By Marcello Cherchi, MD PhD
For patients
The term “ataxia” refers to incoordination or clumsiness. Some forms of ataxia interfere with balance and walking. Of these ataxias, some are genetic and may be inherited. There are many different types, and symptoms can begin at different ages. Your doctor may suspect a genetic ataxia if there is a history of blood relatives with similar symptoms, or if there are other specific clinical features. Confirming the diagnosis (and identifying which specific ataxia it is) usually requires genetic testing. If a genetic ataxia is suspected, a patient should be referred to a specialist in ataxia or a genetic counselor.
For clinicians
Overview
Spinocerebellar ataxias and a few other ataxias (e.g., dentato-rubro-pallido-luysian atrophy, fragile X tremor ataxia syndrome and others) are genetically mediated ataxias, nearly all of which are inherited in an autosomal dominant fashion. The various ataxias have different features (age of onset, ocular motor findings, dysmorphism, association with cognitive and other neurological deficits), but many resemble each other, such that a confident diagnosis is usually not achievable based on history and physical examination alone; genetic testing is the diagnostic modality of choice. None of these ataxias yet has specific treatment; management is symptomatic. The main value in identifying them lies in planning one’s future, and advising offspring.
Discussion
Spinocerebellar ataxias (SCAs) are genetically mediated ataxias. Spinocerebellar ataxia type 1 was described by Orr and colleagues in 1993 (Orr et al. 1993). Since then several dozen additional SCAs have been identified, and nearly all of them are inherited in an autosomal dominant fashion. Many of the initially described diseases had symptoms or signs that potentially localized to spinal tracts, thus the group became referred to as spinocerebellar ataxias. Almost (but not quite) all of these are inherited in an autosomal dominant fashion. There are other ataxias not classified as “spinocerebellar,” but are still reasonable to group with the SCAs because of certain shared clinical features.
The number of genetically identified ataxias is long and growing. The most commonly encountered ones were the first to be identified (SCA types 1 – 8). The remainder are rare.
The Table below is a summary of these ataxias. It is based on information in UpToDate, though we have additionally incorporated information pertaining to ocular motor findings.
|
Disorder |
Distinguishing features |
Gene or locus |
Protein and mutation |
OMIM# |
|
SCA1 | Epidemiology: Accounts for 3 – 16% of autosomal dominant cerebellar ataxias. Broad age range, but peak onset in 3rd – 4th decades. Clinical features: Pyramidal signs, peripheral neuropathy. Ocular motor: Ophthalmoplegia. Pathology: Degeneration of cerebellar Purkinje cells, brainstem cranial nerve nuclei, inferior olivary nuclei and spinocerebellar tracts. |
ATXN1 (6p22.3) |
Ataxin 1; CAG repeat | |
|
SCA2 | Epidemiology: Accounts for 6 – 18% of spinocerebellar ataxia kindreds. Infancy to late adulthood; age of onset inversely proportional to number of trinucleotide repeats. Clinical features: Occasionally parkinsonism, myoclonus, areflexia, dementia. Ocular motor: Slow saccades. |
ATXN2 (12q24) |
Ataxin 2; CAG repeat | |
|
SCA3 (MJD) | Epidemiology: This is the most common autosomal dominant spinocerebellar ataxia, accounting for 21 – 23% of cases in the United States, 12% in Australia and 48% in China. Clinical features: Extrapyramidal signs, muscle cramps and fasciculations, peripheral neuropathy, autonomic dysfunction, cognitive dysfunction, brainstem dysfunction (persistent stare from lid retraction dysarthria, dysphagia, tongue fasciculations). Ocular motor: Slow saccades, saccadic pursuit. |
ATXN3 (14q32) |
Ataxin 3 (MJD1); CAG repeat | |
|
SCA4 |
Clinical features: Sensory axonal neuropathy. |
16q22.1 | ||
|
SCA5 |
Epidemiology: Early onset (3rd decade) but slow progression. Clinical features: Almost purely cerebellar syndrome. Imaging: Cerebellar atrophy. |
SPTBN2 |
Spectrin beta, nonerythrocytic 2 | |
|
SCA6 | Epidemiology: 15 – 17% of dominant cerebellar ataxias. Onset between 20 – 60 years. May lack family history. Clinical features: Similar to SCA5. Ocular motor: “Horizontal and vertical nystagmus,” abnormal vestibulo-ocular reflex. Imaging: Global cerebellar degeneration. |
CACNA1A (19p13) |
Calcium voltage-gated channel subunit alpha1 A; CAG repeat | |
|
SCA7 |
Epidemiology: 2 – 5% of autosomal dominant ataxias. Infancy to adulthood; age of onset inversely proportional to number of trinucleotide repeats. Clinical features: Ataxia, retinal degeneration. When onset is in childhood, may include seizures, myoclonus and cardiac involvement. |
ATXN7 (3p12) |
Ataxin 7; CAG repeat | |
|
SCA8 | Epidemiology: Accounts for 3 – 5% of spinocerebellar ataxias worldwide. Clinical features: Mild disease. Ocular motor: Nystagmus at extreme lateral gaze (Tazon, Badenas et al. 2002). Imaging: Marked cerebellar atrophy. Pathology: Neurodegeneration of Purkinje, inferior olivary and nigral cells, and periaqueductal gliosis, described in one family. |
ATXN8OS |
ATXN8 opposite strand IncRNA; CTG*CAG repeat | |
|
SCA9 |
Not assigned | |||
|
SCA10 |
Clinical features: Variable; can have purely cerebellar manifestations, or include generalized seizures or extrapyramidal findings. |
ATXN10 (22q13) |
Ataxin 10; ATTCT repeat | |
|
SCA11 |
Clinical features: Mild disease, purely cerebellar. |
TTBK2 (15q14-q21.3 |
Tau tubulin kinase 2 | |
|
SCA12 |
Clinical features: Ataxia, often accompanied by tremor and dementia. |
PPP2R2B (5q31-q33) |
Protein phosphatase 2 regulatory subunit Bbeta; CAG repeat in 5′ region | |
|
SCA13 |
Clinical features: Cerebellar ataxia and intellectual disability. |
KCNC3 (19q13) |
Potassium voltage-gated channel subfamily C member 3 | |
|
SCA14 | Epidemiology: Broad age range of onset. Clinical features: Earlier onset can present with myoclonus followed by ataxia. Later onset (≥39 years) can be purely cerebellar. Ocular motor: May show saccadic pursuit (Morita, Yoshida et al. 2006). |
PRKCG (19q13) |
Protein kinase C gamma | |
|
SCA15/16 |
Note: SCA15 and SCA16 were originally thought to be separate disorders. Epidemiology: Onset from mid-childhood to middle age. Clinical features: Slowly progressive; sometimes with myoclonus, dystonia, postural/action tremor. Imaging: Atrophy of cerebellum, particularly in the vermis. |
ITPR1 (3p26.2pter) |
Inositol 1,4,5-triphosphate receptor type 1 | |
|
SCA17 |
Epidemiology: 19 – 48 years. Age of onset inversely proportional to number of trinucleotide repeats. Described in four Japanese families. Clinical features: Gait ataxia, dementia; can present with predominant chorea; may develop bradykinesia, dysmetria, dysdiadochokinesis, hyperreflexia. |
TBP |
TATA-box binding protein; CAG repeat | |
|
SCA18 |
Epidemiology: Described in an American family of Irish ancestry. Clinical features: Pyramidal signs, weakness, sensory axonal neuropathy |
7q22-q32 | ||
|
SCA19/22 | Note: SCA19 and SCA22 were originally thought to be separate disorders. Epidemiology: SCA19 was originally described in a Dutch family, and SCA22 in a Taiwanese family. Clinical features: Predominantly cerebellar syndrome. More severe cases may include cognitive impairment, myoclonus, hand tremor, neuropathy. Ocular motor: May have saccadic abnormalities and down beat nystagmus (Duarri, Jezierska et al. 2012). |
KCND3 |
Potassium voltage-gated channel subfamily D member 3 | |
|
SCA20 | Epidemiology: 19 – 64 years (mean 46.5 years). Described in one family of Anglo-Celtic ancestry and 6 Portuguese families. Clinical features: Dysarthria is the most common initial symptom, and is usually followed by gait or upper limb ataxia. Unusual features include palatal tremor and dysphonia. Ocular motor: May show hypermetric saccades on downward gaze or lateral gaze; saccadic intrusions into smooth pursuit; square wave jerks on primary position of gaze; impaired visual suppression of the vestibulo-ocular reflex (Knight, Gardner et al. 2004), and down beat nystagmus (Coutinho, Cruz et al. 2006). Imaging: Dentate nucleus calcification on CT. |
11q12 |
Contiguous gene duplication syndrome | |
|
SCA21 |
Epidemiology: Early onset. First identified in four generations of a French family. Clinical features: Slow progression. Mild to severe cognitive impairment; motor clumsiness. |
TMEM240 (1p36.33) |
Transmembrane protein 240 | |
|
SCA23 | Epidemiology: Late onset (age >40 years). Described in a Dutch family. Clinical: Slowly progressive. Distal sensory deficits. Variable dysarthria. Ocular motor: Some have ocular dysmetria and slow saccades (Bakalkin, Watanabe et al. 2010). |
PDYN (20p13) |
Prodynorphin | |
|
SCA24 | Notes: Autosomal recessive ataxia, so has been redesignated as SCAR4. Epidemiology: Described in a Slovenian family. Clinical features: Progressive ataxia. May also have corticospinal signs and axonal sensorimotor neuropathy. Ocular motor: Large horizontal saccadic intrusions disrupt visual fixation (Swartz, Burmeister et al. 2002, Seong, Insolera et al. 2018), horizontal saccadic hypermetria, microsaccadic oscillations and increased velocity of larger saccades (Swartz, Li et al. 2003). |
VPS13D (1p36) |
Vacuolar protein sorting 13 homolog D | |
|
SCA25 | Epidemiology: Variable age of onset. Described in a large French family and 3 generations of an Australian family. Clinical features: Variably severe symptoms of ataxia, sensory neuropathy, facial tics, gastrointestinal symptoms. Ocular motor: May exhibit “horizontal” or “vertical” nystagmus, instability of central fixation (Stevanin, Bouslam et al. 2004), square wave jerks, hypermetric saccades, down beat nystagmus, slow saccades, impaired vestibulo-ocular reflex, “mild torsional/see-saw nystagmus,” “very mild up beat nystagmus on upgaze,” “restriction of upper and lateral gaze,” “oculomotor apraxia” (Barbier, Bahlo et al. 2022). |
PNPT1 |
Polyribonucleotide nucleotidyltransferase 1 | |
|
SCA26 |
Epidemiology: Described in a Norwegian family. Clinical features: Slowly progressive pure cerebellar ataxia. |
EEF2 (19p13.3) |
Eukaryotic translation elongation factor 2 | |
|
SCA27 | Epidemiology: Early onset. Described in a large Dutch family and in two generations of a family of French Canadian origin. Clinical features: Cognitive impairment; early-onset hand tremor, orofacial dyskinesia. Ocular motor: Members of the French Canadian family exhibited “sustained horizontal nystagmus,” up beat and down beat nystagmus (Choquet, La Piana et al. 2015). Another report of a multi-generational family described multidirectional nystagmus, “horizontal nystagmus,” “vertical nystagmus,” abnormal smooth pursuit and vertical oscillopsia (!) (Piarroux, Riant et al. 2020). Note: A second variant (GAA repeat expansion in the first intron of FGF14) is recognized as “SCA27B.” This variant has a median onset of 55 years, and about half of patients have episodic ataxia and ocular motor finding of downbeat nystagmus. |
FGF14* (13q34) |
Fibroblast growth factor 14 | |
|
SCA28 | Epidemiology: Juvenile onset (mean age 19.5 years). Described in an Italian family. Clinical features: Ptosis. In some cases pyramidal tract signs. Ocular motor: Ophthalmoparesis. One report merely described “minor abnormalities in ocular movements” (Di Bella, Lazzaro et al. 2010). Another report described ocular motor apraxia (Pierson, Adams et al. 2011). |
AFG3L2 (18p) |
AFG3 like matrix AAA peptidase subunit 2 | |
|
SCA29 | Epidemiology: Early-onset. Clinical features: Nonprogressive ataxia; may be an allelic variant of SCA15. Ocular motor: May have up beat nystagmus (Tomiwa, Baraitser et al. 1987, Dudding, Friend et al. 2004) on primary position of gaze (Jen, Lee et al. 2006), upgaze evoked up beat nystagmus (Furman, Baloh et al. 1985), gaze-evoked horizontal nystagmus (Fenichel and Phillips 1989, Imamura, Tachi et al. 1993, Huang, Chardon et al. 2012). More detailed descriptions also identified intermittent pendular oscillations, rebound nystagmus, defective horizontal pursuit, absent horizontal optokinetic nystagmus, defective visual suppression of rotationally induced nystagmus (Kattah, Kolsky et al. 1983), rotatory nystagmus and impaired vestibulo-ocular reflex gain (Parolin Schnekenberg, Perkins et al. 2015). Imaging: Variable atrophy of cerebellar vermis. |
3p26 | ||
|
SCA30 | Epidemiology: Mid- to late-life onset. Described in an Australian family of Anglo-Celtic ancestry. Clinical features: Slowly progressive, relatively pure ataxia. May have minor pyramidal tract signs. Ocular motor: All have hypermetric saccades, some may have slight gaze-evoked nystagmus (Storey, Bahlo et al. 2009). Imaging: Atrophy of cerebellar vermis and hemispheres. |
4q34.3-q35.1 | ||
|
SCA31 |
Epidemiology: Late onset. Clinical features: Ataxia, decreased muscle tone. Variable hearing loss, vertigo. |
BEAN1 (16q22.1) |
Brain expressed associated with NEDD4 1; (TGGAA)n repeat | |
|
SCA32 |
Epidemiology: Described in a single Chinese family. Clinical features: Cognitive impairment, affected males with azoospermia and testicular atrophy. |
7q32-q33 | ||
|
SCA33 |
Not assigned | |||
|
SCA34 |
Epidemiology: Described in a French Canadian kindred and two Japanese families. Clinical features: Ataxia and pyramidal signs. French Canadian kindred also has skin lesions consisting of papulosquamous erythematous ichthyosiform plaques. Two Japanese families lack the cutaneous findings. |
ELOVL4 |
ELOVL fatty acid elongase 4 | |
|
SCA35 |
Epidemiology: Several families of Han Chinese descent. Late onset, with mean age of onset 44 years. Clinical features: Slowly progressive gait and limb ataxia; cervical dystonia; mild dysarthria. |
TGM6 (20p13) |
Transglutaminase 6 | |
|
SCA36 |
Epidemiology: Late onset. Initially reported in Japanese and Spanish families, but subsequently found in other populations. Clinical features: Truncal ataxia, dysarthria. Japanese families show variable motor neuron disease. Spanish families have sensorineural hearing loss. |
NOP56 |
NOP56 ribonucleoprotein; GGCCTG repeat | |
|
SCA37 | Epidemiology: Late onset (mean 48 years, range 38 – 64 years). Described in a Spanish family. Clinical features: Falls, dysarthria, clumsiness. Ocular motor: Early on patients have abnormal vertical eye movements; later they may develop horizontal eye movement abnormalities as well; the abnormalities consist of hypometric saccades and cogwheel pursuit (Serrano-Munuera, Corral-Juan et al. 2013). Imaging: Cerebellar atrophy. |
DAB1 |
DAB adaptor protein 1 | |
|
SCA38 | Epidemiology: Late onset (34 – 51 years). Described in several European families. Clinical features: Slowly progressive relatively pure cerebellar phenotype; truncal ataxia, limb ataxia; neuropathy. Ocular motor: Almost all patients have gaze-evoked nystagmus; some also have slow saccades (Di Gregorio, Borroni et al. 2014). |
ELOVL5 |
ELOVL fatty acid elongase 5 | |
|
SCA39 |
Not assigned | |||
|
SCA40 | Epidemiology: Late onset (5th decade). Described in a family from China. Clinical features: Truncal and gait ataxia, dysarthria, pyramidal signs (hyperreflexia and spasticity), tremor, parkinsonism. Ocular motor: Ocular dysmetria. |
CCDC88C |
Coiled-coil domain-containing 88C | |
|
SCA41 |
Epidemiology: Described in a single 40-year-old male. Clinical features: Gait ataxia. |
TRPC3 |
Transient receptor potential cation channel subfamily C member 3 | |
|
SCA42 | Epidemiology: Variable age of onset. Reported in multiple French and Japanese families. Clinical features: Early motor delay, hypotonia, speech delay, severe intellectual disability, ataxia, facial myokymia. Ocular motor: Saccadic eye movements, nystagmus. |
CACNA1G |
Calcium voltage-gated channel subunit alpha 1G | |
|
SCA43 |
Epidemiology: Identified in 5 generations of a Belgian family. Clinical features: Gait ataxia, neuropathy, hyporeflexia, tremor. |
MME |
Membrane metalloendopeptidase | |
|
SCA44 |
Epidemiology: Three generations of an English family. Early onset has also been described. Clinical features: Ataxia, dysarthria, dysmetria, dysphagia. |
GRM1 |
Glutamate metabotropic receptor 1 | |
|
SCA45 | Epidemiology: Two generations of a family. Clinical features: Limb and gait ataxia, dysarthria. Ocular motor: Down beat nystagmus. |
FAT2 (5q) |
FAT atypical cadherin 2 | |
|
SCA46 | Epidemiology: Described in a Dutch family. Clinical features: Neuropathy and sensory ataxia affecting lower limbs more than upper limbs. Ocular motor: Saccadic interruption of smooth pursuit, square wave jerks unsuppressed by visual fixation, slow pursuit, hypometric saccades (van Dijk, Wokke et al. 1995). Imaging: Cerebellar atrophy. |
PLD3 |
Phospholipase D family member 3 | |
|
SCA47 |
Epidemiology: Onset usually in adulthood, but early onset form has also been described. Clinical features: Early onset variant has developmental disability, ataxia, chorea, seizures. Later onset variant has ataxia, dysarthria, dysmetria and diplopia. |
PUM1 |
Pumilio RNA binding family member 1 | |
|
SCA48 | Epidemiology: Reported in multiple European families. Clinical features: Gait ataxia, dysarthria, dysphagia, cognitive dysfunction (executive dysfunction) in adulthood, psychiatric manifestations (depression, anxiety, apathy). Ocular motor: May have horizontal nystagmus and dysmetric saccades (Pakdaman, Berland et al. 2021). |
STUB1 |
STIP1 homology and U-box containing protein 1 | |
|
ATX-ATN1 (DRPLA) | Notes: Dentato-rubro-pallido-luysian atrophy. Epidemiology: Wide variability in age of onset. More common in Japan (mean age of onset 47 years), less common in European and North American populations. A variant called “Haw River syndrome” (which lacks the myoclonic epilepsy) has been reported in several families of African American descent in North Carolina. Clinical features: Choreoathetosis, seizures (myoclonic epilepsy), myoclonus, rigidity, hyperreflexia, dementia. Ocular motor: Slow saccades. Imaging: Atrophy of cerebellum and brainstem, calcification of basal ganglia, leukodystrophy. |
ATN1 (12p) |
Atrophin 1; CAG repeat | |
|
FXTAS | Note: Fragile X tremor ataxia syndrome. Epidemiology: Adult-onset. Mostly, though not exclusively, in males. Clinical features: Progressive ataxia and postural tremor. Additional features may include short-term memory loss, executive dysfunction, cognitive decline, parkinsonism, peripheral neuropathy, proximal weakness of lower limbs and autonomic dysfunction. Ocular motor: May have square wave jerks and horizontal nystagmus (Biancalana, Toft et al. 2005). Imaging: MRI shows brain atrophy, T2/FLAIR signal abnormalities in the middle cerebellar peduncle and splenium of the corpus callosum. Pathology: White matter disease with astrocytic pathology, intranuclear inclusions in neurons and astrocytes in brain and spinal cord, amyloid beta within capillaries, and cerebral microbleeds. |
FMR1 |
Fragile X messenger ribonucleoprotein 1 (FMR1). | |
|
ATX-DAB1 |
Epidemiology: Adult-onset. Clinical features: Slowly progressive. |
DAB1 |
DAB adaptor protein 1 | |
|
ATX-DNMT1 |
Clinical features: Sensorineural deafness, narcolepsy, dementia. |
DNMT1 |
DNA methyltransferase 1 | |
|
ATX-EBF3 |
Clinical features: Hypotonia, ataxia, and delayed development syndrome (HADDS). |
EBF3 |
EBF transcription factor 3 | |
|
ATX-LMNB1 |
Epidemiology: Adult onset. Clinical features: Autosomal dominant, demyelinating leukodystrophy (ADLD) |
LMNB1 |
Lamin B1 | |
|
ATX-SAMD9L | Ataxia-pancytopenia syndrome (ATXPC). Ocular motor: Nystagmus (Tesi, Davidsson et al. 2017), particularly horizontal and vertical nystagmus and dysmetria (Chen, Below et al. 2016). |
SAMD9L |
Sterile alpha motif domain containing 9 like | |
|
ATX-SNAP25b |
Epidemiology: Early onset. Clinical features: Myasthenia, developmental delay, intellectual disability, seizures, craniofacial dysmorphism, rarely tremor. |
SNAP25b |
Synaptosome associated protein 25b | |
|
ATX-TUBB2A |
Clinical features: Spasticity, developmental delay, seizures, distal amyotrophy, rarely optic atrophy. |
TUBB2A |
Tubulin beta 2A class IIa | |
|
ATX/HSP-VAMP1(SPAX1) | Clinical features: Spastic ataxia. Ocular motor: “Initially there are problems with saccadic gaze greater than pursuit for vertical movements. Downward gaze is often more impaired than upward and eventually horizontal gaze also becomes affected. However, lateral eyeball movements are clearly much less affected than vertical” (Grewal, Stefanelli et al. 2004). |
VAMP1 |
Vesicle associated membrane protein 1 |
Out of the 50 ataxias listed in the table above, over half (27) have been documented as associated with various eye movement abnormalities compatible with cerebellar or brainstem dysfunction (Salari et al. 2024), and although these are of special interest to otoneurologists, the eye movements are neither sensitive nor specific for these diseases.
In other respects as well, many of these ataxias can resemble each other fairly closely, and even an extremely astute clinician would be reluctant to make a diagnosis based on history and physical examination alone. Practically, when a genetic ataxia is suspected, it is reasonable to refer the patient to an ataxia specialist, neurogeneticist or genetic counselor; these clinical practitioners will usually order a genetic panel which tests for all (or for a large subset) of the known ataxias.
Some of these genetic ataxias may be referred to an otoneurology clinic because of bilateral vestibular weakness (or at least reduced vestibulo-ocular reflexes), which has been reported in (Cherchi 2024):
- SCA1 (Burk et al. 1999).
- SCA3 (Burk et al. 1999; Buttner et al. 1998; Gordon et al. 2003; Kim et al. 2023).
- SCA6 (Kim et al. 2023; Lee et al. 2020).
- SCA7 (Kim et al. 2023).
- SCA27b (Abou Chaar et al. 2024; Nuzhnyi et al. 2024; Pellerin et al. 2024a; Pellerin et al. 2024b; Rafehi et al. 2023).
Practically, what features should raise the suspicion of a genetic ataxia?
- Slowly progressive ataxia, beginning at any age.
- Family history of ataxia or balance problems, especially if it occurs at progressively younger ages with each passing generation, since some of these diseases exhibit anticipation (progressively earlier onset due to trinucleotide repeat expansion with each successive generation).
- Syndromic presentations (e.g., spasticity, dysmorphism, mental retardation, dementia, seizures).
None of these ataxias yet has specific treatment; management is symptomatic. The main value in identifying them lies in planning one’s future, and advising offspring.
References
Abou Chaar W, Eranki AN, Stevens HA, Watson SL, Wong DY, Avila VS, Delfeld M, Gary AJ, Tawde S, Triebold M, Cherchi M, Xie T, Lockhart PJ, Bahlo M, Pellerin D, Dicaire M-J, Danzi M, Zuchner S, Brais BC, Perlman S, Burmeister M, Paulson H, Srinivasan S, Schut L, Bower M, Bushara K, Liao C, Shakkottai VG, Collins J, Clark HB, Das S, Fogel BL, Gomez CM (2024) Clinical, Radiological and Pathological Features of a Large American Cohort of Spinocerebellar Ataxia (SCA27B). Annals of Neurology n/a. doi: https://doi.org/10.1002/ana.27060
Bakalkin G, Watanabe H, Jezierska J, Depoorter C, Verschuuren-Bemelmans C, Bazov I, Artemenko KA, Yakovleva T, Dooijes D, Van de Warrenburg BP, Zubarev RA, Kremer B, Knapp PE, Hauser KF, Wijmenga C, Nyberg F, Sinke RJ, Verbeek DS (2010) Prodynorphin mutations cause the neurodegenerative disorder spinocerebellar ataxia type 23. Am J Hum Genet 87: 593-603. doi: 10.1016/j.ajhg.2010.10.001
Barbier M, Bahlo M, Pennisi A, Jacoupy M, Tankard RM, Ewenczyk C, Davies KC, Lino-Coulon P, Colace C, Rafehi H, Auger N, Ansell BRE, van der Stelt I, Howell KB, Coutelier M, Amor DJ, Mundwiller E, Guillot-Noel L, Storey E, Gardner RJM, Wallis MJ, Brusco A, Corti O, Rotig A, Leventer RJ, Brice A, Delatycki MB, Stevanin G, Lockhart PJ, Durr A (2022) Heterozygous PNPT1 Variants Cause Spinocerebellar Ataxia Type 25. Ann Neurol 92: 122-137. doi: 10.1002/ana.26366
Biancalana V, Toft M, Le Ber I, Tison F, Scherrer E, Thibodeau S, Mandel JL, Brice A, Farrer MJ, Durr A (2005) FMR1 premutations associated with fragile X-associated tremor/ataxia syndrome in multiple system atrophy. Arch Neurol 62: 962-6. doi: 10.1001/archneur.62.6.962
Burk K, Fetter M, Abele M, Laccone F, Brice A, Dichgans J, Klockgether T (1999) Autosomal dominant cerebellar ataxia type I: oculomotor abnormalities in families with SCA1, SCA2, and SCA3. J Neurol 246: 789-97. doi: 10.1007/s004150050456
Buttner N, Geschwind D, Jen JC, Perlman S, Pulst SM, Baloh RW (1998) Oculomotor phenotypes in autosomal dominant ataxias. Arch Neurol 55: 1353-7. doi: 10.1001/archneur.55.10.1353
Chen DH, Below JE, Shimamura A, Keel SB, Matsushita M, Wolff J, Sul Y, Bonkowski E, Castella M, Taniguchi T, Nickerson D, Papayannopoulou T, Bird TD, Raskind WH (2016) Ataxia-Pancytopenia Syndrome Is Caused by Missense Mutations in SAMD9L. Am J Hum Genet 98: 1146-1158. doi: 10.1016/j.ajhg.2016.04.009
Cherchi M (2024) Possible mechanisms connecting cerebellar ataxias and bilateral vestibular weakness: diagnostic and therapeutic implications. Journal of Neurology 272: 14. doi: 10.1007/s00415-024-12794-3
Choquet K, La Piana R, Brais B (2015) A novel frameshift mutation in FGF14 causes an autosomal dominant episodic ataxia. Neurogenetics 16: 233-6. doi: 10.1007/s10048-014-0436-7
Coutinho P, Cruz VT, Tuna A, Silva SE, Guimaraes J (2006) Cerebellar ataxia with spasmodic cough: a new form of dominant ataxia. Arch Neurol 63: 553-5. doi: 10.1001/archneur.63.4.553
Di Bella D, Lazzaro F, Brusco A, Plumari M, Battaglia G, Pastore A, Finardi A, Cagnoli C, Tempia F, Frontali M, Veneziano L, Sacco T, Boda E, Brussino A, Bonn F, Castellotti B, Baratta S, Mariotti C, Gellera C, Fracasso V, Magri S, Langer T, Plevani P, Di Donato S, Muzi-Falconi M, Taroni F (2010) Mutations in the mitochondrial protease gene AFG3L2 cause dominant hereditary ataxia SCA28. Nat Genet 42: 313-21. doi: 10.1038/ng.544
Di Gregorio E, Borroni B, Giorgio E, Lacerenza D, Ferrero M, Lo Buono N, Ragusa N, Mancini C, Gaussen M, Calcia A, Mitro N, Hoxha E, Mura I, Coviello DA, Moon YA, Tesson C, Vaula G, Couarch P, Orsi L, Duregon E, Papotti MG, Deleuze JF, Imbert J, Costanzi C, Padovani A, Giunti P, Maillet-Vioud M, Durr A, Brice A, Tempia F, Funaro A, Boccone L, Caruso D, Stevanin G, Brusco A (2014) ELOVL5 mutations cause spinocerebellar ataxia 38. Am J Hum Genet 95: 209-17. doi: 10.1016/j.ajhg.2014.07.001
Duarri A, Jezierska J, Fokkens M, Meijer M, Schelhaas HJ, den Dunnen WF, van Dijk F, Verschuuren-Bemelmans C, Hageman G, van de Vlies P, Kusters B, van de Warrenburg BP, Kremer B, Wijmenga C, Sinke RJ, Swertz MA, Kampinga HH, Boddeke E, Verbeek DS (2012) Mutations in potassium channel kcnd3 cause spinocerebellar ataxia type 19. Ann Neurol 72: 870-80. doi: 10.1002/ana.23700
Dudding TE, Friend K, Schofield PW, Lee S, Wilkinson IA, Richards RI (2004) Autosomal dominant congenital non-progressive ataxia overlaps with the SCA15 locus. Neurology 63: 2288-92. doi: 10.1212/01.wnl.0000147299.80872.d1
Fenichel GM, Phillips JA (1989) Familial aplasia of the cerebellar vermis. Possible X-linked dominant inheritance. Arch Neurol 46: 582-3. doi: 10.1001/archneur.1989.00520410118036
Furman JM, Baloh RW, Chugani H, Waluch V, Bradley WG (1985) Infantile cerebellar atrophy. Ann Neurol 17: 399-402. doi: 10.1002/ana.410170417
Gordon CR, Joffe V, Vainstein G, Gadoth N (2003) Vestibulo-ocular arreflexia in families with spinocerebellar ataxia type 3 (Machado-Joseph disease). J Neurol Neurosurg Psychiatry 74: 1403-6. doi: 10.1136/jnnp.74.10.1403
Grewal KK, Stefanelli MG, Meijer IA, Hand CK, Rouleau GA, Ives EJ (2004) A founder effect in three large Newfoundland families with a novel clinically variable spastic ataxia and supranuclear gaze palsy. Am J Med Genet A 131: 249-54. doi: 10.1002/ajmg.a.30397
Huang L, Chardon JW, Carter MT, Friend KL, Dudding TE, Schwartzentruber J, Zou R, Schofield PW, Douglas S, Bulman DE, Boycott KM (2012) Missense mutations in ITPR1 cause autosomal dominant congenital nonprogressive spinocerebellar ataxia. Orphanet J Rare Dis 7: 67. doi: 10.1186/1750-1172-7-67
Imamura S, Tachi N, Oya K (1993) Dominantly inherited early-onset non-progressive cerebellar ataxia syndrome. Brain Dev 15: 372-6. doi: 10.1016/0387-7604(93)90124-q
Jen JC, Lee H, Cha YH, Nelson SF, Baloh RW (2006) Genetic heterogeneity of autosomal dominant nonprogressive congenital ataxia. Neurology 67: 1704-6. doi: 10.1212/01.wnl.0000242705.06416.6a
Kattah JC, Kolsky MP, Guy J, O’Doherty D (1983) Primary position vertical nystagmus and cerebellar ataxia. Arch Neurol 40: 310-4. doi: 10.1001/archneur.1983.04050050078012
Kim JM, Nam TS, Choi SM, Kim BC, Lee SH (2023) Clinical value of vestibulo-ocular reflex in the differentiation of spinocerebellar ataxias. Sci Rep 13: 14783. doi: 10.1038/s41598-023-41924-6
Knight MA, Gardner RJ, Bahlo M, Matsuura T, Dixon JA, Forrest SM, Storey E (2004) Dominantly inherited ataxia and dysphonia with dentate calcification: spinocerebellar ataxia type 20. Brain 127: 1172-81. doi: 10.1093/brain/awh139
Lee SU, Kim JS, Kim HJ, Choi JY, Park JY, Kim JM, Yang X (2020) Evolution of the vestibular function during head impulses in spinocerebellar ataxia type 6. J Neurol 267: 1672-1678. doi: 10.1007/s00415-020-09756-w
Morita H, Yoshida K, Suzuki K, Ikeda SI (2006) A Japanese case of SCA14 with the Gly128Asp mutation. J Hum Genet 51: 1118-1121. doi: 10.1007/s10038-006-0063-8
Nuzhnyi E, Abramycheva N, Protsenko A, Belyakova-Bodina A, Larina E, Fedotova E, Klyushnikov S, Illarioshkin S (2024) Clinical and Video-Oculographic Characteristics of Spinocerebellar Ataxia Type 27B (GAA-FGF14 Ataxia): A Single-Center Retrospective Study. Clinical and Translational Neuroscience, vol 8
Orr HT, Chung MY, Banfi S, Kwiatkowski TJ, Jr., Servadio A, Beaudet AL, McCall AE, Duvick LA, Ranum LP, Zoghbi HY (1993) Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nat Genet 4: 221-6. doi: 10.1038/ng0793-221
Pakdaman Y, Berland S, Bustad HJ, Erdal S, Thompson BA, James PA, Power KN, Ellingsen S, Krooni M, Berge LI, Sexton A, Bindoff LA, Knappskog PM, Johansson S, Aukrust I (2021) Genetic Dominant Variants in STUB1, Segregating in Families with SCA48, Display In Vitro Functional Impairments Indistinctive from Recessive Variants Associated with SCAR16. Int J Mol Sci 22. doi: 10.3390/ijms22115870
Parolin Schnekenberg R, Perkins EM, Miller JW, Davies WI, D’Adamo MC, Pessia M, Fawcett KA, Sims D, Gillard E, Hudspith K, Skehel P, Williams J, O’Regan M, Jayawant S, Jefferson R, Hughes S, Lustenberger A, Ragoussis J, Jackson M, Tucker SJ, Nemeth AH (2015) De novo point mutations in patients diagnosed with ataxic cerebral palsy. Brain 138: 1817-32. doi: 10.1093/brain/awv117
Pellerin D, Heindl F, Wilke C, Danzi MC, Traschutz A, Ashton C, Dicaire MJ, Cuillerier A, Del Gobbo G, Boycott KM, Claassen J, Rujescu D, Hartmann AM, Zuchner S, Brais B, Strupp M, Synofzik M (2024a) GAA-FGF14 disease: defining its frequency, molecular basis, and 4-aminopyridine response in a large downbeat nystagmus cohort. EBioMedicine 102: 105076. doi: 10.1016/j.ebiom.2024.105076
Pellerin D, Wilke C, Traschutz A, Nagy S, Curro R, Dicaire MJ, Garcia-Moreno H, Anheim M, Wirth T, Faber J, Timmann D, Depienne C, Rujescu D, Gazulla J, Reilly MM, Giunti P, Brais B, Houlden H, Schols L, Strupp M, Cortese A, Synofzik M (2024b) Intronic FGF14 GAA repeat expansions are a common cause of ataxia syndromes with neuropathy and bilateral vestibulopathy. J Neurol Neurosurg Psychiatry 95: 175-179. doi: 10.1136/jnnp-2023-331490
Piarroux J, Riant F, Humbertclaude V, Remerand G, Hadjadj J, Rejou F, Coubes C, Pinson L, Meyer P, Roubertie A (2020) FGF14-related episodic ataxia: delineating the phenotype of Episodic Ataxia type 9. Ann Clin Transl Neurol 7: 565-572. doi: 10.1002/acn3.51005
Pierson TM, Adams D, Bonn F, Martinelli P, Cherukuri PF, Teer JK, Hansen NF, Cruz P, Mullikin For The Nisc Comparative Sequencing Program JC, Blakesley RW, Golas G, Kwan J, Sandler A, Fuentes Fajardo K, Markello T, Tifft C, Blackstone C, Rugarli EI, Langer T, Gahl WA, Toro C (2011) Whole-exome sequencing identifies homozygous AFG3L2 mutations in a spastic ataxia-neuropathy syndrome linked to mitochondrial m-AAA proteases. PLoS Genet 7: e1002325. doi: 10.1371/journal.pgen.1002325
Rafehi H, Read J, Szmulewicz DJ, Davies KC, Snell P, Fearnley LG, Scott L, Thomsen M, Gillies G, Pope K, Bennett MF, Munro JE, Ngo KJ, Chen L, Wallis MJ, Butler EG, Kumar KR, Wu KH, Tomlinson SE, Tisch S, Malhotra A, Lee-Archer M, Dolzhenko E, Eberle MA, Roberts LJ, Fogel BL, Bruggemann N, Lohmann K, Delatycki MB, Bahlo M, Lockhart PJ (2023) An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA27B/ATX-FGF14. Am J Hum Genet 110: 1018. doi: 10.1016/j.ajhg.2023.05.005
Salari M, Etemadifar M, Rashedi R, Mardani S (2024) A Review of Ocular Movement Abnormalities in Hereditary Cerebellar Ataxias. Cerebellum 23: 702-721. doi: 10.1007/s12311-023-01554-0
Seong E, Insolera R, Dulovic M, Kamsteeg EJ, Trinh J, Bruggemann N, Sandford E, Li S, Ozel AB, Li JZ, Jewett T, Kievit AJA, Munchau A, Shakkottai V, Klein C, Collins CA, Lohmann K, van de Warrenburg BP, Burmeister M (2018) Mutations in VPS13D lead to a new recessive ataxia with spasticity and mitochondrial defects. Ann Neurol 83: 1075-1088. doi: 10.1002/ana.25220
Serrano-Munuera C, Corral-Juan M, Stevanin G, San Nicolas H, Roig C, Corral J, Campos B, de Jorge L, Morcillo-Suarez C, Navarro A, Forlani S, Durr A, Kulisevsky J, Brice A, Sanchez I, Volpini V, Matilla-Duenas A (2013) New subtype of spinocerebellar ataxia with altered vertical eye movements mapping to chromosome 1p32. JAMA Neurol 70: 764-71. doi: 10.1001/jamaneurol.2013.2311
Stevanin G, Bouslam N, Thobois S, Azzedine H, Ravaux L, Boland A, Schalling M, Broussolle E, Durr A, Brice A (2004) Spinocerebellar ataxia with sensory neuropathy (SCA25) maps to chromosome 2p. Ann Neurol 55: 97-104. doi: 10.1002/ana.10798
Storey E, Bahlo M, Fahey M, Sisson O, Lueck CJ, Gardner RJ (2009) A new dominantly inherited pure cerebellar ataxia, SCA 30. J Neurol Neurosurg Psychiatry 80: 408-11. doi: 10.1136/jnnp.2008.159459
Swartz BE, Burmeister M, Somers JT, Rottach KG, Bespalova IN, Leigh RJ (2002) A form of inherited cerebellar ataxia with saccadic intrusions, increased saccadic speed, sensory neuropathy, and myoclonus. Ann N Y Acad Sci 956: 441-4. doi: 10.1111/j.1749-6632.2002.tb02850.x
Swartz BE, Li S, Bespalova I, Burmeister M, Dulaney E, Robinson FR, Leigh RJ (2003) Pathogenesis of clinical signs in recessive ataxia with saccadic intrusions. Ann Neurol 54: 824-8. doi: 10.1002/ana.10758
Tazon B, Badenas C, Jimenez L, Munoz E, Mila M (2002) SCA8 in the Spanish population including one homozygous patient. Clin Genet 62: 404-9. doi: 10.1034/j.1399-0004.2002.620509.x
Tesi B, Davidsson J, Voss M, Rahikkala E, Holmes TD, Chiang SCC, Komulainen-Ebrahim J, Gorcenco S, Rundberg Nilsson A, Ripperger T, Kokkonen H, Bryder D, Fioretos T, Henter JI, Mottonen M, Niinimaki R, Nilsson L, Pronk CJ, Puschmann A, Qian H, Uusimaa J, Moilanen J, Tedgard U, Cammenga J, Bryceson YT (2017) Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms. Blood 129: 2266-2279. doi: 10.1182/blood-2016-10-743302
Tomiwa K, Baraitser M, Wilson J (1987) Dominantly inherited congenital cerebellar ataxia with atrophy of the vermis. Pediatr Neurol 3: 360-2. doi: 10.1016/0887-8994(87)90008-7
van Dijk GW, Wokke JH, Oey PL, Franssen H, Ippel PF, Veldman H (1995) A new variant of sensory ataxic neuropathy with autosomal dominant inheritance. Brain 118 ( Pt 6): 1557-63. doi: 10.1093/brain/118.6.1557
