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:/fibroblasts 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