IllnessAtaxia, autosomal recessive; differential diagnosis

NGS +

Ataxia is a cardinal symptom in cerebellar disorders but may also be an accompanying symptom of hereditary spastic paraplegias, hereditary polyneuropathies, neurodevelopmental disorders and mitochondrial diseases. Recessive ataxias often exhibit complex phenotypes, even more so than their dominant counterparts and may have several associated features, including neuropathy, pyramidal and extrapyramidal involvement, oculomotor abnormalities, cognitive involvement, seizures, retinopathy, hypogonadism and many others. Some disorders have relatively predominant cerebellar involvement as compared to other neurological and non-neurological systems. Other complex motor or multisystem disorders show marked ataxia. Finally, there are disorders that occasionally present with ataxia, but the ataxia is a secondary feature. Certain disorders with minor or secondary ataxic components have not been included here, provided that ataxia is already prominent from the onset as an incidental symptom. In addition, ataxic disorders are allelic to other movement disorders, particularly spinocerebellar ataxias and hereditary spastic paraplegias. The ages at onset can vary from birth to (late) adulthood. Finally, there is a large phenotypic variability between patients from different families and even from a single family with the same mutated gene, depending on the nature of the mutation and its position in the gene. Other factors that influence age at onset and clinical course are likely the presence of modifying genes and environmental exposures. The DNA diagnostic yield is unknown, thus negative results exclude by no means a clinical diagnosis.

References: https://www.ncbi.nlm.nih.gov/books/NBK1138/

https://doi.org/10.1186/s40673-017-0061-y

• Alias: AR (cerebellar) ataxia
• Allelic: Amyotrophic lateral sclerosis 4, juvenile (SETX)
• Allelic: Aniridia (PAX6)
• Allelic: Anterior segment dysgenesis 5, multiple subtypes (PAX6)
• Allelic: Arthrogryposis multiplex congenita 3, myogenic type (SYNE1)
• Allelic: Breast cancer, susceptibility to (ATM)
• Allelic: Cataract 41 (WFS1)
• Allelic: Cataract with late-onset corneal dystrophy (PAX6)
• Allelic: Charcot-Marie-Tooth disease, type 2B2 (PNKP)
• Allelic: Chorea, hereditary benign (NKX2-1)
• Allelic: Deafness, AD 6/14/38 (WFS1)
• Allelic: Diabetes mellitus, noninsulin-dependent, association with (WFS1)
• Allelic: Enlarged vestibular aqueduct, digenic (KCNJ10)
• Allelic: Epilepsy, idiopathic generalized, susceptibility to, 12 (SLC2A1)
• Allelic: Epileptic encephalopathy, early infantile, 28 (WWOX)
• Allelic: Esophageal squamous cell carcinoma, somatic (WWOX)
• Allelic: Foveal hypoplasia 1 (PAX6)
• Allelic: Frontotemporal dementia and/or amyotrophic lateral sclerosis 3 (SQSTM1)
• Allelic: GLUT1 deficiency syndrome 1, infantile onset, severe / childhood onset (SLC2A1)
• Allelic: Glaucoma, normal tension, susceptibility to (OPA1)
• Allelic: Heimler syndrome 2 (PEX6)
• Allelic: Hemosiderosis, systemic, due to aceruloplasminemia (CP)
• Allelic: Hex A pseudodeficiency (HEXA)
• Allelic: Hydrocephalus, congenital, 3, with brain anomalies (WDR81)
• Allelic: Hyperaldosteronism, familial, type II (CLCN2)
• Allelic: Hypoceruloplasminemia, hereditary (CP)
• Allelic: Infantile neuroaxonal dystrophy 1 (PLA2G6)
• Allelic: Kahrizi syndrome [mental retard., cataract, coloboma, kyphosis, AR] (SRD5A3)
• Allelic: Keratitis (PAX6)
• Allelic: Leukemia, acute myeloid (TERT)
• Allelic: Lymphatic malformation (GJC2)
• Allelic: Lymphoma, B-cell non-Hodgkin, somatic (ATM)
• Allelic: Lymphoma, mantle cell, somatic (ATM)
• Allelic: Melanoma, cutaneous malignant, 9 (TERT)
• Allelic: Metabolic syndrome, protection against (MTTP)
• Allelic: Microcephaly, seizures, developmental delay (PNKP)
• Allelic: Mitochondrial DNA depletion syndrome 4A, Alpers type (POLG)
• Allelic: Mitochondrial DNA depletion syndrome 4B, MNGIE type (POLG)
• Allelic: Myopathy, distal, with rimmed vacuoles (SQSTM1)
• Allelic: Oliver-McFarlane syndrome (PNPLA6)
• Allelic: Optic atrophy 1 (OPA1)
• Allelic: Optic atrophy 12 (AFG3L2)
• Allelic: Optic atrophy 3 with cataract (OPA3)
• Allelic: Optic atrophy 9 (ACO2)
• Allelic: Optic nerve hypoplasia (PAX6)
• Allelic: Ovarioleukodystrophy (EIF2B2, EIF2B4, EIF2B5)
• Allelic: Paget disease of bone 3 (SQSTM1)
• Allelic: Pancreatic agenesis 2 (PTF1A)
• Allelic: Peroxisome biogenesis disorder 8A, Zellweger (PEX16)
• Allelic: Peroxisome biogenesis disorder 8B (PEX16)
• Allelic: Perrault syndrome 5 (TWNK)
• Allelic: Progressive external ophthalmoplegia, AD 1 (POLG)
• Allelic: Pulmonary fibrosis and/or bone marrow failure, telomere-related, 1 (TERT)
• Allelic: Rhizomelic chondrodysplasia punctata, type 1 (PEX7)
• Allelic: Stomatin-deficient cryohydrocytosis with neurologic defects (SLC2A1)
• Allelic: T-cell prolymphocytic leukemia, somatic (ATM)
• Allelic: Thyroid cancer, nonmedullary, 1 (NKX2-1)
• Allelic: Wiedemann-Rautenstrauch syndrome (POLR3A)
• 3-methylglutaconic aciduria, type IIIX (OPA3)
• 3-methylglutaconic aciduria, type V; cardiomyopathy, dilated, with ataxia [DCMA] syndrome (DNAJC19)
• AR paraplegia 54 (DDHD2)
• AR spastic paraplegia 56, complex form of disorder, ataxia not yet identified (CYP2U1)
• AR spinocerebellar ataxia 12 (WWOX)
• Abetalipoproteinemia (MTTP)
• Achalasia-addisonianism-alacrimia syndrome (AAAS)
• Alexander disease (GFAP)
• Allelic: Parkinson disease 5, susceptibility to (UCHL1)
• Aniridia, cerebellar ataxia, mental retardation (PAX6)
• Ataxia + hypogonadism Methylmalonic aciduria + homocystinuria, cblC type (MMACHC)
• Ataxia + oculomotor apraxia type 2, AOA2 (SETX)
• Ataxia with 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)
• Ataxia-telangiectasia-like disorder 1 (MRE11)
• Behr syndrome (OPA1)
• Boucher-Neuhauser syndrome [SCA, hypogonad. hypogonadism, chorioretinal dystrophy] (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 + neuropathy, vestibular areflexia syndrome (RFC1)
• Cerebellar ataxia, mental retardation, dysequilibrium syndrome 2 (WDR81)
• Cerebellar ataxia, mental retardation, dysequilibrium syndrome 4 (ATP8A2)
• Cerebellar atrophy with seizures + variable developmental delay (CACNA2D2)
• Cerebellar hypoplasia + mental retardation with/-out quadrupedal locomotion 1 (VLDLR)
• Cerebellofaciodental syndrome (BRF1)
• Cerebrotendinous xanthomatosis (CYP27A1)
• Ceroid lipofuscinosis, neuronal, 2 (TPP1)
• Ceroid lipofuscinosis, neuronal, 5 (CLN5)
• Ceroid lipofuscinosis, neuronal, 6 (CLN6)
• Ceroid lipofuscinosis, neuronal, Kufs type, adult onset (CLN6)
• Childhood ataxia with CNS hypomyelination/vanishing white matter disease (EIF2B1, -2, -3, -4, -5)
• Choreoathetosis, hypothyroidism + neonatal respiratory distress (NKX2-1)
• Chylomicron retention disease (SAR1B)
• Coenzyme Q10 deficiency, primary, 4 (COQ8A)
• Combined oxidative phosphorylation deficiency 25 (MARS2)
• Combined oxidative phosphorylation deficiency 29 (TXN2)
• Combined oxidative phosphorylation deficiency 3 (TSFM)
• Complex phenotypic spectrum from Emery-Dreifuss muscular dystrophy to ataxia SCA8 (SYNE1)
• Cong. disorder of glycosylation, type Iq [coloboma, ichthyosis, brain + endocrine abnorm.] (SRD5A3)
• Congenital disorder of glycosylation, type IIn (SLC39A8)
• Costeff syndrome (OPA3)
• Developmental + epileptic encephalopathy 44 (UBA5)
• Dyskeratosis congenita, AD 2 (TERT)
• Dyskeratosis congenita, AR 4 (TERT)
• Dystonia 9 (SLC2A1)
• Epilepsy, ataxia, developmental delay, cerebellar atrophy (CACNA2D2)
• 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)
• Friedreich ataxia (FXN)
• Friedreich ataxia with retained reflexes (FXN)
• GLUT1 deficiency syndrome 1, infantile, severe; syndrome 2, childhood onset (SLC2A1)
• GM2-gangliosidosis, several forms (HEXA)
• Galloway-Mowat syndrome 1 [CAMOS, Cereb. Ataxia, Ment. retard., Optic atrophy, Skin abn.] (WDR73)
• Glycosylphosphatidylinositol biosynthesis defect 15 (GPAA1)
• Hyperekplexia 1 (GLRA1)
• Hyperekplexia 2 (GLRB)
• Infantile cerebellar-retinal degeneration (ACO2)
• Infantile progressive ataxia + spastic paresis (PEX16)
• Infantile-onset multisystem neurologic, endocrine + pancreatic disease (PTRH2)
• Joubert syndrome 30 (ARMC9)
• Juvenile amyotrophic lateral sclerosis, ALS4; AD ataxia (SETX)
• Laurence-Moon s.: chorioretinop, pituit. dysf., ataxia, periph. neurop., spastic paraplegia (PNPLA6)
• Leukodystrophy, hypomyelinating, 2 (GJC2)
• Leukodystrophy, hypomyelinating, 7, with/-out oligodontia and/or hypogonad. hypogonadism (POLR3A)
• Leukodystrophy, hypomyelinating, 8, with/-out oligodontia and/or hypogonad. 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)
• Marinesco-Sjogren syndrome [cong. cataracts, cereb. ataxia, progr. myopathy, ment. retard.] (SIL1)
• Metachromatic leukodystrophy (ARSA)
• Methylmalonic aciduria + homocystinuria, cblC type (MMACHC)
• Mitochondrial DNA depletion syndrome 14, encephalocardiomyopathic type (OPA1)
• Mitochondrial DNA depletion syndrome 7, hepatocerebral (TWNK)
• Mitochondrial complex III deficiency, nuclear type 2 (TTC19)
• Mitochondrial complex IV deficiency (COX20)
• Mitochondrial recessive ataxia syndrome, includes SANDO (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, ataxia, dystonia, gaze palsy, childhood-onset (SQSTM1)
• Neurodegeneration, childhood-onset, stress-induced, with variable ataxia + seizures (ADPRHL2)
• Neurodegeneration, childhood-onset, stress-induced, with variable ataxia + seizures (ADPRS)
• Neuropathy, hereditary motor and sensory, type VIB (SLC25A46)
• Niemann-Pick disease type C2 (NPC2)
• Niemann-Pick disease types C1 + D (NPC1)
• Optic atrophy plus syndrome (OPA1)
• Pancreatic and cerebellar agenesis (PTF1A)
• Parkinson disease 14 (PLA2G6)
• Parkinson disease 14, AR (PLA2G6)
• Peroxisome biogenesis disorder 4A, Zellweger (PEX6)
• Peroxisome biogenesis disorder 4B (PEX6)
• Peroxisome biogenesis disorder 9B (PEX7)
• Polymicrogyria, bilateral frontoparietal (ADGRG1)
• Polymicrogyria, bilateral perisylvian (ADGRG1)
• Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, cataract (ABHD12)
• Pontocerebellar hypoplasia, type 10 (CLP1)
• Pontocerebellar hypoplasia, type 11 (TBC1D23)
• Pontocerebellar hypoplasia, type 12 (COASY)
• Pontocerebellar hypoplasia, type 1A (VRK1)
• Pontocerebellar hypoplasia, type 1B (EXOSC3)
• Pontocerebellar hypoplasia, type 1C (EXOSC8)
• Pontocerebellar hypoplasia, type 1D (EXOSC9)
• Pontocerebellar hypoplasia, type 2A, 4, 5 (TSEN54)
• Pontocerebellar hypoplasia, type 2B (TSEN2)
• Pontocerebellar hypoplasia, type 2D (SEPSECS)
• 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)
• Pontocerebellar hypoplasia; epilepsy (RARS2)
• Poretti-Boltshauser s. (cereb. dyspl., vermis hypopl., cysts, myopia, ret. dystr., eye mov.] (LAMA1)
• Progressive external ophthalmoplegia with mitochondrial DNA deletions, AD 3 (TWNK)
• Refsum disease [disorders of peroxisomal alpha-, beta, omega-oxidation] (PHYH)
• SESAME [SEizures, Sensorin. deafness, Ataxia, Ment. retard., Electrolyte imbalance] (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 5, AR (AFG3L2)
• Spastic ataxia 8, AR, with hypomyelinating leukodystrophy (NKX6-2)
• 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 [single family] (AMPD2)
• Spastic paraplegia 7 complex forms; range of phenotypes including adult-onset ataxia (SPG7)
• Spastic paraplegia 7, AR (SPG7)
• Spastic paraplegia 76, AR (CAPN1)
• Spastic paraplegia 79, AR (UCHL1)
• Spinocerebellar ataxia 28 (AFG3L2)
• Spinocerebellar ataxia 44 (GRM1)
• Spinocerebellar ataxia 48 (STUB1)
• Spinocerebellar ataxia 5 (SPTBN2)
• Spinocerebellar ataxia, AR 10 (ANO10)
• Spinocerebellar ataxia, AR 11 (SYT4)
• Spinocerebellar ataxia, AR 12 (WWOX)
• Spinocerebellar ataxia, AR 13 (GRM1)
• Spinocerebellar ataxia, AR 14 (SPTBN2)
• Spinocerebellar ataxia, AR 16 (STUB1)
• Spinocerebellar ataxia, AR 17 (CWF19L)
• 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 4 (VPS13D)
• Spinocerebellar ataxia, AR 5 (WDR73)
• Spinocerebellar ataxia, AR 7 (TPP1)
• Spinocerebellar ataxia, AR 8 (SYNE1)
• Spinocerebellar ataxia, AR, infantile onset, IOSCA (TWNK)
• Spinocerebellar ataxia, AR, with axonal neuropathy 1 (TDP1)
• Spinocerebellar ataxia, AR, with axonal neuropathy 2 (SETX)
• Spinocerebellar ataxia, AR, with axonal neuropathy 3 (COA7)
• Tay-Sachs disease (HEXA)
• Wilson disease (ATP7B)
• Wolfram syndrome 1 (WFS1)
• Wolfram-like syndrome, AD (WFS1)