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 ?