Klinische FragestellungErkrankungen der Weißen Hirnsubstanz

NGS +

Leukoenzephalopathien (LE) bezeichnen eine ätiologisch und klinisch heterogene Gruppe seltener Erkrankungen, bei denen es zu Störungen im Aufbau oder im Erhalt der weißen Substanz des zentralen Nervensystems (ZNS) kommt. Leukoenzephalopathien können genetisch bedingt oder erworben sein. Erworbene LE können auf entzündliche, vaskuläre, toxisch-metabolische oder traumatische Ursachen zurückgeführt werden. Genetische LE manifestieren sich vorwiegend im Kindes- und Jugendalter, können aber in jedem Lebensalter auftreten.

Der Krankheitsverlauf kann statisch oder progredient sein. Als Leukodystrophien (LD) werden klinisch progredient verlaufende genetische LE bezeichnet, bei denen es entweder zu einer Demyelinisierung, d. h. Zerstörung der Myelinmembranen des ZNS (in einigen Fällen auch des peripheren Nervensystems, PNS) oder zu einem konstant vermindert bzw. fehlerhaft gebildeten Myelin kommt. Letzteres wird als Hypo- bzw. Dysmyelinisierung bezeichnet. Hiervon abzugrenzen sind psychomotorische Entwicklungsstörungen mit verzögerter Myelinbildung.

Durch bildgebende Verfahren, v. a. die Magnetresonanztomographie (MRT) ist eine frühzeitige und zuverlässige Erkennung von Veränderungen der weißen Substanz des ZNS möglich

Klinische Leitsymptome sind Bewegungsstörungen mit muskulärer Hypotonie, progredienter Spastik oder Ataxie. Typischerweise ist zunächst die Motorik und erst im Verlauf die Kognition betroffen.

Bei den genetischen LE handelt es sich überwiegend um monogen vererbte neurometabolische Erkrankungen. Genetische Erkrankungen sind zum Beispiel die metachromatische Leukodystrophie, Morbus Krabbe, die X-chromosomal vererbte Adrenoleukodystrophie, Morbus Pelizaeus-Merzbacher oder das Aicardi-Goutières-Syndrom. Insgesamt handelt es sich um eine genetisch außerordentlich heterogene Gruppe von Erkrankungen. Ein unauffälliges genetisches Testergebnis schließt die klinische Diagnose nicht aus.

Der Nutzen einer genetischen Untersuchung besteht in der Möglichkeit einer Sicherung der klinischen Diagnose, der differentialdiagnostischen Abklärung, der Prognosestellung und der genetischen Beratung von Betroffenen und deren genetischen Verwandten. Nur für wenige LE gibt es derzeit effektive Behandlungsansätze.

Literatur:

Henneke M, Gärtner J: Neurodegnerative Erkrankungen der weißen Hirnsubstanz (2019). In Hoffmann G et al. (eds) Pädiatrie. Springer Reference Medizin. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-54671-6_255-2

NORD: Leukodystrophy. https://rarediseases.org/rare-diseases/leukodystrophy

• DD: Einschlußkriterien: MRI; Stoffwechseluntersuchungen abgeschlossen
• DD: Ausschlußkriterien: genetische/Umwelt-Ursache (Infektion, Hypoxie...) bekannt
• DD: andere Ursache phänotypisch ausgeschlossen (Cockayne Syndrom...)
• Alias: Leukodystrophie, erblich
• Alias: Leukodystrophy, inherited
• Allelic: 5-fluorouracil toxicity (DPYD)
• Allelic: Angiopathy, hereditary, with nephropathy, aneurysms + muscle cramps (COL4A1)
• Allelic: Atrioventricular septal defect 3 (GJA1)
• Allelic: Cardiomyopathy, dilated, 1GG (SDHA)
• Allelic: Charcot-Marie-Tooth disease, RI, B (KARS1)
• Allelic: Charcot-Marie-Tooth disease, type 4K (SURF1)
• Allelic: Chilblain lupus (TREX1)
• Allelic: Chilblain lupus 2 (SAMHD1)
• Allelic: Combined oxidative phosphorylation deficiency 25 (MARS2)
• Allelic: Deafness, AR 89 (KARS1)
• Allelic: Epilepsy, idiopathic generalized, susceptibility to, 11 (CLCN2)
• Allelic: Epilepsy, juvenile absence, susceptibility to, 2 (CLCN2)
• Allelic: Epilepsy, juvenile myoclonic, susceptibility to, 8 (CLCN2)
• Allelic: Erythrokeratodermia variabilis et progressiva (GJA1)
• Allelic: Fabry disease, cardiac variant (GLA)
• Allelic: Gastrointestinal defects + immunodeficiency syndrome 2 (PI4KA)
• Allelic: Gastrointestinal stromal tumor (SDHB)
• Allelic: Gaucher disease, perinatal lethal (GBA)
• Allelic: Hemorrhage, intracerebral, susceptibility to (COL4A1)
• Allelic: Hemorrhage, intracerebral, susceptibility to (COL4A2)
• Allelic: Hypoplastic left heart syndrome 1 (GJA1)
• Allelic: Lewy body dementia, susceptibility to (GBA)
• Allelic: Lung cancer, susceptibility to (ERCC6)
• Allelic: Lymphatic malformation 3 (GJC2)
• Allelic: Macular degeneration, age-related, 7 (HTRA1)
• Allelic: Macular degeneration, age-related, neovascular type (HTRA1)
• Allelic: Macular degeneration, age-related, susceptibility to, 5 (ERCC6)
• Allelic: Macular dystrophy with central cone involvement (MFSD8)
• Allelic: Mitochondrial DNA depletion syndrome 16, hepatic type (POLG2)
• Allelic: Myofibromatosis, infantile 2 (NOTCH3)
• Allelic: Myopia 6 (SCO2)
• Allelic: Oculodentodigital dysplasia (GJA1)
• Allelic: Oculodentodigital dysplasia, AR (GJA1)
• Allelic: Palmoplantar keratoderma with congenital alopecia (GJA1)
• Allelic: Paraganglioma + gastric stromal sarcoma (SDHB)
• Allelic: Paragangliomas 4 (SDHB)
• Allelic: Parkinson disease 24, AD, susceptibility to (PSAP)
• Allelic: Parkinson disease, late-onset, susceptibility to (GBA)
• 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: Progressive external ophthalmoplegia, AD (POLG)
• Allelic: Progressive external ophthalmoplegia, AR 1 (POLG)
• Allelic: Retinal arteries, tortuosity of (COL4A1)
• Allelic: Syndactyly, type III (GJA1)
• Allelic: Systemic lupus erythematosus, susceptibility to (TREX1)
• Allelic: Tremor, hereditary essential, 6 (NOTCH2NLC)
• Allelic: UV-sensitive syndrome 1 (ERCC6)
• 3-methylglutaconic aciduria, type I (AUH)
• Adrenoleukodystrophy (ABCD1)
• Adrenomyeloneuropathy, adult (ABCD1)
• Aicardi-Goutieres syndrome 1, AD, AR (TREX1)
• Aicardi-Goutieres syndrome 2 (RNASEH2B)
• Aicardi-Goutieres syndrome 3 (RNASEH2C)
• Aicardi-Goutieres syndrome 4 (RNASEH2A)
• Aicardi-Goutieres syndrome 5 (SAMHD1)
• Aicardi-Goutieres syndrome 6 (ADAR)
• Aicardi-Goutieres syndrome 7 (IFIH1)
• Alexander disease (GFAP)
• Allan-Herndon-Dudley syndrome (SLC16A2)
• Aphasia, primary progressive (GRN)
• Bjornstad syndrome (BCS1L)
• Brain abnormalities, neurodegeneration + dysosteosclerosis (CSF1R)
• Brain small vessel disease 2 (COL4A2)
• Brain small vessel disease 3 (COLGALT1)
• Brain small vessel disease with/-out ocular anomalies (COL4A1)
• CARASIL syndrome (HTRA1)
• Canavan disease (ASPA)
• Cerebral arteriopathy with subcortical infarcts + leukoencephalopathy 1 (NOTCH3)
• Cerebral arteriopathy, AD, with subcortical infarcts + leukoencephalopathy, type 2 (HTRA1)
• Cerebrooculofacioskeletal syndrome 1 (ERCC6)
• Cerebrotendinous xanthomatosis (CYP27A1)
• Ceroid lipofuscinosis, neuronal, 1 (PPT1)
• Ceroid lipofuscinosis, neuronal, 10 (CTSD)
• Ceroid lipofuscinosis, neuronal, 11 (GRN)
• Ceroid lipofuscinosis, neuronal, 3 (CLN3)
• Ceroid lipofuscinosis, neuronal, 4, Kufs type, AD (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)
• Charcot-Marie-Tooth neuropathy, XLD, 1 (GJB1)
• Chromosome 5q14.3 deletion syndrome (MEF2C)
• Cockayne syndrome, type A (ERCC8)
• 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)
• Craniometaphyseal dysplasia, AR (GJA1)
• D-2-hydroxyglutaric aciduria (D2HGDH)
• D-bifunctional protein deficiency (HSD17B4)
• De Sanctis-Cacchione syndrome (ERCC6)
• Deafness, congenital + adult-onset progressive leukoencephalopathy (KARS1)
• Deafness, dystonia + cerebral hypomyelination (BCAP31)
• Developmental + epileptic encephalopathy 39 (SLC25A12)
• Dihydropyrimidine dehydrogenase deficiency (DPYD)
• Dyschromatosis symmetrica hereditaria (ADAR)
• Dystonia 32 (VPS11)
• Dystonia 4, torsion, AD (TUBB4A)
• Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy (NAXE)
• Epilepsy, progressive myoclonic 3, with/-out intracellular inclusions (KCTD7)
• Fabry disease (GLA)
• Frontotemporal lobar degeneration with ubiquitin-positive inclusions (GRN)
• Fucosidosis (FUCA1)
• GM1-gangliosidosis, type I, II, III (GLB1)
• GM2-gangliosidosis, several forms (HEXA)
• GRACILE syndrome (BCS1L)
• Gaucher disease, atypical (PSAP)
• Gaucher disease, type I, II, III, IIIC (GBA)
• Giant axonal neuropathy-1 (GAN)
• Glutaric acidemia IIC (ETFDH)
• Glutaricaciduria, type I (GCDH)
• Glycogen storage disease IV (GBE1)
• HMG-CoA lyase deficiency (HMGCL)
• Hex A pseudodeficiency (HEXA)
• Homocystinuria due to MTHFR deficiency (MTHFR)
• Homocystinuria, B6-responsive + nonresponsive types (CBS)
• Hyperaldosteronism, familial, type II (CLCN2)
• Hypomyelinating neuropathy, congenital, 3 (CNTNAP1)
• Hypomyelination with brainstem + spinal cord involvement + leg spasticity (DARS1)
• Immunodeficiency 38 (ISG15)
• Intellectual developmental disorder, AD 21 (CTCF)
• Krabbe disease (GALC)
• Krabbe disease, atypical (PSAP)
• L-2-hydroxyglutaric aciduria (L2HGA)
• L-2-hydroxyglutaric aciduria (L2HGDH)
• Lateral meningocele syndrome (NOTCH3)
• Lethal congenital contracture syndrome 7 (CNTNAP1)
• Leukodystrophy, adult-onset, AD (LMNB1)
• Leukodystrophy, hypomyelinating, 10 (PYCR2)
• Leukodystrophy, hypomyelinating, 11 (POLR1C)
• Leukodystrophy, hypomyelinating, 12 (VPS11)
• Leukodystrophy, hypomyelinating, 16 (TMEM106B)
• Leukodystrophy, hypomyelinating, 2 (GJC2)
• Leukodystrophy, hypomyelinating, 3 (AIMP1)
• Leukodystrophy, hypomyelinating, 4 (HSPD1)
• Leukodystrophy, hypomyelinating, 5 (FAM126A)
• Leukodystrophy, hypomyelinating, 6 (TUBB4A)
• Leukodystrophy, hypomyelinating, 7, +/- oligodontia +/- hypogonadotropic hypogonadism (POLR3A)
• Leukodystrophy, hypomyelinating, 8, +/- 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)
• Leukoencephalopathy with vanishing white matter (EIF2B2)
• Leukoencephalopathy with vanishing white matter (EIF2B3)
• Leukoencephalopathy with vanishing white matter (EIF2B4)
• Leukoencephalopathy with vanishing white matter (EIF2B5)
• Leukoencephalopathy, cerebellar atrophy, mtDNA depletion [panelapp] (LIG3)
• Leukoencephalopathy, cystic, without megalencephaly (RNASET2)
• Leukoencephalopathy, developmental delay, episodic neurologic regression syndrome (EIF2AK2)
• Leukoencephalopathy, diffuse hereditary, with spheroids 1 (CSF1R)
• Leukoencephalopathy, progressive, infantile-onset, with/-out deafness (KARS1)
• Leukoencephalopathy, progressive, with ovarian failure (AARS2)
• Lissencephaly 1 (PAFAH1B1)
• Lissencephaly 5 (LAMB1)
• Mannosidosis, alpha-, types I + II (MAN2B1)
• Mannosidosis, beta (MANBA)
• Megalencephalic leukoencephalopathy with subcortical cysts (MLC1)
• Megalencephalic leukoencephalopathy with subcortical cysts 2A (HEPACAM)
• Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, +/- MR (HEPACAM)
• Mental retardation, Ad 45 (CIC)
• Metachromatic leukodystrophy (ARSA)
• Metachromatic leukodystrophy due to SAP-b deficiency (PSAP)
• Microangiopathy + leukoencephalopathy, pontine, AD (COL4A1)
• Microcephaly 26, primary, AD (LMNB1)
• Mitchell syndrome (ACOX1)
• 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 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 +/- methylmalonic aciduria (SUCLA2)
• 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 (NUPBL)
• 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 1 (SDHA)
• 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 17 (COA8)
• 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)
• Mitochondrial recessive ataxia syndrome, includes SANDO + SCAE (POLG)
• Mucolipidosis IV (MCOLN1)
• Mucopolysaccharidosis type IVB, Morquio (GLB1)
• Multiple mitochondrial dysfunctions syndrome 2 with hyperglycinemia (BOLA3)
• Multiple mitochondrial dysfunctions syndrome 3 (IBA57)
• Multiple mitochondrial dysfunctions syndrome 4 (ISCA2)
• Multiple sulfatase deficiency (SUMF1)
• Multiple system atrophy, susceptibility to (COQ2)
• Neurodegeneration due to cerebral folate transport deficiency (FOLR1)
• Neurodegeneration with ataxia + late-onset optic atrophy (SDHA)
• Neurodevelopmental disorder with hypotonia, stereotypic hand movements, impaired language (MEF2C)
• Neurodevelopmental disorder, ataxic gait, absent speech, decreased cortical white matter (RAB11B)
• Neuronal intranuclear inclusion disease (NOTCH2NLC)
• Niemann-Pick disease, type C1 + D (NPC1)
• Niemann-Pick disease, type C2 (NPC2)
• Oculopharyngodistal myopathy 3 (NOTCH2NLC)
• Ovarioleukodystrophy (EI2B2, EIF2B5)
• PCWH syndrome (SOX10)
• Paragangliomas 5 (SDHA)
• Pelizaeus-Merzbacher disease (PLP1)
• Peroxisomal acyl-CoA oxidase deficiency (ACOX1)
• Peroxisome biogenesis disorders (PEX1, -10, -12, -13, -16, -2, -26, -3, -5, -6)
• Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1 (TYROBP)
• Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2 (TREM2)
• Polyglucosan body disease, adult form (GBE1)
• Polymicrogyria, perisylvian, with cerebellar hypoplasia + arthrogryposis (PI4KA)
• 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)
• Proliferative vasculopathy + hydranencephaly-hydrocephaly syndrome (FLVCR2)
• Proteasome-associated autoinflammatory syndrome 1 + digenic forms (PSMB8)
• Refsum disease (PHYH)
• Retinal dystrophy with leukodystrophy (ABCD5)
• Salla disease (SLC17A5)
• Sandhoff disease, infantile, juvenile + adult forms (HEXB)
• Sialic acid storage disorder, infantile (SLC17A5)
• Singleton-Merten syndrome 1 (IFIH1)
• Singleton-Merten syndrome 2 (DDX58)
• Sjogren-Larsson syndrome (ALDH3A2)
• Spastic ataxia 3, AR (MARS2)
• Spastic ataxia 8, AR, with hypomyelinating leukodystrophy (NKX6-2)
• Spastic paraplegia 13, AD (HSPD1)
• Spastic paraplegia 2, XL (PLP1)
• Spastic paraplegia 35, AR (FA2H)
• Spastic paraplegia 44, AR (GJC2)
• Spastic paraplegia 74, AR (IBA57)
• Spastic paraplegia 84, AR (PI4KA)
• Spondyloenchondrodysplasia with immune dysregulation (ACP5)
• Subcortical laminar heterotopia (PAFAH1B1)
• Tay-Sachs disease (HEXA)
• Thrombosis, hyperhomocysteinemic (CBS)
• Treacher Collins syndrome 3 (POLR1C)
• Trichothiodystrophy 4, nonphotosensitive (MPLKIP)
• Troyer syndrome (SPART)
• UV-sensitive syndrome 2 (ERCC8)
• 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)