TABLE 1.
Genes causing ataxia and HSP (ataxia-HSP spectrum disease genes)
| Gene | Locus | Protein name (UniProt) | Inheritance | OMIM | Remarks | Key references |
|---|---|---|---|---|---|---|
| ABCD1 | ATP-binding cassette subfamily D member 1 | XR | #300100 | Adrenoleukodystrophy (ALD), adrenomyeloneuropathy (AMN); increased very long-chain fatty acids in plasma | 67 | |
| ABHD12 | Monoacylglycerol lipase ABHD12 | AR | #612674 | Peripheral neuropathy, hearing loss, retinitis pigmentosa, cataract (PHARC) | 43 | |
| AFG3L2 | SPAX5 (AR), SCA28 (AD) | AFG3-like protein 2 | AR/AD | #614487 | Catalytic subunit of the m-AAA protease (like paraplegin/SPG7); ophthalmoparesis, slow saccades, ptosis | 4 |
| ARSA | Arylsulfatase A | AR | #250100 | Metachromatic leukodystrophy (MLD): reduced arylsulfatase A activity in leukocytes | 68 | |
| ATN1 | Atrophin-1 | AD | #125370 | Dentatorubral-pallidolysian atrophy (DRPLA); CAG trinucleotide expansion; myoclonic epilepsy, dementia, ataxia, and choreoathetosis; rare outside Japan | 69 | |
| ATP13A2 | SPG78 | Probable cation-transporting ATPase 13A2 | AR | #606693 | Juvenile parkinsonism, vertical gaze palsy, cognitive deficits | 70 |
| ATXN1 | SCA1 | Ataxin-1 | AD | #164400 | CAG trinucleotide expansion | 71 |
| ATXN2 | SCA2 | Ataxin-2 | AD | #183090 | CAG trinucleotide expansion; slow horizontal saccades | 72 |
| ATXN3 | SCA3 | Ataxin-3 | AD | #109150 | CAG trinucleotide expansion; Machado-Joseph disease; frequent SCA in central Europe | 73 |
| ATXN8/ATXN8OS | SCA8 | Ataxin-8; putative protein ATXN8OS | AD | #608768 | Expanded CTG trinucleotide repeat in ATXN8OS gene and complementary CAG repeat in ATXN8 gene | 74 |
| AUH | Methylglutaconyl-CoA hydratase, mitochondrial | AR | #250950 | 3-Methylglutaconic aciduria type 1 (MCGA1): elevated levels of 3-methylglutaconic acid (3-MGA), 3-methylglutaric acid (3-MG) and 3-hydroxyisovaleric acid (3-HIVA) in urine; cognitive deficits | 75 | |
| CAPN1 | SPG76 | Calpain-1 catalytic subunit | AR | #616907 | Upper limb involvement, foot deformities, dysarthria | 76 |
| CYP27A1 | Sterol 26-hydroxylase, mitochondrial | AR | #213700 | Cerebrotendinous xynthomatosis (CTX): juvenile cataract, lipid deposits i.a. in brain, lungs, and Achilles tendons, chronic diarrhea, early atherosclerosis, elevated levels of cholestanol in plasma | 77,78 | |
| CYP7B1 | SPG5 | 25-Hydroxycholesterol 7-alpha-hydroxylase | AR | #270800 | Afferent ataxia due to dorsal column dysfunction, elevated levels of 27-hydroxycholesterol, 25-hydroxycholesterol, and cholestanoic acid in plasma and CSF | 79,80 |
| DARS2 | Aspartate-tRNA ligase, mitochondrial | AR | #611105 | Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) | 81 | |
| EXOSC3 | PCH1B | Exosome complex component RRP40 | AR | #614678 | Pontocerebellar hypoplasia, type 1B | 82 |
| FA2H | SPG35 | Fatty acid 2-hydroxylase | AR | #612319 | Spastic paraplegia, leukodystrophy, and/or brain iron deposition | 18,19 |
| FXN | Frataxin | AR | #229300 | Friedreich ataxia (FRDA); predominant afferent ataxia with pyramidal tract signs | 83 | |
| GALC | Galactocerebrosidase | AR | #245200 | Krabbe disease: infantile forms with extreme irritability, spasticity, and developmental delay; late-adult forms: spasticity, ataxia; reduced GALC enzyme activity | 84 | |
| GAN | Gigaxonin | AR | #256850 | Giant axonal neuropathy (GAN1); infantile form: kinky hair and unique posture of legs | 85 | |
| GBA2 | SPG46 | Nonlysosomal glucosylceramidase | AR | #614409 | Mental impairment, cataracts, cerebral, cerebellar, and corpus callosum atrophy | 33 |
| GFAP | Glial fibrillary acidic protein | AD | #203450 | Alexander disease; infantile form: leukoencephalopathy with macrocephaly, seizures, and psychomotor retardation; adult form: bulbar signs and spasticity, more slowly progressive | 86 | |
| GJC2 | SPG44, HLD2 | Gap junction gamma-2 protein | AR | #613206, #608804 | Hypomyelinating leukodystrophy; Pelizaeus-Merzbacher-like disease (PMLD) | 87 |
| GLB1 | Beta-galactosidase | AR | #230500, #230600, #230650 | GM1-gangliosidosis, type I-III (GLB1); mucopolysaccharidosis type IVB (Morquio syndrome B); reduced beta-galactosidase-1 enzyme activity | 88 | |
| GLRX5 | Glutaredoxin-related protein 5, mitochondrial | AR | #616859 | Increased serum glycine; leukodystrophy and/or lesions in the upper spinal cord | 89 | |
| GRID2 | SCAR18 | Glutamate receptor ionotropic, delta-2 | AR | #616204 | Early-onset cerebellar ataxia, intellectual disability; occasional or persistent tonic upgaze | 90 |
| HEXA | Beta-hexosaminidase subunit alpha | AR | #272800 | Tay-Sachs disease/GM2-gangliosidosis; infantile: developmental retardation, followed by paresis, cognitive decline, and blindness; adult: lower motor neuron damage, psychosis, dementia; reduced hexosamindase A enzyme activity | 91 | |
| KCNA2 | Potassium voltage-gated channel subfamily A member 2 | AD | #616366 | Early infantile epileptic encephalopathy; ataxia, spasticity; often de novo | 30,32 | |
| KCND3 | SCA19 | Potassium voltage-gated channel subfamily D member 3 | AD | #607346 | Allelic with Brugada syndrome 9 | 92 |
| KIF1A | SPG30, HSN2C | Kinesin-like protein KIF1A | AR | #610357, #614213 | Allelic with autosomal-dominant mental retardation 9 (MRD9) | 93 |
| KIF1C | SPG58, SPAX2 | Kinesin-like protein KIF1C | AR | #611302 | Cerebellar ataxia and variable spasticity of the lower limbs in first 2 decades of life | 36,94 |
| MARS2 | SPAX3 | Methionine-tRNA ligase, mitochondrial | AR | #611390 | Often deletions or duplications; decreased activity of mitochondrial complexes I and IV | 95 |
| MECP2 | Methyl-CpG-binding protein 2 | XR | #312750 | Atypical Rett syndrome | 96 | |
| MMADHC | Methylmalonic aciduria and homocystinuria type D protein, mitochondrial | AR | #277410 | Homocystinuria and/or methylmalonic aciduria; usually additional complicating features like developmental delay | 97 | |
| MTPAP | SPAX4 | Poly(A) RNA polymerase, mitochondrial | AR | #613672 | Childhood-onset cerebellar ataxia, spastic paraparesis, dysarthria, and optic atrophy | 98 |
| NPC1 | Niemann-Pick C1 protein | AR | #257220 | Niemann-Pick disease, type C1/D; infantile: often accompanying neurovisceral phenotype; juvenile and adult: often vertical supranuclear gaze palsy or cognitive decline | 55,99 | |
| NPC2 | Epididymal secretory protein E1 | AR | #607625 | Niemann-Pick disease, type C2; infantile: often accompanying neurovisceral phenotype; juvenile and adult: often vertical supranuclear gaze palsy or cognitive decline | 55,99 | |
| OPA1 | Dynamin-like 120-kDa protein, mitochondrial | AD | #125250 | Optic atrophy plus syndrome, in particular, in cases of biallelic OPA1 mutations | 100,101 | |
| OPA3 | Optic atrophy 3 protein | AR | #258501 | Optic atrophy plus syndrome, 3-methylglutaconic aciduria, type III | 102 | |
| PDHX | Pyruvate dehydrogenase protein X component, mitochondrial | AR | #245349 | Lacticacidemia from PDX1 deficiency; often additional mental retardation, delayed psychomotor development and/or seizures | 103 | |
| PEX16 | Peroxisomal membrane protein PEX16 | AR | #614877 | Peroxisome biogenesis disorder 8B; white matter abnormalities; increased VLCFA | 104 | |
| PLA2G6 | NBIA2A | 85/88-kDa calcium-independent phospholipase A2 | AR | #256600, #610217 | Infantile neuroaxonal dystrophy 1 (INAD); neurodegeneration with brain iron accumulation 2B (NBIA2B), autosomal recessive Parkinson’s disease 14 (PARK14) | 105,106 |
| PLP1 | SCA2 | Myelin proteolipid protein | XR | #312920, #312080 | Pelizaeus-Merzbacher disease (PMD); X-linked recessive hypomyelinative leukodystrophy (HLD1) | 107 |
| PNPLA6 | SPG39 | Neuropathy target esterase | AR | #612020, #215470, #275400, #245800 | Boucher-Neuhauser syndrome, Gordon Holmes syndrome; Oliver-McFarlane syndrome, Laurence-Moon syndrome | 12 |
| POLR3A | HLD7 | DNA-directed RNA polymerase III subunit RPC1 | AR | #607694 | Hypomyelinating leukodystrophy 7 (HLD7) with or without oligodontia and/or hypogonadotropic hypogonadism | 108,109 |
| POLR3B | HLD8 | DNA-directed RNA polymerase III subunit RPC2 | AR | #614381 | Hypomyelinating leukodystrophy 8 (HLD8) with or without oligodontia and/or hypogonadotropic hypogonadism, but leukodystrophy might also be missing | 110 |
| PRNP | Major prion protein | AD | #137440 | Familial Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler disease (GSD), fatal familial insomnia (FFI), but also complicated HSP | 111,112 | |
| PSAP | Prosaposin | AR | #249900 | Metachromatic leukodystrophy from SAP-b deficiency; atypical Krabbe disease; atypical Gaucher disease | 113 | |
| PSEN1 | Presenilin-1 | AD | #607822 | Early-onset Alzheimer’s disease, sometimes complicated by spastic paraparesis and/or ataxia | 114 | |
| SACS | SPAX6 | Sacsin | AR | #270550 | Autosomal-recessive spastic ataxia Charlevoix-Saguenay (ARSACS), early-onset ataxia with spastic paraparesis and axonal-demyelinating sensorimotor neuropathy; hypointense pontine stripes on T2-MRI | 59,115 |
| SCN8A | Sodium channel protein type 8 subunit alpha | AD | #614306 | Early infantile epileptic encephalopathy 13 (EIEE13) | 116 | |
| SDHA | Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial | AR | #252011 | Mitochondrial complex II deficiency | 117 | |
| SETX | SCAR1 | Probable helicase senataxin | AR | #606002 | AD mutations in SETX are associated with ALS4 (#602433); AR mutations with early-onset ataxia with elevated alpha-fetoprotein | 118 |
| SLC17A5 | Sialin | AR | #604369, #269920 | Sialic acid storage disorder | 119 | |
| SLC25A15 | Mitochondrial ornithine transporter 1 | AR | #238970 | Hyperornithinemia-hyperammonemiahomocitrullinemia syndrome | 120 | |
| SLC2A1 | DYT9 | Solute carrier family 2, facilitated glucose transporter member 1 | AD | #612126 | GLUT1 deficiency syndrome 1 (GLUT1); DYT9 | 121 |
| SPG11 | SPG11 | Spatacsin | AR | #604360 | cHSP with thin corpus callosum; juvenile-onset amyotrophic lateral sclerosis-5 | 122 |
| ZFYVE26 | SPG15 | Zinc finger FYVE domain-containing protein 26 | AR | #270700 | cHSP with variable mental retardation, hearing and visual defects, and thin corpus callosum | 123 |
| SPG7 | SPG7 | Paraplegin | AR | #607259 | Variable spasticity and cerebellar ataxia | 7 |
| SPR | Sepiapterin reductase | AR | #612716 | Dopa-responsive dystonia because of sepiapterin reductase deficiency | 124 | |
| STUB1 | SCAR16 | E3 ubiquitin-protein ligase CHIP | AR | #615768 | Spasticity and ataxia can be part of a broader multisystemic neurodegeneration, including hypogonadotropic hypogonadism, and cognitive decline | 29,125 |
| SYNE1 | SCAR8 | Nesprin-1 | AR | #610743 | Cerebellar ataxia and variable spasticity and further multisystemic neurologic damage | 23,24 |
| TBP | SCA17 | TATA box-binding protein | AD | #607136 | CAG repeat expansion; Huntington’s disease-like 4; ataxia, pyramidal and extrapyramidal signs, cognitive impairments, psychosis, and seizures | 126 |
| TTC19 | Tetratricopeptide repeat protein 19, mitochondrial | AR | #615157 | Mitochondrial complex III deficiency nuclear type 2 (MC3DN2); sometimes abnormal signals putamen, caudate, and brain stem on T2-MRI | 127 | |
| TTPA | Alpha-tocopherol transfer protein | AR | #277460 | Ataxia with isolated vitamin E deficiency | 128 | |
| TUBB4A | HLD6, DYT4 | Tubulin beta-4A chain | AD | #612438, #128101 | Hypomyelinating leukodystrophy (HLD6); autosomal-dominant dystonia-4 (DYT4) | 129 |
| UCHL1 | PARK5 | Ubiquitin carboxyl-terminal hydrolase isozyme L1 | AR | #615491 | Childhood-onset neurodegeneration with optic atrophy | 130 |
| VAMP1 | SPAX1 | Vesicle-associated membrane protein 1 | AD | #108600 | Newfoundland families | 131 |
| VWA3B | SCAR22 | von Willebrand factor A domain-containing protein 3B | AR | #616948 | Intellectual disability associated with adult-onset cerebellar ataxia and spasticity | 132 |
List of genes causing ataxia-spasticity spectrum disease; we anticipate this list to grow considerably in the future (ie, dynamic, extendable list). The selection contains only genes whose phenotypic descriptions include both manifest ataxia and spasticity (rather than merely pyramidal signs) in subjects from at least 2 different families (rather than merely single cases).
OMIM, Online Mendelian Inheritance in Man; AD, autosomal-dominant; AR, autosomal-recessive; XR, x-chromosomal recessive.