Ethylmalonic encephalopathy (EE) is an inherited error of metabolism (IEM) characterized by elevated excretion of ethylmalonic acid, and affects on several body systems, including the circulatory and gastrointestinal systems, but particularly the nervous system. The neurological features of the disease include progressive neurodevelopmental delay, hypotonia, seizures, and psychomotor regression. Abnormalities may also be visible on brain scans. Other symptoms of the condition include the appearance of recurrent petechia, cyanosis in the hands and feet, and chronic diarrhea. These clinical features may be present at birth, or develop within the first few months. The metabolic picture is that of elevated urinary excretion of ethylmalonic acid, along with methylsuccinic acid, and acylglycines.
EE is a rare disorder, with only about 40 patients having been reported worldwide. Most of these patients originate from the Mediterranean and/or Arab region. Diagnosis is based on the clinical symptoms, and biochemical analysis, although a genetic analysis is required for confirmation. The urinary and serum metabolite profile in EE can resemble that seen in multiple acyl-coA dehydrogenase deficiency or short chain acyl-coA dehydrogenase deficiency. However, the clinical profile of petechia, acrocyanosis and diarrhea is quite unique for EE. Management of the condition involves treatment with L-carnitine, riboflavin, and/or Q10 supplements. However, the prognosis for the condition is generally poor. The neurological problems typically worsen, and most affected patients do not survive beyond childhood.
[See: Yemen > Ozand et al., 1994].
Heberle et al. (2006) described two new cases of EE. The first patient had typical clinical picture and biochemical abnormalities, but also showed certain other atypical features. The second patient was found to have a cytochrome c oxidase deficiency in addition to the clinical features of EE.
Ismail et al. (2009) reported a Kuwaiti girl with ethylmalonic encephalopathy. She presented at the age of 4 months with chronic mucoid diarrhea and delayed psychomotor development, and at 6 months she developed myoclonic epilepsy. She was found to have central hypotonia with pyramidal tract signs, acrocyanosis, and petechia. Plasma lactate level was elevated. Blood spot and urine for organic acids results were consistent with the diagnosis of ethylmalonic encephalopathy. Cerebral MRI showed basal ganglia and white matter changes. Gene mutation study revealed homozygous deletion of exon 4 of the ETHE1 gene. The patient died at 14 months after extensive bronchopneumonia.
Al-Riyami et al. (2012) reported on the types and patterns of IEMs encountered in a sample of 1100 high-risk neonates referred to SQU Hospital in Oman over a 10-year period (1998-2002). MS/MS was used to analyze blood samples from heel pricks. A total of 119 of these neonates were found to test positive for an IEM. Ethylmalonic Encephalopathy was detected in a single female neonate.
Dweikat et al. (2012) reported a Palestinian girl with EE who presented with chronic diarrhea, encephalopathy, petechial rash and acrocyanosis. Subsequently, she developed progressive deterioration of renal function caused by rapidly progressive glomerulonephritis resulting in death within few days. Dweikat et al. (2012) commented about the case as being possibly the first reported occurrence of rapidly progressive glomerulonephritis in a child with ethylmalonic encephalopathy.
Ozand et al. (1994) described five patients from three families, who were affected with ethylmalonic aciduria. Two of these families were Yemeni in origin, while the third was Egyptian. Vascular lesions of the skin, petechia, and ecchymoses, as well as retinal lesions were noticed in all patients. Other clinical features included diarrhea and acrocyanosis. Three of the patients developed sudden emergence of severe basal ganglia, putaminal, and head of caudate lesions, and died. These three patients also developed pulmonary congestion prior to dying. Urinalysis indicated increased excretion of ethylmalonic, methylsuccinic, glutaric, and adipic acids. Patients also showed lactic acidosis. Biopsies from petechia showed no evidence for an immune attack. Ozand et al. (1994) noted that the condition was not responsive to treatment with riboflavin, vitamin C, vitamin E, glycine or carnitine. Only a prolonged large dose of methylprednisolone was able to stabilize one patient.