Klinische FragestellungLeigh-Syndrom, Differentialdiagnose

NGS +

[[Sanger]]

Das Leigh-Syndrom (LS) ist eine schwere neurologische Störung, die in der Regel im ersten Lebensjahr auftritt. Die Erkrankung ist durch fortschreitende psychomotorische Regression gekennzeichnet und führt in der Regel innerhalb von 2-3 Jahren zum Tod, oft aufgrund von Atemversagen. Bei einer kleinen Anzahl von Patienten treten die Symptome erst im Erwachsenenalter auf oder sie verschlimmern sich langsamer. Erste Anzeichen für LS sind in der Regel Erbrechen, Durchfall und Schluckstörungen sowie später Gedeihstörungen. Schwere Muskel- und Bewegungsprobleme sind ebenfalls häufig. Betroffene Personen können Hypotonie, Dystonie, Ataxie und periphere Neuropathie entwickeln. Viele Betroffene weisen eine Ophthalmoparese, Nystagmus oder eine Optikusatrophie auf. Schwere Atemprobleme sind häufig und können zu akutem Atemversagen führen. Einige Patienten entwickeln eine hypertrophe Kardiomyopathie und Laktazidose. Diese Symptome werden zum Teil durch Läsionen im Gehirn (Basalganglien, Kleinhirn, Hirnstamm) durch Demyelinisierung verursacht. LS kann durch Varianten in einem von ~100 verschiedenen Kern-Genen verursacht werden, ~20% der LS-Fälle weisen eine Variante in der mtDNA auf. Die meisten Gene, die mit LS in Verbindung gebracht werden, sind am Prozess der Energie-Erzeugung in den Mitochondrien beteiligt. Eines der am häufigsten veränderten Kern-Gene beim LS ist SURF1, das Vererbungsmuster ist in der Regel autosomal rezessiv. Da die diagnostische Ausbeute mittels Molekulargenetik bei LS-Fällen kaum mehr als 60% beträgt, kann ein negatives DNA-Testergebnis die klinische Diagnose nicht ausschließen.

Referenz: https://www.ncbi.nlm.nih.gov/books/NBK320989/

https://www.ncbi.nlm.nih.gov/books/NBK1173/

• Alias: Leigh syndrome due to mitochondrial complex I-V deficiency
• Allelic: Bjornstad syndrome (BCS1L)
• Allelic: Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2 (COX15)
• Allelic: Cardiomyopathy, dilated, 1GG (SDHA)
• Allelic: Cataract 38, AR (AGK)
• Allelic: Charcot-Marie-Tooth disease, axonal, type 2EE (MPV14)
• Allelic: Charcot-Marie-Tooth disease, axonal, types 2A2A + 2A2B (MFN2)
• Allelic: Charcot-Marie-Tooth disease, type 4K (SURF1)
• Allelic: Deafness, AR 70 (PNPT1)
• Allelic: Deafness, AR 94 (NARS2)
• Allelic: Deafness, AR 94 (NDUFA4)
• Allelic: Deafness, mitochondrial, modifier of (TRMU)
• Allelic: Fanconi renotubular syndrome 5 (NDUFAF2, NDUFAF6)
• Allelic: GRACILE syndrome (BCS1L)
• Allelic: Glaucoma, normal tension, susceptibility to (OPA1)
• Allelic: Hereditary motor + sensory neuropathy VIA (MFN2)
• Allelic: Leukoencephalopathy, progressive, with ovarian failure (AARS2)
• Allelic: Liver failure, transient infantile (TRMU)
• Allelic: Microcephaly, Amish type (SLC25A19)
• Allelic: Multiple system atrophy, susceptibility to (COQ2)
• Allelic: Myopia 6 (SCO2)
• Allelic: Neuropathy, hereditary motor + sensory, type VIB (SLC25A46)
• Allelic: Optic atrophy 1 (OPA1)
• Allelic: Optic atrophy 12 (AFG3L2)
• Allelic: Optic atrophy plus syndrome (OPA1)
• Allelic: Paragangliomas 5 (SDHA)
• Allelic: Perrault syndrome 5 (TWNK)
• Allelic: Portal hypertension, noncirrhotic, 1 (DGUOK)
• Allelic: Seckel syndrome 8 (DNA2)
• Allelic: Spastic ataxia 5, AR (AFG3L2)
• Allelic: Spinocerebellar ataxia 28 (AFG3L2)
• 3-hydroxyisobutryl-CoA hydrolase deficiency (HIBCH)
• 3-methylglutaconic aciduria with deafness, encephalopathy + Leigh-like syndrome (SERAC1)
• 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement + neutropenia (CLPB)
• Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia (APTX)
• Behr syndrome (OPA1)
• Biotinidase deficiency (BTD)
• Cataracts/growth hormone deficiency/sensory neuropathy/sensorineur. hear loss/skel. dyspl. (IARS2)
• Coenzyme Q10 deficiency, primary, 1 (COQ2)
• Coenzyme Q10 deficiency, primary, 2 (PDSS1)
• Coenzyme Q10 deficiency, primary, 3 (PDSS2)
• Coenzyme Q10 deficiency, primary, 4 (COQ8A)
• Coenzyme Q10 deficiency, primary, 5 (COQ9)
• Coenzyme Q10 deficiency, primary, 6 (COQ6)
• Coenzyme Q10 deficiency, primary, 7 (COQ4)
• Combined oxidative phosphorylation deficiency 1 (GFM1)
• Combined oxidative phosphorylation deficiency 12 (EARS2)
• Combined oxidative phosphorylation deficiency 13 (PNPT1)
• Combined oxidative phosphorylation deficiency 14 (FARS2)
• Combined oxidative phosphorylation deficiency 15 (MTFMT)
• Combined oxidative phosphorylation deficiency 23 (GTPBT3)
• Combined oxidative phosphorylation deficiency 24 (NARS2)
• Combined oxidative phosphorylation deficiency 3 (TSFM)
• Combined oxidative phosphorylation deficiency 32 (MRPS34)
• Combined oxidative phosphorylation deficiency 39 (GFM2)
• Combined oxidative phosphorylation deficiency 51 (PTCD3)
• Combined oxidative phosphorylation deficiency 7 (MTRFR)
• Combined oxidative phosphorylation deficiency 8 (AARS2)
• Congenital disorder of glycosylation, type IIn (SLC39A8)
• Dihydrolipoamide dehydrogenase deficiency (DLD)
• Encephalopathy due to defective mitochondrial + peroxisomal fission 2 (MFF)
• Ethylmalonic encephalopathy (ETHE1)
• GABA-transaminase deficiency (ABAT)
• Glutaric acidemia IIC (ETFDH)
• Hyperglycinemia, lactic acidosis + seizures (LIAS)
• Lacticacidemia due to PDX1 deficiency (PDHX)
• Leigh syndrome (BCS1L, SDHA)
• Leigh syndrome due to cytochrome c oxidase deficiency (COX15)
• Leigh syndrome due to mitochondrial COX4 deficiency (COX10)
• Leigh syndrome, due to COX IV deficiency (SURF1)
• Lipoyltransferase 1 deficiency (LIPT1)
• Mitochondrial DNA depletion syndrome 1, MNGIE type (TYMP)
• Mitochondrial DNA depletion syndrome 11 (MGME1)
• Mitochondrial DNA depletion syndrome 12A, cardiomyopathic type, AD (SLC25A4)
• Mitochondrial DNA depletion syndrome 12B, cardiomyopathic type) AR (SLC25A4)
• Mitochondrial DNA depletion syndrome 13, encephalomyopathic type (FBXL4)
• Mitochondrial DNA depletion syndrome 14, encephalocardiomyopathic type (OPA1)
• Mitochondrial DNA depletion syndrome 15, hepatocerebral type (TFAM)
• Mitochondrial DNA depletion syndrome 16, hepatic type (POLG2)
• Mitochondrial DNA depletion syndrome 16B, neuroophthalmic type (POLG2)
• Mitochondrial DNA depletion syndrome 18 (SLC25A21)
• Mitochondrial DNA depletion syndrome 2, myopathic type (TK2)
• Mitochondrial DNA depletion syndrome 3, hepatocerebral type (DGUOK)
• Mitochondrial DNA depletion syndrome 4A, Alpers type + 4B, MNGIE type (POLG)
• Mitochondrial DNA depletion syndrome 5, encephalomyopathic +/- methylmalonic aciduria (SUCLA2)
• Mitochondrial DNA depletion syndrome 6, hepatocerebral type (MPV14)
• Mitochondrial DNA depletion syndrome 7, hepatocerebral type (TWNK)
• Mitochondrial DNA depletion syndrome 8A, encephalomyopathic type with renal tubulopathy (RRM2B)
• Mitochondrial DNA depletion syndrome 8B, MNGIE type (RRM2B)
• Mitochondrial DNA depletion syndrome 9, encephalomyopathic type + methylmalonic aciduria (SUCLG1)
• Mitochondrial complex I deficiency, nuclear type 1 (NDUFS4)
• Mitochondrial complex I deficiency, nuclear type 13 (NDUFA2)
• Mitochondrial complex I deficiency, nuclear type 15 (NDUFAF4)
• Mitochondrial complex I deficiency, nuclear type 16 (NDUFAF5)
• Mitochondrial complex I deficiency, nuclear type 17 (NDUFAF2, NDUFAF6)
• Mitochondrial complex I deficiency, nuclear type 19 (FOXRED1)
• Mitochondrial complex I deficiency, nuclear type 2 (NDUFS8)
• Mitochondrial complex I deficiency, nuclear type 20 (ACAD9)
• Mitochondrial complex I deficiency, nuclear type 21 (NUBPL)
• Mitochondrial complex I deficiency, nuclear type 22 (NDUFA10)
• Mitochondrial complex I deficiency, nuclear type 23 (NDUFA12)
• Mitochondrial complex I deficiency, nuclear type 26 (NDUFA9)
• Mitochondrial complex I deficiency, nuclear type 27 (MTFMT)
• Mitochondrial complex I deficiency, nuclear type 3 (NDUFS7)
• Mitochondrial complex I deficiency, nuclear type 31 (TIMMDC1)
• Mitochondrial complex I deficiency, nuclear type 34 (NDUFAF8)
• Mitochondrial complex I deficiency, nuclear type 4 (NDUFV1)
• Mitochondrial complex I deficiency, nuclear type 5 (NDUFS1)
• Mitochondrial complex I deficiency, nuclear type 6 (NDUFS2)
• Mitochondrial complex I deficiency, nuclear type 7 (NDUFV2)
• Mitochondrial complex I deficiency, nuclear type 8 (NDUFS3)
• Mitochondrial complex II deficiency, nuclear type 2 (SDHAF1)
• Mitochondrial complex III deficiency, nuclear type 1 (BCS1L)
• Mitochondrial complex III deficiency, nuclear type 2 (TTC19)
• Mitochondrial complex III deficiency, nuclear type 4 (UQCRQ)
• Mitochondrial complex IV deficiency (COX10)
• Mitochondrial complex IV deficiency, nuclear type 12 (PET100)
• Mitochondrial complex IV deficiency, nuclear type 15 (COX8A)
• Mitochondrial complex IV deficiency, nuclear type 19 (PET117)
• Mitochondrial complex IV deficiency, nuclear type 2 (SCO2)
• Mitochondrial complex IV deficiency, nuclear type 21 (NDUFA4)
• Mitochondrial complex IV deficiency, nuclear type 5, French-Canadian (LRPPRC)
• Mitochondrial complex IV deficiency, nuclear type 8 (TACO1)
• Mitochondrial recessive ataxia syndrome; includes SANDO + SCAE (POLG)
• Mitochondrial respiratory chain complex II deficiency (SDHA)
• Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (ECHS1)
• Myopathy, mitochondrial progressive, with congenital cataract + developmental delay (GFER)
• Pontocerebellar hypoplasia, type 1E (SLV25A46)
• Progressive external ophthalmoplegia with mitochondrial DNA deletions, AD (TWNK)
• Progressive external ophthalmoplegia with mitochondrial DNA deletions, AD 2 (SLC25A4)
• Progressive external ophthalmoplegia with mitochondrial DNA deletions, AD 4 (POLG2)
• Progressive external ophthalmoplegia with mitochondrial DNA deletions, AD 5 (RRM2B)
• Progressive external ophthalmoplegia with mitochondrial DNA deletions, AD 6 (DNA2)
• Progressive external ophthalmoplegia with mitochondrial DNA deletions, AR 2 (RNASEH1)
• Progressive external ophthalmoplegia with mitochondrial DNA deletions, AR 3 (TK2)
• Progressive external ophthalmoplegia with mitochondrial DNA deletions, AR 4 (DGUOK)
• Progressive external ophthalmoplegia, AD 1 (POLG)
• Progressive external ophthalmoplegia, AR 1 (POLG)
• Pyruvate dehydrogenase E1-beta deficiency (PDHB)
• Pyruvate dehydrogenase E2 deficiency (DLAT)
• Sengers syndrome (AGK)
• Spastic paraplegia 55, AR (MTRFR)
• Spastic paraplegia 7, AR (SPG7)
• Spastic paraplegia 77, AR (FARS2)
• Spinocerebellar ataxia, AR 10 (ANO10)
• Sulfide:quinone oxidoreductase deficiency (SQOR)
• Thiamine metabolism dysfunction syndrome 2, biotin-/thiamine-responsive encephalopathy 2 (SLC19A3)
• Thiamine metabolism dysfunction syndrome 4, progressive polyneuropathy type (SLC25A19)
• Thiamine metabolism dysfunction syndrome 5, episodic encephalopathy type (TPK1)