Klinische FragestellungLeukodystrophie, Frühformen; Differentialdiagnose

NGS +

Leukodystrophien sind eine Gruppe seltener, genetisch bedingter Stoffwechselkrankheiten, die das Gehirn, das Rückenmark und häufig auch die peripheren Nerven betreffen. Jede der vielen Formen der früh beginnenden Leukodystrophie wird durch eine spezifische Gen-Mutation verursacht, die zur gestörten Entwicklung oder Zerstörung der Myelinscheide des Gehirns führt. Jede Art von Leukodystrophie betrifft unterschiedliche Anteile der Myelinscheide, was zu einer langen Reihe von neurologischen Problemen führt. Die Symptome einiger Leukodystrophie-Typen beginnen kurz nach der Geburt, andere entwickeln sich später in der Kindheit (oder sogar erst im Erwachsenenalter). Diese Symptome variieren je nach Typ und können in den frühen Stadien der Erkrankung schwer zu diagnostizieren sein. Das häufigste Symptom ist eine allmähliche Funktionsverschlechterung bei einem Säugling oder Kind, das zuvor gesund erschien. Es kann zum fortschreitenden Verlust des Muskeltonus, des Gangs, des Gleichgewichts, der Sprache, des Sehvermögens, des Hörvermögens, des Verhaltens, zu Entwicklungsverzögerungen und Lernschwierigkeiten, Atemproblemen und/oder Krampfanfällen kommen. Viele Leukodystrophien sind fortschreitende Erkrankungen, die sich im Laufe der Zeit verschlimmern. Einige vererbte Leukoenzephalopathien weisen aber stabile Veränderungen der weißen Substanz auf. Das breite Spektrum der frühen Formen von Leukodystrophie umfasst z.B. das Aicardi-Goutieres-Syndrom (Enzephalopathie mit Basalganglienverkalkung), die Alexander-Krankheit (neonatale und infantile Formen), die zerebrotendinöse Xanthomatose, die klassische Form des Morbus Fabry (Alpha-galactosidase A-Defizienz), Morbus Krabbe (Globoidzell-Leukodystrophie), metachromatische Leukodystrophie (Arylsulfatase-A-Mangel), Pelizaeus-Merzbacher-Krankheit (PLP1-Störung), die zerebrale Form der X-chromosomalen Adrenoleukodystrophie im Kindesalter und die zahlreichen Zellweger-Syndrom-Spektrum-Störungen (z.B. neonatale Adrenoleukodystrophie sowie infantile Refsum-Krankheit). Bei den früh einsetzenden Leukodystrophien werden alle monogenen Vererbungsmuster beobachtet. Die diagnostische Ausbeute liegt bei etwa 70 %, so dass ein negatives DNA-Testergebnis die klinische Diagnose nicht ausschließt.

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• Alias: Leukencephalopathie
• Alias: Leukencephalopathy
• Alias: Leukodystrophie
• Alias: Leukodystrophy
• Alias: Leukoencephalopathy
• Alias: Leukoenzephalopathie
• Allelic: 5-fluorouracil toxicity (DPYD)
• Allelic: Adrenomyeloneuropathy, adult (ABCD1)
• Allelic: Angiopathy, hereditary, with nephropathy, aneurysms + muscle cramps (COL4A1)
• Allelic: Bjornstad syndrome (BCS1L)
• Allelic: Chromosome 5q14.3 deletion syndrome (MEF2C)
• Allelic: Combined SAP deficiency (PSAP)
• Allelic: Dermatofibrosarcoma protuberans (PDGFB)
• Allelic: Dyschromatosis symmetrica hereditaria (ADAR)
• Allelic: Gastrointestinal stromal tumor (SDHB)
• Allelic: Gaucher disease, atypical (PSAP)
• Allelic: Kosaki overgrowth syndrome (PDGFRB)
• Allelic: Krabbe disease, atypical (PSAP)
• Allelic: Lung cancer, susceptibility to (ERCC6)
• Allelic: Lymphatic malformation 3 (GJC2)
• Allelic: Macular degeneration, age-related, susceptibility to, 5 (ERCC6)
• Allelic: Meningioma, SIS-related (PDGFB)
• Allelic: Mitchell syndrome (ABCD1)
• Allelic: Myeloproliferative disorder with eosinophilia (PDGFRB)
• Allelic: Myofibromatosis, infantile, 1 (PDGFRB)
• Allelic: Myopia 6 (SCO2)
• Allelic: Ovarioleukodystrophy (EIF2B2, EIF2B4, EIF2B5)
• Allelic: Paraganglioma + gastric stromal sarcoma (SDHB)
• Allelic: Paragangliomas 4 (SDHB)
• Allelic: Perrault syndrome 1 (HSD17B4)
• Allelic: Perrault syndrome 5 (TWNK)
• Allelic: Pheochromocytoma (SDHB)
• Allelic: Portal hypertension, noncirrhotic, 1 (DGUOK)
• Allelic: Premature ovarian failure 11 (ERCC6)
• Allelic: Retinal arteries, tortuosity of (COL4A1)
• Allelic: Spastic paraplegia 2, XL (PLP1)
• Allelic: Spastic paraplegia 44, AR (GJC2)
• Allelic: Systemic lupus erythematosus, susceptibility to (TREX1)
• Allelic: UV-sensitive syndrome 1 (ERCC6)
• Allelic: UV-sensitive syndrome 2 (ERCC8)
• Adrenoleukodystrophy (ABCD1)
• Aicardi-Goutieres syndrome 1, AD + AR (TREX1)
• Aicardi-Goutieres syndrome 2 (RNASE2B)
• Aicardi-Goutieres syndrome 3 (RNASE2C)
• Aicardi-Goutieres syndrome 4 (RNASE2H)
• Aicardi-Goutieres syndrome 5 (SMAHD1)
• Aicardi-Goutieres syndrome 6 (ADAR)
• Aicardi-Goutieres syndrome 7 (IFIH1)
• Aicardi-Goutieres syndrome 8 (LSM11)
• Alexander disease (GFAP)
• Allan-Herndon-Dudley syndrome (SLC16A2)
• Basal ganglia calcification, idiopathic, 1 (SLC20A2)
• Basal ganglia calcification, idiopathic, 4 (PDGFRB)
• Basal ganglia calcification, idiopathic, 5 (PDGFB)
• Basal ganglia calcification, idiopathic, 6 (XPR1)
• Brain abnormalities, neurodegeneration + dysosteosclerosis (CSF1R)
• Brain small vessel disease with/-out ocular anomalies (COL4A1)
• Canavan disease (ASPA)
• Cerebrooculofacioskeletal syndrome 1 (ERCC6)
• Cerebrooculofacioskeletal syndrome 2 (ERCC2)
• Cerebrooculofacioskeletal syndrome 3 (ERCC5)
• Cerebrooculofacioskeletal syndrome 4 (ERCC1)
• Cerebroretinal microangiopathy with calcifications + cysts (CTC1)
• Cerebrotendinous xanthomatosis (CYP27A1)
• Charcot-Marie-Tooth disease, type 4K (SURF1)
• Charcot-Marie-Tooth neuropathy, XLD, 1 (GJB1)
• Chilblain lupus (TREX1)
• Chilblain lupus 2 (SAMHD1)
• Cockayne syndrome, type A (ERRC8)
• Cockayne syndrome, type B (ERCC6)
• Coenzyme Q10 deficiency, primary, 1 (COQ2)
• Coenzyme Q10 deficiency, primary, 4 (COQ8A)
• Combined SAP deficiency (PSAP)
• Combined oxidative phosphorylation deficiency 1 (GFM1)
• Combined oxidative phosphorylation deficiency 12 (EARS2)
• Combined oxidative phosphorylation deficiency 15 (MTFMT)
• Combined oxidative phosphorylation deficiency 8 (AARS2)
• Congenital disorder of glycosylation, type IIt (GALNT2)
• D-2-hydroxyglutaric aciduria (D2HGDH)
• D-bifunctional protein deficiency (HSD17B4)
• De Sanctis-Cacchione syndrome (ERCC6)
• Deafness, dystonia + cerebral hypomyelination (BCAP31)
• Developmental + epileptic encephalopathy 39 (SLC25A12)
• Dihydropyrimidine dehydrogenase deficiency (DPYD)
• Dystonia 4, torsion, AD (TUBB4A)
• Epilepsy, idiopathic generalized, susceptibility to, 11 (CLCN2)
• Epilepsy, juvenile absence, susceptibility to, 2 (CLCN2)
• Epilepsy, juvenile myoclonic, susceptibility to, 8 (CLCN2)
• Fanconi anemia, complementation group Q (ERCC4)
• Fucosidosis (FUCA1)
• GRACILE syndrome (BCS1L)
• Gaucher disease, atypical (PSAP)
• Glutaric acidemia IIC (ETFDH)
• Glycogen storage disease IV (GBE1)
• Hemorrhage, intracerebral, susceptibility to (COL4A1)
• Hemorrhagic destruction of the brain, subependymal calcification + cataracts (JAM3)
• Hyperaldosteronism, familial, type II (CLCN2)
• Hypomyelination with brainstem and spinal cord involvement + leg spasticity (DARS1)
• Krabbe disease (GALC)
• Krabbe disease, atypical (PSAP)
• L-2-hydroxyglutaric aciduria (L2HGDH)
• L-2-hydroxyglutaric aciduria (LMNB1)
• Leukodystrophy, hypomyelinating, 10 (PYCR2)
• Leukodystrophy, hypomyelinating, 11 (POLR1C)
• Leukodystrophy, hypomyelinating, 16 (TMEM106B)
• Leukodystrophy, hypomyelinating, 2 (GJC2)
• Leukodystrophy, hypomyelinating, 3 (AIMP1)
• Leukodystrophy, hypomyelinating, 5 (FAM126A)
• Leukodystrophy, hypomyelinating, 6 (TUBB4A)
• Leukodystrophy, hypomyelinating, 7, with/-out oligodontia +/- hypogonadotropic hypogonadism (POLR3A)
• Leukodystrophy, hypomyelinating, 8, with/-out oligodontia +/- hypogonadotropic hypogonadism (POLR3B)
• Leukodystrophy, hypomyelinating, 9 (RARS1)
• Leukoencephalopathy with ataxia (CLCN2)
• Leukoencephalopathy with brain stem + spinal cord involvement + lactate elevation (DARS2)
• Leukoencephalopathy with dystonia + motor neuropathy (SCP2)
• Leukoencephalopathy with vanishing white matter (EIF2B1-EIF2B5)
• Leukoencephalopathy, cystic, without megalencephaly (RNASET2)
• Leukoencephalopathy, developmental delay + episodic neurologic regression syndrome (EIF2AK2)
• Leukoencephalopathy, diffuse hereditary, with spheroids (CSF1R)
• Leukoencephalopathy, progressive, with ovarian failure (AARS2)
• Lissencephaly 1 (PAFAH1B1)
• Lissencephaly 5 (LAMB1)
• Megalencephalic leukoenceph. + subcortical cysts 2B, remitting, with/-out ment. retard. (HEPACAM)
• Megalencephalic leukoencephalopathy + subcortical cysts (MLC1)
• Megalencephalic leukoencephalopathy with subcortical cysts 2A (HEPACAM)
• Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with/-out MR (HEPACAM)
• Mental retardation, autosomal dominant 45 (CIC)
• Metachromatic leukodystrophy (ARSA)
• Metachromatic leukodystrophy due to SAP-b deficiency (PSAP)
• Microangiopathy + leukoencephalopathy, pontine, AD (COL4A1)
• Mitchell syndrome (ACOX1)
• Mitochondrial AR ataxia syndrome; includes SANDO + SCAE (POLG)
• 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 16, hepatic type (POLG2)
• Mitochondrial DNA depletion syndrome 16B, neuroophthalmic type (POLG2)
• 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 with/-out methylmalonic aciduria (SUCLA)
• 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 complex I deficiency, nuclear type 1 (NDUFS4)
• Mitochondrial complex I deficiency, nuclear type 11 (NDUFAF1)
• Mitochondrial complex I deficiency, nuclear type 13 (NDUFA2)
• Mitochondrial complex I deficiency, nuclear type 18 (NDUFAF3)
• Mitochondrial complex I deficiency, nuclear type 2 (NDUFS8)
• Mitochondrial complex I deficiency, nuclear type 21 (NUBPL)
• Mitochondrial complex I deficiency, nuclear type 27 (MTFMT)
• Mitochondrial complex I deficiency, nuclear type 3 (NDUFS7)
• 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 II deficiency, nuclear type 2 (SDHAF1)
• Mitochondrial complex II deficiency, nuclear type 4 (SDHB)
• Mitochondrial complex III deficiency, nuclear type 1 (BCS1L)
• Mitochondrial complex III deficiency, nuclear type 8 (LYRM7)
• Mitochondrial complex IV deficiency, nuclear type 1 (SURF1)
• Mitochondrial complex IV deficiency, nuclear type 2 (SCO2)
• Mitochondrial complex IV deficiency, nuclear type 3 (COX10)
• Mitochondrial complex IV deficiency, nuclear type 4 (SCO1)
• Mitochondrial complex IV deficiency, nuclear type 6 (COX15)
• Mitochondrial complex IV deficiency, nuclear type 8 (TACO1)
• Multiple mitochondrial dysfunctions syndrome 3 (IBA57)
• Multiple mitochondrial dysfunctions syndrome 4 (ISCA2)
• Multiple sulfatase deficiency (SUMF)
• Multiple system atrophy, susceptibility to (COQ2)
• Neurodegeneration due to cerebral folate transport deficiency (FOLR1)
• Neurodevelopmental disorder with hypotonia, stereotypic hand movements + impaired language (MEF2C)
• PCWH [periph. demyel. neuropathy, central dysmyel., Waardenburg, Hirschsprung] syndrome (SOX10)
• Parkinson disease 24, AD, susceptibility to (PSAP)
• Pelizaeus-Merzbacher disease (PLP1 syn. PLP)
• Peroxisomal acyl-CoA oxidase deficiency (ABCD1)
• Peroxisomal acyl-CoA oxidase deficiency (ACOX1)
• Pettigrew syndrome (AP1S2)
• Polyglucosan body disease, adult form (GBE1)
• Premature aging syndrome, Penttinen type (PDGFRB)
• 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 4 (POLG2)
• Progressive external ophthalmoplegia with mitochondrial DNA deletions, AD 5 (RRM2B)
• Progressive external ophthalmoplegia with mitochondrial DNA deletions, AR 4 (DGUOK)
• Progressive external ophthalmoplegia, AD (POLG)
• Progressive external ophthalmoplegia, AR 1 (POLG)
• Proliferative vasculopathy + hydranencephaly-hydrocephaly syndrome (FLVCR2)
• Pseudo-TORCH syndrome 1 (OCLN)
• Pseudo-TORCH syndrome 2 (USP18)
• Salla disease (SLC17A5)
• Sialic acid storage disorder, infantile (SLC17A5)
• Singleton-Merten syndrome 1 (IFIH1)
• Sjogren-Larsson syndrome (ALDH3A2)
• Spastic ataxia 8, AR, with hypomyelinating leukodystrophy (NKX6-2)
• Spastic paraplegia 44, AR (GJC2)
• Spastic paraplegia 74, AR (IBA57)
• Subcortical laminar heterotopia (PAFAH1B1)
• Treacher Collins syndrome 3 (POLR1C)
• Trichothiodystrophy 1, photosensitive (ERCC2)
• Trichothiodystrophy 2, photosensitive (ERCC3)
• Vasculopathy, retinal, with cerebral leukoencephalopathy + systemic manifestations (TREX1)
• Waardenburg syndrome, type 2E, with/-out neurologic involvement (SOX10)
• Waardenburg syndrome, type 4C (SOX10)
• Wiedemann-Rautenstrauch syndrome (POLR3A)
• XFE progeroid syndrome (ERCC4)
• Xeroderma pigmentosum, group B (ERCC3)
• Xeroderma pigmentosum, group D (ERCC2)
• Xeroderma pigmentosum, group F (ERCC4)
• Xeroderma pigmentosum, group G (ERCC5)
• Xeroderma pigmentosum, group G/Cockayne syndrome (ERCC5)
• Xeroderma pigmentosum, type F/Cockayne syndrome (ERCC4)