Hypoparathyroidism in mitochondrial trifunctional protein deficiency

The Journal of Pediatrics Volume 129, Number 1

be involveds and were demonstrated by our patients' responses to cardiovascular testing. We included SAECG and measurement of the QTc in our cardiovascular assessment because both have been shown to be modified by autonomic perturbations. 9-11 The duration of the tQRS complex derived from SAECG can be modified by autonomic stiinulation and blockade in healthy subjects. 9 Tilt causes the tQRS to shorten. In patients with decreased sympathetic innervation, including those with idiopathic long QT syndrome and familial dysantonomia, abnormal prolongation of the QTc interval (greater than 440 msec) has been reported. 1°' 11 Therefore a lack of normal shortening or an increase in the tQRS complex with tilt or QTc prolongation would suggest autonomic dysfunction, especially low sympathetic tone. Neither of our patients had abnormal SAECG results or prolongation of the QTc. Time domain analysis ofHR variabilityallows assessrnent of parasympathetic and sympathetic tone. The SD (mean of all 5-minute SDs of R-R intervals) and the index of SDs of means of 5-minute pefiods ofR-R intervals (SDANN index) are more sensitive to lower or sympathetic frequencies. The pNNs0 is sensitive to the highest-frequency components of HR variability, with larger numbers suggesting increased parasympathetic activity.12 Both patients had extremely low pNNs0 values not altered by a&aainistration of bethanechol, suggesting a preganglionic cholinergic lesion. 13 A predominant cholinergic lesion was further supported by responses to tilt. Although the patients exhibited oväaostatic hypotension, they had compensatory tachycardia, indicating continuing sympathetic responses. In conclusion, we suggest that many features of Allgrove syndrome, including autonomic failure, pyramidal and extrapyramidal tract involvement, brain-stem dysfunction, and peripheral neuropathy, can be explained by a progressive loss of cholinergic function.

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REFERENCES

1. Allgrove J, Clayden GS, Grant DB. Familial glucocorticoid deficiency with achalasia of the cardia and deficient tear production. Lancet 1978;1:1284-6. 2. Moore PS, Couch RM, Perry YS, Shuckett EP. Allgrove syndrome: an autosomal recessive syndrome of ACTH insensitivity, achalasia and alaerima. Clin Endocrinol 1991 ;34:107-14. 3. Geffner ME, Lippe BM, Kaplan SA, et al. Selective ACTH insensitivity, achalasia and alacrima: a multisystem disorder presenting in childhood. Pediatr Res 1983;17:532-6. 4. E1-Rayyes K, Hegab S, Besisso M. A syndrome of alacrima, achalasia and neurologic anomalies without adrenocortical insufficieney. J Pediatr Ophthalmol Strabismus 1991;28:35-7. 5. Deumic M, Radich A, Jusic A, StefanouicN, Murko Z. Selective ACTH insensitivityassociatedwith autonomicnervous systemalisorder and sensory polyneuropathy.Eur J Pedialr 1987;146:5924. 6. Stuckey BG, Mastaglia FL, Reed WD, Pullan PT. Glucocorticoid insufficiency, achalasia, alacrima with autonomic and motor neuropathy. Ann Intern Med 1987;106:62-4. 7. Gazarian M, et al. The "4A" syndrome: adrenocortical insufficiency associated with achalasia, alacrima, autonomic and other neurological abnormalities.Eur J Pediatr 1995;154:18-23. 8. Pombo M , Deuesa J, Taborda A, et al. Glucocorticoid deficiency with achalasia of the cardia and lack of lacrimation. Clin Endocrinol 1985;23:237-43. 9. Goldberger JJ, Ahmed MW, Parker MA, Kadish AH. Assessment of effects of autonomic stimulation and blockade. Circulation 1994;89:1656-64. 10. Vincent GM, Timothy KW, Leppert M, Keating M. The spectrum of symptoms and QT intervals in the carriers of the gene for the long-QT syndrome. N Engl J Med 1992;327:846-87. 11. Glickstein JS, Schwartzman D, Friedman D, Rutkowski M, Axelrod FB. QT interval abnormalities in familial dysautonomia as an indicator of autonomic dysfunction. J Pediatr 1993;122:925-8. 12. Bigger JT, Albrecht P, Steinman RC, Rolnitzky LM, Fleiss JL, Cohen RJ. Comparison of time- and frequency domain-based measures of cardiac parasympathetic activity in Holter recordings after myocardial infarction. Am J Cardiol 1989;64:536-8. 13. Khurana RK. Cholinergic dysfunction in Shy-Drager syndrome: effect of bethanechol. Clin Auton Res 1994;4:5-13.

Hypoparathyroidism in mitochondrial trifunctional protein deficiency Carlo Dionisi-Vici, MD, Barbara Garavaglia, MS, Alberto B, Burlina, MD, Enrico Bertini, MD, Isora Saponara, MD, G a e t a n o Sabetta, MD, and Franco Taroni, MD From the Department of Metabolism, Bambino Gesü Hospital, Istituto dl Ricovero e Cura a Caraffere Scientifico, Rome, Italy, the Division of Biochemistry and Genetics, Istituto Nationale Neurologico C. Besta, Milan, Italy, and the Department of Pediatrics, University of Padua, Padua, Italy.

Mitochondrial trifunctional protein deficiency, a recently identified disorder of fatly-acid oxidation, may show characteristic features such as peripheral neuropathy, pigmentary retinopathy, and acute fatty liver degeneration in pregnant women with an affected fetus. We describe a patient with trifunctional protein deficJency whose clinical picture consisted of severe calcium and phosphate abnormalities caused by hypoparathyroidism. (J Pediatr 1996;129:159-62)

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Mitochondrial trifunctional protein deficiency (McKusick 251890) is a recently identified inborn error of fatty-acid oxidation.1, 2 This multifunctional protein is a heterooctamer (c~4134) carrying three different enzyme activities, long-chain enoyl-coenzyme A hydratase and long-chain 3-hydroxyacyl-CoA dehydrogenase activities harbored by the «-subunit, and long-chain 3-keto-thiolase activity, harbored by the [3-subunit.3 Before discovery of trifunctional protein, cases were reported as long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (McKusick 143450). Indeed, MTP-deficient patients can be divided into two groupsS: those with isolated deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase, the majority with a common G-to-C mutation found in position 1528 in the ~x-subunit,4 and those with deficiency of all three enzyme activities. CK CoA FAO iPTH MTP

Creatine kinase Coenzyme A Fatty acid oxidation Intact parathyroid hormone Mitochondrial trifunctional protein

Although the clinical presentation of FAO disorders is variable, patients usually have myopathy, cardioyopathy, Reye-like syndrome, and fasting hypoketotic hypoglycemia. Unique among FAO defects, MTP deficiency may show some additional peculiar feamres such as peripheral neuropathy, pigmentary retinopathy, and acute fatty liver degeneration in pregnant women with an affected fetus. 5-7 We describe a patient with MTP deficiency and hypoparathyroidism. CASE R E P O R T The proband was the second child of healthy, nonconsanguineous parents. The family history was unremarkable, and pregnancy and delivery were unevenfful. Recurrent vomiting was present since birth. At 7 and 13 months, the patient was admitted to a local hospital because of fever, vomiting, and diarrhea. At this time, elevated aminolransferase values were notieed. At the age of 15 months, after 3 days of poor feeding, the child was referred to our hospital. She had severe hypotonia and respiratory failure, requiring assisted ventilation. Weight, height, and head circumference were all normal. Laboratory investigations showed marked elevation of creatine kinase (43.010 U/L; normal values,