Table 1.
Genetic, clinical, and imaging features in degenerative ataxias
| Disease | Gene/Protein (locus) | Typical Age at Onset | Key-symptoms in addition to Cerebellar Ataxia | Morphometric Changes (MRI) | Neurochemistry (MRS), Function and Connectivity (fMRI, DWI) |
|---|---|---|---|---|---|
| AUTOSOMAL RECESSIVE ATAXIAS | |||||
| FRDA | FXN/frataxin (9q13) | Adolescence (around puberty) | Neuromuscular deformities, cardiac hypertrophy, abnormal eye movements | Spinal cord, brainstem, cerebellum; thalamus, and cortical motor areas (later stages) | ↓tNAA*1(/tCr)*1; ↑tCr*1; ↑mI*1; ↓cerebro-cerebellar and ↑cerebro-cerebral connectivity; cerebral compensation/ cerebellar dysfunction |
| AT | AT-mutated (ATM)/ATM protein (11q22–23) | Infancy - early childhood (2–4 years) | Oculomotor apraxia, cutaneous telangiectasias, dystonia chorea, immune-deficiency, malignancy | Cerebellum | ↓tNAA/tCho*1; ↓tCho/tCr*1 |
| AOA (1/2) | APTX/aprataxin (1) SETX/senataxin (2) | Early childhood (1), later childhood (2) | Oculomotor apraxia, movement disorders, pyramidal signs, intellectual disability | Cerebellum | (2): ↓tNAA*1; ↑mI*1,*2 |
| ARSACS | SACS/sacsin (13q12.12) | Infancy (12 – 18 month) | Spasticity, peripheral neuropathy | Cerebellum, parietal lobe (bilateral); linear pontine hypointensities | NA |
| AUTOSOMAL DOMINANT ATAXIAS | |||||
| SCA1 | ATXN1/ataxin-1 (6p22.3) | Early to mid-adulthood | Hypermetric saccades, pyramidal signs | Brainstem, cerebellum (preclinical), and basal ganglia | ↓tNAA*1,*2(/tCr)*1; ↓tCho/tCr*1; ↑tCr*1; ↑mI*2 |
| SCA2 | ATXN2/ataxin-2 (12q24.12) | Early child- to late adulthood | Slow saccades, peripheral neuropathy, motor neuron signs, autonomic dysfunction, cognitive impairment | Pons; cerebellum and brainstem (preclinical) | Altered inter-nodal cerebellar-cerebrum connectivity; ↓tNAA*1,*2(/tCr)*1; ↓tCho*2(/tCr)*1; ↑tCho*1; ↑mI*1,*2(/tCr)*1; ↑tCr*1 |
| SCA3 (Machado– Joseph disease) | ATXN3/ataxin-3 (14q32.12) | Childhood to mid-adulthood | Dystonia, sensory deficits, parkinsonism | Brainstem, cerebellum, basal ganglia; spinal cord, midbrain, substantia nigra (preclinical); cerebrum (later stages) | Microstructural abnormalities in cerebellar and cerebral peduncles (premanifest); ↓tNAA*1,*2(/tCr)*1; ↓tCho/tCr*1; ↑tCr*1; ↑mI*2 |
| SCA6 | CACNA1A (19p13.2) | Early to late adulthood | Almost purely ataxic | Cerebellum | ↓RS FC in attention network; impaired functional activity in SC and SMA; ↓tNAA*1(/tCr)*1; ↑mI*1 |
| SCA7 | ATNX7/ataxin-7 (3p14.1) | Infancy to adulthood | Visual loss, mitochondrial dysfunction | Cerebellum, brainstem | ↓tNAA*1,*2(/tCr)*1; ↓Pi(/PCr) (31P-MRS) in visual cortex during visual task |
| X-LINKED ATAXIAS | |||||
| FXTAS | FMR1 | Late adulthood (> 50 years) | Intention tremor, dementia, and parkinsonism | Midbrain, brainstem, and cerebellum | NA |
| SPORADIC DEGENERATIVE ATAXIAS | |||||
| MSA-C | - | Adulthood | Autonomic dysfunction, dysarthria, oculomotor dysfunction, cognitive impairment | Cerebellum (GM+WM), brainstem (GM+WM), pons; “hot cross bun” sign, middle cerebellar peduncle hyperintensity, putaminal hypointensity, and the hyperintense putaminal rim sign | ↓tNAA*1,*2(/tCr)*1,*2; ↑mI*1,*2; ↑tCr*1; microstructural white matter involvement (DTI); ↓cerebellar fiber density, and impairment of frontal and occipital white matter connectivity (DTI); ↓connectivity of motor networks |
| SAOA | - | Adulthood | sporadic adult progressive cerebellar ataxia of unknown etiology | Cerebellum (GM+WM), brainstem (GM) | Abnormal intra-cerebellar FC |
FRDA = Friedreich Ataxia; AT = Ataxia Telangiectasia; AOA = Ataxia with Oculomotor Apraxia; ARSACS = Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay; SCA = Spinocerebellar Ataxia; FXTAS = Fragile X-Associated Tremor/Ataxia Syndrome; MSA-C = Cerebellar Multiple System Atrophy; SAOA = Sporadic Adult Onset Ataxia; DTI = diffusion tensor imaging; tNAA = total N-acetylaspartate; tCr = total Creatine (creatine + phosphocreatine); tCho = total Choline; mI = myo-Inositol; *1 = in cerebellum (vermis and/or cerebellar hemispheres); *2 = in brainstem (pons); ↓ reduced compared to controls; ↑ increased compared to controls; RS = resting-state; FC = functional connectivity; SC = sensorimotor cortex; SMA = supplementary motor area; Pi/PCr = ratio of inorganic phosphate to phosphocreatine; 31P-MRS = 31-phosphorus magnetic resonance spectroscopy. The listed findings are primarily based on review articles and meta-analyses; therefore, mostly metabolite ratios are displayed for MRS findings, and the respective metabolic reference is indicated in brackets, i.e. (/tCr). The respective “numerator” simultaneously represents the metabolite concentration from individual findings, i.e. tNAA in tNAA(/tCr). In those cases where individual metabolite concentrations are listed, only few findings are available, and meta-analyses are missing (i.e. AOA2) or findings are mixed (i.e. ↑mI in SCA6).