IllnessAtaxia, autosomal recessive [adult]; differential diagnosis

1. NGS + [Sanger]
2. X; FXN gene: first only (GAA)n repeat expansion, then NGS

Cerebellar ataxia with adulthood-onset, slowly progressive spinocerebellar ataxia, gait + appendicular ataxia, dysarthria, ocular movement anomalies ( horizontal, vertical, and/or downbeat nystagmus, hypermetric saccades), increased deep tendon reflexes + progressive cognitive decline. Additionally proximal leg muscle wasting + fasciculations, pes cavus, inspiratory stridor, epilepsy, retinal degeneration, cataracts. Brain imaging reveals marked cerebellar atrophy; electromyography: lower motor neuron involvement

• Allelic: Cataract 41 (WFS1)
• Allelic: Charcot-Marie-Tooth disease, axonal, type 2N (AARS1)
• Allelic: Charcot-Marie-Tooth disease, type 2B2 (PNKP)
• Allelic: Congenital disorder of glycosylation, type Iq (SRD5A3)
• Allelic: Deafness, AD 6/14/38 (WFS1)
• Allelic: Developmental + epileptic encephalopathy 29 (AARS1)
• Allelic: Enlarged vestibular aqueduct, digenic (KCNJ10)
• Allelic: Epilepsy, idiopathic generalized, susceptibility to, 11 (CLCN2)
• Allelic: Hydrocephalus, congenital, 3, with brain anomalies (WDR81)
• Allelic: Hyperaldosteronism, familial, type II (CLCN2)
• Allelic: Infantile neuroaxonal dystrophy 1 (PLA2G6)
• Allelic: Laurence-Moon syndrome (PNPLA6)
• Allelic: Lymphatic malformation 3 (GJC2)
• Allelic: Metabolic syndrome, protection against (MTTP)
• Allelic: Microcephaly, seizures + developmental delay (PNKP)
• Allelic: Myopathy, distal, with rimmed vacuoles (SQSTM1)
• Allelic: Neurodegeneration with ataxia, dystonia + gaze palsy, childhood-onset (SQSTM1
• Allelic: Neuropathy, hereditary motor + sensory, type VIB (SLC25A46)
• Allelic: Oliver-McFarlane syndrome (PNPLA6)
• Allelic: Optic atrophy 1 (OPA1)
• Allelic: Optic atrophy 3 with cataract (OPA3)
• Allelic: Optic atrophy plus syndrome (OPA1)
• Allelic: Paget disease of bone 3 (SQSTM1)
• Allelic: Parkinson disease 5, susceptibility to (UCHL1)
• Allelic: Perrault syndrome 5 (TWNK)
• Allelic: Progressive external ophthalmoplegia with mitochondrial DNA deletions, AD 3 (TWNK)
• Allelic: Spinocerebellar ataxia 44 (GRM1)
• Allelic: Spinocerebellar ataxia 48 (STUB1)
• Allelic: Spinocerebellar ataxia 5 (SPTBN2)
• Allelic: Trichothiodystrophy 8, nonphotosensitive (AARS1)
• Allelic: Wolfram-like syndrome, AD (WFS1)
• 3-methylglutaconic aciduria, type III (OPA3)
• 3-methylglutaconic aciduria, type V (DNAJC19)
• Abetalipoproteinemia (MTTP)
• Achalasia-addisonianism-alacrimia syndrome (AAAS)
• Allelic: Thyroid cancer, nonmedullary, 1 (NKX2-1)
• Ataxia + oculomotor apraxia type 2, AOA2 (SETX)
• Ataxia + vitamin E deficiency (TTPA)
• Ataxia, cerebellar, Cayman type (ATCAY)
• 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)
• 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 +/- quadrupedal locomotion 3 (CA8)
• Cerebellar ataxia, early onset, mild to moderate, progressive [panelapp] (PRDX3)
• Cerebellar ataxia, mental retardation + dysequilibrium syndrome 2 (WDR81)
• Cerebellar ataxia, mental retardation + dysequilibrium syndrome 4 (ATP8A2)
• Cerebellar hypoplasia + mental retardation -/+ quadrupedal locomotion 1 (VLDLR)
• Cerebellofaciodental syndrome (BRF1)
• Cerebrotendinous xanthomatosis (CYP27A1)
• Ceroid lipofuscinosis, neuronal, 2 (TPP1)
• Ceroid lipofuscinosis, neuronal, 4A, Kufs type, AR (CCLN6)
• Ceroid lipofuscinosis, neuronal, 6 (CLN6)
• Chorea, hereditary benign (NKX2-1)
• Choreoathetosis, hypothyroidism + neonatal respiratory distress (NKX2-1)
• Chylomicron retention disease (SAR1B)
• Coenzyme Q10 deficiency, primary, 4 (COQ8A)
• Complex phenotypic spectrum from Emery-Dreifuss muscular dystrophy to ataxia SCA8 (SYNE1)
• Congenital disorder of glycosylation, type IIi (COG5)
• Congenital disorder of glycosylation, type IIn (SLC39A8)
• Developmental + epileptic encephalopathy 28 (WWOX)
• Developmental + epileptic encephalopathy 44 (UBA5)
• Dystonia, dopa-responsive, due to sepiapterin reductase deficiency (SPR)
• Epilepsy, progressive myoclonic 1A, Unverricht + Lundborg (CSTB)
• Epilepsy, progressive myoclonic 1B (PRICKLE1)
• Epilepsy, progressive myoclonic 2A, Lafora (EPM2A)
• Epilepsy, progressive myoclonic 2B, Lafora (NHLRC1)
• Epilepsy, progressive myoclonic 6 (GOSR2)
• Frontotemporal dementia and/or amyotrophic lateral sclerosis 3 (SQSTM1)
• GM2-gangliosidosis, several forms (HEXA)
• Galloway-Mowat syndrome 1 (WDR73)
• Gaze palsy, familial horizontal, with progressive scoliosis, 1 (ROBO3)
• Glycosylphosphatidylinositol biosynthesis defect 15 (GPAA1)
• Hemosiderosis, systemic, due to aceruloplasminemia (CP)
• Hyperekplexia 1 (GLRA1)
• Hyperekplexia 2 Hyperekplexia 2 (GLRB)
• Infantile-onset multisystem neurologic, endocrine + pancreatic disease (PTRH2)
• Joubert syndrome 30 (ARMC9)
• Juvenile amyotrophic lateral sclerosis, ALS4; AD ataxia (SETX)
• Kahrizi syndrome (SRD5A3)
• Krabbe disease (GALC)
• Leukodystrophy, hypomyelinating, 2 (GJC2)
• Leukodystrophy, hypomyelinating, 7, +/- oligodontia +/- hypogonadotropic hypogonadism (POLR3A)
• Leukoencephalopathy with ataxia (CLCN2)
• Leukoencephalopathy with brain stem + spinal cord involvement + lactate elevation (DARS2)
• Leukoencephalopathy with vanishing white matter (EIF2B1, EIF2B2, EIF2B3, EIF2B4, EIF2B5)
• Leukoencephalopathy, hereditary diffuse, with spheroids 2 (AARS1)
• Lichtenstein-Knorr syndrome (SLC9A1)
• Marinesco-Sjogren syndrome (SIL1)
• Metachromatic leukodystrophy (ARSA)
• Methylmalonic aciduria + homocystinuria, cblC type (MMACHC)
• Mitochondrial DNA depletion syndrome 14, encephalocardiomyopathic type (OPA1)
• Mitochondrial DNA depletion syndrome 7, hepatocerebral type (TWNK)
• Mitochondrial complex IV deficiency, nuclear type 11 (COX20)
• Mitochondrial recessive ataxia syndrome, includes SANDO + SCAE (POLG)
• Mitochondrial spinocerebellar ataxia with epilepsy, SCAE (POLG)
• Multiple mitochondrial dysfunctions syndrome 6 (PMPCB)
• Muscular dystrophy-dystroglycanopathy (cong. with brain + eye anomalies), type A, 13 (B4GAT1)
• Muscular dystrophy-dystroglycanopathy (cong. with brain + eye anomalies, type A, 11 (B3GALNT2)
• Myopathy, mitochondrial + ataxia (MSTO1)
• Neurodegeneration due to cerebral folate transport deficiency (FOLR1)
• Neurodegeneration with brain iron accumulation 2B (PLA2G6)
• Neurodegeneration with brain iron accumulation 6 (COASY)
• Neurodegeneration, childhood-onset, stress-induced, with variable ataxia + seizures (ADPRS)
• Neurodevelopmental disorder with epilepsy + hypoplasia of the corpus callosum (LNPK)
• Niemann-Pick disease types C1 + D (NPC1)
• Niemann-Pick disease, type C2 (NPC2)
• Ovarioleukodystrophy (EIF2B2, EIF2B4, EIF2B5)
• Parkinson disease 14, AR (PLA2G6)
• Peroxisome biogenesis disorder 4A, Zellweger (PEX6)
• Peroxisome biogenesis disorder 4B (PEX6)
• Peroxisome biogenesis disorder 5A, Zellweger (PEX2)
• Peroxisome biogenesis disorder 5B (OEX2)
• Peroxisome biogenesis disorder 8A, Zellweger (PEX16)
• Peroxisome biogenesis disorder 8B (PEX16)
• Peroxisome biogenesis disorder 9B (PEX7)
• Polymicrogyria, bilateral frontoparietal (ADGRG1)
• Polymicrogyria, bilateral perisylvian (ADGRG1)
• Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, cataract (ABHD12)
• Pontocerebellar hypoplasia type 1A (VRK1)
• Pontocerebellar hypoplasia type 2A (TSEN54)
• Pontocerebellar hypoplasia type 2B (TSEN2)
• Pontocerebellar hypoplasia type 2D (SEPSECS)
• Pontocerebellar hypoplasia type 4 (TSEN54)
• Pontocerebellar hypoplasia type 5 (TSEN54)
• Pontocerebellar hypoplasia, type 10 (CLP1)
• Pontocerebellar hypoplasia, type 11 (TBC1D23)
• Pontocerebellar hypoplasia, type 12 (COASY)
• Pontocerebellar hypoplasia, type 1B (EXOSC3)
• Pontocerebellar hypoplasia, type 1C (EXOSC8)
• Pontocerebellar hypoplasia, type 1D (EXOSC9)
• Pontocerebellar hypoplasia, type 1E (SLC25A46)
• Pontocerebellar hypoplasia, type 2E (VPS53)
• Pontocerebellar hypoplasia, type 2F (TSEN15)
• Pontocerebellar hypoplasia, type 6 (RARS2)
• Pontocerebellar hypoplasia, type 7 (TOE1)
• Pontocerebellar hypoplasia, type 8 (CHMP1A)
• Pontocerebellar hypoplasia, type 9 (AMPD2)
• Refsum disease [disorders of peroxisomal alpha-, beta, omega-oxidation} (PHYH)
• SESAME syndrome (KCNJ10)
• Sandhoff disease, infantile, juvenile + adult forms (HEXB)
• Sensible atactic neuropathy with dysarthria + ophthalmoplegia, SANDO (POLG)
• Spastic ataxia 2, AR (KIF1C)
• Spastic ataxia 3, AR (MARS2)
• Spastic ataxia 4, AR (MTPAP)
• Spastic ataxia 8, AR, with hypomyelinating leukodystrophy (NKX6-2)
• Spastic ataxia 9, AR (CHP1)
• Spastic ataxia, Charlevoix-Saguenay type (SACS)
• Spastic paraplegia 15, AR (ZFYVE26)
• Spastic paraplegia 39, AR (PNPLA6)
• Spastic paraplegia 44, AR (GJC2)
• Spastic paraplegia 46, AR (GBA2)
• Spastic paraplegia 54, AR (DDHD2)
• Spastic paraplegia 56, AR (CYP2U1)
• Spastic paraplegia 63 (AMPD2)
• Spastic paraplegia 7 complex forms; range of phenotypes including adult-onset ataxia (SPG7)
• Spastic paraplegia 76, AR (CAPN1)
• Spastic paraplegia 79, AR (UCHL1)
• Spinocerebellar ataxia, AAR 13 (GRM1)
• Spinocerebellar ataxia, AR 10 (ANO10)
• Spinocerebellar ataxia, AR 12 (WWOX)
• Spinocerebellar ataxia, AR 14 (SPTBN2)
• 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 24 (UBA5)
• Spinocerebellar ataxia, AR 26 (XRCC1)
• Spinocerebellar ataxia, AR 27 (GDAP2)
• Spinocerebellar ataxia, AR 29 (VPS41)
• Spinocerebellar ataxia, AR 4 (VPS13D)
• Spinocerebellar ataxia, AR 7 (TPP1)
• Spinocerebellar ataxia, AR 8 (SYNE1)
• Spinocerebellar ataxia, AR, with axonal neuropathy 3 (COA7)
• Tay-Sachs disease (HEXA)
• Wiedemann-Rautenstrauch syndrome (POLR3A)
• Wilson disease (ATP7B)
• Wolfram syndrome 1 (WFS1)