Klinische FragestellungEpilepsien, metabolische; Differentialdiagnose

NGS +

[[Sanger]]

Neuro-metabolische Epilepsien sind Erbleiden mit überwiegend epileptischen Manifestationen, oder die Epilepsie ist Teil eines komplexen neurologischen Phänotyps. Mehrere dieser Störungen sind behandelbar, aber es gibt keine spezifischen klinischen oder EEG-Zeichen, die auf metabolische Epilepsien hinweisen. Stoffwechselstörungen können auf dreierlei Arten Anfälle auslösen: Mangel an Substraten, die für den neurozellulären Stoffwechsel oder die Membranfunktion essenziell sind, intrazelluläre Akkumulation neurotoxischer Substanzen und Veränderung der intrazellulären Osmolalität im Gehirn. Etwa die Hälfte der ~400 angeborenen Stoffwechselstörungen, d.h. vielfältige Mutationen in fast 900 Genen, können mit Epilepsien in Verbindung gebracht werden. Eine Suche in den Datenbanken OMIM, PubMed und MEDLINE zeigt, dass die Mehrheit der angeborenen Stoffwechselstörungen bei Epilepsie autosomal rezessiv vererbt wird (87 %), während 6 % mitochondrial, 4 % X-chromosomal und 3 % autosomal dominant vererbt werden. Nach unterschiedlichen Studienergebnissen kann die DNA-Diagnoseausbeute zwischen 25-65% und mehr variieren, so dass unauffällige genetische Befunde dennoch keinen sicheren Ausschluss der klinischen Verdachtsdiagnosen bedeuten.

Referenzen: https://www.ncbi.nlm.nih.gov/books/NBK1195/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369901/

Leitlinie: "Zwar haben die neuesten molekulargenetischen Befunde beigetragen, die Ursachen dieser häufigen idiopathischen Epilepsien etwas besser zu verstehen, doch ist eine routinemäßige genetische Diagnostik derzeit noch nicht sinnvoll.." GRIN2A, KCNT1, KCNQ2, KCNQ3, SCN1A Gene allerdings explizit erwähnt.

• Allelic: Anemia, sideroblastic, 3, pyridoxine-refractory (GLRX5)
• Allelic: Aphasia, primary progressive (GRN)
• Allelic: Behr syndrome (OPA1)
• Allelic: Charcot-Marie-Tooth disease, axonal, type 2EE (MPV17)
• Allelic: Deafness, AD 65 (TBC1D24)
• Allelic: Deafness, AR 86 (TBC1D24)
• Allelic: Dystonia 9 (SLC2A1)
• Allelic: Fanconi renotubular syndrome 1 (GATM)
• Allelic: Frontotemporal lobar degeneration with ubiquitin-positive inclusions (GRN)
• Allelic: Glaucoma, normal tension, susceptibility to (OPA1)
• Allelic: Leiomyomatosis + renal cell cancer (FH)
• Allelic: Macular dystrophy with central cone involvement (MFSD8)
• Allelic: Mitochondrial DNA depletion syndrome 2, myopathic type (TK2)
• Allelic: Optic atrophy 1 (OPA1)
• Allelic: Optic atrophy plus syndrome (OPA1)
• Allelic: Perrault syndrome 5 (TWNK)
• Allelic: Portal hypertension, noncirrhotic, 1 (DGUOK)
• Allelic: Progressive external ophthalmoplegia with mitochondrial DNA deletions, AR 4 (DGUOK)
• Allelic: Progressive external ophthalmoplegia, AD 1 (POLG)
• Allelic: Progressive external ophthalmoplegia, AR 1 (POLG)
• Allelic: Spastic paraplegia 74, AR (IBA57)
• Branched-chain ketoacid dehydrogenase kinase deficiency (BCKDK)
• Cerebral creatine deficiency syndrome 2 (GAMT)
• Cerebral creatine deficiency syndrome 3 (GATM)
• Ceroid lipofuscinosis, neuronal, 1 (PPT1)
• Ceroid lipofuscinosis, neuronal, 10 (CTSD)
• Ceroid lipofuscinosis, neuronal, 11 (GRN)
• Ceroid lipofuscinosis, neuronal, 13, Kufs type, AD (CTSF)
• Ceroid lipofuscinosis, neuronal, 2 (TPP1)
• Ceroid lipofuscinosis, neuronal, 3 (CLN3)
• Ceroid lipofuscinosis, neuronal, 4, Kufs type (DNAJC5)
• Ceroid lipofuscinosis, neuronal, 5 (CLN5)
• Ceroid lipofuscinosis, neuronal, 6A (CLN6)
• Ceroid lipofuscinosis, neuronal, 6B, Kufs type (CLN6)
• Ceroid lipofuscinosis, neuronal, 7 (MFSD8)
• Ceroid lipofuscinosis, neuronal, 8 (CLN8)
• Ceroid lipofuscinosis, neuronal, 8, Northern epilepsy variant (CLN8)
• Coenzyme Q10 deficiency, primary, 4 (COQ8A)
• Constitutional megaloblastic anemia with severe neurologic disease (DHFR)
• DOORS [Deafness, Onychodystrophy, Osteodystrophy, mental Retard.] syndrome (TBC1D24)
• Developmental + epileptic encephalopathy 16 (TBC1D24)
• Epilepsy, idiopathic generalized, susceptibility to, 12 (SLC2A1)
• Epilepsy, progressive myoclonic 3, with/-out intracellular inclusions (KCTD7)
• Epilepsy, pyridoxine-dependent (ALDH7A1)
• Epilepsy, rolandic, with proxysmal exercise-induce dystonia + writer's cramp (TBC1D24)
• Epilepsy-associated gene [Lit.] (SLC8A9)
• Fumarase deficiency (FH)
• GABA-transaminase deficiency (ABAT)
• GLUT1 deficiency syndrome 1, infantile onset, severe (SLC2A1)
• GLUT1 deficiency syndrome 2, childhood onset (SLC2A1)
• Glycine encephalopathy (GCSH)
• Glycine encephalopathy (GLDC)
• Glycine encephalopathy with normal serum glycine (SLC6A9)
• Hyperglycinemia, lactic acidosis + seizures (LIAS)
• Krabbe disease (GALC)
• L-2-hydroxyglutaric aciduria (L2HGDH)
• Megaloblastic anemia with severe neurologic disease (DHFR)
• Metabolic encephalomyopathic crises, recurrent, rhabdomyol., cardiac arrhythmias, neurodeg. (TANGO2)
• Metabolic encephalomyopathic crises, recurrent, rhabdomyolysis, cardiac arrhyth., neurodeg. (TANGO2)
• Methylmalonic acidemia + homocysteinemia, cblX type (HCFC1)
• Mitochondrial DNA depletion syndrome 1, MNGIE type (TYMP)
• 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 3, hepatocerebral type (DGUOK)
• Mitochondrial DNA depletion syndrome 4A, Alpers type (POLG)
• Mitochondrial DNA depletion syndrome 4B, MNGIE type (POLG)
• Mitochondrial DNA depletion syndrome 5, encephalomyopathic +/- methylmalonic aciduria (SULC2)
• Mitochondrial DNA depletion syndrome 6, hepatocerebral type (MPV17)
• 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 with methylmalonic aciduria (SUCLG1)
• Mitochondrial recessive ataxia syndrome (includes SANDO and SCAE] (POLG)
• Molybdenum cofactor deficiency A (MOCS1)
• Molybdenum cofactor deficiency B (MOCS2)
• Molybdenum cofactor deficiency C (GPHN)
• Multiple mitochondrial dysfunctions syndrome 1 (NFU1)
• Multiple mitochondrial dysfunctions syndrome 2 with hyperglycinemia (BOLA3)
• Multiple mitochondrial dysfunctions syndrome 3 (IBA57)
• Myoclonic epilepsy, infantile, familial (TBC1D24)
• Neurodegeneration due to cerebral folate transport deficiency (FOLR1)
• Progressive external ophthalmoplegia with mitochondrial DNA deletions, AD 2 (SLC25A4)
• Progressive external ophthalmoplegia with mitochondrial DNA deletions, AD 3 (TWNK)
• Progressive external ophthalmoplegia with mitochondrial DNA deletions, AD 5 (RRM2B)
• Progressive external ophthalmoplegia with mitochondrial DNA deletions, AR 2 (RNASEH1)
• Progressive external ophthalmoplegia with mitochondrial DNA deletions, AR 3 (TK2)
• Pyridoxamine 5'-phosphate oxidase deficiency (PNPO)
• Sengers syndrome (AGK)
• Spasticity, childhood-onset, with hyperglycinemia (GLRX5)
• Spinocerebellar ataxia, autosomal recessive 7 (TPP1)
• Stomatin-deficient cryohydrocytosis with neurologic defects (SLC2A1)
• Succinic semialdehyde dehydrogenase deficiency (ALDH5A1)
• Sulfite oxidase deficiency (SUOX)