IllnessSpinocerebellar ataxia, autosomal recessive; differential diagnosis

NGS + [X]

[[Sanger]]

Autosomal recessive ataxias (ARCAs; spinocerebellar ataxias, recessive) are a heterogeneous group of rare neurodegenerative genetic disorders that can begin at any age, but typically before early adulthood. Pathophysiologically, two main groups are distinguished, predominantly sensory or afferent ataxias (mainly impaired peripheral input to the cerebellum) and predominantly cerebellar ataxias (preferential cerebellum affection). ARCAs account for more than 50% of all genetic ataxias. The most common forms in the Caucasian population are Friedreich's ataxia, ataxia-telangiectasia and early-onset cerebellar ataxias. Other forms such as ARCA1 caused by SYNE1 mutations are much rarer. Based on clinical genetic criteria, several major types of ARCAs have been distinguished: congenital ataxias, ataxias associated with metabolic disorders, ataxias with DNA repair defects, degenerative ataxias, and ataxias associated with other features. In addition, other complex movement disorders or recessive multisystem disorders may also present with marked ataxia. Furthermore, there are a number of recessive disorders that occasionally present with ataxia, but in which ataxia is a secondary feature. The ataxic movement disorders are usually progressive and often result in the need for walking aids or a wheelchair. Clinical diagnosis is confirmed by complementary tests such as neuroimaging, electrophysiological studies, and mutation analysis. A correct clinical and genetic diagnosis is important not only for appropriate genetic counseling and prognosis, but also for pharmacological treatment in some cases (Q10 deficiency, abetalipoproteinemia etc.). Due to the autosomal recessive inheritance, a positive family history of the patient is unlikely. The differential diagnosis includes more than 120 genes, with an overall yield of >50% in ARCAs. Nevertheless, a negative molecular genetic result does not exclude the clinical diagnosis.

Reference: 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)