RESUMEN
DNAJC6 encodes auxilin, a co-chaperone protein involved in clathrin-mediated endocytosis (CME) at the presynaptic terminal. Biallelic mutations in DNAJC6 cause a complex, early-onset neurodegenerative disorder characterized by rapidly progressive parkinsonism-dystonia in childhood. The disease is commonly associated with additional neurodevelopmental, neurological and neuropsychiatric features. Currently, there are no disease-modifying treatments for this condition, resulting in significant morbidity and risk of premature mortality. To investigate the underlying disease mechanisms in childhood-onset DNAJC6 parkinsonism, we generated induced pluripotent stem cells (iPSC) from three patients harbouring pathogenic loss-of-function DNAJC6 mutations and subsequently developed a midbrain dopaminergic neuronal model of disease. When compared to age-matched and CRISPR-corrected isogenic controls, the neuronal cell model revealed disease-specific auxilin deficiency as well as disturbance of synaptic vesicle recycling and homeostasis. We also observed neurodevelopmental dysregulation affecting ventral midbrain patterning and neuronal maturation. To explore the feasibility of a viral vector-mediated gene therapy approach, iPSC-derived neuronal cultures were treated with lentiviral DNAJC6 gene transfer, which restored auxilin expression and rescued CME. Our patient-derived neuronal model provides deeper insights into the molecular mechanisms of auxilin deficiency as well as a robust platform for the development of targeted precision therapy approaches.
Asunto(s)
Auxilinas , Terapia Genética , Proteínas del Choque Térmico HSP40 , Células Madre Pluripotentes Inducidas , Trastornos Parkinsonianos , Humanos , Terapia Genética/métodos , Proteínas del Choque Térmico HSP40/genética , Proteínas del Choque Térmico HSP40/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Trastornos Parkinsonianos/genética , Trastornos Parkinsonianos/terapia , Trastornos Parkinsonianos/metabolismo , Auxilinas/genética , Auxilinas/metabolismo , Masculino , Femenino , Neuronas Dopaminérgicas/metabolismo , Mutación , Sinapsis/genética , Sinapsis/metabolismo , Endocitosis/fisiología , Endocitosis/genética , NiñoRESUMEN
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.
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Enfermedades Mitocondriales , Encefalomiopatías Mitocondriales , Treonina-ARNt Ligasa , Humanos , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/patología , Encefalomiopatías Mitocondriales/genética , Mutación , Fenotipo , ARN de Transferencia de Treonina/genética , Treonina-ARNt Ligasa/genéticaRESUMEN
PURPOSE: Biallelic variants in TARS2, encoding the mitochondrial threonyl-tRNA-synthetase, have been reported in a small group of individuals displaying a neurodevelopmental phenotype but with limited neuroradiological data and insufficient evidence for causality of the variants. METHODS: Exome or genome sequencing was carried out in 15 families. Clinical and neuroradiological evaluation was performed for all affected individuals, including review of 10 previously reported individuals. The pathogenicity of TARS2 variants was evaluated using in vitro assays and a zebrafish model. RESULTS: We report 18 new individuals harboring biallelic TARS2 variants. Phenotypically, these individuals show developmental delay/intellectual disability, regression, cerebellar and cerebral atrophy, basal ganglia signal alterations, hypotonia, cerebellar signs, and increased blood lactate. In vitro studies showed that variants within the TARS2301-381 region had decreased binding to Rag GTPases, likely impairing mTORC1 activity. The zebrafish model recapitulated key features of the human phenotype and unraveled dysregulation of downstream targets of mTORC1 signaling. Functional testing of the variants confirmed the pathogenicity in a zebrafish model. CONCLUSION: We define the clinico-radiological spectrum of TARS2-related mitochondrial disease, unveil the likely involvement of the mTORC1 signaling pathway as a distinct molecular mechanism, and establish a TARS2 zebrafish model as an important tool to study variant pathogenicity.
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ARN de Transferencia , Pez Cebra , Animales , Humanos , Mutación , Pez Cebra/genética , Diana Mecanicista del Complejo 1 de la Rapamicina , Ligasas , FenotipoRESUMEN
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;92:292-303.
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Hiperglicinemia no Cetósica , Glicina/líquido cefalorraquídeo , Glicina/genética , Humanos , Hiperglicinemia no Cetósica/diagnóstico , Hiperglicinemia no Cetósica/genética , Hiperglicinemia no Cetósica/patología , Mutación , FenotipoRESUMEN
The autosomal recessive defect of aromatic L-amino acid decarboxylase (AADC) leads to a severe neurological disorder with manifestation in infancy due to a pronounced, combined deficiency of dopamine, serotonin and catecholamines. The success of conventional drug treatment is very limited, especially in patients with a severe phenotype. The development of an intracerebral AAV2-based gene delivery targeting the putamen or substantia nigra started more than 10 years ago. Recently, the putaminally-delivered construct, Eladocagene exuparvovec has been approved by the European Medicines Agency and by the British Medicines and Healthcare products Regulatory Agency. This now available gene therapy provides for the first time also for AADC deficiency (AADCD) a causal therapy, leading this disorder into a new therapeutic era. By using a standardized Delphi approach members of the International Working Group on Neurotransmitter related Disorders (iNTD) developed structural requirements and recommendations for the preparation, management and follow-up of AADC deficiency patients who undergo gene therapy. This statement underlines the necessity of a framework for a quality-assured application of AADCD gene therapy including Eladocagene exuparvovec. Treatment requires prehospital, inpatient and posthospital care by a multidisciplinary team in a specialized and qualified therapy center. Due to lack of data on long-term outcomes and the comparative efficacy of alternative stereotactic procedures and brain target sites, a structured follow-up plan and systematic documentation of outcomes in a suitable, industry-independent registry study are necessary.
RESUMEN
AIM: 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). METHOD: 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. RESULTS: 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. INTERPRETATION: 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. WHAT THIS PAPER ADDS: 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.
Asunto(s)
Parálisis Cerebral , Distonía , Trastornos Distónicos , Leucomalacia Periventricular , Recién Nacido , Masculino , Femenino , Niño , Humanos , Lactante , Preescolar , Leucomalacia Periventricular/complicaciones , Leucomalacia Periventricular/diagnóstico por imagen , Leucomalacia Periventricular/epidemiología , Parálisis Cerebral/complicaciones , Parálisis Cerebral/diagnóstico por imagen , Parálisis Cerebral/epidemiología , Espasticidad Muscular , Estudios Retrospectivos , Imagen por Resonancia MagnéticaRESUMEN
AIM: To determine the movement features governing expert assessment of gait dystonia severity in individuals with cerebral palsy (CP). METHOD: In this prospective cohort study, three movement disorder neurologists graded lower extremity dystonia severity in gait videos of individuals with CP using a 10-point Likert-like scale. Using conventional content analysis, we determined the features experts cited when grading dystonia severity. Then, using open-source pose estimation techniques, we determined gait variable analogs of these expert-cited features correlating with their assessments of dystonia severity. RESULTS: Experts assessed videos from 116 participants (46 with dystonia aged 15 years [SD 3] and 70 without dystonia aged 15 years [SD 2], both groups ranging 10-20 years old and 50% male). Variable limb adduction was most commonly cited by experts when identifying dystonia, comprising 60% of expert statements. Effect on gait (regularity, stability, trajectory, speed) and dystonia amplitude were common features experts used to determine dystonia severity, comprising 19% and 13% of statements respectively. Gait variables assessing adduction variability and amplitude (inter-ankle distance variance and foot adduction amplitude) were significantly correlated with expert assessment of dystonia severity (multiple linear regression, p < 0.001). INTERPRETATION: Adduction variability and amplitude are quantifiable gait features that correlate with expert-determined gait dystonia severity in individuals with CP. Consideration of these features could help optimize and standardize the clinical assessment of gait dystonia severity in individuals with CP.
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Parálisis Cerebral , Distonía , Trastornos Distónicos , Trastornos del Movimiento , Humanos , Masculino , Niño , Adolescente , Adulto Joven , Adulto , Femenino , Parálisis Cerebral/complicaciones , Parálisis Cerebral/diagnóstico , Distonía/diagnóstico , Distonía/etiología , Estudios Prospectivos , Marcha , Fenómenos BiomecánicosRESUMEN
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 (<70) compared to patients with a BH4 deficiency (mean IQ 84, range 40-129). Short attention span and distractibility were most frequently mentioned by parents, while patients reported most frequently anxiety and distractibility when asked for behavioral traits. In individuals with succinic semialdehyde dehydrogenase deficiency, self-stimulatory behaviors were commonly reported by parents, whereas in patients with dopamine transporter deficiency, DNAJC12 deficiency, and monoamine oxidase A deficiency, self-injurious or mutilating behaviors have commonly been observed. Phobic fears were increased in patients with 6-pyruvoyltetrahydropterin synthase deficiency, while individuals with sepiapterin reductase deficiency frequently experienced communication and sleep difficulties. Patients with BH4 deficiencies achieved significantly higher quality of life as compared to other groups. This analysis of the iNTD registry data highlights: (a) difference in IQ and subdomains of quality of life between BH4 deficiencies and primary neurotransmitter-related disorders and (b) previously underreported behavioral traits.
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Neurotransmisores/deficiencia , Fenotipo , Calidad de Vida , Adolescente , Adulto , Conducta , Niño , Preescolar , Disfunción Cognitiva/etiología , Femenino , Humanos , Lactante , Inteligencia , Internacionalidad , Masculino , Persona de Mediana Edad , Sistema de Registros , Adulto JovenRESUMEN
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.
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Complejo 4 de Proteína Adaptadora/genética , Cuerpo Calloso/diagnóstico por imagen , Imagen por Resonancia Magnética/tendencias , Paraplejía Espástica Hereditaria/diagnóstico por imagen , Paraplejía Espástica Hereditaria/genética , Adolescente , Adulto , Niño , Preescolar , Estudios de Cohortes , Estudios Transversales , Femenino , Humanos , Lactante , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Sistema de Registros , Adulto JovenRESUMEN
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.
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Parálisis Cerebral/fisiopatología , Distonía/diagnóstico , Marcha/fisiología , Leucomalacia Periventricular/fisiopatología , Espasticidad Muscular/fisiopatología , Adolescente , Parálisis Cerebral/complicaciones , Niño , Preescolar , Distonía/etiología , Distonía/fisiopatología , Femenino , Humanos , Leucomalacia Periventricular/complicaciones , Masculino , Espasticidad Muscular/complicaciones , Adulto JovenRESUMEN
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.
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Distonía , Trastornos Parkinsonianos , Niño , Dopamina , Distonía/diagnóstico por imagen , Distonía/genética , Proteínas del Choque Térmico HSP40/genética , Homeostasis , Humanos , Mutación/genética , Trastornos Parkinsonianos/diagnóstico por imagen , Trastornos Parkinsonianos/genéticaRESUMEN
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.
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Errores Innatos del Metabolismo de los Aminoácidos/fisiopatología , Errores Innatos del Metabolismo de los Aminoácidos/terapia , Descarboxilasas de Aminoácido-L-Aromático/deficiencia , Agonistas de Dopamina/uso terapéutico , Trastornos Distónicos/etiología , Trastornos de la Motilidad Ocular/etiología , Adolescente , Adulto , Factores de Edad , Niño , Preescolar , Agonistas de Dopamina/efectos adversos , Femenino , Terapia Genética , Humanos , Lactante , Internacionalidad , Masculino , Fenotipo , Estudios Retrospectivos , Adulto JovenRESUMEN
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.
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Trastornos del Movimiento/diagnóstico , Trastornos del Movimiento/terapia , Preescolar , Humanos , LactanteRESUMEN
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.
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Parálisis Cerebral/diagnóstico , Diagnóstico Diferencial , Trastornos del Movimiento/diagnóstico , Adenilil Ciclasas/genética , Ataxia/fisiopatología , Ataxia Telangiectasia/diagnóstico , Ataxia Telangiectasia/genética , Ataxia Telangiectasia/fisiopatología , Ataxia Telangiectasia/terapia , Encéfalo/diagnóstico por imagen , Encefalopatías Metabólicas Innatas/diagnóstico , Encefalopatías Metabólicas Innatas/genética , Encefalopatías Metabólicas Innatas/fisiopatología , Encefalopatías Metabólicas Innatas/terapia , Errores Innatos del Metabolismo de los Carbohidratos/diagnóstico , Errores Innatos del Metabolismo de los Carbohidratos/genética , Errores Innatos del Metabolismo de los Carbohidratos/fisiopatología , Errores Innatos del Metabolismo de los Carbohidratos/terapia , Parálisis Cerebral/fisiopatología , Corea/fisiopatología , Creatina/deficiencia , Creatina/genética , Discinesias/diagnóstico , Discinesias/genética , Discinesias/fisiopatología , Discinesias/terapia , Distonía/fisiopatología , Deficiencia de Ácido Fólico/diagnóstico , Deficiencia de Ácido Fólico/genética , Deficiencia de Ácido Fólico/fisiopatología , Deficiencia de Ácido Fólico/terapia , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/genética , Humanos , Hiperargininemia/diagnóstico , Hiperargininemia/genética , Hiperargininemia/fisiopatología , Hiperargininemia/terapia , Síndrome de Lesch-Nyhan/diagnóstico , Síndrome de Lesch-Nyhan/genética , Síndrome de Lesch-Nyhan/fisiopatología , Síndrome de Lesch-Nyhan/terapia , Imagen por Resonancia Magnética , Discapacidad Intelectual Ligada al Cromosoma X/diagnóstico , Discapacidad Intelectual Ligada al Cromosoma X/genética , Discapacidad Intelectual Ligada al Cromosoma X/fisiopatología , Discapacidad Intelectual Ligada al Cromosoma X/terapia , Proteínas de Transporte de Monosacáridos/deficiencia , Proteínas de Transporte de Monosacáridos/genética , Trastornos del Movimiento/genética , Trastornos del Movimiento/fisiopatología , Trastornos del Movimiento/terapia , Deficiencia Múltiple de Carboxilasa/diagnóstico , Deficiencia Múltiple de Carboxilasa/genéticaRESUMEN
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.
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Mutación con Ganancia de Función , Discapacidad Intelectual/genética , Trastornos del Movimiento/genética , Receptores de Ácido Retinoico/genética , Adolescente , Niño , Preescolar , Trastornos Distónicos , Femenino , Humanos , Recién Nacido , Masculino , Modelos Moleculares , Mutación Missense , Conformación Proteica , Receptores de Ácido Retinoico/química , Activación TranscripcionalRESUMEN
A 7-year-old girl presented with persistent anxiety symptoms for several years following gene therapy for an ultrarare neurometabolic disorder (aromatic L-amino acid decarboxylase [AADC] deficiency). AADC is the final enzyme in the monoamine synthesis pathway (Figure 1).1 Its absence results in a severe combined deficiency in serotonin, dopamine, epinephrine, and norepinephrine, causing significant developmental delays, hypotonia, and dystonia. The incidence of AADC deficiency is estimated at â¼1 in 500,000,2 and â¼200 cases have been described.1 Recently available disease-modifying gene therapy for this condition dramatically improves motor symptoms, and received regulatory approval in some regions in 2022.2 There are no data to guide psychiatric care post gene therapy for AADC or other neurologic disorders to date.3.
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Descarboxilasas de Aminoácido-L-Aromático , Terapia Genética , Inhibidores Selectivos de la Recaptación de Serotonina , Humanos , Femenino , Niño , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Descarboxilasas de Aminoácido-L-Aromático/deficiencia , Descarboxilasas de Aminoácido-L-Aromático/genética , Terapia Genética/métodos , Errores Innatos del Metabolismo de los Aminoácidos/genética , Errores Innatos del Metabolismo de los Aminoácidos/terapiaRESUMEN
OBJECTIVE: To determine how caregivers describe dystonia in people with cerebral palsy (CP). METHODS: In this prospective cohort study, paper surveys were administered to caregivers between September 7, 2021 and October 28, 2021 during CP Center visits at a large tertiary care center. Caregivers were asked to describe involuntary movements triggered by voluntary movement or triggered by tactile stimulation in the people with CP they cared for. Their CP Center medical provider separately assessed people with CP for dystonia. Movement features described exclusively by caregivers of people with CP and dystonia were determined using conventional content analysis. RESULTS: 113 caregivers responded on behalf of 56 people with and 57 people without dystonia. If caregivers noted that both voluntary movement and tactile stimulation triggered involuntary movements, that had a 92% positive predictive value for a dystonia diagnosis. Movement features exclusively described in people with CP and dystonia included: (1) stiffening, tensing, or tightening (15% of respondents); (2) involvement of the head (10%), torso (5%), or feet (5%); and (3) triggers of stretching (12.5%), excitement (5%), or transfers (5%). INTERPRETATION: In addition to a thorough exam, asking caregivers of people with CP to describe involuntary movements triggered by voluntary movement or tactile stimulation may inform clinical dystonia diagnosis.
Asunto(s)
Parálisis Cerebral , Distonía , Trastornos Distónicos , Humanos , Parálisis Cerebral/complicaciones , Distonía/diagnóstico , Distonía/etiología , Cuidadores , Estudios Prospectivos , Trastornos Distónicos/diagnósticoRESUMEN
Pediatric movement disorders (PMD) neurologists care for infants, children, and adolescents with conditions that disrupt typical movement; serving as important subspecialist child neurologists in both academic and private practice settings. In contrast to adult movement disorders neurologists whose "bread and butter" is hypokinetic Parkinson disease, PMD subspecialty practice is often dominated by hyperkinetic movement disorders including tics, dystonia, chorea, tremor, and myoclonus. PMD neurology practice intersects with a variety of subspecialties, including neonatology, developmental pediatrics, rehabilitation medicine, epilepsy, child & adolescent psychiatry, psychology, orthopedics, genetics & metabolism, and neurosurgery. Over the past several decades, significant advancements in the PMD field have included operationalizing definitions for distinct movement disorders, recognizing the spectrum of clinical phenotypes, expanding research on genetic and neuroimmunologic causes of movement disorders, and advancing available treatments. Subspecialty training in PMD provides trainees with advanced clinical, diagnostic, procedural, and management skills that reflect the complexities of contemporary practice. The child neurologist who is fascinated by the intricacies of child motor development, appreciates the power of observation skills coupled with a thoughtful physical examination, and is excited by the challenge of the unknown may be well-suited to a career as a PMD specialist.
Asunto(s)
Corea , Neurología , Enfermedad de Parkinson , Adolescente , Adulto , Niño , Lactante , Humanos , Temblor , NeurólogosRESUMEN
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.
Asunto(s)
Encefalopatías Metabólicas Innatas/complicaciones , Transportador de Glucosa de Tipo 1/deficiencia , Anticonvulsivantes/uso terapéutico , Glucemia/metabolismo , Barrera Hematoencefálica , Encefalopatías Metabólicas Innatas/genética , Encefalopatías Metabólicas Innatas/metabolismo , Dieta Cetogénica , Trastornos Distónicos/genética , Electroencefalografía , Epilepsia/tratamiento farmacológico , Epilepsia/genética , Epilepsia/prevención & control , Heterogeneidad Genética , Genotipo , Transportador de Glucosa de Tipo 1/genética , Transportador de Glucosa de Tipo 1/fisiología , Humanos , Discapacidad Intelectual/genética , Trastornos del Lenguaje/genética , Trastornos Mentales/genética , Trastornos del Movimiento/genética , Espasticidad Muscular/genética , FenotipoRESUMEN
Objective: To determine the rates of clinical under-documentation of leg dystonia in people with cerebral palsy (CP). Methods: In this prospective cohort study, we identified independently ambulatory people age 10-20yo with CP-associated spasticity seen in a tertiary care CP center between 1/1/20 to 11/4/21. Three pediatric movement disorders specialists assessed gait videos from these visits for leg dystonia using the Global Dystonia Rating Scale. We compared the gold standard expert consensus assessment for each patient with the clinical documentation of dystonia during a contemporaneous CP Center clinic visit and also with dystonia documentation longitudinally in their medical record. Results: Of 116 people with CP-associated spasticity assessed in this study, 70 were found to have leg dystonia in their gait videos. Only 13% of these 70 individuals (n=9/70) had leg dystonia documented in their contemporaneous CP Center clinic visit, even though they were assessed during this visit by clinicians well-trained in CP and dystonia assessment. Even with repeated assessment, only 54% (n=38/70) of these individuals had leg dystonia documented in their medical record. Conclusions: Leg dystonia is clinically under-documented in people with CP-associated spasticity, even when these people are evaluated by well-trained clinicians. Longitudinal evaluation and vigilance for leg dystonia is critical to address this diagnostic gap.