Table 1
Diagnostic yield for genetic testing in a non-exhaustive selection of prospectively tested movement disorder cohorts from 2021–2023.
| AUTHORS, YEAR, COUNTRY | TEST (NUMBER OF GENES) | COHORT RECRUITMENT CRITERIA | AGE AT ONSET (YEARS) | DIAGNOSTIC YIELD | VUS/GUS YIELD |
|---|---|---|---|---|---|
| Composite Movement Disorder Cohorts | |||||
| Eratne et al. (2021) [117], Australia | ES (N/A) | Patients with movement disorders and age of onset 2–60 years (except if clear family history); exclusion of movement disorders likely due to a specific single gene | Median 40; 1–69 | 21.9% (21/96)
| 11.5% (11/96) |
| Kwong et al. (2021) [77], Hong Kong SAR, China | ES (1394) | Patients with pediatric-onset (< 18 years) movement disorders; unrevealing imaging and neurometabolic investigations | 0–13 | 32.2% (10/31)
| 12.9% (4/31) |
| Ataxia | |||||
| Benkirane et al. (2021) [118], France | ES (490) | Patients with ataxia; exclusion of Friedreich’s ataxia, SCA1, 2, 3 & 6 and ataxia with vitamin E deficiency | Mean 19; 1–53 | 45.9% (168/366) | N/A |
| Galatolo et al. (2021) [119], Italy | TGP (285) | Patients with ataxia; exclusion of acquired etiologies, Friedreich’s ataxia and SCA1, 2, 3, 6, 7, 8, 12 & 17 | N/A | 33.2% (125/377) | 15.6% (59/377) |
| Balakrishnan et al. (2022) [120], India | TP-PCR (4–10) ± ES/GS (N/A) | Patients with ataxia; exclusion of acquired etiologies | N/A | 49.3% (74/150) | N/A |
| Radziwonik et al. (2022) [121], Poland | TGP (152) | Patients with ataxia; exclusion of acquired etiologies, SCA1, 2, 3, 6, 7, 8, 17 & 36 and DRPLA | Mean 32.7; 7–70 | 55.2% (16/29) | 44.8% (13/29) |
| da Graca et al. (2022) [122], Brazil | ES (N/A) | Patients with ataxia; exclusion of acquired etiologies, SCA1, 2, 3, 6, 7 & 10, Friedreich’s ataxia and DRPLA | Mean 25.8; 2–71 | 35.5% (27/76) | N/A |
| Dystonia | |||||
| Wu et al. (2022) [16], Taiwan | TGP (72), MLPA (13) | Patients with dystonia; exclusion of secondary etiologies | Mean 41.6 ± SD 20 | 12.6% (40/318) | 11.9% (38/318) |
| Ahn et al. (2023) [123], South Korea | ES (N/A) | Patients with young-onset (< 40 years) dystonia; exclusion of secondary etiologies, patients with a confirmed genetic dystonia based on single gene tests (TOR1A, SGCE, PRRT2, PANK2, GCH1, DRPLA, SCA1, 2, 3, 6, 7 & 17) and levodopa-responsive patients | Mean 19.6 ± SD 10.9 | 20.9% (9/43) | N/A |
| Li et al. (2023) [124], China | ES (591) | Patients with isolated dystonia | Mean 25.7 ± SD 16; 4–66 | 21.6% (19/88) | 13.6% (12/88) |
| PD* | |||||
| Muldmaa et al. (2021) [125], Estonia | TGP (9) ± MLPA (5) | Patients with PD | Mean 65.2 ± SD 10.1; 35–83 | 9.5% (18/189) | 10.6% (20/189) |
| Hill et al. (2022) [42], USA | GS (49) | Patients with PD; exclusion of patients with dementia | N/A | 13.3% (27/203) | 13.8% (28/203) |
| Hua et al. (2022) [20], China | ES (24), MLPA (6) | Patients with early-onset (< 50 years) PD; exclusion of other neurodegenerative disorders, psychiatric disorders and severe physical illnesses | Mean 43.4 ± SD 7.1 | 9.0% (14/155) | 14/2% (22/155) |
| Kovanda et al. (2022) [126], Slovenia, Croatia & Serbia | ES (35), MLPA (8) | Patients with PD with either early-onset (< 50 years) or history of PD in at least one first-degree relative | Mean 47; 24 – 87 | 10.1% (15/149) | 14.8% (22/149) |
| Do et al. (2023) [127], Vietnam | TGP (20), MLPA (8) | Patients with early-onset (< 50 years) PD | Mean 43.1 ± SD 6.0 | 21.7% (18/83) | 22.9% (19/83) |
| Sun et al. (2023) [19], China | TGP (116) or ES (N/A), MLPA (8) ± TP-PCR (10) | Patients with either early-onset (< 50 years) or history of PD in at least one family member | Median 42, IQR 14 | 26.9% (224/832) | N/A |
| Tay et al. (2023) [128], Malaysia | TGP (115), MLPA (5) | Patients with early-onset (< 50 years) PD | N/A | 21.7% (35/161) | 14.9% (24/161) |
[i] DRPLA, dentatorubral-pallidoluysian atrophy; ES, exome sequencing; GS, genome sequencing; GUS, gene of uncertain significance; HSP, hereditary spastic paraplegia; IQR, interquartile range; MLPA, multiplex ligation-dependent probe amplification; N/A, not available; SCA, spinocerebellar ataxia; SD, standard deviation; TGP, targeted gene panel; TP-PCR, triplet-primed polymerase chain reaction; VUS, variant of uncertain significance.
* Diagnostic yields for PD cohorts include both pathogenic & likely pathogenic disease-causing variants, as well as select moderate- and high-penetrance risk alleles/variants in GBA1 and LRRK2.
Table 2
Examples of specific therapeutic implications for common genetic movement disorders.
| INTERVENTION | CONDITION (GENES/GENES) | TREATMENT/THERAPEUTIC IMPLICATION |
|---|---|---|
| Targeted medication | Aceruloplasminemia (CP) | Iron chelation [129], fresh frozen plasma [130] |
| ADCY5-related dyskinesia (ADCY5) | Caffeine [49] | |
| Aromatic L-amino acid decarboxylase deficiency (DDC) | Pyridoxine, dopamine agonists, monoamine oxidase inhibitors [131] | |
| Benign hereditary chorea (NKX2-1) | Levodopa [132] | |
| Cerebrotendinous xanthomatosis (CYP27A1) | Chenodeoxycholic acid [133] | |
| Dopa-responsive dystonia (GCH1, TH, SPR, PTS, QDPR) | Levodopa [134] | |
| Episodic ataxia type 2 (CACNA1A) and spinocerebellar ataxia 27B (FGF14) | Acetazolamide, 4-aminopyridine [47, 48, 135, 136] | |
| Friedreich’s ataxia (FXN) | Omaveloxolone [50] | |
| Hypermanganesemia with dystonia (SLC30A10, SLC39A14) | Manganese chelation with EDTA [137] | |
| Niemann-Pick disease type C (NPC1, NPC2) | Miglustat [138] | |
| Paroxysmal kinesigenic dyskinesia (PRRT2) | Sodium channel blockers (e.g., carbamazepine) [139] | |
| Rapid onset dystonia-parkinsonism (ATP1A3) | Flunarizine [140] | |
| Spinocerebellar ataxia 38 (ELOVL4) | Docosahexaenoic acid [141] | |
| Wilson’s disease (ATP7B) | Copper chelation [142], zinc [143] | |
| DBS | Parkinson’s disease with GBA1 variants | Cognitive worsening after DBS of subthalamic nucleus [53, 54] |
| Certain genetic dystonias (e.g., TOR1A, TAF1, SGCE, KMT2B, etc.) | Good response to DBS of globus pallidus internus [56, 57, 58] | |
| Rapid onset dystonia-parkinsonism (ATP1A3) | Poor response to DBS [59, 60, 61] | |
| Dietary modification | Abetalipoproteinemia (MTTP) | Low-fat diet and supplementation of fat-soluble vitamins [144] |
| Ataxia telangiectasia | Nicotinamide riboside supplementation [145] | |
| Ataxia with vitamin E deficiency (TTPA) | Vitamin E supplementation [64] | |
| Ataxias with coenzyme Q10 deficiency (ADCK3, ANO10, APTX) | Coenzyme Q10 supplementation [46] | |
| Biotin-thiamine responsive basal ganglia disease (SLC19A3) | Biotin and thiamine supplementation [146] | |
| Cerebral creatine deficiency syndromes (GAMT, GATM) | Creatine supplementation [147] | |
| Cerebral folate transport deficiency (FOLR1) | Folinic acid supplementation [148] | |
| GLUT1 deficiency syndrome (SLC2A1) | Ketogenic diet [65, 66] | |
| Glutaric aciduria type 1 (GCDH) | Low-lysine diet and carnitine supplementation [149] | |
| Refsum’s disease (PHYH, PEX7) | Dietary restriction of phytanic acid [150] | |
| Gene therapy | Aromatic L-amino acid decarboxylase deficiency (DDC) | Eladocagene exuparvovec [68] |
| Trigger avoidance | Alternating hemiplegia of childhood (ATP1A3) | Avoid emotional stress, excess physical exertion, water exposure, and temperature extremes [140] |
| Biotin-thiamine responsive basal ganglia disease (SLC19A3) | Avoid fever [146] | |
| Episodic ataxia type 2 (CACNA1A) | Avoid alcohol, excess physical exertion, emotional stress, and caffeine [135] | |
| Glutaric aciduria type 1 (GCDH) | Avoid catabolic states (e.g., ensure high caloric intake during intercurrent illnesses) [149] | |
| POLG-related mitochondrial disorders (POLG) | Avoid valproic acid [69] | |
| Rapid onset dystonia-parkinsonism (ATP1A3) | Avoid alcohol, excess physical exertion, fever, and emotional stress [44, 70] |
[i] DBS, deep brain stimulation.
Figure 1
Benefits, challenges & limitations of genetic testing for movement disorders.
The balance of benefits, challenges and limitations for genetic testing of movement disorders is dynamic, requiring the routine consideration of both clinical and non-clinical domains. Taking a broad general perspective, the current balance of these ‘pros’ and ‘cons’ likely weighs in favor of genetic testing. However, the exact position of the scales is dependent on individual patient factors, local resource availability and healthcare system contexts. Clinicians must consider these factors holistically when making decisions regarding genetic testing, on a case-by-case basis and in consultation with patients and their families. Emerging opportunities and challenges will continue to shift the balance of these decisions, likely further in favor of genetic testing as improvements in genetic technology and scientific understanding of disease lead to improved diagnosis, prognostication and treatment of genetic movement disorders. GUS, gene of uncertain significance; VUS, variant of uncertain significance.