basal ganglia. Our patient had 2 contrast-enhanced CT scans performed 1 year apart; both failed to reveal any abnormalities in the basal ganglia. This lack of a structural defect suggested that biochemical or metabolic abnormalities in the extrapyramidal system may be the cause of dystonia.

In patients with dystonia, evidence of disordered neurotransmission in the basal ganglia is based on induc- tion of dystonia by neuroleptics and its improvement by certain drugs. Anticholinergic, dopaminergic, and sero- tonergic drugs have been used successfully in treating a number of patients with various types of dystonia [6,7], sug- gesting that the pathways affected by these drugs are in- volved in the etiology of dystonia. Oral tryptophan, the serotonin precursor, was administered to our patient in an attempt to increase the brain serotonin content because decreased pre-tryptophan CSF HIAA concentration indi-

cated possible decreased CNS serotonin concentration. The increase in CSF 5-HIAA concentration after oral trypto- phan suggests that tryptophan entered the CNS and was me- tabolized to serotonin. This finding may be evidence that large oral doses of tryptophan can partially overcome the presumed defect in neutral amino acid transport into the CNS which has been postulated as an explanation for the neuropsychiatric manifestations of HD [5].

Despite high-dose tryptophan given with meals rich in carbohydrates, which are known to induce an increment in brain tryptophan, serotonin, and 5-HIAA [8-10], our patient's dystonia failed to improve significantly. The reason for this lack of improvement is unknown, but several explanations can be offered. First, higher doses of tryp- tophan may have been needed to raise the brain serotonin concentration to normal. The two-fold increase in CSF HIAA concentration after tryptophan is significant, but the absolute HIAA concentration was still below the normal range for her age. Normal CSF 5-HIAA concentration in children 1-2 years of age is 44.95 + 20.12 ng/ml (mean: + 1 S.D.) [11]; our patient's post-tryptophan CSF 5-HIAA concentration was only 13.8 ng/ml. Second, a neurotrans- mitter other than serotonin may be affected in HD and therefore tryptophan would not be expected to improve any of her neurologic deficits. Finally, the dystonia may be in- dependent of HD.

Unfortunately, the diagnosis of HD was ascertained retrospectively in our patient, after the onset of neurologic symptoms; free mass-screening of newborn urine for amino acid disorders was discontinued in Massachusetts the year our patient was born. This lack of information makes it dif- ficult to establish a cause-and-effect relationship between HD and dystonia. Nonetheless, we speculate that there in- deed is a relationship between the metabolic derangements of HD and dystonia in our patient. Without this connection, an idiopathic cause would have to explain her dystonia and other extrapyramidal abnormalities previously reported in other HD patients [4,5]. It would appear unlikely that ex- trapyramidal abnormalities are independent of HD, whereas the pyramidal, cerebellar, and cognitive abnor- malities, which are hallmarks of the disease, are attributable to HD. In addition, a careful review of her family, birth, and other medical histories did not reveal any obvious cause of dystonia.

We conclude that our patient's intermittent dystonia is due to HD, perhaps related to an unidentified abnormality of central neurotransmission. We recommend that HD be considered in children with unexplained dystonia, especial- ly when it is associated with a photosensitive, eczematous skin rash.

The authors thank Dr. John Growdon (Department of Neurology, Massachusetts General Hospital) for spinal fluid HIAA determinations and Dr. Richard J. Wurtman (Program Director, Clinical Research Center, Massachusetts Institute of Technology) for his advice in the dietary management of our patient.

Darras et al: Hartnup Disease 119

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