Encephalopathy, petechiae, and acrocyanosis with ethylmalonic aciduria associated with muscle cytochrome c oxidase deficiency

EDITORIAL CORRESPONDENCE

Encephalopathy, petechiae, and acrocyanosis with ethylmalonic aciduria associated with muscle cytochrome c oxidase deficiency To the Editor." We read with interest the article by Burlina et al. 1 regarding a new syndrome with ethylmalonic aciduria and normal fatty acid oxidation in fibroblasts. We studied a patient with similar clinical and biochemical features who also had severe cytochrome c oxidase (COX) deficiency in muscle. The child was the third born to healthy, unrelated parents. An older sister had died at 7 months of bronchopneumonia and septicemia; she had low birth weight, microcephaly, progressive hypotonia, developmental delay, gastrointestinal and feeding problems, failure to thrive, metabolic acidosis, nephrotic syndrome, and hepatomegaly and microsteatosis. Our patient was breast fed, supplemented with formula, since birth. At 2 months of age feeding difficulties, irritability, and neurologie deterioration developed, and later the infant had gastrointestinal problems and failure to thrive. At 4 months he had progressive hypotonia, episodes of hyperventilation, and metabolic acidosis. Brain magnetic resonance imaging showed bilateral symmetric lesions in corpus striatum with involvement of periventricular white matter. 2 A muscle biopsy specimen showed lipid droplets. At 7 months the infant was admitted to our hospital. He was very hypotonic with pyramidal signs and lethargy. He had hypocarnitinemia and slight lactic acidosis. We found excessive amounts of ethylmalonic acid, 2-methylsuccinic acid, isovalerylglycine, and butyrylglycine in urine samples. A second muscle biopsy specimen showed neither lipid droplets nor ragged-red fibers; however, results of staining in almost all fibers were negative for COX. Muscle biochemistry studies showed severe COX deficiency (7% of control values); the respiratory chain was normal in fibroblasts. Genetic analysis did not show large rearrangements or known point mutations of mitochondrial DNA. Fatty acid oxidation in fibroblasts was normal. At 16 months, petechiae and orthostatic acrocyanosis with distal swelling were first noted (normal platelet and prothrombin time). The infant is now 20 months of age, has microcephaly, and is severely retarded with severe axial hypotonia, spastic tetraplegia, and chronic mucoid diarrea. M. 7". Garcia-Silva, MD, Y. Campos, PhD, A. Ribes, PhD, P. Briones, PhD, A. Cabello, MD, J. Santos Borbujo, MD, J. Arenas, PhD, and B. Garavaglia, PhD Departments of Pediatrics and Neuropathology Hospital 12 de Octubre Madrid, Spain lnstitut de BioqMrnica Clinica Barcelona, Spain Istituto Neurologico C. Besta Milan, Italy 9/35/58766 REFERENCES

1. Burlina AB, Dionisi-Vici C, Benuet M J, et al. A new syndrome with ethylmalonic aciduria and normal fatty acid oxication in fibroblasts. J PEDIATR 1994;124:79-86. The Journal of Pediatrics

2. Barkowich A J, Good WV, Kocck T, et al. Mitochondrial disorders: analysis of their clinical and imaging characteristics. AJNR Am J Neuroradiol 1993;14:1119-37.

Reply To the Editor: Garcia-Silva et al. report a new case of the syndrome we described recently. In addition to a virtually identical phenotype, a severe cytochrome c oxidase (COX) deficiency was documented in skeletal muscle. Although they did not elaborate on the significance of this finding, their observation is consistent with another report, 1 raising the issue whether COX deficiency represents the primary defect responsible for this syndrome or rather a secondary phenomenon. In our experience, the ethylmalonic encephalopathy is associated with a complex clinical phenotype; the muscle manifestations, albeit significant, are overshadowed by many other systemic signs and symptoms including marked cutaneous manifestations. Therefore it is puzzling that a COX deficiency of comparable severity was not detected in skin fibroblasts of affected patients. 2 These findings suggest that the observed COX deficiency may be caused by either mitochondrial DNA depletion or variable tissue expression, two possible nonspecific responses of the skeletal muscle to various pathologic processes) To our knowledge, at least 19 cases of ethylmalonic encephalopathy have been identified worldwide (references 1, 2, and 4; our report; H. Mandel, Haifa, Israel: personal communication, May 1994). The clinical and biochemical findings were remarkably consistent in patients of heterogeneous ethnic background. Because there is no demonstrable biochemical link between ethylmalonate accumulation and impaired muscle COX activity, we postulate that the ethylmalonic encephalopathy is a distinct and separate entity, most likely inherited as an autosomal recessive trait, of which the precise primary defect is yet to be determined. Alberto B. Burlina, MD University of Padua Padua, Italy Piero Rinaldo, MD Yale University Medical School New Haven, CT 06520-8005 9/35/58762 REFERENCES

1. Garavaglia B, Colamaria V, Carrara F, et al. Muscle cytochrome c oxidase deficiency in two Italian patients with ethylmalonic aciduria and peculiar clinical phenotype. J Inherit Metab Dis 1994;17:301-3. 2. Ozand PT, Rashed M, Millington DS, et al. Ethylmalonic aciduria: an organic acidemia with CNS involvement and vasculopathy. Brain Dev (in press). 3. Moraes CT, Shanske S, Tritschler H J, et al. mtDNA depletion with variable tissue expression: novel genetic abnormality in mitochondrial diseases. Am J Hum Genet 1991;48:492-501. 4. Cheu E, Jurecki ER, Rinaldo P, et al. Nephrotic syndrome and November 1994

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