Brain & Development 28 (2006) 329–331 www.elsevier.com/locate/braindev
Case report
Ethylmalonic encephalopathy—report of two cases Lada Cindro Heberle a,*, Asma A. Al Tawari a, Dina G. Ramadan b, Jamila K. Ibrahim a a
Pediatric Neurology Unit, NBK, Al Sabah Hospital, Safat 4078, C.N. 13041, Kuwait b Metabolic Clinic, Endocrine Unit, Al Sabah Hospital, Kuwait
Received 15 April 2005; received in revised form 16 September 2005; accepted 4 October 2005
Abstract Ethylmalonic encephalopathy is a rare metabolic disease presenting in infancy with developmental delay, acrocyanosis, petechiae, chronic diarrhea and early death. The biochemical characteristics of this autosomal recessive disease are urinary organic acid abnormalities. Recently it has been found to be caused by mutations in the ETHE1 gene, located on Ch19q13. Only about 30 patients have been reported, and we describe two additional cases. The first patient showed a typical clinical picture and biochemical abnormalities, with additional atypical clinical features. Neuroimaging studies showed extensive changes. A new homozygous mutation in exon 3 of the ETHE1 gene was found. The second patient was not investigated genetically; however besides the typical clinical picture and biochemical profile he was found to have cytochrome C oxidase deficiency. q 2006 Elsevier B.V. All rights reserved. Keywords: Mitochondrial; Encephalopathy; Petechiae; Organic aciduria
1. Introduction Ethylmalonic encephalopathy (EME), also known as EPEMA syndrome [1], first described by Burlina [2] in 1991, is a devastating infantile metabolic disorder, presenting clinically with developmental delay, acrocyanosis, petechiae, chronic diarrhea and death in infancy [1,3]. The characteristic biochemical features are lactic acidosis and ethylmalonic and methylsuccinic aciduria. Neuroimaging studies reveal basal ganglia changes [4]. The initial assumption that the disorder is very rare might be incorrect [5]. The biochemical phenotype may erroneously lead to the diagnosis of other metabolic disorders, especially fatty acid oxidation defects and respiratory chain disorders [1,6].
2. Case reports Case 1: The patient was born after an uneventful pregnancy and normal delivery. His parents were * Corresponding author. Fax: C965 4814977. E-mail address:
[email protected] (L.C. Heberle).
0387-7604/$ - see front matter q 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2005.10.005
first-degree cousins; his 2 siblings were healthy. He was well till 4 months of age when he developed diarrhea, which lasted for 2 months. Global developmental delay with hypotonia became increasingly evident. On referral to our department at the age of 11 months he was found to have failure to thrive (weight 6.7 kg), microcephaly (head circumference 44.5 cm), mild hepatomegaly, undescended testes, small penis and a petechial rash over the left arm. He fixed on, but did not follow light and exhibited horizontal nystagmus. He had generalized hypotonia with weakness (head lag, inability to roll over), exaggerated deep tendon reflexes and an upgoing plantar response. He was unable to recognize his parents. Laboratory investigations revealed increased values of lactate (2.8 and 7.8 mmol/L in plasma, 12.0 mmol/L in CSF) with normal pyruvate, ammonia and amino acid chromatography. The urinary amino acid screen was normal, but on two occasions there was a clear increase in lactic, ethylmalonic, methylsuccinic, 3-hydroxybutyric, glutaric and dicarboxylic (suberic, adipic) acids and isobutyryl and isovaleryl glycine were detected. Blood butyrylcarnitine was persistently elevated. Brain MRI (Fig. 1) showed multiple areas of low and high signal (T1W & T2W) in the basal ganglia and prominent frontal and temporal subarachnoid spaces. Abdominal US revealed increased liver echogenecity and grade II hydronephrosis.
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seen. Muscle biopsy showed some fibers with increased lipid and scattered cytochrome C oxidase (COX) negative fibers. The child was given Vitamin B1, B2, B6, Q10, carnitine, sodium bicarbonate and Phenobarbitone. He died at the age of eight months. The diagnosis of EME was made several years later after review of the clinical and laboratory data.
3. Discussion
Fig. 1. Prominent frontal and temporal subarachnoid spaces and multiple changes in the basal ganglia.
Echocardiography showed mild tricuspid regurgitation and dilatation of the pulmonary artery. Vitamins B1, B2, B6, C, E, biotin, Q10 and carnitine were prescribed, without effect. Molecular genetic studies showed a homozygous mutation in exon 3 of the ETHE1 gene in the form of an adenine deletion affecting nucleotide position 230 (230 delA), which caused a frame shift at amino acid position 77 with the creation of a stop codon downstream (N77fsX144). The patient died before fibroblasts could be collected for further analysis of the corresponding protein. Case 2: The patient was born at term by normal delivery after an uneventful pregnancy. His parents were healthy, first-degree cousins. They already had 2 healthy children and 1 boy, who had died at 8 months of age, had been diagnosed as having Leigh’s disease with a purpuric skin rash. From the neonatal period the patient was noted to be hypotonic with a weak cry and poor suck. His development was very slow, a skin rash appeared at several months of age and he developed epilepsy. A mild persistent metabolic acidosis, observed from the onset, later progressively deteriorated. The plasma lactate concentration ranged from 2.1– 11.8 mmol/L, while CSF lactate was 6.5 mmol/L. Amino acid chromatography, ammonia and CPK were normal. Urinary organic acids showed markedly increased lactate, pyruvate, fumarate, malate, citrate, hydroxyglutarate, ethylmalonate and methylsuccinate. Neuroimaging studies revealed asymmetry of the frontal horns, prominent sulci of the right hemisphere and areas of altered signal in the lentiform and caudate nuclei. Changes in the cerebral white matter bilaterally were also
EME was first described in 1991 [2]. The disease (OMIM 602473) is inherited in an autosomal recessive manner. Patients present in infancy with developmental delay, acrocyanosis, petechiae and chronic diarrhea [1,3]. Congenital anomalies of the CNS (tethered cord, Chiari I malformation) have been described in a few patients [7]. In addition to the typical clinical presentation, our first patient had grade II hydronephrosis and undescended testes, while echocardiography showed mild tricuspid regurgitation and mild dilatation of the pulmonary artery. Such anomalies were not described in previous patients. EME is biochemically characterized by increased lactate levels and ethylmalonic and methylsuccinic aciduria. Due to lactic acidosis and widespread neuroimaging changes, including the basal ganglia, it is considered in the differential diagnosis of Leigh’s syndrome [8]. This led to the introduction of treatment with vitamins and carnitine. The biochemical profile might point to short-chain acylCoA dehydrogenase and methyl-branched chain acyl-CoA dehydrogenase deficiencies (fatty acid oxidation defects), but these were excluded [3]. Reports of a muscle enzyme (COX) deficiency in EME patients followed [9], but this was later found to be secondary [10]. In our second patient, who revealed COX deficiency, the diagnosis of EME also went unrecognized for a long time. A combination of homozygosity mapping, integration of physical and genomic data sets and mutational screening identified the ETHE1 gene (previously HSCO gene) as the site of mutations causing EME [5]. Tiranti et al. [5] identified the gene on Ch 19q13. ETHE1 protein is targeted to the mitochondrial matrix after energy-dependent cleavage of a short leader peptide. The N-terminal sequence of 24 amino acids is similar to mitochondrial leader peptides. The gene is approximately 1000 nucleotides long and contains 7 exons. ETHE1 has ubiquitous expression as a single transcript. The ETHE1 gene product has an important role in mitochondrial homeostasis and energy metabolism, but its exact role is not known [5]. Up till now 16 different mutations in the ETHE1 gene causing EME have been identified. Most of these cause loss of function, producing a stop, a frame shift, or aberrant splicing; others are entire gene deletions and missense mutations in highly conserved portions. Our first patient had
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a homozygous mutation (230 delA), which has not been previously described.
Acknowledgements We wish to thank the parents of our patients for their cooperation in the study and M. Zeviani, MD, PhD and V. Tiranti, from the Division of Molecular Neurogenetics, Instituto Nazionale Neurologico ‘C. Besta’, Milan (Italy), who performed genetic studies on the first patient. References [1] Garcia-Silva MT, Ribes A, Campos Y, Garavaglia B, Arenas J. Syndrome of encephalopathy, petechiae, and ethylmalonic aciduria. Pediatr Neurol 1997;17:165–70. [2] Burlina A, Zacchello F, Dionisi-Vici C, Bertini E, Sabetta G, Bennet MJ, et al. New clinical phenotype of branched-chain acyl-CoA oxidation defect. (Letter). Lancet 1991;338:1522–3. [3] Burlina AB, Dionisi-Vici C, Bennett MJ, Gibson KM, Servidei S, Bertini E, et al. A new syndrome with ethylmalonic aciduria and normal fatty acid oxidation in fibroblasts. J Pediatr 1994;124:79–86.
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