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The circadian timing system synchronizes cellular function by coordinating rhythmic transcription via a transcription-translational feedback loop. How the circadian system regulates gene expression at the translational level remains a mystery. Here, we show that the key circadian transcription factor BMAL1 associates with the translational machinery in the cytosol and promotes protein synthesis. The mTOR-effector kinase, ribosomal S6 protein kinase 1 (S6K1), an important regulator of translation, rhythmically phosphorylates BMAL1 at an evolutionarily conserved site. S6K1-mediated phosphorylation is critical for BMAL1 to both associate with the translational machinery and stimulate protein synthesis. Protein synthesis rates demonstrate circadian oscillations dependent on BMAL1. Thus, in addition to its critical role in circadian transcription, BMAL1 is a translation factor that links circadian timing and the mTOR signaling pathway. More broadly, these results expand the role of the circadian clock to the regulation of protein synthesis.
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Factores de Transcripción ARNTL/metabolismo , Relojes Circadianos , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , Animales , Citosol/metabolismo , Ratones , Fosforilación , Biosíntesis de Proteínas , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
The mechanistic target of rapamycin (mTOR) is an important signaling hub that integrates environmental information regarding energy availability and stimulates anabolic molecular processes and cell growth. Abnormalities in this pathway have been identified in several syndromes in which autism spectrum disorder (ASD) is highly prevalent. Several studies have investigated mTOR signaling in developmental and neuronal processes that, when dysregulated, could contribute to the development of ASD. Although many potential mechanisms still remain to be fully understood, these associations are of great interest because of the clinical availability of mTOR inhibitors. Clinical trials evaluating the efficacy of mTOR inhibitors to improve neurodevelopmental outcomes have been initiated.
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Trastorno Autístico/metabolismo , Transducción de Señal/fisiología , Serina-Treonina Quinasas TOR/metabolismo , Animales , Trastorno Autístico/genética , Trastorno Autístico/patología , Trastorno Autístico/fisiopatología , Humanos , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/genéticaRESUMEN
Pathogenic variants in ATL1 are a known cause of autosomal-dominantly inherited hereditary spastic paraplegia (HSP-ATL1, SPG3A) with a predominantly 'pure' HSP phenotype. Although a relatively large number of patients have been reported, no genotype-phenotype correlations have been established for specific ATL1 variants. Confronted with five children carrying de novo ATL1 variants showing early, complex and severe symptoms, we systematically investigated the molecular and phenotypic spectrum of HSP-ATL1. Through a cross-sectional analysis of 537 published and novel cases, we delineate a distinct phenotype observed in patients with de novo variants. Guided by this systematic phenotyping approach and structural modelling of disease-associated variants in atlastin-1, we demonstrate that this distinct phenotypic signature is also prevalent in a subgroup of patients with inherited ATL1 variants and is largely explained by variant localization within a three-dimensional mutational cluster. Establishing genotype-phenotype correlations, we find that symptoms that extend well beyond the typical pure HSP phenotype (i.e. neurodevelopmental abnormalities, upper limb spasticity, bulbar symptoms, peripheral neuropathy and brain imaging abnormalities) are prevalent in patients with variants located within this mutational cluster.
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Paraplejía Espástica Hereditaria , Humanos , Estudios Transversales , Análisis Mutacional de ADN , Proteínas de Unión al GTP/genética , Proteínas de la Membrana/genética , Mutación , Linaje , Fenotipo , Paraplejía Espástica Hereditaria/genética , Paraplejía Espástica Hereditaria/patologíaRESUMEN
Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a neurometabolic disorder caused by ALDH5A1 mutations presenting with autism and epilepsy. SSADHD leads to impaired GABA metabolism and results in accumulation of GABA and γ-hydroxybutyrate (GHB), which alter neurotransmission and are thought to lead to neurobehavioral symptoms. However, why increased inhibitory neurotransmitters lead to seizures remains unclear. We used induced pluripotent stem cells from SSADHD patients (one female and two male) and differentiated them into GABAergic and glutamatergic neurons. SSADHD iGABA neurons show altered GABA metabolism and concomitant changes in expression of genes associated with inhibitory neurotransmission. In contrast, glutamatergic neurons display increased spontaneous activity and upregulation of mitochondrial genes. CRISPR correction of the pathogenic variants or SSADHD mRNA expression rescue various metabolic and functional abnormalities in human neurons. Our findings uncover a previously unknown role for SSADHD in excitatory human neurons and provide unique insights into the cellular and molecular basis of SSADHD and potential therapeutic interventions.
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Errores Innatos del Metabolismo de los Aminoácidos , Células Madre Pluripotentes Inducidas , Humanos , Masculino , Femenino , Células Madre Pluripotentes Inducidas/metabolismo , Errores Innatos del Metabolismo de los Aminoácidos/tratamiento farmacológico , Errores Innatos del Metabolismo de los Aminoácidos/genética , Errores Innatos del Metabolismo de los Aminoácidos/metabolismo , Neuronas/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Succionato-Semialdehído Deshidrogenasa/genéticaRESUMEN
Status dystonicus is the most severe form of dystonia with life-threatening complications if not treated promptly. We present consensus recommendations for the initial management of acutely worsening dystonia (including pre-status dystonicus and status dystonicus), as well as refractory status dystonicus in children. This guideline provides a stepwise approach to assessment, triage, interdisciplinary treatment, and monitoring of status dystonicus. The clinical pathways aim to: (1) facilitate timely recognition/triage of worsening dystonia, (2) standardize supportive and dystonia-directed therapies, (3) provide structure for interdisciplinary cooperation, (4) integrate advances in genomics and neuromodulation, (5) enable multicenter quality improvement and research, and (6) improve outcomes. © 2024 International Parkinson and Movement Disorder Society.
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PURPOSE OF REVIEW: We highlight novel and emerging therapies in the treatment of childhood-onset movement disorders. We structured this review by therapeutic entity (small molecule drugs, RNA-targeted therapeutics, gene replacement therapy, and neuromodulation), recognizing that there are two main approaches to treatment: symptomatic (based on phenomenology) and molecular mechanism-based therapy or 'precision medicine' (which is disease-modifying). RECENT FINDINGS: We highlight reports of new small molecule drugs for Tourette syndrome, Friedreich's ataxia and Rett syndrome. We also discuss developments in gene therapy for aromatic l-amino acid decarboxylase deficiency and hereditary spastic paraplegia, as well as current work exploring optimization of deep brain stimulation and lesioning with focused ultrasound. SUMMARY: Childhood-onset movement disorders have traditionally been treated symptomatically based on phenomenology, but focus has recently shifted toward targeted molecular mechanism-based therapeutics. The development of precision therapies is driven by increasing capabilities for genetic testing and a better delineation of the underlying disease mechanisms. We highlight novel and exciting approaches to the treatment of genetic childhood-onset movement disorders while also discussing general challenges in therapy development for rare diseases. We provide a framework for molecular mechanism-based treatment approaches, a summary of specific treatments for various movement disorders, and a clinical trial readiness framework.
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Trastornos del Movimiento , Niño , Humanos , Estimulación Encefálica Profunda , Ataxia de Friedreich/terapia , Ataxia de Friedreich/genética , Terapia Genética/métodos , Trastornos del Movimiento/terapia , Medicina de Precisión/métodos , Síndrome de Rett/genética , Síndrome de Rett/terapia , Síndrome de Tourette/terapia , Síndrome de Tourette/genéticaRESUMEN
In the field of hereditary spastic paraplegia (HSP), progress in molecular diagnostics needs to be translated into robust phenotyping studies to understand genetic and phenotypic heterogeneity and to support interventional trials. ZFYVE26-associated hereditary spastic paraplegia (HSP-ZFYVE26, SPG15) is a rare, early-onset complex HSP, characterized by progressive spasticity and a variety of other neurological symptoms. While prior reports, often in populations with high rates of consanguinity, have established a general phenotype, there is a lack of systematic investigations and a limited understanding of age-dependent manifestation of symptoms. Here we delineate the clinical, neuroimaging and molecular features of 44 individuals from 36 families, the largest cohort assembled to date. Median age at last follow-up was 23.8 years covering a wide age range (11-61 years). While symptom onset often occurred in early childhood [median: 24 months, interquartile range (IQR) = 24], a molecular diagnosis was reached at a median age of 18.8 years (IQR = 8), indicating significant diagnostic delay. We demonstrate that most patients present with motor and/or speech delay or learning disabilities. Importantly, these developmental symptoms preceded the onset of motor symptoms by several years. Progressive spasticity in the lower extremities, the hallmark feature of HSP-ZFYVE26, typically presents in adolescence and involves the distal lower limbs before progressing proximally. Spasticity in the upper extremities was seen in 64%. We found a high prevalence of extrapyramidal movement disorders including cerebellar ataxia (64%) and dystonia (11%). Parkinsonism (16%) was present in a subset and showed no sustained response to levodopa. Cognitive decline and neurogenic bladder dysfunction progressed over time in most patients. A systematic analysis of brain MRI features revealed a common diagnostic signature consisting of thinning of the anterior corpus callosum, signal changes of the anterior forceps and non-specific cortical and cerebellar atrophy. The molecular spectrum included 45 distinct variants, distributed across the protein structure without mutational hotspots. Spastic Paraplegia Rating Scale scores, SPATAX Disability Scores and the Four Stage Functional Mobility Score showed moderate strength in representing the proportion of variation between disease duration and motor dysfunction. Plasma neurofilament light chain levels were significantly elevated in all patients (Mann-Whitney U-test, P < 0.0001) and were correlated inversely with age (Spearman's rank correlation coefficient r = -0.65, P = 0.01). In summary, our systematic cross-sectional analysis of HSP-ZFYVE26 patients across a wide age-range, delineates core clinical, neuroimaging and molecular features and identifies markers of disease severity. These results raise awareness to this rare disease, facilitate an early diagnosis and create clinical trial readiness.
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Paraplejía Espástica Hereditaria , Humanos , Preescolar , Paraplejía Espástica Hereditaria/genética , Estudios Transversales , Diagnóstico Tardío , Proteínas/genética , MutaciónRESUMEN
PURPOSE: LHX2 encodes the LIM homeobox 2 transcription factor (LHX2), which is highly expressed in brain and well conserved across species, but it has not been clearly linked to neurodevelopmental disorders (NDDs) to date. METHODS: Through international collaboration, we identified 19 individuals from 18 families with variable neurodevelopmental phenotypes, carrying a small chromosomal deletion, likely gene-disrupting or missense variants in LHX2. Functional consequences of missense variants were investigated in cellular systems. RESULTS: Affected individuals presented with developmental and/or behavioral abnormalities, autism spectrum disorder, variable intellectual disability, and microcephaly. We observed nucleolar accumulation for 2 missense variants located within the DNA-binding HOX domain, impaired interaction with co-factor LDB1 for another variant located in the protein-protein interaction-mediating LIM domain, and impaired transcriptional activation by luciferase assay for 4 missense variants. CONCLUSION: We implicate LHX2 haploinsufficiency by deletion and likely gene-disrupting variants as causative for a variable NDD. Our findings suggest a loss-of-function mechanism also for likely pathogenic LHX2 missense variants. Together, our observations underscore the importance of LHX2 in the nervous system and for variable neurodevelopmental phenotypes.
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Trastorno del Espectro Autista , Discapacidad Intelectual , Trastornos del Neurodesarrollo , Humanos , Proteínas con Homeodominio LIM/genética , Trastorno del Espectro Autista/genética , Haploinsuficiencia/genética , Trastornos del Neurodesarrollo/patología , Factores de Transcripción/genética , Discapacidad Intelectual/genética , Discapacidad Intelectual/complicacionesRESUMEN
Pathogenic variants in CWF19L1 lead to a rare autosomal recessive form of hereditary ataxia with only seven cases reported to date. Here, we describe four additional unrelated patients with biallelic variants in CWF19L1 (age range: 6-22 years) and provide a comprehensive review of the literature. The clinical spectrum was broad, including mild to profound global developmental delay; global or motor regression in infancy or adolescence; childhood-onset ataxia and cerebellar atrophy; and early-onset epilepsy. Since only two previously reported patients were adults, our cohort expands our understanding of the evolution of symptoms from childhood into early adulthood. Taken together, we describe that CWF19L1-related disorder presents with developmental and epileptic encephalopathy with treatment-resistant seizures and intellectual disability in childhood followed by progressive ataxia and other extrapyramidal movement disorders in adolescence.
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Ataxia Cerebelosa , Enfermedades Cerebelosas , Malformaciones del Sistema Nervioso , Degeneraciones Espinocerebelosas , Adolescente , Adulto , Niño , Humanos , Adulto Joven , Ataxia Cerebelosa/genética , Ataxia Cerebelosa/diagnóstico , Mutación , ConvulsionesRESUMEN
BACKGROUND: Adaptor protein complex 4-associated hereditary spastic paraplegia (AP-4-HSP) is caused by pathogenic biallelic variants in AP4B1, AP4M1, AP4E1, and AP4S1. OBJECTIVE: The aim was to explore blood markers of neuroaxonal damage in AP-4-HSP. METHODS: Plasma neurofilament light chain (pNfL) and glial fibrillary acidic protein (GFAP) levels were measured in samples from patients and age- and sex-matched controls (NfL: n = 46 vs. n = 46; GFAP: n = 14 vs. n = 21) using single-molecule array assays. Patients' phenotypes were systematically assessed using the AP-4-HSP natural history study questionnaires, the Spastic Paraplegia Rating Scale, and the SPATAX disability score. RESULTS: pNfL levels increased in AP-4-HSP patients, allowing differentiation from controls (Mann-Whitney U test: P = 3.0e-10; area under the curve = 0.87 with a 95% confidence interval of 0.80-0.94). Phenotypic cluster analyses revealed a subgroup of individuals with severe generalized-onset seizures and developmental stagnation, who showed differentially higher pNfL levels (Mann-Whitney U test between two identified clusters: P = 2.5e-6). Plasma GFAP levels were unchanged in patients with AP-4-HSP. CONCLUSIONS: pNfL is a potential disease marker in AP-4-HSP and can help differentiate between phenotypic subgroups. © 2023 International Parkinson and Movement Disorder Society.
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Complejo 4 de Proteína Adaptadora , Paraplejía Espástica Hereditaria , Humanos , Complejo 4 de Proteína Adaptadora/genética , Paraplejía Espástica Hereditaria/genética , Filamentos Intermedios/metabolismo , Fenotipo , MutaciónRESUMEN
Deficiency of the adaptor protein complex 4 (AP-4) leads to childhood-onset hereditary spastic paraplegia (AP-4-HSP): SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). This study aims to evaluate the impact of loss-of-function variants in AP-4 subunits on intracellular protein trafficking using patient-derived cells. We investigated 15 patient-derived fibroblast lines and generated six lines of induced pluripotent stem cell (iPSC)-derived neurons covering a wide range of AP-4 variants. All patient-derived fibroblasts showed reduced levels of the AP4E1 subunit, a surrogate for levels of the AP-4 complex. The autophagy protein ATG9A accumulated in the trans-Golgi network and was depleted from peripheral compartments. Western blot analysis demonstrated a 3-5-fold increase in ATG9A expression in patient lines. ATG9A was redistributed upon re-expression of AP4B1 arguing that mistrafficking of ATG9A is AP-4-dependent. Examining the downstream effects of ATG9A mislocalization, we found that autophagic flux was intact in patient-derived fibroblasts both under nutrient-rich conditions and when autophagy is stimulated. Mitochondrial metabolism and intracellular iron content remained unchanged. In iPSC-derived cortical neurons from patients with AP4B1-associated SPG47, AP-4 subunit levels were reduced while ATG9A accumulated in the trans-Golgi network. Levels of the autophagy marker LC3-II were reduced, suggesting a neuron-specific alteration in autophagosome turnover. Neurite outgrowth and branching were reduced in AP-4-HSP neurons pointing to a role of AP-4-mediated protein trafficking in neuronal development. Collectively, our results establish ATG9A mislocalization as a key marker of AP-4 deficiency in patient-derived cells, including the first human neuron model of AP-4-HSP, which will aid diagnostic and therapeutic studies.
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Complejo 4 de Proteína Adaptadora/genética , Complejo 4 de Proteína Adaptadora/metabolismo , Proteínas Relacionadas con la Autofagia/metabolismo , Proteínas de la Membrana/metabolismo , Transporte de Proteínas/genética , Paraplejía Espástica Hereditaria/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Red trans-Golgi/metabolismo , Complejo 4 de Proteína Adaptadora/deficiencia , Subunidades beta de Complejo de Proteína Adaptadora/metabolismo , Adolescente , Autofagosomas/metabolismo , Autofagia/genética , Línea Celular , Niño , Preescolar , Femenino , Fibroblastos/metabolismo , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Hierro/metabolismo , Mutación con Pérdida de Función , Masculino , Proteínas Asociadas a Microtúbulos/metabolismo , Mitocondrias/metabolismo , Neurogénesis/genética , Neuronas/metabolismo , Paraplejía Espástica Hereditaria/genética , Red trans-Golgi/genéticaRESUMEN
Early-onset forms of hereditary spastic paraplegia and inborn errors of metabolism that present with spastic diplegia are among the most common "mimics" of cerebral palsy. Early detection of these heterogenous genetic disorders can inform genetic counseling, anticipatory guidance, and improve outcomes, particularly where specific treatments exist. The diagnosis relies on clinical pattern recognition, biochemical testing, neuroimaging, and increasingly next-generation sequencing-based molecular testing. In this short review, we summarize the clinical and molecular understanding of: 1) childhood-onset and complex forms of hereditary spastic paraplegia (SPG5, SPG7, SPG11, SPG15, SPG35, SPG47, SPG48, SPG50, SPG51, SPG52) and, 2) the most common inborn errors of metabolism that present with phenotypes that resemble hereditary spastic paraplegia.
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Errores Innatos del Metabolismo , Degeneración Retiniana , Paraplejía Espástica Hereditaria , Niño , Humanos , Paraplejía Espástica Hereditaria/diagnóstico , Paraplejía Espástica Hereditaria/genética , Paraplejía Espástica Hereditaria/metabolismo , Fenotipo , Secuenciación de Nucleótidos de Alto Rendimiento , Mutación , Proteínas/genéticaRESUMEN
In 2016, the Movement Disorder Society Task Force for the Nomenclature of Genetic Movement Disorders presented a new system for naming genetically determined movement disorders and provided a criterion-based list of confirmed monogenic movement disorders. Since then, a substantial number of novel disease-causing genes have been described, which warrant classification using this system. In addition, with this update, we further refined the system and propose dissolving the imaging-based categories of Primary Familial Brain Calcification and Neurodegeneration with Brain Iron Accumulation and reclassifying these genetic conditions according to their predominant phenotype. We also introduce the novel category of Mixed Movement Disorders (MxMD), which includes conditions linked to multiple equally prominent movement disorder phenotypes. In this article, we present updated lists of newly confirmed monogenic causes of movement disorders. We found a total of 89 different newly identified genes that warrant a prefix based on our criteria; 6 genes for parkinsonism, 21 for dystonia, 38 for dominant and recessive ataxia, 5 for chorea, 7 for myoclonus, 13 for spastic paraplegia, 3 for paroxysmal movement disorders, and 6 for mixed movement disorder phenotypes; 10 genes were linked to combined phenotypes and have been assigned two new prefixes. The updated lists represent a resource for clinicians and researchers alike and they have also been published on the website of the Task Force for the Nomenclature of Genetic Movement Disorders on the homepage of the International Parkinson and Movement Disorder Society (https://www.movementdisorders.org/MDS/About/Committees--Other-Groups/MDS-Task-Forces/Task-Force-on-Nomenclature-in-Movement-Disorders.htm). © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.
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Distonía , Trastornos Distónicos , Trastornos del Movimiento , Enfermedad de Parkinson , Trastornos Parkinsonianos , Distonía/genética , Trastornos Distónicos/genética , Humanos , Trastornos del Movimiento/genética , Trastornos Parkinsonianos/genética , FenotipoRESUMEN
BACKGROUND: Familial hereditary spastic paraplegia (HSP)-SPAST (SPG4) typically presents with a pure HSP phenotype. OBJECTIVE: The aim of this study was to delineate the genotypic and phenotypic spectrum of children with de novo HSP-SPAST. METHODS: This study used a systematic cross-sectional analysis of clinical and molecular features. RESULTS: We report the clinical and molecular spectrum of 40 patients with heterozygous pathogenic de novo variants in SPAST (age range: 2.2-27.7 years). We identified 19 unique variants (16/40 carried the same recurrent variant, p.Arg499His). Symptom onset was in early childhood (median: 11.0 months, interquartile range: 6.0 months) with significant motor and speech delay, followed by progressive ascending spasticity, dystonia, neurogenic bladder dysfunction, gastrointestinal dysmotility, and epilepsy. The mean Spastic Paraplegia Rating Scale score was 32.8 ± 9.7 (standard deviation). CONCLUSIONS: These results confirm that de novo variants in SPAST lead to a severe and complex form of HSP that differs from classic familial pure HSP-SPAST. Clinicians should be aware of this syndrome in the differential diagnosis for cerebral palsy. © 2022 International Parkinson and Movement Disorder Society.
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Paraplejía Espástica Hereditaria , Preescolar , Humanos , Estudios Transversales , Espasticidad Muscular , Mutación , Fenotipo , Paraplejía Espástica Hereditaria/genética , Paraplejía Espástica Hereditaria/diagnóstico , Espastina/genética , Niño , Adolescente , Adulto Joven , AdultoRESUMEN
Bi-allelic loss-of-function variants in Von Willebrand factor type A (VWA1) were recently discovered to lead to an early onset motor neuropathy or neuromyopathy. What makes this discovery particularly notable is the high frequency of one of the VWA1 (NM_022834.5) founder variants, c.62_71dup (p.Gly25ArgfsTer74), which nears 0.01% in European populations, and suggests that there may be a wide spectrum of disease features and severity. Here, we report two cases from nonconsanguineous families in North America that presented in early childhood with lower extremity weakness and prominent foot deformities, and were found to carry bi-allelic variants in VWA1. We draw focus to upper motor neuron signs and abnormal gait phenotypes as presenting symptoms in VWA1-related disorder and expand the clinical and molecular spectrum.
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Pérdida de Heterocigocidad , Neuronas Motoras , Preescolar , Humanos , Alelos , Fenotipo , Marcha/genética , Proteínas de la Matriz ExtracelularRESUMEN
Childhood-onset forms of hereditary spastic paraplegia are ultra-rare diseases and often present with complex features. Next-generation-sequencing allows for an accurate diagnosis in many cases but the interpretation of novel variants remains challenging, particularly for missense mutations. Where sufficient knowledge of the protein function and/or downstream pathways exists, functional studies in patient-derived cells can aid the interpretation of molecular findings. We here illustrate the case of a 13-year-old female who presented with global developmental delay and later mild intellectual disability, progressive spastic diplegia, spastic-ataxic gait, dysarthria, urinary urgency, and loss of deep tendon reflexes of the lower extremities. Exome sequencing showed a novel splice-site variant in trans with a novel missense variant in B4GALNT1 [NM_001478.5: c.532-1G>C/c.1556G>C (p.Arg519Pro)]. Functional studies in patient-derived fibroblasts and cell models of GM2 synthase deficiency confirmed a loss of B4GALNT1 function with no synthesis of GM2 and other downstream gangliosides. Collectively these results established the diagnosis of B4GALNT1-associated HSP (SPG26). Our approach illustrates the importance of careful phenotyping and functional characterization of novel gene variants, particularly in the setting of ultra-rare diseases, and expands the clinical and molecular spectrum of SPG26, a disorder of complex ganglioside biosynthesis.
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Paraplejía Espástica Hereditaria , Adolescente , Niño , Femenino , Gangliósidos/genética , Humanos , Mutación , Linaje , Enfermedades Raras , Paraplejía Espástica Hereditaria/diagnóstico , Paraplejía Espástica Hereditaria/genéticaRESUMEN
Bi-allelic TECPR2 variants have been associated with a complex syndrome with features of both a neurodevelopmental and neurodegenerative disorder. Here, we provide a comprehensive clinical description and variant interpretation framework for this genetic locus. Through international collaboration, we identified 17 individuals from 15 families with bi-allelic TECPR2-variants. We systemically reviewed clinical and molecular data from this cohort and 11 cases previously reported. Phenotypes were standardized using Human Phenotype Ontology terms. A cross-sectional analysis revealed global developmental delay/intellectual disability, muscular hypotonia, ataxia, hyporeflexia, respiratory infections, and central/nocturnal hypopnea as core manifestations. A review of brain magnetic resonance imaging scans demonstrated a thin corpus callosum in 52%. We evaluated 17 distinct variants. Missense variants in TECPR2 are predominantly located in the N- and C-terminal regions containing ß-propeller repeats. Despite constituting nearly half of disease-associated TECPR2 variants, classifying missense variants as (likely) pathogenic according to ACMG criteria remains challenging. We estimate a pathogenic variant carrier frequency of 1/1221 in the general and 1/155 in the Jewish Ashkenazi populations. Based on clinical, neuroimaging, and genetic data, we provide recommendations for variant reporting, clinical assessment, and surveillance/treatment of individuals with TECPR2-associated disorder. This sets the stage for future prospective natural history studies.
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Proteínas Portadoras/genética , Neuropatías Hereditarias Sensoriales y Autónomas , Discapacidad Intelectual , Proteínas del Tejido Nervioso/genética , Adolescente , Proteínas Portadoras/química , Niño , Preescolar , Estudios de Cohortes , Estudios Transversales , Familia , Femenino , Neuropatías Hereditarias Sensoriales y Autónomas/complicaciones , Neuropatías Hereditarias Sensoriales y Autónomas/diagnóstico , Neuropatías Hereditarias Sensoriales y Autónomas/genética , Neuropatías Hereditarias Sensoriales y Autónomas/patología , Humanos , Lactante , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Imagen por Resonancia Magnética , Masculino , Modelos Moleculares , Mutación Missense , Proteínas del Tejido Nervioso/química , Neuroimagen/métodos , Linaje , Fenotipo , Conformación ProteicaRESUMEN
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
Autophagy is a fundamental and conserved catabolic pathway that mediates the degradation of macromolecules and organelles in lysosomes. Autophagy is particularly important to postmitotic and metabolically active cells such as neurons. The complex architecture of neurons and their long axons pose additional challenges for efficient recycling of cargo. Not surprisingly autophagy is required for normal central nervous system development and function. Several single-gene disorders of the autophagy pathway have been discovered in recent years giving rise to a novel group of inborn errors of metabolism referred to as congenital disorders of autophagy. While these disorders are heterogeneous, they share several clinical and molecular characteristics including a prominent and progressive involvement of the central nervous system leading to brain malformations, developmental delay, intellectual disability, epilepsy, movement disorders, and cognitive decline. On brain magnetic resonance imaging a predominant involvement of the corpus callosum, the corticospinal tracts and the cerebellum are noted. A storage disease phenotype is present in some diseases, underscoring both clinical and molecular overlaps to lysosomal storage diseases. This review provides an update on the clinical, imaging, and genetic spectrum of congenital disorders of autophagy and highlights the importance of this pathway for neurometabolism and childhood-onset neurological diseases.
Asunto(s)
Autofagia/fisiología , Discapacidades del Desarrollo/etiología , Enfermedades Neurodegenerativas/etiología , Agenesia del Cuerpo Calloso/etiología , Agenesia del Cuerpo Calloso/genética , Encéfalo/patología , Catarata/etiología , Catarata/genética , Niño , Discapacidades del Desarrollo/genética , Humanos , Imagen por Resonancia Magnética , Enfermedades Neurodegenerativas/genética , Proteínas/genética , Paraplejía Espástica Hereditaria/etiología , Paraplejía Espástica Hereditaria/genéticaRESUMEN
There are several hundred single-gene disorders that we classify as inborn errors of metabolism. Inborn errors of metabolism are often rare and highly heterogeneous multisystem diseases with non-neurological and neurological manifestations, commonly with onset during childhood. Movement disorders are among the most common neurological problems in inborn errors of metabolism, but, in many cases, remain poorly defined. Although movement disorders are usually not the only and often not the presenting symptom, their recognition can facilitate a diagnosis. Movement disorders contribute substantially to the morbidity in inborn errors of metabolism and can have a significant impact on quality of life. Common metabolic movement disorders include the monoamine neurotransmitter disorders, disorders of amino and organic acid metabolism, metal storage disorders, lysosomal storage disorders, congenital disorders of autophagy, disorders of creatine metabolism, vitamin-responsive disorders, and disorders of energy metabolism. Importantly, disease-modifying therapies exist for a number of inborn errors of metabolism, and early recognition and treatment can prevent irreversible CNS damage and reduce morbidity and mortality. A phenomenology-based approach, based on the predominant movement disorder, can facilitate a differential diagnosis and can guide biochemical, molecular, and imaging testing. The complexity of metabolic movement disorders demands an interdisciplinary approach and close collaboration of pediatric neurologists, neurologists, geneticists, and experts in metabolism. In this review, we develop a general framework for a phenomenology-based approach to movement disorders in inborn errors of metabolism and discuss an approach to identifying the "top ten" of treatable inborn errors of metabolism that present with movement disorders-diagnoses that should never be missed. © 2018 International Parkinson and Movement Disorder Society.