Malattie mitocondriali: coinvolgimento extraneurologico

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  • Malattie Mitocondriali: il coinvolgimento extraneurologicoCarlo Dionisi ViciUOC Patologia Metabolica, Ospedale Pediatrico Bambino GesRoma

  • Mayr JIMD 2015Le Malattie Mitocondriali sono MOLTO NUMEROSE

  • Le Malattie Mitocondriali sono MULTISISTEMICHE

  • NATURE REVIEWS | NEPHROLOGY 2016 Le Malattie Mitocondriali sono MULTISISTEMICHE

  • Alcune forme (raramente) si contraddistinguono per interessamento esclusivo di un singolo organo/apparato (es. cuore, rene, fegato)

    Frequentemente linteressamento di singoli organi/apparati associate a coinvolgimento del SNC/muscolo

    E possibile un interessamento differenziato nel tempo dei vari organi/apparati

    Le forme estremamente severe sono ad alto rischio di scompenso metabolico con insufficienza multiorgano

  • NATURE REVIEWS | NEPHROLOGY 2016 steroid-resistant nephrotic syndrome

  • Malattie Mitocondriali: il coinvolgimento epatico

  • Malattie Mitocondriali: il coinvolgimento epatico

    DeletionsK, H, E, CNS, MPancytopenia, hypoparathyroidism, RTAMPV17GI, CNS, MHypoglicemiaDGUOKE, K, CNS, MNeonatal cholestasis, hypoglycemia, opsoclonusSUCLG1MOF, CNS, MNeonatal multi organ failurePOLG1CNS, MLiver failure, seizures, poliodystrophyTWINKLECNS, MAtaxia, dev. delayTPGI, CNS, MMNGIE, liver steatosis

  • DGUOK & Neonatal hemochromatosis Liver disease onset in 1st week Hyperlactemia, hypoglycemia MRI or biopsy consistent with NNHFerritin levels 2000 and above DGUOK mutations Dimmock et. al./Human Mutation 2008 Feb;29(2):330-1 Birth weight between 5th-10th percentile Elevated Tyrosine on NBS Ferritin>900 Neurological symptoms (nystagmus, hypotonia, psychomotor delay) Moderate iron on liver DGUOK mutations


  • Long-Term SurvivorsThe 1-year survival rate was 64%. 5/14 LT patients with DGUOK deficiency (36%) survived for a long time (>5 years). The follow-up time for these survivors ranged from 5 to 23 years (mean513 years).3 hypotonia1 mild cognitive impairment1 ADHD2 renal signs5/5 harbored at least 1 mutation that predicted a DGUOK protein with some potential residual activity

    Non-survivors8/14 patients died within 2 years of LT, and 3 of these patients died in the context of severe pulmonary hypertension. 4/8 patients werereported to have severe progressive neurological disease before death. One patient had an onset of neurological disease after LT, and 1 patient died from postoperative multiorgan failure.8/8 were carriers of truncating mutations on both chromosomes

  • CI in MIDs includes cardiomyopathy, arrhythmias, heart failure, pulmonary hypertension, dilation of the aortic root, pericardial effusion, coronary heart disease, autonomous nervous system dysfunction, congenital heart defects, or sudden cardiac death. The most frequent among the cardiomyopathies is hypertrophic cardiomyopathy, followed by dilated cardiomyopathy and noncompaction.

  • Esordio ad 1 anno di cardiomiopatia ipertrofica

    Iperlattacidemia, intermedi del Krebs al dosaggio acidi organici urinari

    Difetto di COX e deplezione dellmt-DNA nel muscolo cardiaco ma non in quello scheletrico

    Alla BNGE riduzione CI e CIV, e difettoso assemblaggio CV

    Follow-up di >10 anni, controlli cardiaci, lieve ritardo cognitiveCardiomyopathy associated with a mitochondrial DNA depletion syndrome is a rare condition. We report on a child with a hypertrophic cardiomyopathy and a mitochondrial depletion syndrome who was successfully treated by heart transplantation, given the tissue-specificnature of her mitochondrial disorder.Esoma identifica mutazioni in ELAC2 (gene coinvolto nel processing dellmRNA mitocondriale)

  • At 3 months > worsening of his general conditions and failure to thrive. Physical examination: mild dysmorphic features, systolic murmur, hepatosplenomegalyRoutine blood tests revealed severe anemia without a hemolytic component

    Hb: 5.96.3 g/dl; RBC: 2.20 106 l; MCV: 91.6 fl, RET%: 2.68Metabolic acidosis and hyperlactacidemia (4.28.2 mmol/l).Bone marrow: non-specific abnormalities, notes of dyserythropoiesis

    Treatment with folic acid, iron and erythropoietin > no benefit > the patient required regular transfusional therapy with red cells from the age of 5 months

    The presence of ring sideroblasts, led to make the diagnosis of sideroblastic anemia

  • Le Malattie Mitocondriali sono MULTISISTEMICHE Nata ottobre 2005Anemia > pancitopenia - politrasfusa

    3 anni trapianto di midollo: anemia di Blackfand Diamond

  • Single large-scale mitochondrial DNA deletions (SLSMDs)Pearson marrowpancreas syndromeKearnsSayre syndrome (KSS),Chronic Progressive External Ophthalmoplegia (CPEO or (C)PEO-plus

  • Skin lesions in inherited metabolic diseasesVascular lesions

    Skin eruptions


    Papular and nodular

    skin lesions

    Abnormal pigmentation


    Hair disorders

    Skin Laxity

  • 3 pazienti ETHE1

  • 3 pazienti SURF1

  • *unpublished, presented at the EMG meeting Zurich 2014

  • Tortuosity and elongation of the arteriesRisk of aneurysm formation and vascular dissectionAberrant origin of aortic branches, pulmonary valve and pulmonary arteries stenosisOnset in childhood

    Soft/velvety/hyperextensible skin, cutis laxaJoint hypermobilityAbdominal herniasMildly dysmorphic facial features

    Mutations in SLC2A/Glut10

    Glut10 facilitates transport of D-glu, D-gal & dehydro ascorbic acid and is essential for cardiovasculardevelopment by facilitating both mitochondrial respiration and TGF signalingGLUT10/SLC2A: arterial tortuosity syndromeRitelli et al. BMC Med Genet 2014; Bhat J Clin Imag Sci 2014

  • Lassit cutanea: un nuovo segno clinicodi malattia mitocondriale ?