Abstract
Background
Dystonia with anarthria and/or aphonia (DAnAp) represents a distinctive phenotype manifesting across lifespan. Frequently associated with genetic disorders, early recognition is critical for diagnosis and management.
Objectives
To provide practical recommendations for the clinical evaluation of patients with DAnAp, enhancing recognition and facilitating targeted diagnostic workup.
Methods
We retrospectively reviewed patients with dystonia and anarthria/aphonia due to established genetic causes across the lifespan at The Hospital for Sick Children and Toronto Western Hospital. Demographic, clinical, genetic, and neuroradiological data were reviewed. Cases were categorized based on the age of onset of neurological symptoms: neonatal (0–4 weeks), infantile (4 weeks – 1 year), early childhood (1–8 years), late childhood/adolescence (8–18 years) and adulthood (>18 years).
Results
Fifty‐four patients were included, with a mean age of 15.8 years at last assessment (range: 17 months–53 years). We identified 39 distinct genetic etiologies including channelopathies, G‐protein‐related disorders, developmental and epileptic encephalopathies and metabolic disorders. Most (92%) presented before the age of 8 years, with symptom onset in infancy (37%), early childhood (32%) and neonatal period (24%); only four presented later. Early‐onset cases demonstrated more severe phenotypes, including global developmental delay (100% of neonatal cases), seizures (54% of neonatal cases) and absent speech acquisition. Therapeutic interventions included deep brain stimulation in 12 patients, targeted gene or disease‐specific therapies were available for three patients in our cohort.
Conclusion
Dystonia with anarthria/aphonia is genetically heterogeneous and predominantly early‐onset, with severe neurodevelopmental impairment. Early genetic diagnosis is essential to guide management as targeted therapies emerge.
Keywords: dystonia, anarthria, Aphonia
Dystonia is characterized by sustained or intermittent muscle contractions, leading to abnormal postures, repetitive movements, or both. 1 It can manifest in isolation or as part of a broader neurological syndrome and varies in severity, age of onset, and distribution of affected muscles. While in certain syndromes, such as dystonia with myoclonus 2 the differential diagnosis is relatively narrow and most causative genes are well known, other less common syndromic associations like dystonia with anarthria or aphonia (DAnAp) can involve a wide spectrum of underlying conditions, demanding careful diagnostic workup. 3 Importantly, recent genomic studies have expanded the spectrum of etiologies, including those presenting with anarthria and/or aphonia revealing marked heterogeneity. 4 , 5 , 6 These advances, alongside emerging targeted therapies, underscore the need for precise diagnostic strategies. However, systematic literature on DAnAp remains limited. The only systematic cohort study to date, published in 2016, identified DAnAp in 32 of 860 patients (3.7%) with dystonia as the predominant motor feature, highlighting the relative rarity of this phenotypic association. 3 The underlying etiologies were heterogeneous and included a range of neurogenetic and metabolic disorders. 3
In this study, we present the largest cohort to date of genetically confirmed pediatric and adult patients with DAnAp. Our objective is to describe the clinical characteristics and relevant investigations in patients with dystonia and anarthria/aphonia and link them to distinct, recognizable genetic etiologies. By characterizing clinical associations, we aim to provide practical recommendations for the clinical evaluation of patients with DAnAp, thereby enhancing recognition and facilitating targeted diagnostic workup.
Methods
This retrospective study included both pediatric and adult patients evaluated by the movement disorders services at two major centers in Toronto, Canada. Patients from the Toronto Western Hospital registry were included from July 1999 to September 2025, and from The Hospital for Sick Children from 2021 to October 2024. Inclusion dates correspond to the timeframe of data availability in the database.
Patients with DAnAp with a genetic diagnosis, consisting of likely pathogenic/pathogenic variants, were included in this study. Aphonia was defined as a complete absence of vocal sound production, including the inability to produce intentional phonation, despite preserved effort and communicative intent. This distinction is particularly important in the pediatric population, where developmental and behavioral factors can obscure the clinical picture. Anarthria describes the complete loss of the ability to articulate speech due to severe motor pathway dysfunction. Patients with acquired causes of dystonia, those without a confirmed genetic diagnosis, and those where parkinsonism or ataxia were the predominant phenotype were excluded.
Demographic data, clinical characteristics, including age at onset of neurological and movement disorder symptoms, onset of anarthria/aphonia, genetic findings, neuroimaging results, relevant laboratory investigations, and therapeutic interventions with their outcome were reviewed. Video recordings were reviewed to confirm clinical descriptions and extract additional observations when necessary. Six representative cases were selected to illustrate the clinical diversity of neuroimaging findings within the cohort. Descriptive statistics were generated using Excel to summarize key cohort characteristics.
Cases were categorized based on the age of onset of neurological symptoms: neonatal (0–4 weeks), infantile (4 weeks – 1 year), early childhood (1–8 years), late childhood/adolescence (8–18 years) and adulthood onset (>18 years). The age categories were chosen to reflect key stages in neurological development, as these stages influence both clinical presentation and diagnostic strategies. Neurological symptom onset was defined as the point in time documented in the chart when any neurological symptoms, such as abnormal movement patterns, seizures or developmental delay began. In addition, we collected the specific onset ages of the movement disorder and of aphonia/anarthria when available and noted cases where this information could not be reliably determined.
The study was approved by the The Hospital for Sick Children REB committee (REB number 1000081661, approved June 2024) as well as the UHN REB (CAPCR ID 24–5646, approved November 2024). The requirement for informed consent was waived by both REC/REBs due to the retrospective nature of the study and the use of de‐identified data, in accordance with institutional and national ethical guidelines.
Data Availability
De‐identified individual participant data that support the findings of this study, as well as related study documentation, will be made available upon reasonable request from qualified investigators for purposes of replicating procedures and results. Requests will be reviewed by the corresponding author.
Results
Fifty‐four children and adults with DAnAp were identified.
Demographic characteristics of the cohort are summarized in Table 1. The average age at study inclusion was 15.8 years with an age spectrum ranging from 17 months to 53 years. The cohort included 24 females and 30 males. Seven patients (12.9%) were deceased prior to the start of the data collection.
TABLE 1.
Demographic characteristics of the cohort
| Total number of patients | 54 |
| Mean age at study inclusion | 15.8 years |
| Age range | 17 months – 53 years |
| Sex distribution | 24 females (44.4%), 30 males (55.6%) |
| Deceased prior to data collection | 7 patients (12.7%) between the age of 17 months and 13 years |
| Symptom onset timing | |
|
13 patients (24%) |
|
20 patients (37%) |
|
17 patients (31.5%) |
|
1 patient (1.9%) |
|
3 patient (5.6%) |
| Etiologies | 39 different genetic diagnosis identified |
| Neuroimaging | 44/54 MRI available |
|
6 patients (13.6%) |
|
14 patients (31.8%) |
A total of 39 distinct genetic conditions were identified among individuals in our cohort.
The largest group of patients, comprising 20 cases (37%), had symptom onset during infancy and exhibited severe early developmental delay. Seventeen (31.5%) developed symptoms in early childhood, 13 (24%) had neonatal onset of neurological symptoms, whereas one (1.9%) patient's symptom emerged in late childhood and three (5.6%) developed symptoms in adulthood. Speech was never acquired in the majority of cases (n = 33, 61%), while in the remaining cases onset of anarthria varied across the lifespan (early childhood n = 6, 11%; late childhood n = 2, 4%; adulthood n = 5, 9%). In 15% of cases onset had not been captured. Detailed clinical information is provided in Table S1, an overview of the age of onset for all genetic conditions is provided in Figure 1.
Figure 1.
Age at onset and associated genetic etiologies in patients with dystonia and anarthria/aphonia. Genetic etiologies are shown according to age at onset (neonatal, infancy, early childhood, late childhood/adolescence, and adulthood). Overlaps reflect genes associated with variable age of presentation.
Neuroimaging was available in 44 of the 54 patients (81%). Six scans (13.6%) were reported as normal. Nineteen MRIs (43%) demonstrated nonspecific cerebral atrophy, while disease‐specific changes in the basal ganglia were observed in 14 cases (31.8%). Figure 2 shows eight representative images illustrating characteristic features of the underlying diagnoses.
Figure 2.
Exemplary MRI findings in patients with dystonia and anarthria/aphonia. (A) Microcephaly with marked reduction in the parenchymal volumes and ill‐defined T2 hyperintense signal changes within the cerebral hemispheres relative to the vermis with pontocerebellar hypoplasia type 2A (Case 9). (B) Diffuse T2 white matter signal abnormality with sparing of the subcortical U‐fibers with small dark thalami and parenchymal volume loss in Krabbe Disease (Case 17). (C) Delay in myelination with T2 hypointense thalami and microcephaly in Fumerase deficiency (Case 26). (D) Macrocephaly, extensive abnormal T2 signal hyperintensity including U‐fibers in Canavan Disease (Case 27). (E) Volume loss and cystic changes involving bilateral basal ganglia (arrows) in Thiamine and Biotin responsive basal ganglia disease (Case 28). (F) T2 signal abnormality in bilateral globus pallidi (arrows) in PKAN (Case 31). (G) Extensive bilateral chronic atrophic changes associated with encephalomalacia, secondary to previous extensive insults in the context of MELAS (Case 43). (H) Extensive parieto‐occipital T2 white matter abnormalities with involvement of splenium and corpus callosum in X‐ALD (Case 52).
Five representative cases illustrating the spectrum of DanAp are presented in Video 1.
Video 1.
Selected videos of patients with dystonia and anarthria/aphonia. Case 4 presents a 9 y.o. girl with generalized dystonia, including jaw‐opening dystonia and anarthria due to KCNQ2‐related epileptic encephalopathy. Case 10 shows a 12 y.o. girl with combined oxidative phosphorylation deficiency who is wheelchair‐bound, with generalized dystonia, jaw‐opening dystonia, and anarthria. Case 20 is a 14 y.o. young women with ADCY5‐related disorder and continuous choreatic movements of the face and dystonic posturing of the limbs, who due aphonia relies on a communication device. Case 28 shows a 7 y.o. boy with generalized dystonia and aphonia due to biotin‐ and thiamine‐responsive basal ganglia disease. Case 43 is a 16 y.o. young women, who is wheelchair‐.bound, with poor axial control, dystonia and anarthria due to a homozygous variant in COX15 (previously reported by AlFaris et al. 10 ).
Onset during Neonatal Age (n = 13)
All patients with neonatal‐onset neurological symptoms exhibited global developmental delay (GDD).
The majority were diagnosed with channelopathies (SCN1A (case 8), SCN2A (case 6), KCNQ2 (cases 3–5), ATP1A3 (case 11)). Two children (cases 1 and 2) had G‐protein‐related disorder caused by pathogenic variants in the GNAO1 gene. One patient was diagnosed with Aromatic L‐amino Acid Decarboxylase (AADC) deficiency (case 13), a disorder of monoamine neurotransmitter synthesis. Another child (case 12), who later developed developmental and epileptic encephalopathy (DEE) carried a pathogenic variant in the CAMK4 gene (previously published 7 ). One child presented with severe dystonia from the neonatal period alongside profound developmental delay and was found to carry a pathogenic variant in EARS2 (case 10). Mitochondrial involvement was identified in another child (case 7) diagnosed with spinocerebellar ataxia type 28 (SCA28), and one child (case 9) was diagnosed with pontocerebellar hypoplasia type 2A (PCH2A).
Neonatal seizures were present in seven cases (cases 2–6, 8, 11), while one patient (case 12) developed seizures later in life. Out of the 13 patients, 12 remained anarthric/aphonic, but one patient (case 8) was able to produce single sounds after a few years. The onset of dystonia in these children ranged from the neonatal period (n = 4) and infancy (n = 7) to early (n = 1) and late childhood (n = 1). All children were severely affected and showed generalized dystonia over time. Four of the 13 children experienced status dystonicus.
Neuroimaging of most cases (n = 7) showed global brain atrophy. Basal ganglia abnormalities were found in three children (cases 4, 10 and 12), while delayed myelination was observed in two (cases 3 and 9). In three cases where serial MRI scans were conducted, a progressive worsening of cerebral atrophy was noted over time (cases 3, 6 and 7).
Laboratory investigations showed nonspecific findings in most cases, with abnormalities observed only during episodes of acute illness over the years. One child (case 10) with a pathogenic EARS2 variant demonstrated mild baseline elevation of lactate and nonspecific increases in amino acid levels. In the one child with AADC deficiency (case 13), cerebrospinal fluid (CSF) neurotransmitter analysis revealed elevated levels of 3‐O‐methyldopa and decreased levels of homovanillic acid and 5‐hydroxyindoleacetic acid consistent with this diagnosis.
Three children (cases 2,6,7) eventually underwent deep brain stimulation (DBS). The child with GNAO1‐ associated neurodevelopmental disorder (case 2) was implanted with bilateral GPi DBS in status dystonicus as well as the child with SCN2A variant (case 6), in both cases status dystonicus could be stopped by implantation. The child with SCA28 (case 7) had significant improvement of dystonia after GPi implantation. One child with AADC deficiency (case 13) regained the ability to walk following gene therapy. 8
Onset during Infancy (n = 20)
Metabolic disorders were most common disease in this group (n = 10). Lesch–Nyhan syndrome was the most frequent diagnosis (n = 3, cases 14–16) in this group. There were two cases (cases 18, 31) of pantothenate kinase‐associated neurodegeneration (PKAN), along with one case each of Canavan disease (case 27), Krabbe disease (case 17), fumarase deficiency (case 26), and biotin‐ and thiamine‐responsive basal ganglia disease (BTRBGD) (case 28), as well as GLUT1 deficiency syndrome (case 33). Developmental encephalopathies also played a significant role, with pathogenic variants detected in BCAP31 (n = 2, cases 23, 24), SLC16A2 (n = 1, case 21), and VPS41 (n = 1, case 30). Other diagnoses included FOXG1‐related disorder (n = 1, case 22), Rett syndrome due to variants in MECP2 (n = 1, case 25), and DiGeorge syndrome (n = 1, case 32). One patient had a pathogenic variant in ADCY5 (case 20), another had STXBP1‐related epileptic encephalopathy (case 19), and one presented with a channelopathy linked to ATP1A3 (case 29).
Of the 20 patients with symptom onset during infancy, 18 patients presented with GDD, while seven developed seizures over time. The majority did not acquire any communication skills and remained anarthic/aphonic. Most patients developed dystonia during infancy; in only three cases did dystonia emerge during early childhood. Most children presented with generalized dystonia, while four initially had segmental or multifocal dystonia that progressed to a generalized form over time. Two children (cases 20, 31) experienced recurrent episodes of status dystonicus.
In this age group, imaging findings were more specific to the underlying pathology. In a total of six patients the imaging findings were specific for the underlying diagnosis, for example white matter signal abnormalities were characteristic of leukodystrophies, while basal ganglia changes were observed in conditions such as BCAP31‐related disorder (case 24), PKAN (cases 18, 31), and BTRBGD (case 28).
Laboratory evaluation in one child with Allan‐Herndon‐Dudley (AHD) syndrome (case 21) revealed a disease‐specific thyroid profile, characterized by elevated triiodothyronine (T3), normal thyroid‐stimulating hormone (TSH), and reduced thyroxine (T4). This constellation is typical for AHD and reflects impaired thyroid hormone transport due to pathogenic variants in the SLC16A2 (MCT8) gene, resulting in central hypothyroidism with peripheral thyrotoxicosis. Other laboratory findings in this age group were not specific to the underlying diagnosis.
Five children underwent DBS implantation (cases 15, 16, 28, 30, 31), with mixed outcomes. Both children with Lesh‐Nyhan syndrome (cases 15, 16) had a positive initial response to GPi DBS with worsening of dystonia after some time. The child with BTRBGD (case 28) responded well to GPi DBS, so did the child with VPS41‐related disorder (case 30). The child with PKAN (case 31) had a good response of his dystonia to DBS, but worsened again after explantation due to hardware infection. The child with AHD (case 21) was treated with triiodothyroacetic acid (TRIAC), 9 a thyroid hormone analogue that mimics the action of T3, without clear neurological benefit.
The child with Canavan disease (case 27) underwent gene therapy with benefit regarding his alertness but no clear improvement of his dystonia or seizures.
Onset in Early Childhood (n = 17)
The most common disorders in this age group were etiologies that lead to developmental and neurodegenerative disorders (n = 9), followed by inborn errors of metabolism (n = 5). The first group included a disorder with regression, abnormal movements, anarthria and seizures (NEDAMSS, IRF2BPL variant, n = 1, case 34), neurodevelopmental disorder with eye movement abnormalities and ataxia (NEDEMA, FRMD5 variant, n = 1, case 39), KLHL20‐related neurodevelopmental disorder (n = 1, case 41), Rett syndrome (n = 2, cases 44, 45), Angelman syndrome (n = 2, cases 47, 48), KMT2B‐related dystonia (n = 1, case 38), and STXBP1‐related disorder (n = 1, case 40). Inborn errors of metabolism included mitochondrial myopathy, encephalopathy, lactic acidosis and stroke‐like episodes (MELAS, n = 1, case 42), COX15‐related mitochondrial disorder (n = 1, case 43), 10 and ALG3‐CDG (n = 1, case 49). Additionally, three cases of neurodegeneration with brain iron accumulation (NBIA) were identified: beta‐propeller protein‐associated neurodegeneration (BPAN, n = 2, cases 35, 36) and infantile neuroaxonal dystrophy (INAD, n = 2, case 37, 50). One patient was diagnosed with a GNB1‐related neurodevelopmental disorder (case 46).
In patients with early childhood symptom onset, only 10 developed language skills, seven experienced developmental regression including language skills and became anarthric/aphonic. Four patients initially presented with focal dystonia, which progressed to generalized dystonia.
MRI scans were available in 13 patients of which three were completely normal. Generalized brain atrophy was the most common finding (n = 8). Disease‐specific basal ganglia changes were found in the two NBIA cases. Generalized brain atrophy was the most common finding in eight cases. No disease‐specific laboratory findings were observed in this group.
Three children (cases 38, 41, 45) underwent DBS implantation (see Table S1). The children with KMT2B‐related disorder (case 38) and KLHL20‐related disorder (case 41) showed a stable course of dystonia after DBS implantation, the child with Rett syndrome (case 45) showed initial improvement with lack of response to DBS adjustments after a few years.
Onset in Late Childhood/Adolescence (n = 1)
This patient had a confirmed diagnosis of X‐linked adrenoleukodystrophy (X‐ALD). He presented at 8 years of age with progressive dystonia and anarthria. Brain MRI showed disease‐specific extensive white matter abnormalities with a Loes score of 14.5. Laboratory investigations revealed borderline adrenal insufficiency. The patient underwent bone marrow transplantation, but no neurological improvement was observed.
Onset in Adulthood (n = 3)
Two cases (cases 53, 54) were diagnosed with Wilson's disease with demonstrated variants in ATP7B and one case with neuronal ceroid lipofuscinosis (NCL) (case 52). Neurological symptoms included progressive generalized dystonia with dysarthria which progressed to anarthria, tremor and parkinsonism. MRI revealed SWI blooming and T2 hyperintensity in the basal ganglia, along with brainstem and cerebellar atrophy in the cases of Wilson's disease. Laboratory findings indicated hepatic involvement, and liver transplantation led to neurological improvement in one case. Treatment with D‐penicillamine resulted in deterioration, while transition to Zinc therapy was associated with partial recovery of motor function in the other case. DBS implantation was performed in the NCL case with improvement of cervical dystonia (See Table S1).
Discussion
This study presents a comprehensive analysis of the genetic causes of DAnAp in the largest lifespan cohort of pediatric and adult patients. We identified 39 distinct genetically confirmed disorders, highlighting the remarkable heterogeneity contributing to this complex clinical presentation, namely channelopathies, disorders of neurotransmitter synthesis, mitochondrial function, and transcriptional regulation, neurodevelopmental disorders, and inborn errors of metabolism. Importantly, anarthria/aphonia was not merely an associated feature but a core component of the clinical phenotype across this cohort, as reflected by the fact that the majority of patients in our cohort never acquired speech. 3
Most patients had symptom onset during the neonatal period, infancy, or early childhood (92.5% of cases), highlighting critical neurodevelopmental windows when genetic defects lead to significant motor and communication deficits. However, age at onset showed variability across disorders and several conditions may present earlier or later in life than observed in this cohort, therefore emphasizing that age of onset should be interpreted as a guiding diagnostic feature. Research has shown that neural circuit development occurs in two key stages: an early, genetically programmed phase and a later, activity‐dependent refinement phase. 11 Disruptions in neuronal development, function and structure during these stages can result in lasting motor impairments, potentially explaining the mechanisms underlying dystonia 12 and the profound difficulties with speech. Yet, it is unclear how mechanisms vary among genetic subtypes of dystonia, how they drive severe communication impairments like aphonia or anarthria and which developmental pathways are most at risk.
Neuroimaging findings in this cohort highlight the age‐dependent diagnostic utility of brain MRI in patients with dystonia and anarthria/aphonia. In neonates, nonspecific cerebral atrophy was common but often lacked diagnostic specificity. Imaging beyond the neonatal period became more informative, with infants and young children showing disease‐specific features such as white matter abnormalities in leukodystrophies, with for example diffuse, supratentorial T2 hyperintensities sparing the U‐fibers and parenchymal volume loss in the child with Krabbe disease (Fig. 1A). Basal ganglia involvement was notable in BCAP31‐related disease, presenting as bilateral putaminal T2 hyperintensity, the pathognomonic “eye‐of‐the‐tiger” sign in PKAN (Fig. 1D) and iron deposition on susceptibility imaging in the NBIA spectrum disorders. In the adult‐onset group, imaging changes typical of Wilson's disease were presented in the two patients with this diagnosis.
While the previously proposed diagnostic algorithm for patients with dystonia and anarthria/aphonia 3 remains a valuable framework that emphasizes neuroimaging as an initial step followed by genetic and metabolic investigations, our findings highlight the need to shift toward an age‐adapted, genomics‐driven approach. This is particularly relevant to neonatal and very early‐onset DAnAp, in which neuroimaging and metabolic investigations often yielded nonspecific findings, whereas the genetic spectrum was broad and included channelopathies and developmental encephalopathies. Clinical exome sequencing has markedly improved diagnostic precision in dystonia, particularly in childhood‐onset forms, and genome sequencing and reanalysis continues to increase diagnostic yield. 13 , 14 We therefore suggest prioritizing rapid genomic testing in very early‐onset cases, particularly where timely diagnosis may enable gene‐targeted or disease‐modifying therapy. By contrast, neuroimaging may have greater etiological discriminatory value in adult‐onset presentations, although confirmatory genetic testing and periodic reanalysis remain important across age groups.
Accompanying neurological features may further refine genomic interpretation and help prioritize candidate diagnoses. Examples include early‐onset seizures in channelopathies such as KCNQ2‐, SCN2A‐, and SCN1A‐related disorders; characteristic hand stereotypies, seizures, and developmental regression in Rett syndrome; and ataxia in CAMK4‐ or EARS2‐related disorders. Such clinical constellations can guide variant interpretation and selectively prompt complementary investigations, including neuroimaging or metabolic studies, for syndromic characterization. These associations are necessarily illustrative rather than exhaustive, given the marked phenotypic variability of DAnAp and the 39 distinct genetic conditions represented in our cohort.
Two children in our cohort received targeted gene therapy. The emergence and growing availability of gene‐targeted and disease‐modifying therapies reinforce the importance of early and accurate diagnosis in affected patients as these treatments are most effective when initiated early and may alter disease trajectories, survival, and quality of life. 15 In our cohort, disease‐modifying or gene therapies are available for three disorders: AADC deficiency treated with eladocagene exuparvovec (AAV2‐based gene therapy delivering a functional DDC gene), 8 Angelman syndrome with rugonersen (antisense oligonucleotide that unsilences the paternal UBE3A allele) 16 and Rett syndrome with trofinetide (synthetic analog of glycine‐proline‐glutamate). 17 Gene therapy on research basis is under investigation for Canavan disease. 18 These therapies are also likely to reshape the clinical presentation of the disorders, resulting in new phenotypes that require adjustments in management and care strategies in the future. 19
DBS of the globus pallidus internus (GPi) was performed in 12 patients (22%) for medically refractory dystonia, underscoring the severity of motor involvement in this population. Patients undergoing surgical intervention likely represent a subgroup with advanced and treatment‐resistant disease. Clinical outcomes following GPi DBS were heterogeneous, reflecting the broad range of underlying genetic etiologies. Consistent with prior work, response to GPi DBS in dystonia appears to be influenced by both etiology and clinical phenomenology. 20
Limitations of this study include its retrospective design, which introduces the possibility of missing or incomplete data, particularly the severity of dystonia or aphonia/anarthria and the exact phenomenological presentation of dystonia could not always be thoroughly assessed. The long inclusion period also introduces a partial reporting bias, as earlier cases may not have undergone comprehensive genetic testing, potentially missing variants in more recently identified genes. Additionally, the cohort was drawn from two tertiary care centers (The Hospital for Sick Children and Toronto Western Hospital), potentially introducing selection bias favoring more severe or diagnostically challenging cases. Finally, this study was restricted to patients with a confirmed genetic diagnosis and therefore does not capture the full clinical spectrum of DAnAp, including acquired or genetically unresolved cases.
Our findings highlight the profound genetic and clinical heterogeneity underlying DAnAp, with most cases presenting in early childhood. The potential for life‐altering or life‐limiting disease courses, especially as gene‐targeted therapy strategies emerge, underscores the need for early, accurate diagnosis.
Genetic testing should be prioritized in neonatal‐onset cases, as neuroimaging is often nonspecific early on but becomes more informative with age. In resource‐limited settings, familiarity with gene–phenotype and imaging correlations remains essential to guide clinical decisions.
Author Roles
(1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique.
A.M.: 1A, 1B, 1C, 3A.
E.R.: 1A, 1C.
M.E.A.: 1A, 1C.
S.H.F.: 3B.
A.E.L.: 3B.
G.M.I.: 3B.
Ca.Go.: 1A, 3B.
Ch.Ga.: 1A, 3B.
Disclosures
Ethical Compliance Statement: This study was approved by the Research Ethics Board (REB) of The Hospital for Sick Children (REB No. 1000081661; approved June 2024) and by the University Health Network (UHN) Research Ethics Board (CAPCR ID 24‐5646; approved November 2024). Both REBs granted a waiver of informed consent due to the retrospective design of the study and the use of de‐identified data. Informed patient consent was therefore not required for this work. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.
Financial Disclosures and Conflicts of Interest: Author disclosures are available in the Supporting Information.
Supporting information
TABLE S1. Clinical information of the cohort. Detailed clinical, genetic, neuroradiological, treatment and outcome data for all 54 included patients with dystonia and anarthria/aphonia. Patients are grouped according to age at onset of neurological symptoms.
Data S1. Supporting information.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
TABLE S1. Clinical information of the cohort. Detailed clinical, genetic, neuroradiological, treatment and outcome data for all 54 included patients with dystonia and anarthria/aphonia. Patients are grouped according to age at onset of neurological symptoms.
Data S1. Supporting information.
Data Availability Statement
De‐identified individual participant data that support the findings of this study, as well as related study documentation, will be made available upon reasonable request from qualified investigators for purposes of replicating procedures and results. Requests will be reviewed by the corresponding author.
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.