BACKGROUND:Spinocerebellar ataxia type 3 (SCA3), the most common autosomal dominant ataxia, is driven by the accumulation of polyglutamine-expanded (polyQ) ATXN3 proteins. While promising as biomarkers, their longitudinal trajectories across multiple biofluids remain poorly defined. OBJECTIVES:To quantify polyQ ATXN3 levels in cerebrospinal fluid (CSF), plasma, and urine within a comprehensive cohort, utilizing serial measurements to map protein dynamics. METHODS:We employed a validated immunoassay to quantify polyQ ATXN3 in 97 symptomatic and 13 presymptomatic SCA3 patients, correlating levels with clinical features, ancestry, disease status, and longitudinal progression. RESULTS:Asian participants exhibited lower plasma but elevated urinary polyQ ATXN3 levels relative to other ancestries. While CSF levels were higher in symptomatic patients at baseline, they showed a significant longitudinal decline. CONCLUSIONS:PolyQ ATXN3 is a viable multi-biofluid biomarker. Declining CSF levels likely reflect neurodegeneration, supporting its role in tracking progression and emphasizing the need for ancestry-based adjustment in trials. © 2026 International Parkinson and Movement Disorder Society.

Background Whether the traditional distinction between segmental and multifocal dystonia is clinically or scientifically useful remains unclear.Objective To evaluate whether idiopathic isolated adult-onset segmental and multifocal dystonia can be differentiated based on clinical features other than the contiguity of affected body regions.Methods We compared data on segmental and multifocal dystonia from two large dystonia databases established in the USA and Italy that used similar criteria for patient recruitment and assessment.Results Compared to segmental dystonia, multifocal dystonia was characterized by a higher proportion of men, a younger age at dystonia onset, a greater frequency of upper limb dystonia, and a lower frequency of cranial dystonia at both onset and last examination. Segmental and multifocal dystonia had a similar frequency of alleviating maneuvers, non-motor eye symptoms in blepharospasm, and neck pain and tremor in cervical dystonia. Although the initial spread pattern from focal to segmental or multifocal appeared faster in the segmental dystonia group, adjusting the analysis for the initial body site involved revealed no significant differences between the two groups. Segmental and multifocal dystonia starting in the same body site showed similar age, sex, and spread characteristics. The observed differences and similarities were consistent across both independent databases.Conclusions Segmental and multifocal dystonia share differences and similarities. The observed differences may reflect a difference in the predominant site of dystonia onset. From a clinical perspective, therefore, the segmental/multifocal distinction is probably not valuable in the dystonia classification scheme, although further data may be needed from a pathophysiological perspective.

OBJECTIVE:Dystonia is one of the most prevalent movement disorders, characterized by significant clinical and etiological heterogeneity. Despite considerable heritability (~25%), the etiology in most patients remains elusive. Moreover, understanding correlations between clinical manifestations and genetic variants has become increasingly complex. METHODS:Exome sequencing was conducted on 1924 genetically unsolved, mainly late-onset isolated dystonia patients, recruited primarily from two dystonia registries (DysTract and the Dystonia Coalition). Rare variants in genes previously linked to dystonia (n = 406) were examined, confirmed via Sanger sequencing, and analyzed for segregation when possible. RESULTS:We identified 137 distinct likely pathogenic/pathogenic variants (according to ACMG criteria) across 51 genes in 163/1924 patients, including 153/1895 index patients (diagnostic yield 8.1%). The strongest predictors of a genetic diagnosis were generalized dystonia (28.6% yield) and age at onset (20.4% yield in patients with onset < 30 years). Notably, 56.2% of these variants were novel, with recurrent variants in EIF2AK2, VPS16, KCNMA1, and SLC2A1. Additionally, 321 index patients (16.9%) harbored variants of uncertain significance in 102 genes. The most frequently implicated genes included VPS16, THAP1, GCH1, SGCE, GNAL, and KMT2B. Presumably pathogenic variants in less well-established dystonia genes were also found, including KCNMA1, KIF1A, and ZMYND11. At least six variants (in ADCY5, GNB1, IR2BPL, KCNN2, KMT2B, and VPS16) occurred de novo, supporting pathogenicity. INTERPRETATION:This study provides valuable insights into the genetic landscape of dystonia, underscores the utility of exome sequencing for diagnosis, substantiates several candidate genes, and expands the phenotypic spectrum of some genes to include prominent, sometimes isolated dystonia.

Homeostatic plasticity is essential for information processing and the stability of neuronal circuits, however its relevance to neuropsychiatric disorders remains unclear. The 16p11.2 duplication (BP4-BP5) is a genetic risk factor that strongly predisposes to a range of severe mental illnesses including autism, schizophrenia, intellectual disability, and epilepsy. The duplication consists of a 600 kb region on chromosome 16, including 27 protein-coding genes, with poorly defined effects on neuronal structure and function. Here, we used a mouse model of the 16p11.2 duplication to investigate the impact of this variant on synaptic structure and downstream homeostatic plasticity. We find that 16p11.2 duplication neurons exhibit overly branched dendritic arbors and excessive spine numbers, which host an overabundance of surface AMPA receptor subunit GluA1. Using a homeostatic plasticity paradigm, we show that 16p11.2 duplication neurons fail to undergo synaptic upscaling upon activity deprivation, consistent with disrupted structural plasticity. We also observe that the increased surface abundance of GluA1 occludes further insertion events, a critical mechanism for synaptic plasticity. Finally, we show that genetically correcting the dosage of 16p11.2-encoded Prrt2 to wild-type levels rescues structural spine phenotypes. Our work suggests that aberrant plasticity could contribute to the etiology of neuropsychiatric disorders.

Heterozygous loss-of-function GNAL mutations are one established cause of isolated dystonia and hyposmia. Homozygous GNAL mutations have been reported in siblings with generalized dystonia and intellectual disability. GNAL encodes major [NM_001369387.1; Gα(olf)] and long [NM_182978.4; XLGα(olf)] isoforms. In striatal medium spiny neurons, dopamine D1 receptors and adenosine A2a receptors are coupled to adenylyl-cyclase through a heterotrimeric G-protein complex composed of Gα(olf), Gβ2, and Gγ7 subunits. In the cerebellum, Gα(olf) colocalizes with cell-surface corticotropin-releasing factor receptors (CRF-RI/II) which take part in climbing fiber signaling. In contrast, XLGα(olf) may take part in cell-cycle control and development. In situ hybridization (ISH) showed that XLGα(olf) mRNA was more broadly distributed in mouse brain than Gα(olf) mRNA. In the cerebellum, XLGα(olf) mRNA was seen in all layers of cerebellar cortex while Gα(olf) mRNA was mainly limited to Purkinje cells. Gα(olf) showed higher expression than XLGα(olf) in the olfactory bulb and striatum, and lower expression than XLGα(olf) in cerebral cortex, cerebellar cortex, and hippocampus. Dysregulated genes identified in Gnal +/- mouse brain contribute to signaling (Slc5a7, Cbln2, Glra3, Rtn4rl2), anatomical structure development including dendritogenesis (Slc5a7, Cbln2, Glra3, Rtn4rl2, XLr3b, Mmp12, Rtn4rl2, Cd74, Kirrel2), and DNA-templated transcription (Lhx9, Basp1, Mmp12, Cd74). Analyses of ClinVar and gnomAD databases suggest that highly deleterious GNAL variants isolated to Exon 1 of the long isoform are less likely to be pathogenic than those isolated to Exon 1 of the major isoform. This work forms a platform for continued study of Gα(olf) and XLGα(olf) in dystonia, hyposmia, and intellectual disability.

Background and ObjectivesASPEN-1 was a phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy, duration of response, and safety of 2 doses of DaxibotulinumtoxinA for Injection (DAXI), a novel botulinum toxin type A formulation in participants with cervical dystonia (CD).MethodsAdults (aged 18–80 years) with moderate-to-severe CD (Toronto Western Spasmodic Torticollis Rating Scale [TWSTRS] total score ≥20) were enrolled at 60 sites across 9 countries in Europe and North America. Participants were randomized (3:3:1) to single-dose intramuscular DAXI 125U, 250U, or placebo and followed for up to 36 weeks after injection. The primary end point was change from baseline in TWSTRS total score averaged across weeks 4 and 6. Key secondary end points included duration of effect, Clinical and Patient Global Impression of Change (CGIC, PGIC), TWSTRS subscale scores, and safety. Multiplicity-adjusted intent-to-treat hypothesis tests with multiple imputation were performed using ANCOVA and Cochran-Mantel-Haenszel analyses.ResultsOf 444 individuals screened, 301 were randomized to DAXI 125U (n = 125) or 250U (n = 130) or placebo (n = 46). DAXI 125U and 250U significantly improved the mean TWSTRS total score vs placebo (least squares mean [standard error] difference vs placebo: DAXI 125U, −8.5 [1.93], p < 0.0001; DAXI 250U, −6.6 [1.92], p = 0.0006). The median duration of effect (time from treatment until loss of ≥80% of the peak improvement in average TWSTRS total score achieved at weeks 4 and 6) was 24.0 (95% confidence interval 20.3–29.1) weeks with DAXI 125U and 20.3 (16.7–24.0) weeks with DAXI 250U. Significant improvements were also observed with DAXI in CGIC and PGIC responder rates and TWSTRS subscales. Treatment-related treatment-emergent adverse events (TEAEs) were reported by 29.6% of participants with DAXI 125U, 23.8% with DAXI 250U, and 17.4% with placebo, with injection site pain being the most common overall. The most frequently reported treatment-related TEAEs of interest in DAXI 125U, DAXI 250U, and placebo, respectively, were muscular weakness (4.8%, 2.3%, 0%), musculoskeletal pain (2.4%, 3.1%, 0%), and dysphagia (1.6%, 3.8%, 0%).DiscussionThis study demonstrated that DAXI, at doses of 125U and 250U, is an effective, safe, long-acting, and well-tolerated treatment for CD.Trial Registration InformationClinicalTrials.gov identifier (NCT03608397, submitted July 11, 2018) and EU Clinical Trials Register (ClinicalTrialsRegister.eu EudraCT identifier 2018-000446-19, submitted September 13, 2018). First participant enrolled on June 11, 2018. Trial registration was performed in accordance with the Food and Drug Administration Amendments Act (FDAAA 801), which stipulates that the responsible party register an applicable clinical trial not later than 21 calendar days after enrolling the first human participant (42 CFR 11.24).Classification of EvidenceThis study provides Class I evidence that in adults with moderate-to-severe idiopathic cervical dystonia, DAXI reduces dystonia more effectively than placebo.

Background: Cervical dystonia (CD) is the most common form of focal dystonia encountered in the clinic. Approximately one-third of CD patients have co-existing tremor in the head and hands. Assessment of tremor as regular or irregular in context of its oscillation trajectory, frequency, and amplitude is a major clinical challenge and can confound the diagnosis of CD. The misdiagnosis may lead to therapeutic failures, poor quality of life, and poor utilization of medical and financial resources.Methods: We analyzed the largest cohort of CD patients (n = 3117) available to date, collected from 37 movement disorder centers in North America, Europe, and Asia. We used machine learning to determine what clinical features from clinician reports predicted the presence of tremor as well as its regular or irregular appearance.Results: Out of 3,117 CD patients, 1,367 had neck tremor. The neck tremor was interpreted as irregular in 1,022, regular in 345, and mixed (both irregular and regular) in 442. A feature importance analysis determined that greater severity of CD, longer disease duration, and older age, in descending order, predicted the presence of neck tremor. The probability of neck tremor was reduced if the dystonia affected other body parts in addition to the neck. We also found a significantly heightened risk for developing neck tremor in women. An additional feature importance analysis indicated that increased severity of dystonia affecting other body parts, severity of CD, and prolonged disease duration was associated with a lower likelihood of regular neck tremor while increased age predicted a higher likelihood.Conclusion: Machine learning recognized the most relevant clinical features that can predict concurrent neck tremor and its irregularity in a large multi-center dystonia cohort. These results may facilitate a more accurate description of neck tremor and improved care path in CD.

Introduction: In preceding work, a deleterious REEP4 variant [GRCh38/hg38, NC_000008.11:g.22140245G>A, NM_025232.4:c.109C>T, p.Arg37Trp] was found to co-segregate with blepharospasm (BSP) in a large African-American pedigree. Other REEP4 variants have been reported in genetic screening studies of dystonia. The REEP4 paralogs, REEP1 and REEP2, are associated with spastic paraplegia. The causal contributions of REEP4 variants to dystonia and other neurological disorders remains indecisive.Methods: Sanger sequencing was used to screen subjects (N = 307) with BSP and BSP-plus dystonia affecting additional anatomical segments (BSP+) phenotypes for variants in REEP4. In silico tools were used to examine the deleteriousness of reported (ClinVar) and previously published REEP4 variants.Results: No highly deleterious variant was identified in coding or contiguous splice site regions of REEP4 in our cohort of 307 subjects. In silico analysis identified numerous deleterious REEP4 variants in published screening studies of dystonia and several highly deleterious single nucleotide REEP4 variants in ClinVar.Conclusion: Highly deleterious REEP4 variants are rare in BSP and BSP+ phenotypes.

Background:Despite considerableheritability, previous smaller genome-wide associationstudies (GWASs) have not identified any robustgenetic risk factors for isolated dystonia.Objective:The objective of this study was to perform alarge-scale GWAS in a well-characterized, multicenter sample of >6000 individuals to identify genetic risk fac-tors for isolated dystonia. Methods:Array-based GWASs were performed onautosomes for 4303 dystonia participants and 2362healthy control subjects of European ancestry with sub-group analysis based on age at onset, affected bodyregions, and a newly developed clinical score. Another736 individuals were used for validation. Results:This GWAS identified no common genome-wide significant loci that could be replicated despitesufficient power to detect meaningful effects. Poweranalyses imply that the effects of individual variantsare likely very small. Conclusions:Moderatesingle-nucleotidepolymor-phism-based heritability indicates that common variantsdo not contribute to isolated dystonia in this cohort.Sequence-basedGWASs(eg,bywhole-genome sequencing) might help to better understand the geneticbasis. (c) 2024 The Author(s).Movement Disorderspubli-shed by Wiley Periodicals LLC on behalf of InternationalParkinson and Movement Disorder Society.

Due to financial constraints, a patient with Wilson disease required transitioning his maintenance pharmacotherapy from zinc acetate to zinc gluconate. Herein, we report the clinical and laboratory outcomes of this switch and review the relevant literature on the treatment of Wilson disease with zinc. Zinc gluconate can be a viable treatment option for patients with Wilson disease and may be associated with fewer gastrointestinal side effects than zinc acetate and, accordingly, improved long-term compliance and improved clinical outcomes.

BACKGROUND:Prior studies have indicated that female individuals outnumber male individuals for certain types of dystonia. Few studies have addressed factors impacting these sex differences or their potential biological mechanisms. OBJECTIVES:To evaluate factors underlying sex differences in the dystonias and explore potential mechanisms for these differences. METHODS:Data from individuals with various types of dystonia were analyzed in relation to sex. Data came from two different sources. One source was the Dystonia Coalition database, which contains predominantly idiopathic adult-onset focal and segmental dystonias. The second source was the MDSGene database, which contains predominantly early-onset monogenic dystonias. RESULTS:The 3222 individuals from the Dystonia Coalition included 71% female participants and 29% male participants for an overall female-to-male ratio (F:M) of 2.4. This ratio varied according to body region affected and whether dystonia was task-specific. The female predominance was age-dependent. Sex did not have a significant impact on co-existing tremor, geste antagoniste, depression or anxiety. In the 1377 individuals from the MDSGene database, female participants outnumbered male participants for some genes (GNAL, GCH1, and ANO3) but not for other genes (THAP1, TH, and TOR1A). CONCLUSIONS:These results are in keeping with prior studies that have indicated female individuals outnumber male individuals for both adult-onset idiopathic and early onset monogenic dystonias. These results extend prior observations by revealing that sex ratios depend on the type of dystonia, age, and underlying genetics.

Polymerase I (Pol I) is at the epicenter of ribosomal RNA (rRNA) synthesis. Pol I is a target for the treatment of cancer. Given the many cellular commonalities between cancer and neurodegeneration (i.e., different faces of the same coin), it seems rational to consider targeting Pol I or, more generally, rRNA synthesis for the treatment of disorders associated with the death of terminally differentiated neurons. Principally, ribosomes synthesize proteins, and, accordingly, Pol I can be considered the starting point for protein synthesis. Given that cellular accumulation of abnormal proteins such as α-synuclein and tau is an essential feature of neurodegenerative disorders such as Parkinson disease and fronto-temporal dementia, reduction of protein production is now considered a viable target for treatment of these and closely related neurodegenerative disorders. Abnormalities in polymerase I activity and rRNA production may also be associated with nuclear and nucleolar stress, DNA damage, and childhood-onset neuronal death, as is the case for the UBTF E210K neuroregression syndrome. Moreover, restraining the activity of Pol I may be a viable strategy to slow aging. Before starting down the road of Pol I inhibition for treating non-cancerous disorders of the nervous system, many questions must be answered. First, how much Pol I inhibition can neurons tolerate, and for how long? Should inhibition of Pol I be continuous or pulsed? Will cells compensate for Pol I inhibition by upregulating the number of active rDNAs? At present, we have no effective and safe disease modulatory treatments for Alzheimer disease, α-synucleinopathies, or tauopathies, and novel therapeutic targets and approaches must be explored.

ABSTRACT Background There are several widely used clinical rating scales for documenting the severity and distribution of various types of dystonia. Objectives The goal of this study was to evaluate the performance of the most commonly used scales in a large group of adults with the most common types of isolated dystonia. Methods Global Dystonia Rating Scale (GDRS) and the Burke‐Fahn‐Marsden Dystonia Rating Scale (BFM) scores were obtained for 3067 participants. Most had focal or segmental dystonia, with smaller numbers of multifocal or generalized dystonia. These scales were also compared for 209 adults with cervical dystonia that had Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) scores and 210 adults with blepharospasm that had Blepharospasm Severity Scale (BSRS) scores. Results There were strong correlations between the GDRS and BFM total scores ( r = 0.79) and moderate correlations for their sub scores ( r > 0.5). Scores for both scales showed positive skew, with an overabundance of low scores. BFM sub‐scores were not normally distributed, due to artifacts caused by the provoking factor. Relevant sub‐scores of the GDRS and BFM also showed moderate correlations with the TWSTRS ( r > 0.5) for cervical dystonia and the BSRS ( r > 0.5) for blepharospasm. Conclusions The BFM is more widely used than the GDRS, but these results suggest the GDRS may be preferable for focal and segmental dystonias. The overabundance of very low scores for both scales highlights challenges associated with discriminating very mild dystonia from other abnormal movements or variants of normal behavior.

Most commonly, hemichorea associated with nonketotic and ketotic hyperglycemia resolves with normalization of blood glucose. Herein, we present a case of hyperosmolar hyperglycemic left hemichoreoathetosis-hemidystonia that has persisted for over 1 year. The subject presented to the emergency room with dysarthria and manifested left hemichoreoathetosis-hemidystonia within 36 h of admission. Initial computed tomography (CT) showed hyperdensity in the right putamen and left caudate. Magnetic resonance imaging (MRI) showed T1 hyperintensity within the right putamen. Failure to detect these classic imaging abnormalities during hospitalization resulted in a delayed etiologic diagnosis. Modest symptomatic improvement in the severity of hemichoreoathetosis-hemidystonia has been noted with low dose tetrabenazine.

Background: Genetic factors have been implicated in the pathogenesis of blepharospasm (BSP), a dystonia characterized by excessive blinking and involuntary eyelid closure.Previous research identified a co-segregating deleterious TOR2A variant (GRCh38/hg38, NC_000009.12:g.127733410G>A, NM_001085347.3:c.568C>T,p. Arg190Cys) in three subjects with BSP and three carriers within a multi-generation pedigree.Other TOR2A variants have been reported in patients with dystonia.Methods: Sanger sequencing was used to screen a cohort of 307 subjects with isolated BSP or BSP-plus dystonia affecting additional anatomical segments (BSP+).We also utilized computational tools to uniformly assess the deleteriousness and potential pathogenicity of previously reported TOR2A variants.Results: There were no highly deleterious TOR2A variants in the coding or contiguous splice site regions of TOR2A within our cohort of 307 subjects.Discussion: Highly deleterious variants in TOR2A are rare in patients with BSP/BSP+ phenotypes. Highlights:Over 300 patients with BSP were screened for variants in TOR2A, a TOR1A (DYT1) homologue.No highly deleterious variants were identified in our cohort.The role of TOR2A in BSP and other forms of dystonia remains indeterminant.

Neuropsychiatric disorders (NPDs) are frequently co-morbid with epilepsy, but the biological basis of shared risk remains poorly understood. The 16p11.2 duplication is a copy number variant that confers risk for diverse NPDs including autism spectrum disorder, schizophrenia, intellectual disability and epilepsy. We used a mouse model of the 16p11.2 duplication (16p11.2dup/+) to uncover molecular and circuit properties associated with this broad phenotypic spectrum, and examined genes within the locus capable of phenotype reversal. Quantitative proteomics revealed alterations to synaptic networks and products of NPD risk genes. We identified an epilepsy-associated subnetwork that was dysregulated in 16p11.2dup/+ mice and altered in brain tissue from individuals with NPDs. Cortical circuits from 16p11.2dup/+ mice exhibited hypersynchronous activity and enhanced network glutamate release, which increased susceptibility to seizures. Using gene co-expression and interactome analysis, we show that PRRT2 is a major hub in the epilepsy subnetwork. Remarkably, correcting Prrt2 copy number rescued aberrant circuit properties, seizure susceptibility and social deficits in 16p11.2dup/+ mice. We show that proteomics and network biology can identify important disease hubs in multigenic disorders, and reveal mechanisms relevant to the complex symptomatology of 16p11.2 duplication carriers.

The UBTF E210K neuroregression syndrome is a predominantly neurological disorder caused by recurrent de novo dominant variants in Upstream Binding Factor, that is, essential for transcription of the ribosomal RNA genes. This unusual form of ribosomopathy is characterized by a slow decline in cognition, behavior, and sensorimotor functioning during the critical period of development. UBTF (or UBF) is a multi-HMGB-box protein that acts both as an epigenetic factor to establish "open" chromatin on the ribosomal genes and as a basal transcription factor in their RNA Polymerase I transcription. Here we review the possible mechanistic connections between the UBTF variants, ribosomal RNA gene transcription and the neuroregression syndrome, and suggest that DNA topology may play an important role.

Medical students are taught that an exacting neurologic examination is the cornerstone of neurology and permits lesion localization in the nervous system. This is certainly the case for bitemporal hemianopsia, with lesions of the optic chiasm and discreet sensorimotor deficits with compressive neuropathies in the peripheral nervous system. In the CNS, classically and most commonly, the tetrad of dyscalculia, dysgraphia, finger agnosia, and left-right disorientation (Gerstmann syndrome) is associated with damage to the angular and supramarginal gyri of the dominant hemisphere. Also classically, but often incorrectly, involuntary movements such as dystonia, tremor, chorea, ballism, athetosis, dyskinesia, and tics are linked to dysfunction of the basal ganglia. In this issue of Neurology ®, Ekmen et al.1 used voxel-based morphometry, fixel-based analysis, and spectral dynamic causal modeling in a well-defined cohort of patients with paroxysmal kinesigenic dyskinesias (PKD) due to mutations in PRRT2 to provide rigorous support for the concept that abnormal cerebellar output can drive dystonia. Dystonia was the sole involuntary movement in this PKD cohort. Patients with PRRT2 had decreased gray matter volume in cerebellar lobule V and medial prefrontal cortex, as well as microstructural alterations of white matter in the cerebellum and tracts connecting the cerebellum to the striatum and cortical motor areas. On the basis of these structural findings in combination with the results of transcranial magnetic stimulation of the cerebellum and spectral dynamic causal modeling, the authors propose that striatal dysfunction in PKD results from upstream abnormalities of cerebellar signaling.

Transcription of the ~200 mouse and human ribosomal RNA genes (rDNA) by RNA Polymerase I (RPI/PolR1) accounts for 80% of total cellular RNA, around 35% of all nuclear RNA synthesis, and determines the cytoplasmic ribosome complement. It is therefore a major factor controlling cell growth and its misfunction has been implicated in hypertrophic and developmental disorders. Activation of each rDNA repeat requires nucleosome replacement by the architectural multi-HMGbox factor UBTF to create a 15.7 kbp nucleosome free region (NFR). Formation of this NFR is also essential for recruitment of the TBP-TAFI factor SL1 and for preinitiation complex (PIC) formation at the gene and enhancer-associated promoters of the rDNA. However, these promoters show little sequence commonality and neither UBTF nor SL1 display significant DNA sequence binding specificity, making what drives PIC formation a mystery. Here we show that cooperation between SL1 and the longer UBTF1 splice variant generates the specificity required for rDNA promoter recognition in cell. We find that conditional deletion of the TAF1B subunit of SL1 causes a striking depletion of UBTF at both rDNA promoters but not elsewhere across the rDNA. We also find that while both UBTF1 and -2 variants bind throughout the rDNA NFR, only UBTF1 is present with SL1 at the promoters. The data strongly suggest an induced-fit model of RPI promoter recognition in which UBTF1 plays an architectural role. Interestingly, a recurrent UBTF-E210K mutation and the cause of a pediatric neurodegeneration syndrome provides indirect support for this model. E210K knock-in cells show enhanced levels of the UBTF1 splice variant and a concomitant increase in active rDNA copies. In contrast, they also display reduced rDNA transcription and promoter recruitment of SL1. We suggest the underlying cause of the UBTF-E210K syndrome is therefore a reduction in cooperative UBTF1-SL1 promoter recruitment that may be partially compensated by enhanced rDNA activation.