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While the drug development literature provides numerous estimates of the financial costs to bring a new drug to market, the investment of patient-participants in the research process has not been described. Trial participants and their caregivers, like companies, invest time and undertake risk when they participate in prelicense trials. We determined the average number of patient-participants needed to develop a novel neurological drug. We created a cohort of 108 unapproved drugs first tested for efficacy between 2006 and 2011 and used ClinicalTrials.gov to capture enrollment in all subsequent prelicense trials of these drugs over a 9-year period. Our primary outcome was the average number of patients enrolled in prelicense neurological drug trials per drug that ultimately attained FDA approval, including patients who participated in both successful and unsuccessful development efforts. Five drugs (4.6%) were FDA approved, and 66,751 patient-participants were enrolled across successful and unsuccessful drug development efforts, resulting in an average of 13,350 patients for each drug attaining approval (95% CI 7155 to 54,954). Our estimates reveal the substantial amount patients and their caregivers contribute to private drug development.

To determine the prevalence of dystonia in individuals with periventricular leukomalacia (PVL) and spastic cerebral palsy (CP), but without basal ganglia and thalamic injury (BGTI) on brain magnetic resonance imaging (MRI).This was a retrospective study of individuals with spastic CP and PVL on MRI evaluated between 2005 and 2018 in a CP center. Individuals with non-PVL brain lesions on MRI, including BGTI, were excluded. Dystonia was assessed via blinded review of neurological exam videos by pediatric movement disorders specialists.Eighty-five participants (45 males, 40 females; mean age at videotaping 12 years [standard deviation 5 years 6 months], range 4-26 years) met inclusion and exclusion criteria. Of these participants, 50 (59%) displayed dystonia in their exam videos. The most common locations of dystonia were the fingers and hip adductors. The prevalence of dystonia was unaffected by the gestational age or severity of PVL, and was affected by Gross Motor Function Classification System level.Dystonia is common in individuals with spastic CP and PVL, even without BGTI on MRI. Our findings suggest vigilance for dystonia in individuals with spastic CP should remain high, even without MRI evidence of BGTI.Individuals with spastic cerebral palsy and isolated periventricular leukomalacia on magnetic resonance imaging commonly display dystonia. Common sites of dystonia are in the fingers and hip adductors.

TARS2 encodes human mitochondrial threonyl tRNA-synthetase that is responsible for generating mitochondrial Thr-tRNAThr and clearing mischarged Ser-tRNAThr during mitochondrial translation. Pathogenic variants in TARS2 have hitherto been reported in a pair of siblings and an unrelated patient with an early onset mitochondrial encephalomyopathy and a combined respiratory chain enzyme deficiency in muscle. We here report five additional unrelated patients with TARS2-related mitochondrial diseases, expanding the clinical phenotype to also include epilepsy, dystonia, hyperhidrosis and severe hearing impairment. In addition, we document seven novel TARS2 variants—one nonsense variant and six missense variants—that we demonstrate are pathogenic and causal of the disease presentation based on population frequency, homology modeling and functional studies that show the effects of the pathogenic variants on TARS2 stability and/or function.

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare genetic disorder characterized by deficient synthesis of dopamine and serotonin. It presents in early infancy, and causes severe developmental disability and lifelong motor, behavioral, and autonomic symptoms including oculogyric crises (OGC), sleep disorder, and mood disturbance. We investigated the safety and efficacy of delivery of a viral vector expressing AADC (AAV2-hAADC) to the midbrain in children with AADC deficiency (ClinicalTrials.gov Identifier NCT02852213). Seven (7) children, aged 4–9 years underwent convection-enhanced delivery (CED) of AAV2-hAADC to the bilateral substantia nigra (SN) and ventral tegmental area (VTA) (total infusion volume: 80 µL per hemisphere) in 2 dose cohorts: 1.3 × 1011 vg (n = 3), and 4.2 × 1011 vg (n = 4). Primary aims were to demonstrate the safety of the procedure and document biomarker evidence of restoration of brain AADC activity. Secondary aims were to assess clinical improvement in symptoms and motor function. Direct bilateral infusion of AAV2-hAADC was safe, well-tolerated and achieved target coverage of 98% and 70% of the SN and VTA, respectively. Dopamine metabolism was increased in all subjects and FDOPA uptake was enhanced within the midbrain and the striatum. OGC resolved completely in 6 of 7 subjects by Month 3 post-surgery. Twelve (12) months after surgery, 6/7 subjects gained normal head control and 4/7 could sit independently. At 18 months, 2 subjects could walk with 2-hand support. Both the primary and secondary endpoints of the study were met. Midbrain gene delivery in children with AADC deficiency is feasible and safe, and leads to clinical improvements in symptoms and motor function., Aromatic L-amino acid decarboxylase deficiency (AADC) is a rare neurodevelopmental disorder. Here the authors describe a clinical trial of MR-guided delivery of AAV2-AADC for the treatment of AADC.

OBJECTIVE: Glycine encephalopathy, also known as nonketotic hyperglycinemia (NKH), is an inherited neurometabolic disorder with variable clinical course and severity, ranging from infantile epileptic encephalopathy to psychiatric disorders. A precise phenotypic characterization and an evaluation of predictive approaches are needed. METHODS: Longitudinal clinical and biochemical data of 25 individuals with NKH from the patient registry of the International Working Group on Neurotransmitter Related Disorders were studied with in silico analyses, pathogenicity scores, and molecular modeling of GLDC and AMT variants. RESULTS: Symptom onset (p < 0.01) and diagnosis occur earlier in life in severe NKH (p < 0.01). Presenting symptoms affect the age at diagnosis. Psychiatric problems occur predominantly in attenuated NKH. Onset age = 3 months (66% specificity, 100% sensitivity, area under the curve [AUC] = 0.87) and cerebrospinal fluid (CSF)/plasma glycine ratio = 0.09 (57% specificity, 100% sensitivity, AUC = 0.88) are sensitive indicators for attenuated NKH, whereas CSF glycine concentration = 116.5µmol/l (100% specificity, 93% sensitivity, AUC = 0.97) and CSF/plasma glycine ratio = 0.15 (100% specificity, 64% sensitivity, AUC = 0.88) are specific for severe forms. A ratio threshold of 0.128 discriminates the overlapping range. We present 10 new GLDC variants. Two mild variants resulted in attenuated, whereas 2 severe variants or 1 mild and 1 severe variant led to severe phenotype. Based on clinical, biochemical, and genetic parameters, we propose a severity prediction model. INTERPRETATION: This study widens the phenotypic spectrum of attenuated NKH and expands the number of pathogenic variants. The multiparametric approach provides a promising tool to predict disease severity, helping to improve clinical management strategies. ANN NEUROL 2022.

ObjectiveTo contextualize the role of child neurologists and neurodevelopmentalists (CNs/NDDs) in cerebral palsy (CP) care, we review the changing landscape of CP diagnosis and survey stakeholder CNs/NDDs regarding their roles in CP care.MethodsThe optimal roles of the multiple specialties involved in CP care are currently unclear, particularly regarding CP diagnosis. We developed recommendations regarding the role of CNs/NDDs noting (1) increasing complexity of CP diagnosis given a growing number of genetic etiologies and treatable motor disorders that can be misdiagnosed as CP and (2) the views of a group of physician stakeholders (CNs/NDDs from the Child Neurology Society Cerebral Palsy Special Interest Group).ResultsCNs/NDDs felt that they were optimally suited to diagnose CP. Many (76%) felt that CNs/NDDs should always be involved in CP diagnosis. However, 42% said that their patients with CP were typically not diagnosed by CNs/NDDs, and 18% did not receive referrals to establish the diagnosis of CP at all. CNs/NDDs identified areas of their expertise critical for CP diagnosis including knowledge of the neurologic examination across development and early identification of features atypical for CP. This contrasts with their views on CP management, where CNs/NDDs felt that they could contribute to the medical team, but were necessary primarily when neurologic coexisting conditions were present.DiscussionGiven its increasing complexity, we recommend early referral for CP diagnosis to a CN/NDD or specialist with comparable expertise. This contrasts with current consensus guidelines, which either do not address or do not recommend specific specialist referral for CP diagnosis.

Inherited disorders of neurotransmitter metabolism are a group of rare diseases, which are caused by impaired synthesis, transport, or degradation of neurotransmitters or cofactors and result in various degrees of delayed or impaired psychomotor development. To assess the effect of neurotransmitter deficiencies on intelligence, quality of life, and behavior, the data of 148 patients in the registry of the International Working Group on Neurotransmitter Related Disorders (iNTD) was evaluated using results from standardized age-adjusted tests and questionnaires. Patients with a primary disorder of monoamine metabolism had lower IQ scores (mean IQ 58, range 40-100) within the range of cognitive impairment (, Dietmar Hopp Stiftung (DE); Medical Faculty of the University of Heidelberg.

BACKGROUNDWolfram syndrome is a rare ER disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Although there is no treatment for Wolfram syndrome, preclinical studies in cell and rodent models suggest that therapeutic strategies targeting ER calcium homeostasis, including dantrolene sodium, may be beneficial.METHODSBased on results from preclinical studies on dantrolene sodium and ongoing longitudinal studies, we assembled what we believe is the first-ever clinical trial in pediatric and adult Wolfram syndrome patients with an open-label phase Ib/IIa trial design. The primary objective was to assess the safety and tolerability of dantrolene sodium in adult and pediatric Wolfram syndrome patients. Secondary objectives were to evaluate the efficacy of dantrolene sodium on residual pancreatic β cell functions, visual acuity, quality-of-life measures related to vision, and neurological functions.RESULTSDantrolene sodium was well tolerated by Wolfram syndrome patients. Overall, β cell functions were not significantly improved, but there was a significant correlation between baseline β cell functions and change in β cell responsiveness (R2, P = 0.004) after 6-month dantrolene therapy. Visual acuity and neurological functions were not improved by 6-month dantrolene sodium. Markers of inflammatory cytokines and oxidative stress, such as IFN-γ, IL-1β, TNF-α, and isoprostane, were elevated in subjects.CONCLUSIONThis study justifies further investigation into using dantrolene sodium and other small molecules targeting the ER for treatment of Wolfram syndrome.TRIAL REGISTRATIONClinicalTrials.gov identifier NCT02829268FUNDINGNIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (DK112921, DK113487, DK020579), NIH/National Center for Advancing Translational Sciences (NCATS) (TR002065, TR000448), NIH training grant (F30DK111070), Silberman Fund, Ellie White Foundation, Snow Foundation, Unravel Wolfram Syndrome Fund, Stowe Fund, Eye Hope Foundation, Feiock Fund, Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from NIH/NCATS, Bursky Center for Human Immunology & Immunotherapy Programs.

This article provides an overview of the clinical features and disorders associated with movement disorders in childhood. This article discusses movement disorder phenomena and their clinical presentation in infants and children and presents a diagnostic approach to suspected genetic disorders with a focus on treatable conditions.Technologic advances in molecular genetic testing over the past decade continue to lead to the discovery of new diseases. This article discusses the clinical presentation and early experience with treatment for several recently described genetic forms of infantile-onset and childhood-onset dystonia and chorea.The clinical spectrum of pediatric movement disorders is broad and heterogeneous, ranging from acute or transient self-limited conditions to conditions that cause profound lifelong motor disability. Most movement disorders in childhood are chronic, and the large number of rare, genetic conditions associated with pediatric movement disorders can pose a significant diagnostic challenge. Recognition of distinctive diagnostic clues in the history and examination can facilitate the diagnosis of potentially treatable disorders.

The term "cerebral palsy mimic" is used to describe a number of neurogenetic disorders that may present with motor symptoms in early childhood, resulting in a misdiagnosis of cerebral palsy. Cerebral palsy describes a heterogeneous group of neurodevelopmental disorders characterized by onset in infancy or early childhood of motor symptoms (including hypotonia, spasticity, dystonia, and chorea), often accompanied by developmental delay. The primary etiology of a cerebral palsy syndrome should always be identified if possible. This is particularly important in the case of genetic or metabolic disorders that have specific disease-modifying treatment. In this article, we discuss clinical features that should alert the clinician to the possibility of a cerebral palsy mimic, provide a practical framework for selecting and interpreting neuroimaging, biochemical, and genetic investigations, and highlight selected conditions that may present with predominant spasticity, dystonia/chorea, and ataxia. Making a precise diagnosis of a genetic disorder has important implications for treatment, and for advising the family regarding prognosis and genetic counseling. © 2019 International Parkinson and Movement Disorder Society.

Paroxysmal kinesigenic dyskinesia (PKD) (MIM# 128200) is a movement disorder characterized by brief episodes of involuntary movements consisting of dystonia, chorea, or myoclonus, usually triggered by sudden voluntary movements.1 Pathogenic variants in PRRT2 (MIM# 614386), located on chromosome 16p11.2, have been identified as the most common cause of PKD.2 Most of the reported patients (approximately 80%) had the frameshift pathogenic variant c.649dupC (p. Arg217Profs*8), which causes a premature stop codon. Other reported variants are nonsense, frameshift, or rarely missense that are predicted to cause a truncated protein, absence of protein product through nonsense-mediated mRNA decay, or nonfunctional protein.3 Isolated PKD is typically associated with heterozygous intragenic variants in PRRT2 . Symptomatic PKD has been reported in 6 patients with 16p11.2 microdeletion syndrome (MIM# 611913).4 PKD is thus postulated to result from PRRT2 haploinsufficiency. The reciprocal chromosome 16p11.2 duplication syndrome (MIM# 614671) is associated with autism, ADHD, developmental delay, intellectual disability, epilepsy, hypotonia, congenital anomalies, and microcephaly5,6 but has not until now been associated with PKD.

Background: Nonketotic hyperglycinemia (NKH) is a inherited neurometabolic disorder with variable clinical course and severity, in a spectrum ranging from infantile epileptic encephalopathy to psychiatric disorders. A precise phenotypic characterization and an evaluation of predictive approaches are needed. We report the results of the patient registry of the International Working Group on Neurotransmitter related Disorders (iNTD). Methods: The iNTD patient registry is a multicenter, uncontrolled, non-randomized, open, unblinded observational study (registered on DRKS, DRKS00007878). Longitudinal clinical and biochemical data of 25 individuals with NKH were studied with in silico analyses, pathogenicity scores and molecular modeling of GLDC and AMT variants. Findings: Age of onset (p=0 · 004) and diagnosis are earlier in life in severe NKH( p=0 · 005). Presenting symptoms affect the age at diagnosis. Psychiatric problems occur predominantly in attenuated NKH. Onset-age ≥3 months (66% specificity, 100% sensitivity, AUC = 0·87) and cerebrospinal fluid (CSF)/plasma glycine ratio ≤0 · 09 (57% specificity, 100% sensitivity, AUC = 0·88) are sensitive indicators for attenuated NKH while CSF glycine concentration ≥116 · 5 µmol/L (100% specificity, 93% sensitivity, AUC = 0·97) and CSF/plasma glycine ratio ≥0 · 15 15 (100% specificity, 64% sensitivity, AUC = 0·88) are specific for severe forms. A ratio threshold of 0 · 128 discriminates the overlapping range. In our study, we present ten new GLDC variants, two mild variants resulting in attenuated phenotype. Two severe variants and a combination of one mild and one severe variant lead to severe phenotype. Interpretation: This study widens the phenotypic spectrum of attenuated NKH and expands the number of pathogenic variants. The multiparametric approach provides a promising tool to predict disease severity, helping to improve clinical management and decision-making strategies. Trial Registration: This study was registered German Clinical Trials Register, https://www.drks.de, DRKS00007878). Funding: Ministry of Health of the Czech Republic (RVO-VFN 64165 GJIH-0599-00-7-846, ProgresQ26/LF1), FIS P118/00111 and PI19/00348 “Instituto de Salud Carlos III”, “Fondo Europeo de desarrollo regional (FEDER)”, and Dietmar Hopp Foundation. Declaration of Interest: A.G.C. has received teaching honorarium from PTC Therapeutics GT, Inc. G.F.H. receives teaching as well as consultancy honorarium from PTC Therapeutics GT, Inc. O.K.H. has received teaching honorarium from PTC Therapeutics GT, Inc. T.O. receives teaching honorarium and research support from PTC. GFH has received honoraria as a speaker from Takeda and consultancy honoraria from PTC Therapeutics International GT. T.S.P receives consulting honoraria from Teva Pharmaceuticals. The other authors declare no potential conflict of interest. Ethical Approval: iNTD registry study was approved by the Institutional Research Ethics Board (IRB) Heidelberg University Hospital (S-471/2014)

Aim To determine the features cited by motor phenotyping experts when identifying dystonia in people with cerebral palsy (CP). Method Dystonia identification in CP, particularly when comorbid with spasticity, can be difficult. The dystonia diagnostic criterion standard remains subjective visual identification by expert consensus. For this qualitative study, we conducted an inductive thematic analysis of consensus-building discussions between three pediatric movement disorder physicians as they identified the presence or absence of dystonia in gait videos of 40 participants with spastic CP and periventricular leukomalacia. Results Unanimous consensus about the presence or absence of dystonia was achieved for 34 out of 40 videos. Two main themes were present during consensus-building discussions as videos were evaluated for dystonia: (1) unilateral leg or foot adduction that was variable over time, and (2) difficulty in identifying dystonia. Codes contributing to the first theme were more likely to be cited by a discussant when they felt dystonia was present (as opposed to absent) in a video (χ2 test, p=0.004). Discussion These results describe the gait features cited by experts during consensus-building discussion as they identify dystonia in ambulatory people with CP. Qualitative thematic analysis of these discussions could help codify the subjective process of dystonia diagnosis.

BACKGROUND Wolfram syndrome is a rare ER disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Although there is no treatment for Wolfram syndrome, preclinical studies in cell and rodent models suggest that therapeutic strategies targeting ER calcium homeostasis, including dantrolene sodium, may be beneficial. METHODS Based on results from preclinical studies on dantrolene sodium and ongoing longitudinal studies, we assembled what we believe is the first-ever clinical trial in pediatric and adult Wolfram syndrome patients with an open-label phase Ib/IIa trial design. The primary objective was to assess the safety and tolerability of dantrolene sodium in adult and pediatric Wolfram syndrome patients. Secondary objectives were to evaluate the efficacy of dantrolene sodium on residual pancreatic β cell functions, visual acuity, quality-of-life measures related to vision, and neurological functions. RESULTS Dantrolene sodium was well tolerated by Wolfram syndrome patients. Overall, β cell functions were not significantly improved, but there was a significant correlation between baseline β cell functions and change in β cell responsiveness (R2, P = 0.004) after 6-month dantrolene therapy. Visual acuity and neurological functions were not improved by 6-month dantrolene sodium. Markers of inflammatory cytokines and oxidative stress, such as IFN-γ, IL-1β, TNF-α, and isoprostane, were elevated in subjects. CONCLUSION This study justifies further investigation into using dantrolene sodium and other small molecules targeting the ER for treatment of Wolfram syndrome. TRIAL REGISTRATION ClinicalTrials.gov identifier NCT02829268 FUNDING NIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (DK112921, DK113487, DK020579), NIH/National Center for Advancing Translational Sciences (NCATS) (TR002065, TR000448), NIH training grant (F30DK111070), Silberman Fund, Ellie White Foundation, Snow Foundation, Unravel Wolfram Syndrome Fund, Stowe Fund, Eye Hope Foundation, Feiock Fund, Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from NIH/NCATS, Bursky Center for Human Immunology & Immunotherapy Programs.

BackgroundWolfram syndrome is a rare endoplasmic reticulum disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Although there is currently no treatment to delay, halt, or reverse the progression of Wolfram syndrome, preclinical studies in cell and rodent models suggest that therapeutic strategies targeting endoplasmic reticulum calcium homeostasis, including dantrolene sodium, may be beneficial.MethodsBased on the results from preclinical studies on dantrolene sodium and ongoing longitudinal studies, our group put together the first-ever clinical trial in pediatric and adult patients with Wolfram syndrome. An open-label phase 1b/2a trial design was chosen. The primary objective of the study was to assess the safety and tolerability of dantrolene sodium in adult and pediatric patients with Wolfram syndrome. Secondary objectives were to evaluate the efficacy of dantrolene sodium on residual pancreatic β-cell functions, visual acuity, quality of life measures related to vision, and neurological functions.ResultsThe results indicate that dantrolene sodium is well tolerated by patients with Wolfram syndrome. Although the study was small, a select few patients seemed to have improvements in β-cell function, which might correlate with a positive trend in other outcome measures, including visual acuity and neurological functions.ConclusionThis study justifies further investigation into using dantrolene sodium and other small molecules targeting the endoplasmic reticulum for the treatment of Wolfram syndrome.Trial registrationClinicalTrials.gov Identifier NCT02829268Key PointsQuestionIs dantrolene sodium safe and effective for the treatment of adult and pediatric patients with Wolfram syndrome?FindingsThe results of this open-label clinical trial show that dantrolene sodium is well tolerated by patients with Wolfram syndrome. Although the study was small, a select few patients seemed to have improvements in β-cell function, which might correlate with a positive trend in other outcome measures, including visual acuity and neurological functions.MeaningDantrolene sodium is well tolerated by patients with Wolfram syndrome. Some patients may experience an increase in β cell function when taking dantrolene.ImportanceWolfram syndrome is a rare endoplasmic reticulum disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Although there is currently no treatment to delay, halt, or reverse the progression of Wolfram syndrome, preclinical studies in cell and rodent models suggest that targeting endoplasmic reticulum calcium homeostasis, including dantrolene sodium, is an emerging therapeutic strategy.ObjectiveThe primary objective of the study was to assess the safety and tolerability of dantrolene sodium in adult and pediatric subjects with Wolfram syndrome. Secondary objectives were to evaluate the efficacy of dantrolene sodium on residual pancreatic β-cell functions, visual acuity, quality of life measures related to vision, and neurological functions.DesignOpen-label phase 1b/2a trial of dantrolene sodium over a 6-month treatment period.SettingSingle site, academic medical center.ParticipantsAdult and pediatric subjects with a genetically confirmed diagnosis of Wolfram syndrome.InterventionsAll subjects received increasing doses of dantrolene sodium.Main Outcomes and MeasuresThe safety and tolerability of dantrolene sodium administered orally at the upper end of therapeutic dose range for 6 months, and the efficacy of dantrolene sodium on residual pancreatic β-cell functions using a mixed-meal tolerance test, visual acuity using LogMar scores, quality of life measures related to vision using Visual Functioning Questionnaire – 25, and neurological functions using the Wolfram Unified Rating Scale (WURS) and standard neurological assessments.ResultsThe results indicate that dantrolene sodium is well tolerated by subjects with Wolfram syndrome. Although the study was small, a select few subjects seemed to have improvements in β-cell function, which might be correlated with a positive trend in visual acuity.Conclusions and RelevanceThis study justifies further investigation into using dantrolene sodium and other small molecules targeting the endoplasmic reticulum for the treatment of Wolfram syndrome.Trial RegistrationRegistered with clinicaltrials.gov, NCT02829268, (https://clinicaltrials.gov/ct2/show/NCT02829268?term=NCT02829268&draw=2&rank=1)

BACKGROUND: Juvenile forms of parkinsonism are rare conditions with onset of bradykinesia, tremor and rigidity before the age of 21 years. These atypical presentations commonly have a genetic aetiology, highlighting important insights into underlying pathophysiology. Genetic defects may affect key proteins of the endocytic pathway and clathrin-mediated endocytosis (CME), as in DNAJC6-related juvenile parkinsonism. OBJECTIVE: To report on a new patient cohort with juvenile-onset DNAJC6 parkinsonism-dystonia and determine the functional consequences on auxilin and dopamine homeostasis. METHODS: Twenty-five children with juvenile parkinsonism were identified from a research cohort of patients with undiagnosed pediatric movement disorders. Molecular genetic investigations included autozygosity mapping studies and whole-exome sequencing. Patient fibroblasts and CSF were analyzed for auxilin, cyclin G-associated kinase and synaptic proteins. RESULTS: We identified 6 patients harboring previously unreported, homozygous nonsense DNAJC6 mutations. All presented with neurodevelopmental delay in infancy, progressive parkinsonism, and neurological regression in childhood. (123) I-FP-CIT SPECT (DaTScan) was performed in 3 patients and demonstrated reduced or absent tracer uptake in the basal ganglia. CSF neurotransmitter analysis revealed an isolated reduction of homovanillic acid. Auxilin levels were significantly reduced in both patient fibroblasts and CSF. Cyclin G-associated kinase levels in CSF were significantly increased, whereas a number of presynaptic dopaminergic proteins were reduced. CONCLUSIONS: DNAJC6 is an emerging cause of recessive juvenile parkinsonism-dystonia. DNAJC6 encodes the cochaperone protein auxilin, involved in CME of synaptic vesicles. The observed dopamine dyshomeostasis in patients is likely to be multifactorial, secondary to auxilin deficiency and/or neurodegeneration. Increased patient CSF cyclin G-associated kinase, in tandem with reduced auxilin levels, suggests a possible compensatory role of cyclin G-associated kinase, as observed in the auxilin knockout mouse. DNAJC6 parkinsonism-dystonia should be considered as a differential diagnosis for pediatric neurotransmitter disorders associated with low homovanillic acid levels. Future research in elucidating disease pathogenesis will aid the development of better treatments for this pharmacoresistant disorder. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Tetrahydrobiopterin (BHAlthough the total body of evidence in the literature was mainly rated as low or very low, these consensus guidelines will help to harmonize clinical practice and to standardize and improve care for BH

BackgroundDystonia diagnosis is subjective and often difficult, particularly when co-morbid with spasticity as occurs in cerebral palsy.ObjectiveTo develop an objective clinical screening method for dystoniaMethodsWe analyzed 30 gait videos (640×360 pixel resolution, 30 frames/second) of subjects with spastic cerebral palsy acquired during routine clinic visits. Dystonia was identified by consensus of three movement disorders specialists (15 videos with and 15 without dystonia). Limb position was calculated using deep neural network-guided pose estimation (DeepLabCut) to determine inter-knee distance variance, foot angle variance, and median foot angle difference between limbs.ResultsAll gait variables were significant predictors of dystonia. An inter-knee distance variance greater than 14 pixels together with a median foot angle difference greater than 10 degrees yielded 93% sensitivity and specificity for dystonia.ConclusionsOpen-source automated video gait analysis can identify features of expert-identified dystonia. Methods like this could help clinically screen for dystonia.

AimTo determine the specific movement features in children with cerebral palsy (CP) that prompt expert identification of dystoniaMethodsDystonia identification in CP, particularly when co-morbid with spasticity, can be difficult. For this retrospective case-control study, we conducted a qualitative thematic analysis of consensus-building discussions between three pediatric movement disorders physicians as they attempted to identify the presence or absence of dystonia in gait videos of 40 subjects with spastic CP and periventricular leukomalacia.ResultsInitial unanimous consensus regarding the presence or absence of dystonia was achieved in 12 videos (30%). Following consensus building discussion, 22 additional videos (55%) yielded unanimous consensus. Two main themes were generated: 1) Unilateral leg or foot adduction that was variable over time, and 2) Difficulty in identifying dystonia. Codes contributing to Theme 1 were more likely to appear when a discussant was favoring the presence of dystonia in a video (Chi-square, p=0.004).DiscussionThese results provide specific movement features that could aid dystonia diagnosis in ambulatory children with CP. However, these results also suggest that, even amongst putative motor phenotyping experts, visual dystonia diagnosis in CP remains difficult, highlighting the need for developing and using objective dystonia diagnosis measures.What this paper adds-Dystonia identification is visually difficult, even for experts-Unilateral lower extremity variable adduction could represent gait dystonia in cerebral palsy-Qualitative thematic analysis objectively identifies expert-cited dystonia features in cerebral palsy

Movement disorders in childhood can be difficult to diagnose early. Disease processes present variably and can mimic each other. It is particularly important to remain vigilant for the subset of these movement disorders that are treatable. These disorders can be managed with (1) treatments specific to the disease that substantially reduce symptoms; (2) treatments that can prevent progression; (3) treatments that can hasten recovery; or (4) surveillance and management of the associated, sometimes life-threatening, comorbidities. Here, we present a practical and phenomenology-oriented framework for diagnosing and managing these treatable movement disorders of infancy and early childhood.

BackgroundTetrahydrobiopterin (BH4) deficiencies comprise a group of six rare neurometabolic disorders characterized by insufficient synthesis of the monoamine neurotransmitters dopamine and serotonin due to a disturbance of BH4biosynthesis or recycling. Hyperphenylalaninemia (HPA) is the first diagnostic hallmark for most BH4deficiencies, apart from autosomal dominant guanosine triphosphate cyclohydrolase I deficiency and sepiapterin reductase deficiency. Early supplementation of neurotransmitter precursors and where appropriate, treatment of HPA results in significant improvement of motor and cognitive function. Management approaches differ across the world and therefore these guidelines have been developed aiming to harmonize and optimize patient care. Representatives of the International Working Group on Neurotransmitter related Disorders (iNTD) developed the guidelines according to the SIGN (Scottish Intercollegiate Guidelines Network) methodology by evaluating all available evidence for the diagnosis and treatment of BH4deficiencies.ConclusionAlthough the total body of evidence in the literature was mainly rated as low or very low, these consensus guidelines will help to harmonize clinical practice and to standardize and improve care for BH4deficient patients.

Broad-scale untargeted biochemical phenotyping is a technology that supplements widely accepted assays, such as organic acid, amino acid, and acylcarnitine analyses typically utilized for the diagnosis of inborn errors of metabolism. In this study, we investigate the analyte changes associated with 4-aminobutyrate aminotransferase (ABAT, GABA transaminase) deficiency and treatments that affect GABA metabolism. GABA-transaminase deficiency is a rare neurodevelopmental and neurometabolic disorder caused by mutations in

Aromatic l‐amino acid decarboxylase deficiency (AADCD) is a rare, autosomal recessive neurodevelopmental disorder characterized by impaired synthesis of dopamine, noradrenaline, adrenaline and serotonin, leading to a complex syndrome of motor, behavioral, and autonomic symptoms. This retrospective study assessed the symptoms and developmental outcome of a large international cohort of patients with AADCD via physician and/or caregiver responses to a detailed, standardized questionnaire. Sixty‐three patients (60% female; ages 6 months‐36 years, median 7 years; 58 living) from 23 individual countries participated. Common symptoms at onset (median age 3 months, range 0‐12 months) were hypotonia, developmental delay, and/or oculogyric crises. Oculogyric crises were present in 97% of patients aged 2 to 12 years, occurred in the majority of patients in all age groups, and tended to be most severe during early childhood. Prominent non‐motor symptoms were sleep disturbance, irritable mood, and feeding difficulties. The majority of subjects (70%) had profound motor impairment characterized by absent head control and minimal voluntary movement, while 17% had mild motor impairment and were able to walk independently. Dopamine agonists were the medications most likely to produce some symptomatic benefit, but were associated with dose‐limiting side effects (dyskinesia, insomnia, irritability, vomiting) that led to discontinuation 25% of the time. The age distribution of our cohort (70% of subjects under age 13 years) and the observation of a greater proportion of patients with a more severe disease phenotype in the younger compared to the older patients, both suggest a significant mortality risk during childhood for patients with severe disease.

Objective:To describe a characteristic paroxysmal eye–head movement disorder that occurs in infants with Glut1 deficiency syndrome (Glut1 DS).Methods:We retrospectively reviewed the medical charts of 101 patients with Glut1 DS to obtain clinical data about episodic abnormal eye movements and analyzed video recordings of 18 eye movement episodes from 10 patients.Results:A documented history of paroxysmal abnormal eye movements was found in 32/101 patients (32%), and a detailed description was available in 18 patients, presented here. Episodes started before age 6 months in 15/18 patients (83%), and preceded the onset of seizures in 10/16 patients (63%) who experienced both types of episodes. Eye movement episodes resolved, with or without treatment, by 6 years of age in 7/8 patients with documented long-term course. Episodes were brief (usually Conclusions:Paroxysmal eye–head movements, for which we suggest the term aberrant gaze saccades, are an early symptom of Glut1 DS in infancy. Recognition of the episodes will facilitate prompt diagnosis of this treatable neurodevelopmental disorder.

Wolfram syndrome is a rare, progressive neurodegenerative disorder characterized by juvenile-onset diabetes, optic nerve atrophy and mutation of the WFS1 gene. Calcium dyshomeostasis is a key mechanism underlying neuronal and pancreatic β-cell death and dysfunction in this endoplasmic reticulum (ER) disorder. Dantrolene sodium is an FDA-approved muscle relaxant that preserves ER calcium through inhibition of ryanodine receptor (RyR) activity. We therefore hypothesized that dantrolene could have therapeutic potential for Wolfram syndrome. Our preclinical studies showed that dantrolene improves β-cell and neuronal cell survival in mouse and induced pluripotent stem (iPS) cell models of Wolfram syndrome. To translate these findings to humans, we conducted the first clinical trial in 19 Wolfram syndrome patients through a 6-month phase 1b/2 study of dantrolene sodium with an optional extension phase up to 24-months (NCT02829268). The endpoints of this study were to assess: (1) dantrolene safety and tolerability in pediatric and adult Wolfram syndrome patients and (2) its effects on remaining β-cell, visual and neurologic functions and quality of life measures. Among pediatric subjects, dantrolene was well-tolerated at a daily dose of 0.5mg/kg in those < 50kg and 2mg/kg in those > 50kg. Adults tolerated dantrolene well at 50mg - 100mg daily. Common adverse events included mild fatigue, diarrhea, headache and hypoglycemia. A mild increase in 30-minute mixed-meal-stimulated C-peptide was observed in subjects after 6- and 12-months of dantrolene treatment. No significant changes were observed in visual or neurological functions or quality of life measures, although mild improvement in disease severity was noted by the Wolfram Unified Rating Scale. These findings suggest that dantrolene is safe for use in Wolfram syndrome at the specified doses and support further study of dantrolene in a randomized, placebo-controlled trial. Disclosure D. Abreu: None. T.S. Pearson: None. R.C. Bucelli: None. A. Simpson: None. C.M. Brown: None. K. Kries: None. H. Gu: None. S.I. Stone: Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases. Speaker’s Bureau; Self; AbbVie Inc. L. Tychsen: None. G. Van Stavern: None. N.H. White: None. B.A. Marshall: None. T. Hershey: Research Support; Spouse/Partner; Sage Pharmaceuticals. F. Urano: Board Member; Self; Healthbeat. Research Support; Self; Aetas, Amylyx, JDRF, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. Stock/Shareholder; Self; CytRx. Other Relationship; Self; Novus Biologicals. Funding National Institutes of Health (R21DK113487-02)

Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.0–49.3 years). While the mean age at symptom onset was 0.8 ± 0.6 years [standard deviation (SD), range 0.2–5.0], the mean age at diagnosis was 10.2 ± 8.5 years (SD, range 0.1–46.3). We define a set of core features: early-onset developmental delay with delayed motor milestones and significant speech delay (50% non-verbal); intellectual disability in the moderate to severe range; mild hypotonia in infancy followed by spastic diplegia (mean age: 8.4 ± 5.1 years, SD) and later tetraplegia (mean age: 16.1 ± 9.8 years, SD); postnatal microcephaly (83%); foot deformities (69%); and epilepsy (66%) that is intractable in a subset. At last follow-up, 36% ambulated with assistance (mean age: 8.9 ± 6.4 years, SD) and 54% were wheelchair-dependent (mean age: 13.4 ± 9.8 years, SD). Episodes of stereotypic laughing, possibly consistent with a pseudobulbar affect, were found in 56% of patients. Key features on neuroimaging include a thin corpus callosum (90%), ventriculomegaly (65%) often with colpocephaly, and periventricular white-matter signal abnormalities (68%). Iron deposition and polymicrogyria were found in a subset of patients. AP4B1-associated SPG47 and AP4M1-associated SPG50 accounted for the majority of cases. About two-thirds of patients were born to consanguineous parents, and 82% carried homozygous variants. Over 70 unique variants were present, the majority of which are frameshift or nonsense mutations. To track disease progression across the age spectrum, we defined the relationship between disease severity as measured by several rating scales and disease duration. We found that the presence of epilepsy, which manifested before the age of 3 years in the majority of patients, was associated with worse motor outcomes. Exploring genotype-phenotype correlations, we found that disease severity and major phenotypes were equally distributed among the four subtypes, establishing that SPG47, SPG50, SPG51 and SPG52 share a common phenotype, an ‘AP-4 deficiency syndrome’. By delineating the core clinical, imaging, and molecular features of AP-4-associated hereditary spastic paraplegia across the age spectrum our results will facilitate early diagnosis, enable counselling and anticipatory guidance of affected families and help define endpoints for future interventional trials.

Retinoic acid (RA) signaling plays a key role in the development and function of several systems in mammals. We previously discovered that the de novo mutations c.1159C>T (p.Arg387Cys) and c.1159C>A (p.Arg387Ser) in the RA Receptor Beta (RARB) gene cause microphthalmia and diaphragmatic hernia. However, the natural history of affected subjects beyond the prenatal or neonatal period was unknown. Here, we describe nine additional subjects with microphthalmia who have de novo mutations in RARB, including the previously described p.Arg387Cys as well as the novel c.887G>C (p.Gly296Ala) and c.638T>C (p.Leu213Pro). Moreover, we review the information on four previously reported cases. All subjects who survived the neonatal period (n = 10) displayed severe global developmental delay with progressive motor impairment due to spasticity and/or dystonia (with or without chorea). The majority of subjects also showed Chiari type I malformation and severe feeding difficulties. We previously found that p.Arg387Cys and p.Arg387Ser induce a gain-of-function. We show here that the p.Gly296Ala and p.Leu213Pro RARB mutations further promote the RA ligand-induced transcriptional activity by twofold to threefold over the wild-type receptor, also indicating a gain-of-function mechanism. These observations suggest that precise regulation of RA signaling is required for brain development and/or function in humans.

This article aims to provide a practical review of pediatric dystonia from a clinician's perspective. The focus is on the underlying genetic causes, recent findings, and treatable conditions. Dystonia can occur in an isolated fashion or accompanied by other neurological or systemic features. The clinical presentation is often a complex overlap of neurological findings with a large differential diagnosis. We recommend an approach guided by thorough clinical evaluation, brain magnetic resonance imaging (MRI), biochemical analysis, and genetic testing to hone in on the diagnosis. This article highlights the clinical and genetic complexity of pediatric dystonia and underlines the importance of a genetic diagnosis for therapeutic considerations.

Object Randomized clinical trials have established that lumbar selective dorsal rhizotomy (SDR) reduces lower-extremity tone and improves functional outcome in children with spastic cerebral palsy. Significant data exist to support a secondary effect on upper-extremity function in patients with upper-extremity spasticity. The effects of SDR on upper-extremity tone, however, are not well characterized. In this report, the authors sought to assess changes in upper-extremity tone in individual muscle groups after SDR and tried to determine if these changes could be predicted preoperatively. Methods The authors retrospectively reviewed 42 children who underwent SDR at Columbia University Medical Center/Morgan Stanley Children's Hospital of NewYork-Presbyterian between 2005 and 2011. Twenty-five had upper-extremity spasticity. All underwent pre- and postoperative examination for measuring tone (Modified Ashworth Scale) and assessing functional outcome. Follow-up examinations with therapists were performed at least once at a minimum of 2 months postoperatively (mean 15 months). Results In the upper extremities, 23 (92%) of 25 patients had improvements of at least 1 Ashworth point in 2 or more independent motor groups on the Modified Ashworth Scale, and 12 (71%) of 17 families surveyed reported increases in motor control or spontaneous movement. The mean Modified Ashworth Scale scores for all upper-extremity muscle groups demonstrated an improvement from 1.34 to 1.22 (p < 0.001). Patients with a mean preoperative upper-extremity tone of 1.25–1.75 were most likely to benefit from reduction in tone (p = 0.0019). Proximal and pronator muscle groups were most likely to demonstrate reduced tone. Conclusions In addition to improvements in lower-extremity tone and function, SDR has demonstrable effects on upper extremities. Greater than 90% of our patients with elevated upper-extremity tone demonstrated reduction in tone in at least 2 muscle groups postoperatively. Patients with a mean Modified Ashworth Scale upper-extremity score of 1.25–1.75 may encounter the greatest reduction in upper-extremity tone.

GNAO1 encephalopathy comprises a spectrum of neurologic phenotypes that result from de novo heterozygous mutations in GNAO1 , a gene coding for the subunit of a G protein that is highly expressed in the CNS and is involved in second messenger signaling. De novo heterozygous mutations in the gene were first described in patients with a severe, infantile-onset epileptic encephalopathy known as Ohtahara syndrome.1 However, patients with a predominant motor disorder, characterized by infantile hypotonia developing into severe chorea and dystonia, have also been identified.2,3 While it is not unusual for novel neurogenetic disorders to have some degree of phenotypic range, the discrepancy between these 2 phenotypes in patients with GNAO1 encephalopathy is striking. What may account for this phenotypic variability?

Our objective is to characterize the long-term course of Glut1 deficiency syndrome. Longitudinal outcome measures, including Columbia Neurological Scores, neuropsychological tests, and adaptive behavior reports, were collected for 13 participants with Glut1 deficiency syndrome who had been followed for an average of 14.2 (range = 8.9-23.6) years. A parent questionnaire assessed manifestations throughout development. The 6-Minute Walk Test captured gait disturbances and triggered paroxysmal exertional dyskinesia. All longitudinal outcomes remained stable over time. Epilepsy dominated infancy and improved during childhood. Dystonia emerged during childhood or adolescence. Earlier introduction of the ketogenic diet correlated with better long-term outcomes on some measures. Percent-predicted 6-Minute Walk Test distance correlated significantly with Columbia Neurological Scores. We conclude that Glut1 deficiency syndrome is a chronic condition, dominated by epilepsy in infancy and by movement disorders thereafter. Dietary treatment in the first postnatal months may effect improved outcomes, emphasizing the importance of early diagnosis and treatment.

Randomized clinical trials have established that lumbar selective dorsal rhizotomy (SDR) reduces lower-extremity tone and improves functional outcome in children with spastic cerebral palsy. Significant data exist to support a secondary effect on upper-extremity function in patients with upper-extremity spasticity. The effects of SDR on upper-extremity tone, however, are not well characterized. In this report, the authors sought to assess changes in upper-extremity tone in individual muscle groups after SDR and tried to determine if these changes could be predicted preoperatively.The authors retrospectively reviewed 42 children who underwent SDR at Columbia University Medical Center/Morgan Stanley Children's Hospital of NewYork-Presbyterian between 2005 and 2011. Twenty-five had upper-extremity spasticity. All underwent pre- and postoperative examination for measuring tone (Modified Ashworth Scale) and assessing functional outcome. Follow-up examinations with therapists were performed at least once at a minimum of 2 months postoperatively (mean 15 months).In the upper extremities, 23 (92%) of 25 patients had improvements of at least 1 Ashworth point in 2 or more independent motor groups on the Modified Ashworth Scale, and 12 (71%) of 17 families surveyed reported increases in motor control or spontaneous movement. The mean Modified Ashworth Scale scores for all upper-extremity muscle groups demonstrated an improvement from 1.34 to 1.22 (p0.001). Patients with a mean preoperative upper-extremity tone of 1.25-1.75 were most likely to benefit from reduction in tone (p = 0.0019). Proximal and pronator muscle groups were most likely to demonstrate reduced tone.In addition to improvements in lower-extremity tone and function, SDR has demonstrable effects on upper extremities. Greater than 90% of our patients with elevated upper-extremity tone demonstrated reduction in tone in at least 2 muscle groups postoperatively. Patients with a mean Modified Ashworth Scale upper-extremity score of 1.25-1.75 may encounter the greatest reduction in upper-extremity tone.

Glut1 deficiency syndrome (Glut1 DS) was originally described in 1991 as a developmental encephalopathy characterized by infantile onset refractory epilepsy, cognitive impairment, and mixed motor abnormalities including spasticity, ataxia, and dystonia. The clinical condition is caused by impaired glucose transport across the blood brain barrier. The past 5 years have seen a dramatic expansion in the range of clinical syndromes that are recognized to occur with Glut1 DS. In particular, there has been greater recognition of milder phenotypes. Absence epilepsy and other idiopathic generalized epilepsy syndromes may occur with seizure onset in childhood or adulthood. A number of patients present predominantly with movement disorders, sometimes without any accompanying seizures. In particular, paroxysmal exertional dyskinesia is now a well-documented clinical feature that occurs in individuals with Glut1 DS. A clue to the diagnosis in patients with paroxysmal symptoms may be the triggering of episodes during fasting or exercise. Intellectual impairment may range from severe to very mild. Awareness of the broad range of potential clinical phenotypes associated with Glut1 DS will facilitate earlier diagnosis of this treatable neurologic condition. The ketogenic diet is the mainstay of treatment and nourishes the starving symptomatic brain during development.