Mi3 syndrome. Myasthenia, migraine, myelopathy. New ultrarare disease

Blasco, Felipe; Guillamó, Ana E.

doi:10.1016/j.medcle.2019.03.039

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Myasthenia, migraine, myelopathy. New ultrarare disease" "tieneTextoCompleto" => true "saludo" => "Dear Editor," "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "323" "paginaFinal" => "324" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Felipe Blasco, Ana E. Guillamó" "autores" => array:2 [ 0 => array:4 [ "nombre" => "Felipe" "apellidos" => "Blasco" "email" => array:1 [ 0 => "fblasco@torrevieja-salud.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "Ana E." "apellidos" => "Guillamó" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Unidad de diagnóstico médico y enfermedades minoritarias, Servicio de Medicina Interna, Hospital Universitario de Torrevieja, Torrevieja, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Síndrome Mi3. Miastenia, migraña y mielopatía. Nueva entidad clínica ultrarrara" ] ] "textoCompleto" => "The real impact of mitochondrial diseases is unknown. An incidence of 1/11,000–16,000 is described, although most of the studies coincide in the underestimation of the data due to the infant mortality inherent in these processes and the difficulty in detecting patients who survive due to the heterogeneity of the phenotypes with which they can express themselves and because of the complexity of their diagnosis.We report the case of a 25-year-old woman who, at age 21, began with a self-limiting condition of headache and myalgias at rest. A lumbar puncture and a brain MRI were performed, without findings of interest. In the following 2 years the patient visited the neurology department on several occasions, first for recurrent episodes of migraine with left hemiplegia that disappeared in weeks, then it associated blepharoptosis and diplopia, and finally progressive loss of muscle tone in the 4 limbs and respiratory musculature that forced the patient to maintain invasive mechanical ventilation. A repetitive stimulation EMG showed a significant drop in potential, compatible with myasthenia gravis, although antibodies against the acetylcholine receptor, anti-MUSK and antibodies against calcium channels were negative. There was a partial and transitory improvement with pyridostigmine. No response to plasmapheresis, immunoglobulins, azathioprine, rituximab or cyclophosphamide. The genetic study of congenital myasthenic syndrome and hemiplegic migraine was negative. The last symptom that developed was a sensory loss in the lower limbs. Somatosensory evoked potentials showed dysfunction in the posterior funiculus. MRI of the spinal cord was normal.The case was referred for evaluation to the medical diagnosis and rare diseases unit. Lactic acidaemia was not evident. The plasma CK, ammonium, and carnitine levels were normal. The muscle biopsy showed no histological abnormalities, so a sample was sent for analysis of the respiratory chain to the Department of Cellular and Bioenergetic Pathophysiology of the Pablo de Olavide University in which a decrease in the joint activity of the I and III complexes was described, suggestive of mitochondrial dysfunction.Following this finding, the exome was analysed by genetic sequencing at the Institute of Cellular and Molecular Studies, which revealed 15 mutations in our patient, considering as pathological the variant mt 6489 C>A of the gene MT-CO1, which was homoplasmic in relation to the proband phenotype.The mitochondrially encoded cytochrome c oxidase I (MT-CO1) is a protein, encoded by the gene MT-CO1, which forms the cytochrome C oxidase together with 2 other subunits. In this variant the amino acid leucine has been replaced by isoleucine at position 196, which causes changes in the physicochemical properties of the protein. This variant is classified as pathogenic in ClinVar.<a class="elsevierStyleCrossRef" href="#bib0030">1</a>The mutations of MT-CO1 have been associated with Leber's optic neuropathy, idiopathic sideroblastic anaemia and mitochondrial complex IV deficiency, which has a wide variety of manifestations that include liver dysfunction, muscle weakness and exercise intolerance, hypertrophic cardiomyopathy and psychomotor retardation. The final phenotype of our patient can be named Mi3 (Spanish acronym for miopatía miasteniforme, migraña hemipléjica y mielopatía); myasthenic myopathy, hemiplegic migraine and myelopathy of posterior funiculus.There are few cases reported in the medical literature of myasthenia gravis of mitochondrial origin.<a class="elsevierStyleCrossRefs" href="#bib0035">2,3</a> Clinical expression is similar to what we describe. Initially they were diagnosed with myasthenia gravis based on EMG and a positive response to anticholinesterase drugs, but in the absence of a response to treatment, a muscle biopsy was performed that confirmed the diagnosis of mitochondrial myopathy. Based on the foregoing, a mitochondrial disease should be ruled out before starting treatment when a seronegative myasthenia gravis condition occurs, even with compatible EMG and with response to anticholinesterase.With regard to migraine, its prevalence in patients with mitochondrial diseases is very high compared to the general population, regardless of phenotype and genotype.<a class="elsevierStyleCrossRef" href="#bib0045">4</a> Although no specific DNA mutations have been detected in several reviews. Myelopathy is not uncommon; in most cases it is associated with a multisystemic condition. It can manifest, as in our case, as paraparesis and sensory loss, also as monoparesis, hypotonia, spasticity, or urinary or anal sphincter dysfunction.<a class="elsevierStyleCrossRef" href="#bib0050">5</a> The diagnosis is based on the findings of the somatosensory evoked potentials; evidence of a lesion could be observed through an MRI only in case of spinal atrophy." "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Blasco F, Guillamó AE. Síndrome Mi3. Miastenia, migraña y mielopatía. Nueva entidad clínica ultrarrara. Med Clin (Barc). 2020;154:323–324." ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:5 [ 0 => array:3 [ "identificador" => "bib0030" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Clinical variant. Available from: <a target="_blank" href="http://www.ncbi.nlm.nih.gov/clinvar/">http://www.ncbi.nlm.nih.gov/clinvar/</a>" ] ] ] 1 => array:3 [ "identificador" => "bib0035" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A rare association of myasthenia gravis and mitochondrial myopathy: a clinical, biochemical and morphologic study of one case" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "K. Plewnia" 1 => "M.T. Dotti" 2 => "A. Malandrini" 3 => "L. Manneschi" 4 => "C. 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