Table 1 Clinical features and exome sequencing results of 88 patients identified with pathogenic/suspected diagnostic variants
Patient no. | Gender | Age at testing (years); age of onset, if available (years) | Ataxia type | Brain MRI findings | Additional clinical features | Known family history? | Gene | Disease-causing variant(s)a | OMIM disease [inheritance pattern] | Family history/ results of follow-up testing |
|---|---|---|---|---|---|---|---|---|---|---|
001 | F | 15 | C | Vermis atrophy, T2 signal alterations in cerebellum and vermis | Intractable seizures, DA, global DD, strabismus | Y | ADCK3 | c.1334_1335del (p.Thr445Argfs*52) | Primary coenzyme Q10 deficiency-4 [AR] | Brother affected |
002 | F | 20 | NOS | CA, cortical atrophy | DD | Y | ADCK3 | c.1532C>T (p.Thr511Met) [hmz] | Primary coenzyme Q10 deficiency-4 [AR] | Sister affected |
003 | F | 45 | C | NK | NP | Y | ADCK3 | c.1042C>T (p.Arg348*); c.1750_1752del (p.Thr584del) | SCAR 19 (coenzyme Q10 deficiency, primary 4) [AR] | Sister affected |
004 | M | 31; 25 | C, P | NK | Dystonia, myoclonus, DA, truncal tremor, appendicular and hemibody dystaxia, tremulous seizures of the neck, trunk, abdomen | N | ADCK3 | c.811C>T (p.Arg271Cys); c.1000C>T (p.Arg334Trp) | SCAR 19 (coenzyme Q10 deficiency, primary 4) [AR] | Both variants present in affected brother; c.1000C>T variant inherited from mother; father unavailable for testing |
005 | F | 33 | C | BSA | Seizures, shaking of right hand | N | ADCK3 | c.1651G>A (p.Glu551Lys); c.901C>T (p.Arg301Trp) | SCAR 19 (coenzyme Q10 deficiency, primary 4) [AR] | NA |
006 | F | 8 | C, P | Generalized brain atrophy | DD | N | ADCK3 | c.901C>T (p.Arg301Trp); c.1229G>A (p.Arg410Gln) | SCAR 19 (coenzyme Q10 deficiency, primary 4) [AR] | c.901C>T variant inherited from father; c.1229G>A variant inherited from mother |
007 | F | 44; 38 | C | CA | Hyperreflexia | Y | AFG3L2 | c.2062C>G (p.Pro688Ala) | Spinocerebellar ataxia-28 [AD] | Mother and brother affected |
008 | F | 68 | C | CA | DA | Y | ANO10 | c.132dup (p.Asp45Argfs*9) [hmz] | Autosomal recessive spinocerebellar ataxia-10 [AR] | Sister affected |
009 | M | 63; 17 | C, P | CA | Nystagmus | Y | ANO10 | c.132dup (p.Asp45Argfs*9) [hmz] | Autosomal recessive spinocerebellar ataxia-10 [AR] | Brother affected |
010 | F | 57; 20s | C, P | CA | DA, dysdiadochokinesia, nystagmus, muscle weakness | Y | ANO10 | c.96del (p.Glu33Asnfs*3); c.306C>A (p.Tyr102*) | Autosomal recessive spinocerebellar ataxia-10 [AR] | Sister affected |
011 | M | 44; 30 | C, P | CA | DA | Y | APOB | c.13025del (p.Pro4342Hisfs*7) | Familial hypo-betalipoproteinemia-1 [AR] | Brother affected |
012 | F | 9; infancy | C | CA | DA, cognitive impairment, DD | N | APTX | c.837G>A (p.Trp279*); c.875-2A>G (p.?) | Early-onset ataxia with oculomotor apraxia and hypoalbuminemia [AR] | c.837G>A variant inherited from father; c.875-2A>G variant inherited from mother |
013 | F | 3; 1 | E, P | NP | Telangiectasies | N | ARSA | c.1010A>T (p.Asp337Val); c.1283C>T (p.Pro428Leu) | Metachromatic leukodystrophy [AR] | Subsequent enzyme and urinalysis testing confirmed markedly decreased enzyme activity and marked increase in urine sulfatide |
014 | F | 25 | NOS | NK | NK | N | ATM | c.103C>T (p.Arg35*); c.7271T>G (p.Val2424Gly) | Ataxia-telangiectasia [AR] | NA |
015 | F | 22; 15 | C, P, S | CA | Sensory motor neuropathy; cognitive impairment (decreased concentration), DA, fatigue | N | ATM | c.2720_2723del (p.Cys907*) | Ataxia-telangiectasia [AR] | NA |
016 | F | 13 | NOS | CA, heterotopia or dysplasia of left posterior white matter | Cognitive impairment, developmental regression, seizures, hemiplegia | N | ATP1A3 | c.2401G>C (p.Asp801His) | Alternating hemiplegia of childhood-2/CAPOS/dystonia-12 [AD] | Identical twin sister affected |
017 | F | 3; 2 | C | NP | Wide gait, DD, febrile seizures, dysmorphic facies | Y | ATP1A3 | c.2452G>A (p.Glu818Lys) | Alternating hemiplegia of childhood-2/CAPOS/dystonia-12 [AD] | Father and brother affected |
018 | M | 20; 3 (onset deafness), 19 (onset ataxia) | C, E | NK | Myoclonus, sensorineural deafness | Y | ATP1A3 | c.2452G>A (p.Glu818Lys) | Alternating hemiplegia of childhood-2/CAPOS/dystonia-12 [AD] | NA |
019 | M | 37 | C, P | CA | Bradykinesia, DA, suspected oculomotor apraxia, nystagmus | N | ATP1A3 | c.1027C>T (p.Arg343Trp) | Alternating hemiplegia of childhood-2/CAPOS/dystonia-12 [AD] | NA |
020 | F | 4 | NOS | NK | Hand tremors, DD, dysmorphic facies, mild overgrowth | N | ATP7B | c.2806T>G (p.Leu936Val) | Wilson disease [AR] | NA |
021 | F | 25; 15 | C, P | “Eye of the tiger” sign | Spasticity, DA, dementia, hyperreflexia, cognitive impairment (moderate), hallucinations, self-mutilation, optic atrophy | N | C19ORF12 | c.187G>C (p.Ala63Pro); c.194-2del (p.?) | NBIA-4 [AR] | NA |
022 | F | 61 | C, P | NK | DA | N | CACNA1A | c.593G>A (p.Arg198Gln) | Episodic ataxia type 2 [AD] | NA |
023 | F | 55 | E | NP | Seizures, mild cognitive impairment, DA | Y | CACNA1A | c.1482_1483del (p.Ser495Phefs*60) | Episodic ataxia type 2 [AD] | Mother affected |
024 | F | 10 | NOS | CA | DD, DA | N | CACNA1A | c.1997C>T (p.Thr666Met) | Episodic ataxia type 2 [AD] | NA |
025 | F | 14 | C, E, P | CA | Seizures, cognitive impairment, developmental delay, behavioral abnormalities, nystagmus and other eye abnormalities | N | CACNA1A | c.3414del (p.Lys1139Argfs*48) | Episodic ataxia type 2 [AD] | NA |
026 | M | 8 | C | NP | DD, intention tremor | N | CACNA1A | c.653C>T (p.Ser218Leu) | Episodic ataxia type 2 [AD] | NA |
027 | F | 2; infancy | C, P | NP | Spasticity, mild global DD, hyperactivity | N | CACNA1A | c.1039G>A (p.Gly347Ser) | Episodic ataxia type 2 [AD] | c.1039G>A variant inherited from mother who is asymptomatic (incomplete penetrance reported) |
028 | M | 76; 68 | C, P | CA | DA, restless leg syndrome | Y | CACNA1G | c.5144G>A (p.Arg1715His) | Spinocerebellar ataxia-42 [AD] | Father, paternal aunt and cousin affected |
029 | M | 17; 10 | C, P | CA | Seizures, DA, developmental regression | Y | CLN8 | c.470A>G (p.His157Arg) | Neuronal ceroid lipofuscinosis-8 [AR] | Sister affected |
030 | F | 21 | C, P | NP | Seizures, myoclonus, DA, neuropathy, developmental regression | N | CSTB | c.67-1G>C (p.?) | Myoclonic epilepsy of Unverricht and Lundborg [AR] | NA |
031 | M | 60; 50s | C, P | CA | Cognitive impairment | Y | ELOVL4 | c.512T>C (p.Ile171Thr) | Spinocerebellar ataxia-34 [AD] | AD pedigree with four generations affected; multiple affected family members tested and carry c.512T>C variant |
032 | M | 33; teens | C, P | Leuko-dystrophy | Tremor | N | ERCC6 | c.229C>T (p.Arg77*); c.2058G>A (p.Trp686*) | Cockayne syndrome B [AR] | NA |
033 | F | 4 | C | CA | DA, muscle weakness, microcephaly, short stature | N | ERCC6 | c.2551T>C (p.Trp851Arg) | Cockayne syndrome B [AR] | NA |
034 | F | 5; 2 | E | Progressive volume loss | Nystagmus, myopathy, developmental regression, peripheral neuropathy | N | GALC | c.331G>A (p.Gly111Ser) | Krabbe disease [AR] | NA |
035 | F | 12; early childhood | NOS | NK | Areflexia, seizures, encephalopathy, DD | N | HEPACAM | c.614C>T (p.Thr205Ile) [hmz] | Megalencephalic leukoencephalopathy with subcortical cysts 2A [AR] | Consanguineous family |
036 | M | 2 | NOS | “Molar tooth” sign | Macrocephaly, hypotonia, DA, DD, oculomotor apraxia | N | INPP5E | c.875G>A (Arg292His) | Joubert syndrome-1 [AR] | NA |
037 | M | 6; 3 | C | CA, Dandy–Walker malformation | NP | N | ITPR1 | c.2129A>C (p.Lys710Thr) | Spinocerebellar ataxia-15; spinocerebellar ataxia-29 [AD] | NA |
038 | F | 52; 48 | NOS | CA (mild) | Headaches; mild cognitive impairment | Y | KCNA1 | c.76C>T (p.Arg26Trp) | Episodic ataxia-1 [AD] | Father and brother affected |
039 | F | 25; 23 | C, P | CA | Spasticity | Y | KCNC3 | c.1259G>A (p.Arg420His) | Spinocerebellar ataxia-13 [AD] | NA |
040 | F | 13 | C | CA, vermis atrophy | DD, unstable gait, peripheral neuropathy | N | KIF1A | c.173C>T (p.Ser58Leu) | Autosomal dominant mental retardation-9 [AD] | NA |
041 | F | 3; 0.5 | C | CA | Optic atrophy, moderate DD, seizures, muscle weakness | N | KIF1A | c.919C>G (p.Arg307Gly) | Autosomal dominant mental retardation-9 [AD] | NA |
042 | M | 3; 3 | C | NP | Hypotonia, global DD, dysmorphic facial features, strabismus | N | KIF7 | c.1220C>A (p.Ala407Asp); c.1262G>A (p.Ser421Asn) | Acrocallosal syndrome/Joubert syndrome 12 [AR] | c.1220C>A and c.1262G>A variants in trans based on NGS data |
043 | F | 12 | NOS | NK | Seizures, DD, muscle weakness | N | MECP2 | c.397C>T (p.Arg133Cys) | Rett syndrome [X-linked] | NA |
044 | M | 17; adolescence | C, P | CA, vermis atrophy | Tremor, developmental regression, neurofibromatosis, epidermolysis bullosa | N | NF1 | c.3826C>T (p.Arg1276*) | Neurofibromatosis type I [AD] | NA |
045 | M | 44; late 20s | C, P | BSA, CA | Spasticity, dystonia, DA | N | NIPA1 | c.746A>G (p.Asn249Ser) | Spastic paraplegia 6 [AD] | NA |
046 | F | 40; 2 | C | NP | NP | Y | NKX2-1 | c.635A>C (p.Gln212Pro) | Choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction [AD] | Father, brother and paternal half-sister affected; c.635A>C variant present in affected child |
047 | F | 56; 50 | C, P | NP | NP | Y | PDYN | c.583G>A (p.Gly195Arg) | Spinocerebellar ataxia 23 [AD] | Mother and sister affected |
048 | F | 2; 1 | NOS | CA | Dystonia, DD, possible regression, abnormal EEG, encephalopathy | N | PLA2G6 | c.2370_2371del (p.Tyr790del*); c.1506G>C (p.Lys502Asp); c.321-?_894+?del (ex 3-6 del) | Infantile neuroaxonal dystrophy (INAD) [AR] | c.2370_2371 inherited from mother, c.1506G>C and exon 3–6 deletion inherited from father. All 3 variants present in affected sibling |
049 | F | 34 | C | NP | Sensory neuropathy | N | POLG | c.1880G>A (p.Arg627Gln); c.2869G>C (p.Ala957Pro) | Mitochondrial recessive ataxia syndrome [AR] | NA |
050 | F | 4; 1 | C | CA | Hypotonia, moderate DD | N | POMGNT2 | c.745C>T (p.Gln249*) | Muscular dystrophy–dystroglycanopathy with brain and eye anomalies (type A8), limb-girdle muscular dystrophy, ID [AR] | NA |
051 | F | 59 | C | NK | NP | Y | PRKCG | c.154T>A (p.Cys52Ser) | Spinocerebellar ataxia 14 [AD] | Mother and maternal grandmother affected |
052 | F | 43; 34 | C, P | CA | NP | Y | PRKCG | c.197G>A (p.Cys66Arg) | Spinocerebellar ataxia 14 [AD] | NA |
053 | F | 6 | NOS | NP | Intention tremor, global DD | N | RARS2 | c.370del (p.Gln124Argfs*27); c.1438G>A (p.Gly480Arg) | Pontocerebellar hypoplasia type 6 [AR] | c.370del variant inherited from mother; c.1438G>A variant inherited from father |
054 | M | 37; childhood | C, P | Small cerebellar vermis | DA | Y | SACS | c.13527dup (p.Glu4510Argfs*4) [hmz] | Spastic ataxia of the Charlevoix–Saguenay type [AR] | Brother affected |
055 | M | 8 | P | Unilateral periventricular heterotopia | Spasticity, dystonia, DA, oculomotor apraxia | N | SACS | c.1919_1920del (p.His640Profs*5); c.10906C>T (p.Arg3636*) | Spastic ataxia of the Charlevoix–Saguenay type [AR] | NA |
056 | F | 40 | NP | NP | Spastic paraplegia, lower extremity spasticity | N | SACS | c.3427C>A (p.Gln1143Lys); c.10982C>T (p.Ala3661Val) | Spastic ataxia of the Charlevoix–Saguenay type [AR] | c.3427C>A variant inherited from father; mother not available for testing |
057 | F | 3; 0.5 | Static | NP | Hypotonia, absent deep tendon reflexes, elevated acylcarnitine profile | N | SLC52A2 | c.505C>T (p.Arg169Cys) [hmz] | Brown–Vialetto–Van Laere syndrome-2 [AR] | NA |
058 | M | 61 | C, P | NP | Spasticity | N | SOD1 | c.272A>C (p.Asp91Ala) [hmz] | Amyotrophic lateral sclerosis-1 [AR/AD] | NA |
059 | M | 54 | C, P | CA | Hyperreflexia, progressive external ophthalmoplegia, oculomotor apraxia | N | SPG7 | c.1529C>T (p.Ala510Val); c.2181+5G>A (p.?) | Spastic paraplegia-7 [AR] | c.1529C>T and c.2181+5G>A variants confirmed in trans by RNA studies, both variants absent in father, 2 unaffected siblings carry p.Ala510Val variant. Mother unavailable for testing |
060 | M | 18; 13 | NOS | Trace chronic gliosis | Lower extremity spasticity, gait abnormalities, ADHD | Y | SPG7 | c.1529C>T (p.Ala510Val) | Spastic paraplegia-7 [AR] | NA |
061 | F | 36; 20s | C | CA | Spasticity, dystonia, DA, nystagmus, dysmetria, dysdiadochokinesia | N | SPG7 | c.1904C>T (p.Ser635Leu); c.2254C>G (p.His752Asp) | Spastic paraplegia-7 [AR] | c.1904C>T variant inherited from father; c.2254C>G variant inherited from mother |
062 | F | 62 | C, P, S | NK | Spasticity, hyperreflexia, oculomotor apraxia | N | SPG7 | c.861dup (p.Asn288*); c.1529C>T (p.Ala510Val) | Spastic paraplegia-7 [AR] | NA |
063 | M | 82; 72 | C, P | NK | Mild nystagmus | N | SPG7 | Exon 6 deletion [hg19, chr16:89595862-89596061×1] | Spastic paraplegia-7 [AR] | NA |
064 | M | 70; 40s | C, P | CA | Neuropathy | N | SPG7 | c.1529C>T (p.Ala510Val) [hmz] | Spastic paraplegia-7 [AR] | NA |
065 | M | 49 | C, P | Spasticity | N | SPG7 | c.1454_1462del (p.Arg485_Glu487del); c.1033G>C (p.Ala345Pro) | Spastic paraplegia-7 [AR] | c.1454_1462del variant inherited from father; c.1033G>C variant inherited from mother | |
066 | F | 67 | C, P | CA | Spasticity, DA, nystagmus | Y | SPG7 | c.988-1G>A (p.?); c.1529C>T (p.Ala510Val) | Spastic paraplegia-7 [AR] | 2 affected siblings |
067 | M | 18 | C | CA | Seizures, encephalopathy, hypotonia, dementia, hyporeflexia, cognitive impairment, moderate DD | N | SPTAN1 | c.6943C>G (p.Gln2315Glu) | Early infantile epileptic encephalopathy-5 [AD] | De novo |
068 | M | 61; 37 | C, P | CA (mild, stable) | Memory problems | Y | SPTBN2 | c.172G>A (p.Val58Met) | Spinocerebellar ataxia-5 [AD] | c.172G>A variant present in similarly affected sibling |
069 | F | 9 | C | CA | Hypotonia, DA, hyperreflexia, nystagmus | N | SPTBN2 | c.181A>G (p.Lys61Glu) | Spinocerebellar ataxia-5 [AD] | De novo |
070 | F | 28 | C | CA | DA, cognitive impairment | Y | SPTBN2 | c.1043A>T (p.Asn348Ile) | Spinocerebellar ataxia-5 [AD] | Daughter affected; c.1043A>T variant not present in asymptomatic mother. Father unavailable for testing |
071 | M | 5 | E | NK | Hyperreflexia, DD and regression | N | SPTBN2 | c.91T>C (p.Ser31Pro) | Spinocerebellar ataxia-5 [AD] | Present in asymptomatic father (age 43). Variable age of onset and anticipation described for SPTBN2 |
072 | M | 24 | C, P | NK | Spasticity, DA, hypogonadotropic hypogonadism | N | STUB1 | c.694_699del (p.Cys232_Gly233del); c.721C>G (p.Arg241Gly) | Autosomal recessive spinocerebellar ataxia-16 [AR] | NA |
073 | M | 28; early 20s | C, P | CA | Cognitive decline | N | STUB1 | c.433A>C (p.Lys145Gln); c.646dup (p.Ser216Phefs*5) | Autosomal recessive spinocerebellar ataxia-16 [AR] | NA |
074 | M | 37; mid 20s | C | CA | NP | N | SYNE1 | c.1042G>T (p.Glu348*) [hmz] | Autosomal recessive spinocerebellar ataxia-8 [AR] | Consanguineous family |
075 | F | 55 | C, P | CA | NP | N | SYNE1 | c.16208C>A (p.Ser5403*) | Autosomal recessive spinocerebellar ataxia-8 [AR] | NA |
076 | F | 37; 25 | C, P | CA | Spasticity, DA, hyperreflexia | Y | SYNE1 | c.22195G>T (p.Glu7399*); c.22788dup (p.Leu7597Thrfs*12) | Autosomal recessive spinocerebellar ataxia-8 [AR] | 2 affected siblings |
077 | F | 2; <1 | NOS | CA | Tremors, developmental regression | N | SYNE1 | c.24865C>T (p.Gln8289*) | Autosomal recessive spinocerebellar ataxia-8 [AR] | NA |
078 | F | 31; ~10 | C, P | CA | DA, DD, lower extremity sensory loss and weakness | Y | SYNE1 | c.6898del (p.Glu2300Lysfs*2); c.16024-13C>G (p.?) | autosomal recessive spinocerebellar ataxia-8 | Twin sister affected; c.6898del variant inherited from mother. Father not available for testing |
079 | F | 40; 30 | C | CA | Progressively slurred speech | Y | SYNE1 | c.1954-2A>G (p.?) | Autosomal recessive spinocerebellar ataxia-8 [AR] | NA |
080 | M | 48; 34 | C, P | BSA, CA | DA, facial masking | N | SYNE1 | c.503_504del (p.Ser168*) [hmz] | Autosomal recessive spinocerebellar ataxia-8 [AR] | NA |
081 | F | 37; 30 | C, P | CA | Mild hyperreflexia | N | SYNE1 | c.5182G>T (p.Glu1728*) [hmz] | Autosomal recessive spinocerebellar ataxia-8 [AR] | Consanguineous family |
082 | M | 69 | C, P | CA | Dementia, cognitive impairment, nystagmus | N | TGM6 | c.379C>T (p.Arg127Trp) | Spinocerebellar ataxia-35 [AD] | NA |
083 | M | 4 | P | NP | dysmetria | Y | TGM6 | c.956G>A (p.Arg319Gln) | Spinocerebellar ataxia-35 [AD] | Father and half brother possibly affected |
084 | F | 40 | NP | NK | Spasticity, hyperreflexia | N | TMEM240 | c.223G>A (p.Glu75Lys) | Spinocerebellar ataxia-21 [AD] | NA |
085 | M | 48; 44 | C, P | CA | NP | N | TMEM240 | c.344T>C (p.Val115Ala) | Spinocerebellar ataxia-21 [AD] | c.344T>C variant present in mother who has not been clinically evaluated |
086 | F | 39 | C | CA | Tremor, cognitive impairment | N | TMEM240 | c.509C>T (p.Pro170Leu) | Spinocerebellar ataxia-21 [AD] | c.509C>T variant present in affected child |
087 | F | 22 | P | Gliosis | Chorea, encephalopathy, DA, hyperreflexia, neuropathy, developmental regression | N | TTC19 | c.817G>T (p.Glu273*) [hmz] | Mitochondrial complex III deficiency nuclear type 2 [AR] | Consanguineous family |
088 | M | 2 | E | NP | Spasticity, tremors, moderate global DD, gastrointestinal reflux | N | UBE3A | c.2304G>A (p.Trp768*) | Angelman syndrome [AD] | NA |
