Klinische FragestellungSpinozerebelläre Ataxie, autosomal rezessiv; Differentialdiagnose

NGS + [X]

[[Sanger]]

Autosomal rezessive Ataxien (ARCAs; spinozerebelläre Ataxien, rezessiv) sind eine heterogene Gruppe seltener neurodegenerativer genetischer Störungen, die in jedem Lebensalter beginnen können, typischerweise allerdings vor dem frühen Erwachsenenalter. Pathophysiologisch werden zwei Hauptgruppen unterschieden, vorwiegend sensorische oder afferente Ataxien (hauptsächlich gestörter peripherer Input zum Kleinhirn) und vorwiegend zerebelläre Ataxien (Kleinhirn bevorzugt betroffen). ARCAs machen mehr als 50% aller genetisch bedingten Ataxien aus. Die häufigsten Formen in der kaukasischen Bevölkerung sind Friedreich-Ataxie, Ataxie-Telangiektasie und früh einsetzende Kleinhirnataxie mit erhaltenen Sehnenreflexen. Andere Formen wie z. B. ARCA1, die durch SYNE1-Mutationen verursacht werden, sind weitaus seltener. Auf der Grundlage klinisch-genetischer Kriterien wurden mehrere Haupttypen von ARCAs unterschieden: kongenitale Ataxien, Ataxien in Verbindung mit Stoffwechselstörungen, Ataxien mit DNA-Reparaturdefekten, degenerative Ataxien und Ataxien in Verbindung mit anderen Merkmalen. Darüber hinaus können auch andere komplexe Bewegungsstörungen oder rezessive Multisystemerkrankungen eine ausgeprägte Ataxie aufweisen. Weiterhin gibt es eine ganze Reihe rezessiver Erkrankungen, die gelegentlich mit Ataxie einhergehen, bei denen die Ataxie jedoch ein sekundäres Merkmal ist. Die ataktischen Bewegungsstörungen sind meist progressiv und führen häufig dazu, dass Gehhilfen oder ein Rollstuhl benötigt wird. Die klinische Diagnose wird durch ergänzende Tests wie Neuroimaging, elektrophysiologische Untersuchungen und Mutationsanalysen bestätigt. Eine korrekte klinische und genetische Diagnose ist nicht nur für angemessene genetische Beratung und Prognose wichtig, sondern in einigen Fällen auch für die pharmakologische Behandlung (Q10-Mangel, Abetalipoproteinämie usw.). Aufgrund des autosomal-rezessiven Erbgangs ist eine aussagekräftige Familienanamnese des Patienten unwahrscheinlich. Die DNA-Differenzialdiagnostik umfasst mehr als 120 Gene, wobei die Ausbeute bei ARCAs insgesamt >50 % beträgt. Dennoch schließt ein negatives molekulargenetisches Ergebnis die klinische Diagnose nicht aus.

Referenz: https://pubmed.ncbi.nlm.nih.gov/29325611/

• Alias: AR Ataxia with cerebellar anomalies
• Alias: Cerebellar ataxia, AR
• Alias: SCA, autosomal recessive
• Allelic: Amyotrophic lateral sclerosis 4, juvenile (SETX)
• Allelic: Breast cancer, susceptibility to (ATM)
• Allelic: Laurence-Moon syndrome (PNPLA6)
• Allelic: Lymphoma, B-cell non-Hodgkin, somatic (ATM)
• Allelic: Lymphoma, mantle cell, somatic (ATM)
• Allelic: Oliver-McFarlane syndrome (PNPLA6)
• Allelic: Rhizomelic chondrodysplasia punctata, type 1 (PEX7)
• Allelic: Spastic paraplegia 39, AR (PNPLA6)
• Allelic: T-cell prolymphocytic leukemia, somatic (ATM)
• 3-methylglutaconic aciduria, type III (OPA3)
• 3-methylglutaconic aciduria, type V (DNAJC19)
• Abetalipoproteinemia (MTTP)
• Achalasia-addisonianism-alacrimia syndrome (AAAS)
• Allelic: Anemia, sideroblastic, 3, pyridoxine-refractory (GLRX5)
• Allelic: Developmental + epileptic encephalopathy 44 (UBA5)
• Allelic: Gastrointestinal defects and immunodeficiency syndrome 2 (PI4KA)
• Allelic: Hemosiderosis, systemic, due to aceruloplasminemia (CP)
• Allelic: Hyper-IgD syndrome (MVK)
• Allelic: Hypoceruloplasminemia, hereditary (CP)
• Allelic: Optic atrophy 12 (AFG3L2)
• Allelic: Porokeratosis 3, multiple types (MVK)
• Allelic: Spinocerebellar ataxia 15 (ITPR1)
• Allelic: Spinocerebellar ataxia 28 (AFG3L2)
• Allelic: Spinocerebellar ataxia 29, congenital nonprogressive (ITPR1)
• Aniridia, cerebellar ataxia, and mental retardation [panelapp] (PAX6)
• Ataxia with isolated vitamin E deficiency (TTPA)
• Ataxia, cerebellar, Cayman type (ADCAY)
• Ataxia, early-onset, with oculomotor apraxia + hypoalbuminemia (APTX)
• Ataxia, posterior column, with retinitis pigmentosa (FLVCR1)
• Ataxia-oculomotor apraxia 4 (PNKP)
• Ataxia-telangiectasia (ATM)
• Ataxia-telangiectasia-like disorder 1 (MRE11)
• Bardet-Biedl syndrome 1 (BBS1)
• Behr syndrome (OPA1)
• Boucher-Neuhauser syndrome (PNPLA6)
• Brown-Vialetto-Van Laere syndrome 2 (SLC52A2)
• Cerebellar ataxia (CP)
• Cerebellar ataxia + hypogonadotropic hypogonadism (RNF216)
• Cerebellar ataxia + mental retardation with/-out quadrupedal locomotion 3 (CA8)
• Cerebellar ataxia, mental retardation + dysequilibrium syndrome 2 (WDR81)
• Cerebellar ataxia, mental retardation + dysequilibrium syndrome 4 (ATP8A2)
• Cerebellar ataxia, neuropathy + vestibular areflexia syndrome (RFC1)
• Cerebellar dysfunction, impaired intellectual development, hypogonadotropic hypogonadism (PRDM13)
• Cerebellar hypoplasia + mental retardation with/-out quadrupedal locomotion 1 (VLDLR)
• Cerebrotendinous xanthomatosis (CYP27A1)
• Ceroid lipofuscinosis, neuronal, 5 (CLN5)
• Ceroid lipofuscinosis, neuronal, 6 (CLN6)
• Chylomicron retention disease (SAR1B)
• Coenzyme Q10 deficiency, primary, 4 (COQ8A)
• Combined oxidative phosphorylation deficiency 15 (MTFMT)
• Combined oxidative phosphorylation deficiency 29 (TXN2)
• Combined oxidative phosphorylation deficiency 3 (TSFM)
• Congenital disorder of glycosylation, type Iq (SRD5A3)
• D-bifunctional protein deficiency (HSD17B4)
• Developmental and epileptic encephalopathy 50 (CAD)
• Dystonia, dopa-responsive, due to sepiapterin reductase deficiency (SPR)
• Encephalopathy, progressive, early-onset, brain edema +/- leukoencephalopathy (NAXE)
• Epilepsy, progressive myoclonic 1A, Unverricht + Lundborg (CSTB)
• Epilepsy, progressive myoclonic 2A [Lafora] (EPM2A)
• Epilepsy, progressive myoclonic 2B [Lafora] (NHLRC1)
• Epilepsy, progressive myoclonic 6 (GOSR2)
• GLUT1 deficiency syndrome 1, infantile onset, severe; + 2Childhood onset (SLC2A1)
• GM1-gangliosidosis, type I, II, III (GLB1)
• GM2-gangliosidosis, several forms (HEXA)
• Galloway-Mowat syndrome 1 (WDR73)
• Gaze palsy, familial horizontal, with progressive scoliosis, 1 (ROBO3)
• Gillespie syndrome (ITPR1)
• Glycosylphosphatidylinositol biosynthesis defect 15 (GPAA1)
• Harel-Yoon syndrome (ATAD3A)
• Hydrops, lactic acidosis, and sideroblastic anemia (LARS2)
• Infantile cerebellar-retinal degeneration (ACO2)
• Kahrizi syndrome (SRD5A3)
• Leukodystrophy, hypomyelinating, 13 (HIKESHI)
• Leukodystrophy, hypomyelinating, 23, ataxia, deafness, liver dysf., dilated cardiomyopathy (RNF220)
• Leukodystrophy, hypomyelinating, 4 (HSPD1)
• Leukodystrophy, hypomyelinating, 7, with/-out oligodontia +/- hypogonadotropic hypogonadism (POLR3A)
• Leukodystrophy, hypomyelinating, 8, with/-out oligodontia +/- hypogonadotropic hypogonadism (POLR3B)
• Leukoencephalopathy with ataxia (CLCN2)
• Leukoencephalopathy with brain stem + spinal cord involvement + lactate elevation DARS2)
• Leukoencephalopathy with vanishing white matter (EIF2B1, EIF2B2, EIF2B3, EIF2B4, EIF2B5)
• Lichtenstein-Knorr syndrome (SLC9A1)
• Lissencephaly 2 [Norman-Roberts type] (RELN)
• Marinesco-Sjogren syndrome (SIL1)
• Megalencephalic leukoencephalopathy with subcortical cysts 2A (HEPACAM)
• Metachromatic leukodystrophy (ARSA)
• Methylmalonic aciduria and homocystinuria, cblC type (MMACHC)
• Mevalonic aciduria (MVK)
• Mitochondrial Ar ataxia syndrome [includes SANDO + SCAE] (POLG)
• Mitochondrial DNA depletion syndrome 13, encephalomyopathic type (FBXL4)
• Mitochondrial DNA depletion syndrome 14, encephalocardiomyopathic type (OPA1)
• Mitochondrial DNA depletion syndrome 7 [hepatocerebral type] (TWNK)
• Mitochondrial complex I deficiency, nuclear type 27 (MTFMT)
• Mitochondrial complex III deficiency, nuclear type 2 (TTC19)
• Mitochondrial complex IV deficiency (COX20)
• Mucopolysaccharidosis type IVB, Morquio (GLB1)
• Multiple mitochondrial dysfunctions syndrome 6 (PMPCB)
• Muscular dystrophy-dystroglycanopathy (cong. + brain/eye anomalies), type A, 6 (LARGE1)
• Muscular dystrophy-dystroglycanopathy (cong. with brain + eye anomalies), type A, 1 (POMT1)
• Muscular dystrophy-dystroglycanopathy (cong. with brain + eye anomalies), type A, 13 (B4GAT1)
• Muscular dystrophy-dystroglycanopathy (cong. with brain + eye anomalies), type A, 14 (GMPPB)
• Muscular dystrophy-dystroglycanopathy (cong. with brain + eye anomalies), type A, 2 (POMT2)
• Muscular dystrophy-dystroglycanopathy (cong. with brain + eye anomalies), type A, 3 (POMGNT1)
• Muscular dystrophy-dystroglycanopathy (cong. with brain + eye anomalies), type A, 4 (FKTN)
• Muscular dystrophy-dystroglycanopathy (cong. with brain + eye anomalies), type A, 5 (FKRP)
• Muscular dystrophy-dystroglycanopathy (cong. with brain + eye anomalies), type A, 6 (LARGE1)
• Muscular dystrophy-dystroglycanopathy (cong. with brain + eye anomalies), type A, 7 (CRPPA)
• Muscular dystrophy-dystroglycanopathy (cong. with brain + eye anomalies, type A, 11 (B3GALNT2)
• Muscular dystrophy-dystroglycanopathy (cong. with brain + eye anomalies, type A, 8 (POMGNT2)
• Muscular dystrophy-dystroglycanopathy (cong. with brain/eye anomalies), type A, 10 (RXYLT1)
• Muscular dystrophy-dystroglycanopathy (cong., impaired intell. development), type B, 6 (LARGE1)
• Myopathy, mitochondrial, and ataxia (MSTO1)
• NOR polyagglutination syndrome (A4GALT)
• Neurodegeneration due to cerebral folate transport deficiency (FOLR1)
• Neurodegeneration with ataxia, dystonia + gaze palsy, childhood-onset (SQSTM1)
• Neurodegeneration with brain iron accumulation 2B (PLA2G6)
• Neurodegeneration, childhood-onset, stress-induced, with variable ataxia + seizures (ADPRS)
• Neurodevelopmental disorder with impaired intellectual development, hypotonia, ataxia (DOCK3)
• Neuropathy, hereditary motor and sensory, type VIB (SLC25A46)
• Niemann-Pick disease, type C1 (NPC1)
• Niemann-pick disease, type C2 (NPC2)
• Pancreatic and cerebellar agenesis (PTF1A)
• Peroxisome biogenesis disorder 4A, Zellweger (PEX6)
• Peroxisome biogenesis disorder 8A (Zellweger) + 8B (PEX16)
• Peroxisome biogenesis disorder 9B (PEX7)
• Perrault syndrome 1 (HSD17B4)
• Perrault syndrome 4 (LARS2)
• Polymicrogyria, bilateral frontoparietal (ADGRG1)
• Polymicrogyria, perisylvian, with cerebellar hypoplasia + arthrogryposis (PI4KA)
• Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (ABHD12)
• Pontocerebellar hypoplasia type 1A (VRK1)
• Pontocerebellar hypoplasia type 2A, 4, 5 (TSEN54)
• Pontocerebellar hypoplasia type 2B (TSEN2)
• Pontocerebellar hypoplasia type 2C (TSEN34)
• Pontocerebellar hypoplasia type 2D (SEPSECS)
• Pontocerebellar hypoplasia, hypotonia, respiratory insuff. syndrome, neonatal lethal (ATAD3A)
• Pontocerebellar hypoplasia, type 10 (CLP1)
• Pontocerebellar hypoplasia, type 16 (MINPP1)
• Pontocerebellar hypoplasia, type 17 (PRDM13)
• Pontocerebellar hypoplasia, type 1B (EXOSC3)
• Pontocerebellar hypoplasia, type 6 (RARS2)
• Pontocerebellar hypoplasia, type 7 (TOE1)
• Pontocerebellar hypoplasia, type 8 (CHMP1A)
• Pontocerebellar hypoplasia, type 9 (AMPD2)
• Poretti-Boltshauser syndrome (LAMA1)
• Refsum disease (PHYH)
• SESAME syndrome (KCNJ10)
• Salla disease (SLC17A5)
• Sandhoff disease, infantile, juvenile + adult forms (HEXB)
• Sialic acid storage disorder, infantile (SLC17A5)
• Spastic ataxia 2, AR (KIF1C)
• Spastic ataxia 3, AR (MARS2)
• Spastic ataxia 5, AR (AFG3L2)
• Spastic ataxia 8, AR, with hypomyelinating leukodystrophy (NKX6-2)
• Spastic ataxia, Charlevoix-Saguenay type (SACS)
• Spastic paraplegia 35, AR (FA2H)
• Spastic paraplegia 44, AR (GJC2)
• Spastic paraplegia 46, Ar (GBA2)
• Spastic paraplegia 54, AR (DDHD2)
• Spastic paraplegia 56, AR (CYP2U1)
• Spastic paraplegia 7, AR (SPG7)
• Spastic paraplegia 76, AR (CAPB1)
• Spastic paraplegia 79B, AR (UCHL1)
• Spastic paraplegia 84, AR (PI4KA)
• Spasticity, childhood-onset, with hyperglycinemia (GLRX5)
• Spinocerebellar ataxia [panelapp] (MTCL1)
• Spinocerebellar ataxia, AR 10 (ANO10)
• Spinocerebellar ataxia, AR 11 (SYT14)
• Spinocerebellar ataxia, AR 12 (WWOX)
• Spinocerebellar ataxia, AR 13 (GRM1)
• Spinocerebellar ataxia, AR 14 (SPTBN2)
• Spinocerebellar ataxia, AR 15 (RUBCN)
• Spinocerebellar ataxia, AR 16 (STUB1)
• Spinocerebellar ataxia, AR 17 (CWF19L1)
• Spinocerebellar ataxia, AR 18 (GRID2)
• Spinocerebellar ataxia, AR 2 (PMPCA)
• Spinocerebellar ataxia, AR 20 (SNX14)
• Spinocerebellar ataxia, AR 21 (SCYL1)
• Spinocerebellar ataxia, AR 22 (VWA3B)
• Spinocerebellar ataxia, AR 23 (TDP2)
• Spinocerebellar ataxia, AR 24 (UBA5)
• Spinocerebellar ataxia, AR 25 (ATG5)
• Spinocerebellar ataxia, AR 26 (XRCC1)
• Spinocerebellar ataxia, AR 27 (GDAP2)
• Spinocerebellar ataxia, AR 28 (THG1L)
• Spinocerebellar ataxia, AR 29 (VPS41)
• Spinocerebellar ataxia, AR 30 (PITRM1)
• Spinocerebellar ataxia, AR 31 (ATGT)
• Spinocerebellar ataxia, AR 32 (PRDX3)
• Spinocerebellar ataxia, AR 4 (VPS13D)
• Spinocerebellar ataxia, AR 7 (TPP1)
• Spinocerebellar ataxia, AR 8 (SYNE1)
• Spinocerebellar ataxia, AR, with axonal neuropathy 1 (TDP1)
• Spinocerebellar ataxia, AR, with axonal neuropathy 2 (SETX)
• Spinocerebellar ataxia, AR, with axonal neuropathy 3 (COA7)
• Succinic semialdehyde dehydrogenase deficiency (ALDH5A1)
• Tay-Sachs disease (HEXA)
• Wolfram syndrome 1 (WFS1)
• Yoon-Bellen neurodevelopmental syndrome (OGDHL)