Klinische FragestellungMentale Retardierung, hirnorganisch; Differentialdiagnose

NGS +

[Sanger]

Mentale Retardierung (aktuell akzeptierter englischer Begriff, intellectual deficits) ist ein lebenslang schwächender Zustand, von dem bis zu 2-3% der Bevölkerung in westlichen Ländern betroffen sind. Während die kausale Pathogenese extrem unterschiedlich ist, stellen genetische Ätiologien die häufigste Ursache dar, die bei >50% der Patienten nachweisbar ist. Dieser Prozentsatz nimmt angesichts von effizienten NGS-Technologien zu. Hirnfehlbildungen verursachen nicht wenige Fälle von intellektuellen Defiziten und umfassen eine Gruppe von genetischen Entwicklungsstörungen des Gehirns, die in der Kindheit mit intellektueller Behinderung (und anderen neurologischen Merkmalen) auftreten. In einigen Fällen entstehen Fehlbildungen des Vorder-, Mittel-/Hinterhirns und der Kortikalis durch de novo oder somatische Mutationsereignisse im Gameten- oder Postzygotenstadium, aber viele Fälle von Hirnfehlbildungen sind das Ergebnis seltener, vererbbarer Ursachen. Insbesondere werden hier Genmutationen für Holoprosenzephalie, Agenesie des Corpus callosum, Septo-optische Dysplasie, pontozerebelläre und zerebelläre Hypoplasie, Dandy-Walker-Fehlbildung, "Molar tooth sign", Mikrozephalie, Megalenzephalie, Lissenzephalie, Heterotopie, Polymikrogyrie, Schizenzephalie und fokale kortikale Dysplasien behandelt. Autosomal dominante und rezessive sowie X-chromosomale Erbgänge werden beobachtet. Die DNA-diagnostische Ausbeute nimmt zwar zu, ist aber derzeit insgesamt nicht genau zu quantifizieren. Die klinische Diagnose kann durch ein negatives molekulargenetisches Ergebnis keinesfalls ausgeschlossen werden.

Referenzen: Medizinische Genetik 3/2018

• Alias: Intellectual disability, brain organic
• Alias: Psycho-motor retardation, btrain organic
• Allelic: Autism susceptibility 15 (CNTNAP2)
• Allelic: Epilepsy, familial temporal lobe, 7 (RELN)
• Allelic: Fibrosis of extraocular muscles, congenital, 3A (TUBB3)
• Allelic: Focal segmental glomerulosclerosis 9 (CRB2)
• Allelic: Hennekam lymphangiectasia-lymphedema syndrome 2 (FAT4)
• Allelic: Hydranencephaly with abnormal genitalia (ARX)
• Allelic: Leukemia, juvenile myelomonocytic (NF1)
• Allelic: Lymphangioleiomyomatosis (TSC1)
• Allelic: Lymphatic malformation 3 (GJC2)
• Allelic: Microhydranencephaly (NDE1)
• Allelic: Microphthalmia with coloboma 5 (SHH)
• Allelic: Neurofibromatosis, familial spinal (NF1)
• Allelic: Optic atrophy 9 (ACO2)
• Allelic: Parkinson disease 14, AR (PLA2G6)
• Allelic: Parkinson disease 24, AD, susceptibility to (PSAP)
• Allelic: Pitt-Hopkins like syndrome 1 (CNTNAP2)
• Allelic: Single median maxillary central incisor (SHH)
• Allelic: Sotos syndrome 3 (APC2)
• Allelic: Spastic paraplegia 44, AR (GJC2)
• Allelic: Spastic paraplegia 63 (AMPD2)
• Allelic: Subcortical laminar heterotopia (PAFAH1B1)
• Allelic: Symmetric circumferential skin creases, congenital, 1 (TUBB)
• Allelic: Vissers-Bodmer syndrome (CNOT1)
• Allelic: Watson syndrome (NF1)
• Adrenoleukodystrophy (ABCD1)
• Adrenomyeloneuropathy, adult (ABCD1)
• Agenesis of the corpus callosum with peripheral neuropathy (SLC12A6)
• Alkuraya-Kucinskas syndrome (KIAA1109))
• Band heterotopia (EML1)
• Cerebellar ataxia + mental retardation with/-out quadrupedal locomotion 3 (CA8)
• Cerebellar ataxia, nonprogressive, with mental retardation (CAMTA1)
• Cerebellar atrophy, visual impairment + psychomotor retardation (EMC1)
• Cerebellar hypoplasia + mental retardation with/-out quadrupedal locomotion 1 (VLDLR)
• Ceroid lipofuscinosis, neuronal, 1 (PPT1)
• Ceroid lipofuscinosis, neuronal, 10 (CTSD)
• Ceroid lipofuscinosis, neuronal, 2 (TPP1)
• Ceroid lipofuscinosis, neuronal, 3 (CLN3)
• Ceroid lipofuscinosis, neuronal, 4A [Kufs type], AR (CLN6)
• Ceroid lipofuscinosis, neuronal, 5 (CLN5)
• Ceroid lipofuscinosis, neuronal, 6 (CLN6)
• Ceroid lipofuscinosis, neuronal, 8 (CLN8)
• Ceroid lipofuscinosis, neuronal, 8, Northern epilepsy variant (CLN8)
• Combined SAP deficiency (PSAP)
• Cortical dysplasia, complex, with other brain malformations 1 (TUBB3)
• Cortical dysplasia, complex, with other brain malformations 10 (APC2)
• Cortical dysplasia, complex, with other brain malformations 2 (KIF5C)
• Cortical dysplasia, complex, with other brain malformations 3 (KIF2A)
• Cortical dysplasia, complex, with other brain malformations 4 (TUBG1)
• Cortical dysplasia, complex, with other brain malformations 5 (TUBB2A)
• Cortical dysplasia, complex, with other brain malformations 6 (TUBB)
• Cortical dysplasia, complex, with other brain malformations 7 (TUBB2B)
• Cortical dysplasia, complex, with other brain malformations 8 (TUBA8)
• Cortical dysplasia-focal epilepsy syndrome (CNTNAP2)
• Cortical malformations, occipital (LAMC3)
• Culler-Jones syndrome (GLI2)
• Developmental + epileptic encephalopathy 1 (ARX)
• Dystonia 4, torsion, AD (TUBB4A)
• Encephalopathy, progressive, early-onset, with brain atrophy + thin corpus callosum (TBCD)
• Epilepsy, progressive myoclonic 3, with/-out intracellular inclusions (KCTD7)
• FG syndrome 4 (CASK)
• Focal cortical dysplasia, type II, somatic (MTOR)
• Focal cortical dysplasia, type II, somatic (TSC1)
• Gaucher disease, atypical (PSAP)
• Hiatt-Neu-Cooper neurodevelopmental syndrome (RALA)
• Holoprosencephaly 11 (CDON)
• Holoprosencephaly 12, with/-out pancreatic agenesis (CNOT1)
• Holoprosencephaly 2 (SIX3)
• Holoprosencephaly 3 (SHH)
• Holoprosencephaly 4 (TGIF1)
• Holoprosencephaly 5 (ZIC2)
• Holoprosencephaly 9 (GLI2)
• Hypomyelination with brainstem + spinal cord involvement + leg spasticity (DARS1)
• Infantile cerebellar-retinal degeneration (ACO2)
• Infantile neuroaxonal dystrophy 1 (PLA2G6)
• Krabbe disease, atypical (PSAP)
• Leukodystrophy, hypomyelinating, 10 (PYCR2)
• Leukodystrophy, hypomyelinating, 14 (UFM1)
• Leukodystrophy, hypomyelinating, 18 (DEGS1)
• Leukodystrophy, hypomyelinating, 2 (GJC2)
• Leukodystrophy, hypomyelinating, 3 (AIMP)
• Leukodystrophy, hypomyelinating, 5 (FAM126A)
• Leukodystrophy, hypomyelinating, 6 (TUBB4A)
• Leukodystrophy, hypomyelinating, 7, with/-out oligodontia +/- hypogonadotr. hypogonadism (POLR3A)
• Leukodystrophy, hypomyelinating, 8, with/-out oligodontia +/- hypogonadotr. hypogonadism (POLR3B)
• Leukoencephalopathy with brain stem + spinal cord involvement + lactate elevation (DARS2)
• Leukoencephalopathy with vanishing white matter (EIF2B5)
• Leukoencephalopathy, cystic, without megalencephaly (RNASET2)
• Lissencephaly 1 (PAFAH1B1)
• Lissencephaly 2 [Norman-Roberts type] (RELN)
• Lissencephaly 3 (TUBA1A)
• Lissencephaly 4 [with microcephaly] (NDE1) Lissencephaly 8 (TMTC3)
• Lissencephaly 5 (LAMB1)
• Lissencephaly 9 with complex brainstem malformation (MACF1)
• Lissencephaly, XL (DCX)
• Lissencephaly, XL 2 (ARX)
• Megalencephalic leukoencephalopathy with subcortical cysts (MLC1)
• Megalencephalic leukoencephalopathy with subcortical cysts 2A (HEPACAM)
• Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitt., +/- ment. retard. (HEPACAM)
• Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3 (CCND2)
• Mental retardation, AR 34, with variant lissencephaly (CRADD)
• Mental retardation, XL 29 + others (ARX)
• Mental retardation, XL, with cerebellar hypoplasia + distinctive facial appearance (OPHN1)
• Mental retardation, microcephaly with pontine + cerebellar hypoplasia (CASK)
• Mental retardation, with or without nystagmus (CASK)
• Metachromatic leukodystrophy due to SAP-b deficiency (PSAP)
• Muscular dystrophy-dystroglycanopathy (cong. with brain + eye anomalies), type A, 10 (RXYLT1)
• Neurodegeneration with brain iron accumulation 2B (PLA2G6)
• Neurodegeneration with brain iron accumulation 5 (WDR45)
• Neurodegeneration, childhood-onset, with brain atrophy (UBTF)
• Neurodevelopmental disorder with microcephaly, cortical malformations + spasticity (TMX2)
• Neurodevelopmental disorder with structural brain anomalies + dysmorphic facies (RAC3)
• Neurofibromatosis, type 1 (NF1)
• Neurofibromatosis-Noonan syndrome (NF1)
• Ovarioleukodystrophy (EIF2B5)
• Partington syndrome (ARX)
• Pelizaeus-Merzbacher disease (PLP1)
• Periventricular heterotopia with microcephaly (ARFGEF2)
• Polymicrogyria, bilateral frontoparietal (ADGRG1)
• Polymicrogyria, bilateral perisylvian (ADGRG1)
• Pontocerebellar hypoplasia type 10 (CLP1)
• Pontocerebellar hypoplasia type 11 (TBC1D23)
• Pontocerebellar hypoplasia type 1A (VRK1)
• Pontocerebellar hypoplasia type 1B (EXOC3)
• Pontocerebellar hypoplasia type 2A (TSEN54)
• Pontocerebellar hypoplasia type 2B (TSEN2)
• Pontocerebellar hypoplasia type 2C (TSEN34)
• Pontocerebellar hypoplasia type 2D (SEPSECS)
• Pontocerebellar hypoplasia type 2E (VPS53)
• Pontocerebellar hypoplasia type 4 (TSEN54)
• Pontocerebellar hypoplasia type 5 (TSEN54)
• Pontocerebellar hypoplasia type 6 (RARS2)
• Pontocerebellar hypoplasia type 8 (CHMP1A)
• Pontocerebellar hypoplasia type 9 (AMPD2)
• Pontocerebellar hypoplasia, type 7 (TOE1)
• Proud syndrome (ARX)
• Pseudo-TORCH syndrome 1 (OCLN)
• Schizencephaly (EMX2)
• Schizencephaly (SHH)
• Schizencephaly (SIX3)
• Smith-Kingsmore syndrome (MTOR)
• Spastic paraplegia 2, XL (PLP1)
• Speech-language disorder-1 (FOXP2)
• Spinocerebellar ataxia, AR 20 (SNX14)
• Spinocerebellar ataxia, AR 7 (TPP1)
• Subcortical laminal heterotopia, XL (DCX)
• Tuberous sclerosis-1 (TSC1)
• Van Maldergem syndrome 2 (FAT4)
• Ventriculomegaly with cystic kidney disease (CRB2)
• Wiedemann-Rautenstrauch syndrome (POLR3A)