We report a child initially diagnosed with promethazine-induced dystonia despite a lack of response to diphenhydramine therapy. On further evaluation, the child was diagnosed with glutaric acidemia, type I (GA-I), an autosomal recessive inborn error of metabolism caused by the deficiency of glutaryl-CoA dehydrogenase. The characteristic clinical feature of GA-I is an acute encephalopathic and neurologic crisis typically occurring during a catabolic state. Despite slow improvement, many patients do not fully recover from a neurologic crisis, and residual neurologic morbidity can be significant. Although newborn screening using tandem mass spectrometry is expected to enable presymptomatic diagnosis of GA-I, this patient was not detected by newborn screening with tandem mass spectrometry. Therefore, a high suspicion of GA-I must be maintained in the evaluation of childhood dystonia, even when newborn screening results are reportedly normal.
Glutaric acidemia, type I (GA-I) is an autosomal recessive inborn error of metabolism with an incidence of about 1 in 30 000.1 It is caused by the deficiency of glutaryl-CoA dehydrogenase, an essential enzyme in the catabolism of the amino acids tryptophan, lysine, and hydroxylysine. As a result of this metabolic block, excessive glutaryl-CoA is shunted into alternate metabolic pathways leading to accumulation of the metabolites glutaric acid, 3-hydroxyglutaric acid, and glutarylcarnitine. Like many metabolic disorders, GA-I is often difficult to diagnose because of its nonspecific and intermittent presentation. Typically, patients with GA-I present late in infancy with dystonia, and occasionally acidosis. Postnatal macrocephaly is seen in the majority of affected individuals from late infancy onward. Accurate diagnosis requires metabolic testing, including urine organic acid analysis and, more recently, plasma acylcarnitine analysis. Urine organic acid analysis characteristically reveals elevated glutaric and 3-hydroxyglutaric acids (the latter metabolite is pathognomonic), although the urine organic acid analysis result may be normal in asymptomatic individuals.1 The plasma or blood spot acylcarnitine profile reveals elevated glutarylcarnitine, which also may be intermittent.2 In GA-I and other disorders of metabolism, samples for biochemical testing obtained when the patient is symptomatic are most likely to be informative. Ultimately, deficiency of glutaryl-CoA dehydrogenase may be demonstrated in cultured fibroblasts (skin biopsy) and leukocytes.1,3
Confusion with other, common disorders may delay the diagnosis GA-I, and the differential diagnosis includes trauma (given the presence of subdural hematomas), benign macrocephaly, drug toxicity, and cerebral palsy.4,5 We report here a patient with GA-I presenting at 11 months of age with acute-onset dystonia after gastroenteritis and administration of promethazine.
The patient was born at term via spontaneous vaginal delivery weighing 3409 g. The immediate neonatal period was unremarkable, and she was discharged from the hospital at 24 hours of age. At that time, a pilot study of newborn screening by tandem mass spectrometry (MS/MS) was being conducted in North Carolina, and this patient had an abnormal initial acylcarnitine newborn screen with mildly elevated glutarylcarnitine. A repeat sample appeared to be normal, and according to the state laboratory protocol for evaluation of abnormal newborn screens at that time no additional diagnostic testing was recommended. The patient was breastfed for the first 6 months of life and was weaned to low iron cow's milk-based formula and solid foods without difficulty. She received regular well-child care including scheduled immunizations. Psychomotor development progressed normally: at 11 months of age she had several recognizable words, used crawling for locomotion, and was taking rare steps.
At 11 months of age, she developed symptoms consistent with a viral gastroenteritis including vomiting and diarrhea. She reportedly had adequate fluid intake and urinary output. Promethazine suppositories were prescribed to control vomiting, and 2 doses were given (6.25 mg, 6 hours apart; 0.6 mg/kg/dose). She was found in her crib that evening with dystonic posturing consisting of leftward eye deviation and intermittent stiffness of the left side of her body alternating with extreme hypotonia. No tonic-clonic movements were seen. At the local emergency room, midazolam was administered before loading doses of phenobarbital and phenytoin for presumed new-onset seizures. Evaluation for acute infection was unrevealing; however, ceftriaxone was administered empirically. Serum electrolytes were normal (calcium, phosphorus and magnesium were not measured). A computed tomography scan of the head was reported to show no intracranial lesions or structural abnormalities. Alternating dystonic posturing and hypotonia continued despite anticonvulsant therapy. The patient was transferred to a tertiary care center for hospital admission and additional evaluation.
Physical examination at the time of admission revealed a fussy infant with intermittent left-sided body stiffening and head position preference, and the remainder of the physical examination was unremarkable. Given the apparent lack of clinical response to adequate anticonvulsant therapy, the diagnostic possibility of promethazine-associated dystonia was suspected and treatment with approximately 1 mg/kg intravenous diphenhydramine every 6 hours was started. The patient's dystonia improved slowly during the subsequent 48 hours, although hypotonia with intermittent, sporadic movements, primarily involving the tongue, continued. The patient was discharged from the hospital with a prescription for oral diphenhydramine to treat intermittent episodes of abnormal posturing. Intermittent dystonic movements continued over the next week.
Neurology evaluation 1 week after the initial presentation revealed clinical improvement in muscle tone and voluntary motor control, with residual continuous choreoathetoid movements of the hands, facial dyskinesia, and intermittent stiffening of the legs (Fig 1). Baclofen (Watson Laboratories, Corona, CA) , 5 mg twice a day, was initiated for treatment of spasticity. Additional evaluation for persistent dystonia included urine organic acids that showed modest elevations of glutaric acid and 3-hydroxyglutaric acid, and a plasma acylcarnitine profile (Fig 2) that revealed elevated glutarylcarnitine (ratio to internal standard 0.38, normal <0.11). These abnormalities were consistent with the diagnosis of GA-I. Therapy consisting of restricted protein intake and supplemental riboflavin (100 mg/d) and carnitine (100 mg/kg/d) was initiated when these results became available.
The family history was significant for consanguinity with the patient's parents being second cousins. There was no family history of seizures, movement disorders, birth defects, genetic diseases, or metabolic disorders.
At 1- and 3-month follow-up visits after diagnosis the patient had slow, but steady, improvement in motor skills. The patient's parents reported that she continued to have intermittent abnormal movements of her tongue, right foot, and both hands, especially when fatigued. She laughed, smiled, and vocalized, but had no recognizable words. She had not resumed crawling but did pull to a stand and walk in a walker. Growth parameters, including head circumference, were normal. Physical examination revealed some posturing of the extremities, with no facial grimacing. Reflexes were brisk, without clonus, and there was no spasticity. Follow-up urine organic acids showed a mild elevation of 3-hydroxyglutaric acid. A concurrent plasma acylcarnitine profile revealed elevated glutarylcarnitine with a signal to internal standard ratio of 0.33. Nutritional therapy consisting of restricted tryptophan (10 mg/kg/d) and lysine (60 mg/kg/d) and protein (1.2 g/kg/d) was initiated. Supplemental riboflavin (100 mg/d) and carnitine (100 mg/kg/d) were continued.
A magnetic resonance imaging examination of the brain at 18 months of age revealed subtle linear bands of signal abnormality involving the lateral aspects of the putamen bilaterally, compatible with known GA-I. There was no frontotemporal atrophy or widening of the Sylvian fissures, findings commonly seen in patients with symptomatic GA-I.
The presenting symptoms of this infant, a neurologic crisis late in infancy with dystonia, choreoathetoid movements and hypotonia, is typical for GA-I. Unfortunately, the diagnosis was confounded by the administration of promethazine, another well-documented cause of acute onset dystonia especially in infants and young children. Although it is a phenothiazine, promethazine has significant antiemetic and antihistamine properties and is reported to have very few psychotropic effects. In general, the phenothiazines have well-documented neurologic adverse effects including neuroleptic malignant syndrome, seizures, and extrapyramidal syndromes consisting of acute dystonic reactions, akathisia, akinesia, and tardive dyskinesia.6,7 These adverse effects are more common in younger children (<2 years of age) and when given in relatively high doses. Anticholinergic therapy with 1 or 2 parenteral doses (1 mg/kg given intravenously or intramuscularly) of diphenhydramine reportedly ameliorates promethazine-induced dystonia within 15 to 30 minutes.8Additional childhood medications commonly associated with acute dystonic reactions include the antiemetic and promotility agents cisapride and metoclopramide (Reglan, A. H. Robins Company, Richmond, VA),9 and dextromethorphan.10 The potential toxicity of ingested medications must always be considered with the onset of new symptoms in an ill child.
Fortunately for this patient, alternative diagnoses were considered and appropriate biochemical testing ultimately led to the correct diagnosis, appropriate treatment, and family education regarding GA-I. The additional historical information that her parents were second cousins raised the likelihood of a genetic disorder, as consanguinity is not uncommon in rare, autosomal recessive conditions. A high index of suspicion for disorders of metabolism in children with neurologic crises will ensure the prompt acquisition of metabolic testing and arrival at the appropriate diagnosis.
Individuals with GA-I have signs and symptoms resulting from excess glutaric acid and related metabolites, primarily within the central nervous system. The characteristic clinical feature of GA-I is the acute neurologic crisis typically after a catabolic state such as an acute illness with fever, decreased oral intake, or vomiting. The neurologic crisis is best described as encephalopathic with irritability and lethargy that can progress to coma. Additional neurologic findings may include repetitive movements, seizures, or abnormal posturing. Despite slow improvement, many patients do not fully recover from a neurologic crisis. Residual morbidity can be significant; hypotonia, ataxia, choreoathetoid movements, spasticity, dystonia, and dyskinesia have all been reported.
The most significant physical sign in GA-I is macrocephaly; in fact, macrocephaly may be the only physical sign in otherwise asymptomatic infants. Most commonly, infants develop progressive macrocephaly with markedly accelerated rates of head circumference growth in the first few months of life.11 Not all children with GA-I have macrocephaly; this patient did not.
In patients with GA-I, the main therapeutic goal is to prevent neurologic crises, associated neurologic symptoms, and neurodevelopmental decline. The mainstay of treatment is to reduce the dietary intake of tryptophan and lysine thus reducing stress across the metabolic block caused by the deficiency of glutaryl-CoA dehydrogenase. A dietary prescription typically involves a generalized protein restriction, using age-appropriate foods or formula/breast milk, and use of a supplemental medical formula lacking lysine and tryptophan to provide the recommended daily allowances for the essential amino acids. Additional recommended therapy includes pharmacologic doses of riboflavin (100 mg/d, by mouth), which serves as a cofactor for glutaryl-CoA dehydrogenase and facilitates any residual enzyme activity. In GA-I, dietary therapy and riboflavin supplementation has been shown to significantly reduce the risk of neurologic complications.4 Carnitine supplementation (50–100 mg/kg/d divided twice a day, by mouth) has been shown to increase the urinary excretion of glutaric acid and replenish reduced body carnitine stores.4 During an acute neurologic crisis, additional protein restriction and carbohydrate supplementation are introduced to prevent or reverse endogenous protein catabolism.
The major impetus for early diagnosis of metabolic disorders is the availability of effective therapy. Newborn screening programs that include acylcarnitine analysis by MS/MS hold significant promise for early and presymptomatic detection of a variety of these inborn errors of metabolism.2,12,13 Although the patient described here had an abnormal blood acylcarnitine profile at birth, the repeat specimen was reported to be normal, thus, newborn screening ultimately failed to indicate the diagnosis of GA-I.
Newborn screening is a powerful tool to potentially diagnose presymptomatic infants; however, it should not be considered a diagnostic test. The experience of this case and others has prompted the North Carolina State Laboratory to adjust the signal ratio cutoff for glutarylcarnitine to increase the sensitivity of the newborn screening test for GA-I, and this is now suggested as a general recommendation for laboratories screening for GA-I by MS/MS. To allow presymptomatic diagnosis and treatment of GA-I, we recommend a complete evaluation, including both a plasma acylcarnitine profile and a urine organic acid analysis, of any patient with elevated glutarylcarnitine in a blood spot acylcarnitine profile. A recently developed stable-isotope dilution assay for 3-hydroxyglutaric acid14 in urine by gas chromatography/mass spectrometry shows promise for detection of patients with GA-I, because 3-hydroxyglutaric acid was consistently present in urine of the patients studied. This assay should be considered for additional evaluation of infants with elevated glutarylcarnitine in the newborn screen, when urine organic acids and the plasma acylcarnitine profile are normal. If thorough follow-up evaluations are pursued for infants with abnormalities in newborn screening suggestive of GA-I, additional patients could treated before the onset of symptoms.
- Received July 21, 2000.
- Accepted October 5, 2000.
Reprint requests to (D.D.K.) Division of Medical Genetics, Duke University Medical Center, DUMC 3528, Durham, NC 27710. E-mail:
- GA-I =
- glutaric acidemia, type I •
- MS/MS =
- tandem mass spectrometry
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- Copyright © 2001 American Academy of Pediatrics