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Malattie Mitocondriali: il coinvolgimento extraneurologico
Carlo Dionisi ViciUOC Patologia Metabolica, Ospedale Pediatrico Bambino Gesù
Roma
Mayr JIMD 2015
Le 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 l’interessamento di singoli organi/apparati è 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
Deletions K, H, E, CNS, M Pancytopenia, hypoparathyroidism, RTA
MPV17 GI, CNS, M Hypoglicemia
DGUOK E, K, CNS, M Neonatal cholestasis, hypoglycemia, opsoclonus
SUCLG1 MOF, CNS, M Neonatal multi organ failure
POLG1 CNS, M Liver failure, seizures, poliodystrophy
TWINKLE CNS, M Ataxia, dev. delay
TP GI, CNS, M MNGIE, liver steatosis
DGUOK & Neonatal hemochromatosis
• Liver disease onset in 1st week• Hyperlactemia, hypoglycemia• MRI or biopsy consistent with NNH•Ferritin 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 SurvivorsLong-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 hypotonia•1 mild cognitive impairment•1 ADHD•2 renal signs•5/5 harbored at least 1 mutation that predicted a DGUOK protein with some potential residual activity
Non-survivorsNon-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 dell’mt-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 cognitive
Cardiomyopathy 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 dell’mRNA mitocondriale)
• At 3 months > worsening of his general conditions and failure to thrive. • Physical examination: mild dysmorphic features, systolic murmur,
hepatosplenomegaly• Routine blood tests revealed severe anemia without a hemolytic component Hb: 5.9–6.3 g/dl; RBC: 2.20 × 106 μl; MCV: 91.6 fl, RET%: 2.68• Metabolic acidosis and hyperlactacidemia (4.2–8.2 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 2005•Anemia > pancitopenia - politrasfusa 3 anni trapianto di midollo: anemia di Blackfand Diamondanemia di Blackfand Diamond
• Ipocalcemia > ipoparatiroidismo secondario a emosiderosisecondario a emosiderosi
• Deficit di crescita, stipsi, difficoltà alimentazione > PEG
• Shock ipovolemico in corso di sepsi > IRA Acidosi tubulare renale secondaria a pregressa IRAsecondaria a pregressa IRA
• Anomalie ecografiche fegato e pancreas
• Deficit intellettivo Ptosi palpebrale Distrofia retinica Tremori• RM diffusa atrofia cerebrale, lesioni nuclei della base, picco lattato
Maggio 2016 > Siondrome di Pearson - common deletion positiva su fibro (40%) e urine (68%)Maggio 2016 > Siondrome di Pearson - common deletion positiva su fibro (40%) e urine (68%)
Single large-scale mitochondrial DNA deletions (SLSMDs)•Pearson marrow–pancreas syndrome•Kearns–Sayre syndrome (KSS),•Chronic Progressive External Ophthalmoplegia (CPEO or (C)PEO-plus
Skin lesions in inherited metabolic diseases
• Vascular lesions
• Skin eruptions
• Ichthyosis
• Papular and nodular skin lesions
• Abnormal pigmentation
• Photosensitivity
• Hair disorders
• Skin Laxity
3 pazienti ETHE1
3 pazienti SURF1
*unpublished, presented at the EMG meeting Zurich 2014
• Tortuosity and elongation of the arteries• Risk of aneurysm formation and vascular dissection• Aberrant origin of aortic branches, pulmonary valve
and pulmonary arteries stenosis• Onset in childhood
• Soft/velvety/hyperextensible skin, cutis laxa• Joint hypermobility• Abdominal hernias• Mildly dysmorphic facial features
• Mutations in SLC2A/Glut10
• Glut10 facilitates transport of D-glu, D-gal & dehydro ascorbic acid and is essential for cardiovascular
development by facilitating both mitochondrial respiration and TGFβ signaling
GLUT10/SLC2A: arterial tortuosity syndrome
Ritelli et al. BMC Med Genet 2014; Bhat J Clin Imag Sci 2014
Lassità cutanea: un nuovo segno clinicodi malattia mitocondriale ?
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