Thiamine-responsive intermittent branched-chain ketoaciduria

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An intriguing feature of acquired autonomic dysfunction syndromes is their relationship to other motility abnormalities of the gastrointestinal tract, such as idiopathic pseudoobstruction syndrome. Maldonado et al 9 described three examples of idiopathic pseudoobsiruction syndrome in which sweating abnormalities were present. Schuffler and Pope TM have demonstrated esophageal motility abnormalities that are similar to those in our patient and in patients with familial dysautonomia. The radiographic features of the esophagus in our patient were also similar to previously described examples of idiopathic pseudoobstruction syndrome.H The autonomic dysfunction present in this child supports the possible etiology of neurogenic disease as a cause of motility disorders of the gastrointestinal tract. An extensive evaluation of autonomic function is indicated in these patients. REFERENCES 1. Axelrod FB, Nachtigal R, and Dancis J: Familial dysautonomia: diagnosis, pathogenesis and management, Adv Pediatr 21:75, 1974. 2. Arndorfer RC, Stef JJ, Dodds WJ, et al: Improved infusion

The Journal of Pediatrics April 1979

3.

4.

5. 6. 7. 8.

9.

10.

11.

system for intraluminal esophageal manometry, Gastroenterology 73:23, 1977. Fryer DG: Diseases of the autonomic nervous system-a review and report of a unique case, Bull Mason Clin 27:25, 1973. Giflow SE, Bertani LM, Wilk E, et al: Excretion ofcatecholamine metabolites by children with familial dysautonomia, Pediatrics 46:5!3, 1970. Yahr MD, and Frontera AT: Acute autonomic neuropathy, Arch Neurol 32:132, 1975. Hopkins A, Neville B, and Bannister R: Autonomic neuropathy of acute onset, Lancet 1:769, 1974. Grunebaum M: Radiologieal manifestations in familial dysautonomia, Am J Dis Child 128:176, 1974. Brunt PW, and McKusick VA: Familial dysautonomia: a report of genetic and clinical studies with a review of the literature, Medicine 49:343, 1970. Maldonado JE, Gregg JA, Green PA, et al: Chronic idiopathic intestinal~pseudo-obstruction, Am J Med 49:203, 1970. Schuttter MD, and Pope CE: Esophageal motor dysfunction in idiopathic intestinal pseudoobstruction, Gastroenterology 70:677, 1976. Schuflter MD, Rohrmann CA, and Templeton FE: The radiologic manifestations of idiopathic intestinal pseudoobstruction, Am J Roentgenol 127:729, 1976.

Thiamine-responsive intermittent branched-chain ketoaciduria Siegfried M. Pueschel, M.D., M.P.H.,* Michael J. Bre~aan, M.D., Vivian E. Shih, M.D., and Harvey L. Levy, M.D., Providence, R.I., and Boston, Mass.

A s I D E from the classical type of branched-chain ketoaciduria, several variant forms have been identified and classified as intermittent, mild (intermediate), and thiamine-responsive BCKA? -~~Children with the intermittent form usually do not become symptomatic during the newborn period. However, in the presence of an increased protein intake or an exaggerated catabolic state due to an intercurrent illness, the branched-chain amino acids and their keto acid analogues may accumulate in large quantities and lead to lethargy, ataxia, and vomiting. The following report will highlight clinical investigations, biochemical studies, and dietary management of a patient with the intermittent form of BCKA. From the Department of Pediatrics, Rhode Island Hospital, Section of Reproductive and Developmental Medicine, Brown University, and the Department of Pediatrics and Neurology, Harvard University. *Reprint address: Child Development Center, Rhode Island Hospital, 593 Eddy St., Providence,RI 02902.

CASE REPORT Patient P.G., a 4-year-old white boy, was the product of an uncomplicated, term pregnancy. He was born out of wedlock to a gravida 2, para 1, 26-year-old mother. Labor, delivery, and neonatal period were uneventful.

Abbreviation used BCKA: branched-chain ketoaciduria The patient's early psychomotor development was normal. At 13 months of age the parents began to observe a right head tilt, some unsteadiness in walking, uncoordinated motor behavior, and intermittent irritability. Shortly thereafter, he was admitted to a local hospital. A neurologic work-up was essentially unrevealing. A diagnosis of acute cerebellar ataxia was made and a short course of steroids was administered. After initial slight improvement, the patient continued to regress. Soon he was unable to walk, sit, or follow simple commands. He became increasingly drowsy and hypotonic. He had decreased use of his

0022-3476/79/400628 +04500.40/0 9 1979 The C. V. Mosby Co.

Volume 94 Number 4

Brief clinical and laboratory observations

629

,0,/2

mg/dl

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Fig. L Leucine loading studies (50 mg/kg), with o - - - o administration. upper extremities and occasional "staring spells" were Observed. Subsequently, the patient was transferred to Children's Hospital Medical Center in Boston. Upon admission he had marked truncal ataxia. Frequent vertical and pendular horizontal conjugate movements of the eyes were noted. We also observed mild ptosis, and expressionless facies with drooling, increased muscle tone, brisk deep tendon reflexes, and a positive Babinski sign bilaterally. Extensive neur01ogic investigations, including skull radiographs, sonar scans~ nerve conduction studies, aryl sulfatase, and vanillmandelic acid determinations, lumbar puncture, and repeat electroencephalogram, did not uncover any significant abnormality. Right carotid and bilateral vertebral arteriography showed a questionable enlarged midbrain. Biochemical investigations as well as bacterial, viral, and immunologic studies were all normal except the urine amino acid chromatography, which revealed a marked increase in ieucine, isoleucine, and valine, suggesting a disturbance in branchedchain amino acid metabolism. METHODS Samples of the patient's urine were examined by two-dimensional paper chromatography and by ionexchange chromatography with a Beckman 12 1 M amino acid analyzer. Skin biopsy was obtained from the right

f~

24 hours

and without x-x, thiamine hydrochloride (10 mg)

l o w e r forearm and fibroblasts were grown in Eagle (MEM) medium. Enzyme assays were performed on skin fibroblasts grown on tissue culture. RESULTS Two separate loading tests with L-leucine (50 mg/kg) were administered. The first study was performed without the addition of thiamine hydrochloride. During the second study l0 mg of thiamine hydrochloride was administered together with the leucine. Fig. 1 demonstrates the results of the two leucine challenges, which suggest that thiamine in large amounts enhanced the oxidative decarboxylation of the keto acids. The next step in the investigation was directed toward finding the most suitable diet for the patient which could be safely utilized in the home environment, and which would prevent accumulation of branched-chain amino acids and neurologic impairment. At three separate time periods, the patient was given a diet with a protein content that was low (1.5 gm/kg), medium (3.0 gm/kg), or high (4.5 gm/kg). The diets with low- and medium-protein content were well tolerated. However, while on a highprotein diet, the patient again became symptomatic; he

630

Brief clinical and laboratory observations

The Journal of Pediatrics April 1979

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Fig. 2. Leucine x-x, valine o --- o, and isoleucine A . . . . A serum concentrations dunng periods of low 0.5 gm/kg), medium (3.0 gm/kg), and high (4.5 gm/kg) protein intake. appeared drowsy and slightly ataxic. The branched-chain amino acid concentrations in serum during the three study periods are shown in Fig. 2. Psychologic assessment using the form board of the Merrill-Palmer and selected items from the Bayley Scale of Infant Development indicated the presence of average psychomotor function. The enzyme studies o f skin fibroblasts showed 4.5% of normal ability to produce radioactive COs from 1-1'CDL-leucine. DISCUSSION The clinical information, as weU as the special investigations described above, suggest that our patient has the intermittent form of BCKA, which is at least partially responsive to thiamine. The past medical history documents the intermittent nature of our patient's disorder. Acute intercurrent illnesses and increased protein intake had led to neurologic impairment and increase in the branched-chain amino acid concentration. After the administration of thiamine hydrochloride, prompt clinical and biochemical improvement was observed. It would seem that this is the first patient with intermittent BCKA

reported to be thiamine responsive. The only other example of BCKA reported to be responsive to thiamine was an intermediate variant.* It is important that the diagnosis of the intermittent form of BCKA be made promptly, since if unrecognized and untreated it may be life-threatening 3, 6.9 or may cause mental retardation. ~-~ ' During the evaluation of patients presenting with cerebellar ataxia, lethargy, somnolence, and vomiting, one should examine blood and urine for branched-chain amino acids. The astute clinician will not fail to detect the conspicuous sweet maple syrup odor in the urine of most of these patients. These findings, together with a positive test for ketone bodies in the urine and a negative test result for glucose and other reducing substances, should suggest a possible defect in the BCKA metabolism. Although the latter tests might not always be helpful, 7 a simple urine and serum amino acid chromatographic amino acid analysis will assist in further identification of a possible inborn error of branched-chain amino acid metabolism. Early identification and appropriate individualized dietary management of patients with the intermittent form of BCKA will prevent secondary central nervous 6ystem insult.

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B r i e f clinical a n d laboratory observations

REFERENCES 1. Dancis J, Hurzler J, Snyderman SE, and Cox RP: Enzyme activity in classical and variant forms of maple syrup urine disease, J PEDIATR81:312, 1972. 2. Fischer MH, and Gerritsen T: Biochemical studies on a variant of branched-chain ketoaciduria in a 19-year-old female, Pediatrics 48:795, 1971. 3. Goedde HW, Langenbeck U, Brackertz D, Keller W, Rokkones T, Halvorsen S, Kill R, and Morton B: Clinical and biochemical-genetic aspects of intermittent branchedchain ketoaciduria, Acta Paediatr Scand 59:83, 1970. 4. Gompertz D, and Draffan GH: The gas-chromatographic diagnosis of intermittent maple syrup urine disease (branched-chain ketoaciduria), Clin Chim Acta 40:5, 1972. 5. Irwin WC, Martel SB, and Goluboff N: Intermittent branched-chain ketonuria (variant of maple syrup urine disease), Clin Biochem 4:52, 1971.

63 1

6. Morris MD, Fisher DA, and Fiser R: Late-onset branchedchain ketoaciduria (maple syrup urine disease), J Lancet 86:149, 1966. 7. Scriver CR, Mackenzie S, Clow CL, and Delvin E: Thiamine-responsive maple-syrup-urine disease, Lancet 1:310, 1971. 8. Steen-Johnsen J, Vellan EJ, and Gjessing LR: Maple syrup urine disease variant amino acid patterns and problems of treatment during acute attacks, Acta Paediatr Scand 59:71, 1970. 9. Valman HB, Patrick AD, Seakins JWT, Platt JW, and Gompertz D: Family with intermittent maple syrup urine disease, Arch Dis Child 48:225, 1973. 10. Van der Horst JL, and Wadman SK: A variant form of branched-chain ketoaciduria, Acta Paediatr Scand 60:594, 1971.

Severe hyponatremia in congenital hypothyroidism Carlos Robles-Vald6s, M.D.,* Jaime A. Ramirez Mayans, M.D., and Jos6 I. Alclntara Lomeli, M.D., Mexico City, Mexico

THE ASSOCIATIO~q of hypothyroidism with hyponatremia and disturbances of water metabolism is well known. There are at least four previous reports of an association between the syndrome of inappropriate antidiuretic hormone secretion and h y p o t h y r o i d i s m - a l l of them ocurring in elderly people. 1 We report the occurrence o f severe hyponatremia in an infant with congenital hypothyroidism. CASE R E P O R T A 21/2-month-old girl was admitted to the Emergency Room with a history of failure to thrive, hypothermia, coarse cry, and constipation since birth. Examination disclosed height and weight below the third percentile, temperature 35.5~ and classic findings of congenital hypothyroidism. Initial laboratory tests showed a serum sodium concentration of 115 mEq/l. The diagnosis of hypothyroidism was confirmed by a bone age less than 36 weeks of gestation, thyroid scan with absent uptake of technetium 99, and high thyroid-stimulating hormone (40 uU/ml RIA) low protein-bound iodine (2.6 #g/dl), low tri-iodothyronine (2 ng/ml radioimmunoassay), and low thyroxine (5/tg/dl) values. Abnormal renal and adrenal functions were ruled out, based upon normal concentrations of blood urea nitrogen and creatinine, normal AM and PM plasma cortisol values, and urinary pregnanetriol excretion of 0.02 mg/24 hours. From the Hospital del Niho., D.I.F. *Reprint address: Servicio de Endocrinologla, Hospital del Niho, D.I.F., Av. Insurgentes Sur 3700-C, Mexico City, 20, D.F., Mexico.

0022-3476/79/400631 +02500.20/0 9 1979 The C. V. Mosby Co.

While waiting for test results, the infant was treated with a standard formula 150 ml/kg and thyroglobulin (16 to 32 mg/ day). As is seen in the Table, low serum sodium values persisted for at least six days, as well as low serum osmolality combined with a disproportionate high urinary specific gravity and high urinary sodium excretion. By day 13, serum sodium concentration was normal. Because the diagnosis of a possible syndrome of inappropiate antidiuretic hormone secretion was not suspected earlier, no other metabolic studies were done. DISCUSSION A b n o r m a l renal function and hyponatremia occur in hypothyroidism, with a reduction in glomerular filtration, limited ability to excrete water, and lower than normal creatinine clearance; tubular transport capacity, measured by diodrast or p-aminohippufic acid, is consistently below normal. Most authors agree on the dilutional nature of the hyponatremia. 2 Since circulating A D H levels could not be measured until very recently, direct confirmation of the presence of excessive antiduretic hormone in our patient is lacking. Based on metabolic balance studies, the presence o f syndrome of inappropriate antidiuretic hormone secretion has been questioned in hypothyroidism, 3 but studies in thyroidectomized sheep, using a very sensitive radioimmunoassay for antidiuretic hormone, reveal basal levels four times higher and production rates 12 times higher than in control animals.'