IllnessErkrankungen der Weißen Hirnsubstanz

NGS +

Leukoencephalopathies (LE) refer to an etiologically and clinically heterogeneous group of rare diseases in which there are disorders in the structure or maintenance of the white matter of the central nervous system (CNS). Leukoencephalopathies can be genetic or acquired. Acquired LE can be attributed to inflammatory, vascular, toxic-metabolic or traumatic causes. Genetic LE manifests itself predominantly in childhood and adolescence, but can occur at any age.

The course of the disease can be static or progressive. Leukodystrophies (LD) are defined as clinically progressive genetic LE in which there is either demyelination, i.e. destruction of the myelin membranes of the CNS (in some cases also of the peripheral nervous system, PNS) or constantly reduced or incorrectly formed myelin. The latter is referred to as hypo- or dysmyelination. This must be distinguished from psychomotor developmental disorders with delayed myelin formation.

Imaging techniques, especially magnetic resonance imaging (MRI), enable early and reliable detection of changes in the white matter of the CNS

The main clinical symptoms are movement disorders with muscular hypotonia, progressive spasticity or ataxia. Typically, motor function is affected first and cognition is affected later.

Genetic LE are predominantly monogenically inherited neurometabolic diseases. Genetic diseases include metachromatic leukodystrophy, Krabbe disease, X-linked adrenoleukodystrophy, Pelizaeus-Merzbacher disease and Aicardi-Goutières syndrome. Overall, this is a genetically extremely heterogeneous group of diseases. An inconspicuous genetic test result does not rule out a clinical diagnosis.

The benefits of genetic testing include the possibility of confirming the clinical diagnosis, differential diagnosis, prognosis and genetic counseling for affected individuals and their genetic relatives. There are currently only effective treatment approaches for a few LE.

Literature:

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)