Enrico Bertini, Convegno Mitocon 2014
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Enrico Bertini, Convegno Mitocon 2014 Enrico Bertini, Convegno Mitocon 2014 Presentation Transcript

  • Encefalopatie ed epatopatie nelle patologia mitocondriali Dr. Enrico Bertini, OBG Hospital, Rome, Italy bertini@opbg.net
  • Clinical, biochemical and neuroimaging Classification • Leigh syndromes • Encephalopathy and recurrent Strokes • Encephalopathy and ataxia • Developmental malformations • Leukodystrophies • Poliodystrophies • Pan-encephalopathies Mitochondrial Encephalopathies
  • Leigh syndromes Disease Abbreviation MIM # Gene Hints from clinical findings or routine studies Diagnostic tests Leigh syndrome LS MILS MtDNA LS 256000 ND1-ND6 CO3 ATP6 tRNA Leu tRNA Lys tRNA Trp tRNA Val MRI: pattern characteristic, (MRS): lactate elevated Complex I defect Complex III defect Complex IV defect Complex V defect MolGenet Leigh syndrome nDNA LS 20111 603647 600857 602694 609653 602137 238331 612392 185620 603646 603846 161015 602141 613622 601825 SUCLA2 SUCLG1 BCS1L NDUFS4 NDUFAF2 NDUFA2 NDUFS3 NDUFV1 NDUFA9 NDUFS8 NDUFS7 NDUFAF5 NDUFAF6 NDUFA10 SURF-1 PDH DLD SDHA C8orf38 COX15 COX10 FOXRED1 LRPPRC TACO1 C12orf65 MTFMT NDUFA12 MRI: pattern characteristic, (MRS): lactate elevated Complex I defect Complex II defect Complex III defect Complex IV defect Complex V defect MG Biochemistry
  • 2002 2008 2009 2008 2009 9 year old female, ND5 13513G>A
  • MTT: mamillothalamic tracts ML: medial lemniscus STT: spinothalamic tracts FG: fasciculus gracilis MLF: medial longitudinal fasciculus NDUFA12L female girl, consanguinity, complex 1 defect Barghuti et al; Molecular Genetics and Metabolism 94 (2008) 78–82
  • NDUFV1, boy, consangunity, complex I defect Vilain et al., Clin Genet, 2011
  • LRPPRC; Leigh syndrome with cytochrome c oxidase deficiency Debray et al., J Med Genet 2011;48:183-189
  • Encephalopathy and recurrent Strokes Disease Abeviation MIM # Gene Hints from clinical findings or routine studies Diagnostic tests MELAS MT TK 611105 tRNA Le 3243u MRI: pattern characteristic, (MRS): lactate elevated MG MELAS/MERFF MTTL 590060 tRNA Lys T8356C same MG MELAS MTTF 590070 tRNA Phe G583A same MG MELAS/MERFF MTTH, 590040 tRNA His G12147A same MG MELAS MTTQ 590030 tRNA Glu 1-BP INS, 4366A same MG MELAS/ Pakinsonism MTCYB 516020 Cytb 4-bp deletion same MG MELAS MTND3-MTND5 516002 516003 516006 ND3-ND5 same MG Encephalopathy MTDPS4A 271245 POLG1 MRI: pattern characteristic, (MRS): lactate elevated MG
  • 8 year old Male, one brother and 2 affected cousins MELAS 3243 tRNA LEU (50% in blood) 2004 2003
  • Encephalopathy and ataxia Disease Abbreviation MIM # Gene Hints from clinical findings or routine studies Diagnostic tests Mitochondrial encephalopathy ragged red fibres MERFF 545000 A8344G mtDNA tRNA Lys MRI: pattern characteristic, (MRS): lactate elevated MG Sensory ataxia with neuropathy, dysarthria and ophthalmoparesis SANDO 607459 POLG1 MRI: cerebellar atrophy, neuropathy MG Mitochondrial recessive ataxia syndrome MIRAS 607459 POLG1 MRI: cerebellar atrophy MG Ubiquinone deficiency with cerebellar ataxia and seizures CABC1/COQ8 606980 ADK3 MRI: cerebellar atrophy Muscle:biopsy:/fibrobl asts reduction CoQ10 MG Infantile-onset spinocerebellar ataxia IOSCA/MTDPS7 606075 Twinkle C10orf2 Ataxia, neuropathy MG
  • Developmental malformations Disease Abbreviation MIM # Gene Hints from clinical findings or routine studies Diagnostic tests PDH deficiency PDH defect 300502 Ε1α MRI: CC disgenesis; cerebral atrophy (MRS): lactate elevated MG Cerebellar hypoplasia and brainstem thinning mtDNA deletion MRI: CC dysgenesis; cerebellar hypoplasia; brainstem hypoplasia MG Neonatal onset lactic acidosis/fetal disruption syndrome Complex I and IV def. ? Microcephaly; MRI: ependimal cysts; cortical heterotopia; polymicrogyria; agenesis CC MRI; biochemistry Mitochondrial elongation factor EFTu EFTu 602389 EFTu MRI: cystic lesions, affecting basal ganglia MG
  • Female. PDH deficiency, epilepsy refractory to AED treatement
  • mtDNA deletion, 2 yar old female Biancheri et al., J Inherit Metab Dis. 2011
  • Neonatal onset lactis acidosis/fetal disruption syndrome
  • Leukodystrophies Leukodystrophy Abbreviation MIM # Gene Hints from clinical findings/ studies Diagnostic tests Leukoencephalopathy with Brain stem and Spinal cord Involvement and elevated Lactate LBSL 611105 DARS2 MRI: pattern characteristic, (MRS): lactate elevated MG Progressive cavitating leukoencephalopathy PCL NDUFS1 COX6B1 A8344G mtDNA C6ORF66 NDUFV1 MRI: cystic lesions, affecting corpus callosum MG Succinate dehydrogenase def. SDH 612848 SDHAF1 MRI: vacuolating leukodystrophy MG Complex 1 defect riboflavin responsive NDUFS1 NDUFV1 MRI: vacuolating leukodystrophy MG Leigh Syndrome with prominent leukodystrophy MIT 185620 SURF1 MRI: vacuolating leukodystrophy MG Mitochondrial elongation factor EFTu EFTu 602389 EFTu MRI: cystic lesions, affecting basal ganglia MG
  • Gene Inheritance Protein function Biochemical defects NDUFV1, NDUFS1 AR Subunits of complex I Complex I NUBPL AR Incorporating the Fe/S clusters into complex I Complex I SDHAF1 AR Complex II assembly factor Complex II SURF1 AR understood, probably to stabilize subcomplexes during complex IV assembly Complex IV COX6B1 AR Subunits of complex IV Complex IV EF-Tu AR Mitochondrial elongation factor Multiple MRC EGF1 AR Mitochondrial elongation factor Multiple MRC PDHA1 X-linked α subunit of the first catalytic enzyme of the PDHC PDHC DARS2 AR Aspartyl-tRNA synthetase Biochemical inconsistency EARS2 AR Glutamate-tRNA synthetase Multiple MRC TYMP-MNGIE AR thymidine phosphorylase Multiple MRC and multiple deletions Mitochondrial disorders presenting as Leukoencephalopathy
  • Suc Lac
  • Van der Knapp et al. Annals of Neurol. 2003; 53:252-258 Leukoencephalopathy with Brain stem and Spinal cord Involvement and elevated Lactate
  • PCL: Pt 2 SC Female Sib/Pt1 Ages 3, 5&7 yrs PCL: Pt 2 SC Female Sib/Pt1 Ages 3, 5&7 yrs 1991 1994 1996
  • CSF CENTRUM SEMIOVALE CYST CENTRUM SEMIOVALE GRAY MATTER P55296.3.15.15.001 PPM 4.0 3.0 2.0 1.0 P55296.3.13.16.001 PPM 4.0 3.0 2.0 1.0 P55296.3.15.21.001 PPM 4.0 3.0 2.0 1.0 P55296.3.18.9.001 PPM 4.0 3.0 2.0 1.0 P55296.3.19.16.001 PPM 4.0 3.0 2.0 1.0 Cho Cr NAA Lac Lac Lac PCL:Pt 4, MD, F, 33 m
  • Pt 9
  • A B C Pt. 7
  • Pt. 10
  • Ferreira et al., Neurogenetics, 2011 NDUFS1 (p.Thr595Ala)
  • C6ORF66-NDUFAF4, fatal panencephalopathy, consanguinty, neonatal lactic acidosis Saada et al., The American Journal of Human Genetics, 2009 84: 718–727
  • EARS
  • Poliodystrophies Disease Abbreviati on MIM # Gene Hints from clinical findings or routine studies Diagnostic tests Alpers syndrome MTDPS4A 271245 POLG1 MRI pattern , (MRS): lactate elevated MG Alpers syndrome Combined oxidative phosphorylation deficiency 14 #614946 FARS2 MRI pattern MG PDH deficiency PDH 300502 E1α MRI: cortical atrophy; (MRS): lactate elevated MG Mitochondrial aspartate– glutamate carrier isoform 1 AGC1 612949 AGC1 MRI: cortical atrophy MG Mitochondrial Hsp60 Chaperon HSP60 612233 MRI: cortical atrophy and hypomyelination MG Mitochondrial elongation factor G1 GFM1 606639 GFM1 MRI: cortical atrophy MG X-linked Mitochondrial Encephalomyopathy/ Cowchock syndrome Combined oxidative phosphorylation deficiency 6 *300169 AIFM1 MRI: cortical atrophy Neurogenic atrophy MG; COX defect
  • 7 year old girl, Alpers syndrome, POLG heterozygous mutation 2 year old girl, PDH defect
  • Hsp60 chaperonopathy Magen et al., Am J Hum Genet 83, 30–42, July 2008 AGC1 Deficiency Wibom et al., N Engl J Med 2009;361:489-95.
  • Pan-encephalopathies Abbreviation MIM # Gene Hints from clinical findings or routine studies Diagnostic tests Severe neonatal panenecephalopathy with intractable seizures PCH6 611523 RARS2 MRI: pattern characteristic, (MRS): lactate elevated MG Mutant deoxynucleotide carrier Amish microcephaly MCPHA 607196 MCPHA MRI: simplified gyral patter, PCH high concentrations of urinary α- ketoglutarate MG Progressive cerebellocerebral atrophy PCCA 613811 SepSecS MRI: cortical atrophy and cerebella r atrophy MG
  • PCCA/SepSecs Agamy et al., Am J Hum Gene87, 538–544, October 8, 2010
  • Siu et al., Am J Med Genet Part A 152A:1747–175, 2010. Amish Microcephaly Kelley et al., Am J Med Genet Part A 112:318–326, 2002.
  • Hepatocerebral syndromes #203700 Mitochondrial DNA depletion syndrome 4 (ALPERS) POLG #256810 Mitochondrial DNA depletion syndrome 6 MPV17 *606075 Mitochondrial DNA Depletion Syndrome 7 TWINKLE C10ORF2 #614946 Combined oxidative phosphorylation deficiency 14 FARS2 (PheRS) Leigh syndrome #220111 Leigh syndrome, French-Canadian type; LSFC (COX defect) LRPPRC Myopathic type and Leigh syndrome type with hepathopathy #614739 MEGDEL or MEGDHEL SERAC1 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome Liver failure #251880 Mitochondrial DNA depletion syndrome 3 (hepatocerebral type) DGUOK Transient Liver failure *610230 Liver failure, transient infantile TRMU *191330 Mitochondrial complex III deficiency, nuclear type 3 UQCRB Mitochondrial Hepatopathies Clinical, and biochemical classification
  • Other syndromes #124000 Mitochondrial complex III deficiency, nuclear type 1 BCS1L • Encephalopathy, and delayed psychomotor development. Visceral involvement, including hepatopathy and renal tubulopathy. • GRACILE (growth retardation, amino aciduria, cholestasis, iron overload, lactic acidosis, and early death) • Bjornstad syndrome sensorineural hearing loss and pili torti. #611126 ACAD9 deficiency acyl-CoA dehydrogenase-9 acute metabolic acidosis, hypertrophic cardiomyopathy, and muscle weakness associated with a deficiency of mitochondrial complex I activity in muscle, liver, Liver failure – HCM #615595 Combined oxidative phosphorylation deficiency 19 LYRM4 One family Lebanese and Syrian ancestry : respiratory distress, hypotonia, and severe lactic acidosis in the newborn period; slow improvement #609060 Combined oxidative phosphorylation deficiency 1 GFM1 mitochondrial elongation factor G1 Early fatal progressive hepatoencephalopathy
  • Laboratory of Molecular Medicine Rosalba Carrozzo, PhD Fiorella Piemonte, PhD Giulia Tozzi, PhD Alessandra Torraco, PhD Maria Chiara Meschini, PhD Marzia Bianchi. PhD Teresa Rizza, PhD Daniela Verrigni, PhD Unit of Metabolic Disease Carlo Dionisi Vici, MD Diego Martinelli, MD