{"orpha":457406,"name":"Multiple mitochondrial dysfunctions syndrome type 4","type":"Disease","group":"Disorder","status":"active","flags":[],"synonyms":["MMDS4"],"definition":"A rare, severe, genetic, neurometabolic disease characterized by infantile-onset of progressive neurodevelopmental regression, optic atrophy with nystagmus and diffuse white matter disease. Affected individuals usually have central hypotonia that progresses to limb spasticity and hyperreflexia, eventually resulting in a vegetative state. Recurrent chest infections are frequently associated and seizures (usually generalized tonic-clonic) may occasionally be observed. Brain magnetic resonance imaging shows diffuse bilateral symmetric abnormalities in the cerebral periventricular white matter, with variable lesions in other areas but sparing the basal ganglia.","note":null,"url":"https://raremap.alftech.space/d/ORPHA-457406/","orphanet_url":"https://www.orpha.net/en/disease/detail/457406","names":{"fr":{"name":"Syndrome de dysfonctionnements mitochondriaux multiples type 4","definition":"Maladie neurométabolique rare, grave, d'origine génétique, caractérisée par une régression progressive du développement neurologique à début infantile, une atrophie optique avec nystagmus et une atteinte diffuse de la substance blanche. Les personnes touchées présentent généralement une hypotonie centrale qui évolue vers une spasticité et une hyperréflexie des membres et qui aboutit à un état végétatif. Des infections récurrentes des voies respiratoires sont fréquemment associées et des convulsions (généralement tonico-cloniques généralisées) peuvent être observées dans certains cas. L'imagerie par résonance magnétique cérébrale met en évidence des anomalies symétriques bilatérales diffuses de la substance blanche cérébrale périventriculaire, et des lésions variables affectant d'autres zones mais épargnant les ganglions de la base."},"de":{"name":"Syndrom der multiplen mitochondrialen Dysfunktionen Typ 4","definition":"Eine seltene, schwere, genetisch bedingte neurometabolische Erkrankung, die durch eine im Kindesalter beginnende, progressive Rückbildung der neurologischen Entwicklung, Optikusatrophie mit Nystagmus und diffuser Erkrankung der weißen Substanz gekennzeichnet ist. Betroffene Personen haben in der Regel eine zentrale Hypotonie, die zu einer Spastik der Gliedmaßen und Hyperreflexie fortschreitet und schließlich zu einem vegetativen Zustand führt. Rezidivierende Brustinfektionen sind häufig assoziiert und gelegentlich können Krampfanfälle (meist generalisierte tonisch-klonische) beobachtet werden. Die Magnetresonanztomographie des Gehirns zeigt diffuse bilaterale symmetrische Anomalien in der zerebralen periventrikulären weißen Substanz, mit variablen Läsionen in anderen Bereichen, wobei die Basalganglien verschont bleiben."},"es":{"name":"Síndrome de disfunción mitocondrial múltiple tipo 4","definition":"Es una enfermedad neurometabólica grave, de origen genético y poco frecuente, caracterizada por el inicio en la lactancia de una regresión progresiva del neurodesarrollo, atrofia óptica con nistagmo y enfermedad difusa de la sustancia blanca. Por lo general, los individuos afectados presentan hipotonía central que progresa a espasticidad e hiperreflexia de las extremidades, evolucionando eventualmente hacia un estado vegetativo. El síndrome se asocia con frecuencia a infecciones torácicas recurrentes y en ocasiones se pueden observar crisis epilépticas (por lo general tónico-clónicas generalizadas). La RM cerebral muestra anomalías simétricas bilaterales difusas en la sustancia blanca periventricular con lesiones variables en otras áreas, aunque con conservación de los ganglios basales."},"it":{"name":"Sindrome da disfunzioni mitocondriali multiple tipo 4","definition":"Si tratta di una malattia neurometabolica genetica rara e grave, che esordisce nella prima infanzia con regressione progressiva dello sviluppo neurologico, atrofia ottica con nistagmo e alterazioni diffuse della sostanza bianca. Di solito i pazienti presentano ipotonia centrale che progredisce nella spasticità degli arti e nell'iperreflessia, esitando in uno stato vegetativo. Spesso si associa ad infezioni toraciche ricorrenti e, occasionalmente, a crisi epilettiche (di solito tonico-cloniche generalizzate). La risonanza magnetica del cervello evidenzia anomalie simmetriche bilaterali diffuse nella sostanza bianca cerebrale periventricolare, e lesioni variabili localizzate in altre aree (ad eccezione dei gangli basali)."},"nl":{"name":"Multipele mitochondriale disfuncties-syndroom type 4","definition":"Een zeldzame, ernstige, genetische, neurometabole ziekte gekarakteriseerd door infantiele aanvang van progressieve regressie van de neurologische ontwikkeling, opticusatrofie met nystagmus en diffuse wittestofziekte. Getroffen individuen hebben meestal centrale hypotonie die evolueert tot spasticiteit en hyperreflexie van de ledematen, en uiteindelijk leidt tot een vegetatieve toestand. Recurrente infecties van de borst zijn frequent geassocieerd en insulten (meestal gegeneraliseerd tonisch-clonisch) kunnen occasioneel waargenomen worden. Beeldvorming van de hersenen met magnetische resonantie toont diffuse, bilaterale, symmetrische afwijkingen in de cerebrale periventriculaire witte stof, met variabele letsels in andere gebieden maar niet aan de basale ganglia."},"pt":{"name":"Síndrome de disfunção mitocondrial múltipla, forma fatal tipo 4"},"pl":{"name":"Śmiertelny zespół mnogich dysfunkcji mitochondrialnych typu 4","synonyms":["MMDS4"]},"cs":{"name":"Syndrom fatálních mnohočetných mitochondriálních dysfunkcí, typ 4","synonyms":["MMDS4"]},"uk":{"name":"Синдром множинних мітохондріальних дисфункцій, тип 4","synonyms":["MMDS4"],"definition":"A rare, severe, genetic, neurometabolic disease characterized by infantile-onset of progressive neurodevelopmental regression, optic atrophy with nystagmus and diffuse white matter disease. Affected individuals usually have central hypotonia that progresses to limb spasticity and hyperreflexia, eventually resulting in a vegetative state. Recurrent chest infections are frequently associated and seizures (usually generalized tonic-clonic) may occasionally be observed. Brain magnetic resonance imaging shows diffuse bilateral symmetric abnormalities in the cerebral periventricular white matter, with variable lesions in other areas but sparing the basal ganglia."},"zh":{"name":"多发性线粒体功能障碍综合征4型","synonyms":["MMDS4"],"definition":"一种罕见严重的遗传性神经代谢性疾病，其特征是婴儿期开始的进行性神经发育退行、视神经萎缩伴眼球震颤和弥漫性白质疾病。受影响者通常有中枢性肌张力低下，并进展为肢体痉挛和反射亢进，最终导致植物人状态。常伴有反复的胸部感染，偶尔可观察到癫痫发作（通常为全身性强直-阵挛）。脑磁共振成像显示脑室周围白质呈弥漫性双侧对称性异常，其他区域病变不一，但基底节不受影响。"},"tr":{"name":"Çoklu mitokondriyal disfonksiyon sendromu tip 4","synonyms":["MMDS4"]}},"xrefs":[{"source":"OMIM","code":"616370","qualifier":"E","icd_relation":null,"validated":true},{"source":"ICD-10","code":"E88.8","qualifier":"NTBT","icd_relation":"attributed","validated":true},{"source":"ICD-11","code":"5C53.2Y","qualifier":"NTBT","icd_relation":"attributed","validated":true,"icd11_uri":"null"},{"source":"MONDO","code":"0014611","qualifier":"E","icd_relation":null,"validated":true},{"source":"UMLS","code":"C4225348","qualifier":"E","icd_relation":null,"validated":true}],"associations":[],"incoming_associations":[],"preferential_parent":{"orpha":68367,"name":"Rare inborn error of metabolism"},"parents":[{"orpha":183500,"name":"Genetic neurodegenerative disease","classifications":[156]},{"orpha":68356,"name":"Leukodystrophy","classifications":[156,181]},{"orpha":289573,"name":"Multiple mitochondrial dysfunctions syndrome","classifications":[150,156,181]},{"orpha":182070,"name":"Rare neurodegenerative disease","classifications":[181]},{"orpha":441434,"name":"Syndromic hereditary optic neuropathy","classifications":[156,189]}],"children":[],"genes":[{"symbol":"ISCA2","name":"iron-sulfur cluster assembly 2","gene_type":"gene with protein product","association":"Disease-causing germline mutation(s) in","status":"Assessed","source":"25539947[PMID]","hgnc":"19857","ensembl":"ENSG00000165898","omim":"615317","loci":["14q24.3"]}],"genes_via_subtypes":[],"inheritance":["Autosomal recessive"],"onset":["Infancy"],"prevalence":[{"type":"Cases/families","qualification":"Case(s)","class":null,"value":8.0,"area":"Worldwide","status":"Validated","source":"25539947[PMID]"},{"type":"Point prevalence","qualification":"Class only","class":"<1 / 1 000 000","value":0.0,"area":"Worldwide","status":"Validated","source":"ORPHANET_25539947[PMID]"}],"phenotypes":{"validation_status":"y","online":"y","validation_date":"2026-01-30","source":"32424628[PMID]_31106229[PMID]_31279336[PMID]_29470032[PMID]","terms":[{"hpo":"HP:0034353","label":"Appendicular spasticity","frequency":"Very frequent (99-80%)","criteria":null},{"hpo":"HP:0002376","label":"Developmental regression","frequency":"Very frequent (99-80%)","criteria":null},{"hpo":"HP:0001263","label":"Global developmental delay","frequency":"Very frequent (99-80%)","criteria":null},{"hpo":"HP:0000648","label":"Optic atrophy","frequency":"Very frequent (99-80%)","criteria":null},{"hpo":"HP:0000572","label":"Visual loss","frequency":"Very frequent (99-80%)","criteria":null},{"hpo":"HP:0001252","label":"Hypotonia","frequency":"Frequent (79-30%)","criteria":null},{"hpo":"HP:0002415","label":"Leukodystrophy","frequency":"Frequent (79-30%)","criteria":null},{"hpo":"HP:0000639","label":"Nystagmus","frequency":"Frequent (79-30%)","criteria":null},{"hpo":"HP:0031358","label":"Vegetative state","frequency":"Frequent (79-30%)","criteria":null},{"hpo":"HP:0008314","label":"Decreased activity of mitochondrial complex II","frequency":"Occasional (29-5%)","criteria":null},{"hpo":"HP:0008347","label":"Decreased activity of mitochondrial complex IV","frequency":"Occasional (29-5%)","criteria":null},{"hpo":"HP:0001332","label":"Dystonia","frequency":"Occasional (29-5%)","criteria":null},{"hpo":"HP:0034893","label":"Elevated brain glycine level by MRS","frequency":"Occasional (29-5%)","criteria":null},{"hpo":"HP:0012707","label":"Elevated brain lactate level by MRS","frequency":"Occasional (29-5%)","criteria":null},{"hpo":"HP:0002154","label":"Hyperglycinemia","frequency":"Occasional (29-5%)","criteria":null},{"hpo":"HP:0001347","label":"Hyperreflexia","frequency":"Occasional (29-5%)","criteria":null},{"hpo":"HP:0500200","label":"Increased CSF glutamate concentration","frequency":"Occasional (29-5%)","criteria":null},{"hpo":"HP:0500230","label":"Increased CSF glycine concentration","frequency":"Occasional (29-5%)","criteria":null},{"hpo":"HP:0002490","label":"Increased CSF lactate","frequency":"Occasional (29-5%)","criteria":null},{"hpo":"HP:0002151","label":"Increased circulating lactate concentration","frequency":"Occasional (29-5%)","criteria":null},{"hpo":"HP:0002205","label":"Recurrent respiratory infections","frequency":"Occasional (29-5%)","criteria":null},{"hpo":"HP:0001250","label":"Seizure","frequency":"Occasional (29-5%)","criteria":null}]}}