Letter to the Editor
Ethylmalonic encephalopathy: phenotype-genotype description and review of its management
Encefalopatía etilmalónica: descripción fenotipo-genotipo y revisión de su manejo
a Servicio de Pediatría, Hospital Regional Universitario Materno-Infantil de Málaga, Málaga, Spain
b Servicio de Pediatría (lactantes), Hospital Regional Universitario Materno-Infantil de Málaga, Málaga, Spain
c Sección de Neurología Pediátrica, Grupo IBIMA, Servicio de Pediatría, Hospital Regional Universitario Materno-Infantil de Málaga, Málaga, Spain
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Cardelo Autero, A.M. Cordón Martínez, J.M. Ramos-Fernández" "autores" => array:3 [ 0 => array:3 [ "nombre" => "N." "apellidos" => "Cardelo Autero" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 1 => array:3 [ "nombre" => "A.M." "apellidos" => "Cordón Martínez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:4 [ "nombre" => "J.M." "apellidos" => "Ramos-Fernández" "email" => array:1 [ 0 => "dr.jmramos@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Servicio de Pediatría, Hospital Regional Universitario Materno-Infantil de Málaga, Málaga, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Pediatría (lactantes), Hospital Regional Universitario Materno-Infantil de Málaga, Málaga, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Sección de Neurología Pediátrica, Grupo IBIMA, Servicio de Pediatría, Hospital Regional Universitario Materno-Infantil de Málaga, Málaga, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Encefalopatía etilmalónica: descripción fenotipo-genotipo y revisión de su manejo" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 673 "Ancho" => 1305 "Tamanyo" => 75066 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Brain MRI scan: bilateral signal alterations in the putamen and head of the caudate nucleus; hyperintense lesions on T2-weighted (left) and FLAIR sequences (right: arrows). No globus pallidus or internal capsule involvement were observed. No loss of parenchymal volume was observed at the supra- or infratentorial levels.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Ethylmalonic encephalopathy (EE) is an extremely rare disease caused by a recessive defect of the <span class="elsevierStyleItalic">ETHE1</span> gene; it presents in infancy and follows a progressive course characterised by psychomotor retardation, hypotonia, and generalised microvascular damage. Delayed growth with diarrhoea and dysphagia is a common symptom. Neurological impairment is accelerated in the context of intercurrent infectious diseases, and patients typically do not live beyond the first decade of life.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Diagnosis is based on clinical and laboratory findings. Patients with EE frequently present elevated levels of lactic acid, C4- and C5-acylcarnitine, and thiosulphate in the blood, and ethylmalonic acid in the urine. Diagnosis is usually confirmed in genetic studies.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,4</span></a> Treatment is currently symptomatic.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">We present the clinical, biochemical, radiological, and genetic data of a new patient with EE who was diagnosed during an infectious decompensation, and review the available evidence on this rare entity and its management.</p><p id="par0020" class="elsevierStylePara elsevierViewall">The patient was a boy of 1.3 years of age with no relevant family or perinatal history who presented developmental delay, mild language regression with the loss of the 3 words he had learnt, hypotonia, and failure to thrive since the age of 10 months. He also presented capillary fragility, manifesting as petechiae on the limbs.</p><p id="par0025" class="elsevierStylePara elsevierViewall">He was admitted to hospital due to acute decompensation in the context of fever and diarrhoea, with metabolic acidosis (pH, 7.21; pCO<span class="elsevierStyleInf">2</span>, 14 mm Hg; HCO<span class="elsevierStyleInf">3</span>, 8.8 mmol/L), hyperlactacidaemia (3.8 mmol/L), hyperglycaemia (glucose, 264 mg/dL), and ketonaemia (3.8 mmol/L); the patient was transferred to the intensive care unit for stabilisation. Examination at the paediatric ward revealed body weight of 7.4 kg (< p1; –3.2 SD), length of 72 cm (< p1; –3.24 SD), head circumference of 45.5 cm (p12; –1.18 SD), and a phenotype with dolichocephaly, prominent forehead, retrognathia, low-set ears, and a small mouth with thin lips. He presented petechiae, mainly on the forearms and popliteal and antecubital fossae. Interaction was good, with scarce language (2 or 3 doubtfully referential disyllables), good visual tracking, bilateral grasping, and marked global hypotonia; the patient was able to sit with support but could not stand nor walk. He was unable to push up to hands and knees from a prone position, and presented generalised hyperreflexia, sustained clonus, and bilateral Babinski sign.</p><p id="par0030" class="elsevierStylePara elsevierViewall">Brain MRI (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>) revealed signal alterations in the putamen and the head of the caudate nucleus bilaterally.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">The metabolic study of amino acids, blood acylcarnitines, and urine organic acids at 24 hours revealed elevated excretion of ethylmalonic acid. A targeted genetic panel revealed a homozygous pathogenic mutation of the <span class="elsevierStyleItalic">ETHE1</span> gene (<span class="elsevierStyleItalic">c.488 G > A</span> [<span class="elsevierStyleItalic">p.Arg163Gln</span>]); both parents were asymptomatic carriers of the mutation.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Treatment was started with biotin, coenzyme Q10, vitamin E, riboflavin, thiamine, and L-carnitine due to suspicion of mitochondrial disease; metronidazole and N-acetylcysteine were subsequently added. Two months after admission, we observed considerable improvements in nutrition and in psychomotor development. We continued treatment with a low-protein diet, coenzyme Q10, riboflavin, L-carnitine, metronidazole, and N-acetylcysteine, which stabilised the patient, although failure to thrive and developmental delay (predominantly in motor areas) persisted. At the age of 2.5 years, he was able to walk with the assistance of one hand, uttered words but not sentences, and showed good interaction with his surroundings.</p><p id="par0045" class="elsevierStylePara elsevierViewall">The genetic basis of EE was first described in 2004<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>. The <span class="elsevierStyleItalic">ETHE1</span> gene, located on chromosome 19, encodes a metallo-β-lactamase involved in the mitochondrial pathway, which is needed for the catabolism of hydrogen sulphide (H<span class="elsevierStyleInf">2</span>S). This defect causes accumulation of H<span class="elsevierStyleInf">2</span>S and its derivatives (thiosulphate) in various fluids and tissues, and induces direct damage to cell membranes and inhibits cytochrome c oxidase and short-chain acyl-CoA dehydrogenase. It increases levels of lactic acid, ethylmalonic acid, and C4- and C5-acylcarnitine.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,5,6</span></a> Various mutations have been identified, the majority originating in the Mediterranean and the Middle East,<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,6</span></a> with variability between families.<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4,7,8</span></a> The characteristic mucocutaneous manifestations are caused by microvascular toxicity and include recurring petechiae, cutis marmorata, haemorrhagic mucosal suffusion, and/or distal orthostatic acrocyanosis.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,8</span></a> Hydronephrosis, cryptorchidism, and cardiac anomalies have also been described.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">The typical brain MRI alterations are irregular contrast-enhancing hyperintense lesions in the basal ganglia,<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7,9</span></a> as in our patient, resembling those involved in Leigh syndrome. Other abnormalities described in the literature include hyperintensities in the brainstem, cortical atrophy, diffuse leukoencephalopathy, and congenital malformations such as tethered spinal cord and Chiari malformation.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Gene sequencing is recommended for diagnosis. If pathogenic variants are not identified, or are found in a single allele, then targeted deletion and duplication analysis of the gene should be performed.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,10</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Treatment should aim to guarantee adequate nutritional support.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Treatment with riboflavin, L-carnitine, and coenzyme Q10, as administered in our patient, seems beneficial.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Diets with restricted intake of sulphurated amino acids also improve symptoms and biochemical markers.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Combined use of metronidazole and N-acetylcysteine has been shown to control accumulation of H<span class="elsevierStyleInf">2</span>S by reducing the abundance of the bacteria producing sulphide and neutralising H<span class="elsevierStyleInf">2</span>S, respectively.<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12,13</span></a> These patients occasionally require renal replacement therapy.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Liver transplantation seems to be a therapeutic option,<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> and gene therapy with adeno-associated viral vectors is currently under study.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">Finally, it should be noted that the phenotype associated with the <span class="elsevierStyleItalic">c.488 G > A</span> (<span class="elsevierStyleItalic">p.Arg163Gln</span>) mutation of <span class="elsevierStyleItalic">ETHE1</span> behaves as a mitochondrial disease, associated with capillary fragility and failure to thrive, and responds well to mitochondrial stimulation, antioxidants, and gastrointestinal decontamination.</p><span id="sec1040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect1100">Conflicts of interest</span><p id="par0180" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec1040" "titulo" => "Conflicts of interest" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2020-11-04" "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Cardelo Autero N, Cordón Martínez AM, Ramos-Fernández JM. Encefalopatía etilmalónica: descripción fenotipo-genotipo y revisión de su manejo. Neurología. 2021;36:729–731.</p>" ] ] "multimedia" => array:1 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 673 "Ancho" => 1305 "Tamanyo" => 75066 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Brain MRI scan: bilateral signal alterations in the putamen and head of the caudate nucleus; hyperintense lesions on T2-weighted (left) and FLAIR sequences (right: arrows). No globus pallidus or internal capsule involvement were observed. No loss of parenchymal volume was observed at the supra- or infratentorial levels.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:15 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Ethylmalonic encephalopathy is caused by mutations in ETHE1, a gene encoding a mitochondrial matrix protein" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "V. Tiranti" 1 => "P. D’Adamo" 2 => "E. Briem" 3 => "G. Ferrari" 4 => "R. Mineri" 5 => "E. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 7 | 0 | 7 |
| 2024 October | 39 | 6 | 45 |
| 2024 September | 70 | 16 | 86 |
| 2024 August | 37 | 24 | 61 |
| 2024 July | 32 | 13 | 45 |
| 2024 June | 43 | 10 | 53 |
| 2024 May | 47 | 9 | 56 |
| 2024 April | 35 | 6 | 41 |
| 2024 March | 43 | 9 | 52 |
| 2024 February | 37 | 4 | 41 |
| 2024 January | 30 | 4 | 34 |
| 2023 December | 44 | 11 | 55 |
| 2023 November | 41 | 16 | 57 |
| 2023 October | 51 | 9 | 60 |
| 2023 September | 19 | 4 | 23 |
| 2023 August | 14 | 10 | 24 |
| 2023 July | 30 | 4 | 34 |
| 2023 June | 38 | 4 | 42 |
| 2023 May | 64 | 15 | 79 |
| 2023 April | 39 | 5 | 44 |
| 2023 March | 15 | 6 | 21 |
| 2023 February | 14 | 13 | 27 |
| 2023 January | 10 | 7 | 17 |
| 2022 December | 25 | 6 | 31 |
| 2022 November | 40 | 19 | 59 |
| 2022 October | 12 | 14 | 26 |
| 2022 September | 19 | 6 | 25 |
| 2022 August | 24 | 13 | 37 |
| 2022 July | 20 | 8 | 28 |
| 2022 June | 23 | 10 | 33 |
| 2022 May | 15 | 13 | 28 |
| 2022 April | 15 | 6 | 21 |
| 2022 March | 13 | 5 | 18 |
| 2022 February | 22 | 9 | 31 |
| 2022 January | 45 | 7 | 52 |
| 2021 December | 32 | 19 | 51 |
| 2021 November | 17 | 15 | 32 |
| 2021 October | 2 | 12 | 14 |
| 2021 September | 0 | 3 | 3 |
| 2021 August | 0 | 4 | 4 |
| 2021 July | 0 | 3 | 3 |
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