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Patatin-like phospholipase domain-containing lipase 8 (PNPLA8), one of the calcium-independent phospholipase A2 enzymes, is involved in various physiological processes through the maintenance of membrane phospholipids. Biallelic variants in PNPLA8 have been associated with a range of paediatric neurodegenerative disorders. However, the phenotypic spectrum, genotype-phenotype correlations and the underlying mechanisms are poorly understood. Here, we newly identified 14 individuals from 12 unrelated families with biallelic ultra-rare variants in PNPLA8 presenting with a wide phenotypic spectrum of clinical features. Analysis of the clinical features of current and previously reported individuals (25 affected individuals across 20 families) showed that PNPLA8-related neurological diseases manifest as a continuum ranging from variable developmental and/or degenerative epileptic-dyskinetic encephalopathy to childhood-onset neurodegeneration. We found that complete loss of PNPLA8 was associated with the more profound end of the spectrum, with congenital microcephaly. Using cerebral organoids generated from human induced pluripotent stem cells, we found that loss of PNPLA8 led to developmental defects by reducing the number of basal radial glial cells and upper-layer neurons. Spatial transcriptomics revealed that loss of PNPLA8 altered the fate specification of apical radial glial cells, as reflected by the enrichment of gene sets related to the cell cycle, basal radial glial cells and neural differentiation. Neural progenitor cells lacking PNPLA8 showed a reduced amount of lysophosphatidic acid, lysophosphatidylethanolamine and phosphatidic acid. The reduced number of basal radial glial cells in patient-derived cerebral organoids was rescued, in part, by the addition of lysophosphatidic acid. Our data suggest that PNPLA8 is crucial to meet phospholipid synthetic needs and to produce abundant basal radial glial cells in human brain development.
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Intracellular trafficking involves an intricate machinery of motor complexes including the dynein complex to shuttle cargo for autophagolysosomal degradation. Deficiency in dynein axonemal chains as well as cytoplasmic light and intermediate chains have been linked with ciliary dyskinesia and skeletal dysplasia. The cytoplasmic dynein 1 heavy chain protein (DYNC1H1) serves as a core complex for retrograde trafficking in neuronal axons. Dominant pathogenic variants in DYNC1H1 have been previously implicated in peripheral neuromuscular disorders (NMD) and neurodevelopmental disorders (NDD). As heavy-chain dynein is ubiquitously expressed, the apparent selectivity of heavy-chain dyneinopathy for motor neuronal phenotypes remains currently unaccounted for. Here, we aimed to evaluate the full DYNC1H1-related clinical, molecular and imaging spectrum, including multisystem features and novel phenotypes presenting throughout life. We identified 47 cases from 43 families with pathogenic heterozygous variants in DYNC1H1 (aged 0-59 years) and collected phenotypic data via a comprehensive standardized survey and clinical follow-up appointments. Most patients presented with divergent and previously unrecognized neurological and multisystem features, leading to significant delays in genetic testing and establishing the correct diagnosis. Neurological phenotypes include novel autonomic features, previously rarely described behavioral disorders, movement disorders, and periventricular lesions. Sensory neuropathy was identified in nine patients (median age of onset 10.6 years), of which five were only diagnosed after the second decade of life, and three had a progressive age-dependent sensory neuropathy. Novel multisystem features included primary immunodeficiency, bilateral sensorineural hearing loss, organ anomalies, and skeletal manifestations, resembling the phenotypic spectrum of other dyneinopathies. We also identified an age-dependent biphasic disease course with developmental regression in the first decade and, following a period of stability, neurodegenerative progression after the second decade of life. Of note, we observed several cases in whom neurodegeneration appeared to be prompted by intercurrent systemic infections with double-stranded DNA viruses (Herpesviridae) or single-stranded RNA viruses (Ross-River fever, SARS-CoV-2). Moreover, the disease course appeared to be exacerbated by viral infections regardless of age and/or severity of NDD manifestations, indicating a role of dynein in anti-viral immunity and neuronal health. In summary, our findings expand the clinical, imaging, and molecular spectrum of pathogenic DYNC1H1 variants beyond motor neuropathy disorders and suggest a life-long continuum and age-related progression due to deficient intracellular trafficking. This study will facilitate early diagnosis and improve counselling and health surveillance of affected patients.
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PPP1R21 encodes for a conserved protein that is involved in endosomal maturation. Biallelic pathogenic variants in PPP1R21 have been associated with a syndromic neurodevelopmental disorder from studying 13 affected individuals. In this report, we present 11 additional individuals from nine unrelated families and their clinical, radiological, and molecular findings. We identified eight different variants in PPP1R21, of which six were novel variants. Global developmental delay and hypotonia are neurological features that were observed in all individuals. There is also a similar pattern of dysmorphic features with coarse faces as a gestalt observed in several individuals. Common findings in 75% of individuals with available brain imaging include delays in myelination, wavy outline of the bodies of the lateral ventricles, and slight prominence of the bodies of the lateral ventricles. PPP1R21-related neurodevelopmental disorder is associated with a consistent phenotype and should be considered in highly consanguineous individuals presenting with developmental delay/intellectual disability along with coarse facial features.
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Trastornos del Neurodesarrollo , Fenotipo , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/patología , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Mutación , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/patología , LinajeRESUMEN
Heterozygous variants in the Poly(U) Binding Splicing Factor 60kDa gene (PUF60) have been associated with Verheij syndrome, which has the key features of coloboma, short stature, skeletal abnormalities, developmental delay, palatal abnormalities, and congenital heart and kidney defects. Here, we report five novel patients from unrelated families with PUF60-related disorders exhibiting novel genetic and clinical findings with three truncating variants, one splice-site variant with likely reduced protein expression, and one missense variant. Protein modeling of the patient's missense variant in the PUF60 AlphaFold structure revealed a loss of polar bonds to the surrounding residues. Neurodevelopmental disorders were present in all patients, with variability in speech, motor, cognitive, social-emotional and behavioral features. Novel phenotypic expansions included movement disorders as well as immunological findings with recurrent respiratory, urinary and ear infections, atopic diseases, and skin abnormalities. We discuss the role of PUF60 in immunity with and without infection based on recent organismic and cellular studies. As our five patients showed less-severe phenotypes than classical Verheij syndrome, particularly with the absence of key features such as coloboma or palatal abnormalities, we propose a reclassification as PUF60-related neurodevelopmental disorders with multi-system involvement. These findings will aid in the genetic counseling of patients and families.
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Coloboma , Trastornos del Neurodesarrollo , Humanos , Mutación Missense , Trastornos del Neurodesarrollo/genética , Fenotipo , Factores de Empalme de ARN/genéticaRESUMEN
Autosomal-recessive mutations in the Alsin Rho guanine nucleotide exchange factor (ALS2) gene may cause specific subtypes of childhood-onset progressive neurodegenerative motor neuron diseases (MND). These diseases can manifest with a clinical continuum from infantile ascending hereditary spastic paraplegia (IAHSP) to juvenile-onset forms with or without lower motor neuron involvement, the juvenile primary lateral sclerosis (JPLS) and the juvenile amyotrophic lateral sclerosis (JALS). We report 11 patients from seven unrelated Turkish and Yemeni families with clinical signs of IAHSP or JPLS. We performed haplotype analysis or next-generation panel sequencing followed by Sanger Sequencing to unravel the genetic disease cause. We described their clinical phenotype and analyzed the pathogenicity of the detected variants with bioinformatics tools. We further reviewed all previously reported cases with ALS2-related MND. We identified five novel homozygous pathogenic variants in ALS2 at various positions: c.275_276delAT (p.Tyr92CysfsTer11), c.1044C>G (p.Tyr348Ter), c.1718C>A (p.Ala573Glu), c.3161T>C (p.Leu1054Pro), and c.1471+1G>A (NM_020919.3, NP_065970.2). In our cohort, disease onset was in infancy or early childhood with rapid onset of motor neuron signs. Muscle weakness, spasticity, severe dysarthria, dysphagia, and facial weakness were common features in the first decade of life. Frameshift and nonsense mutations clustered in the N-terminal Alsin domains are most prevalent. We enriched the mutational spectrum of ALS2-related disorders with five novel pathogenic variants. Our study indicates a high detection rate of ALS2 mutations in patients with a clinically well-characterized early onset MND. Intrafamilial and even interfamilial diversity in patients with identical pathogenic variants suggest yet unknown modifiers for phenotypic expression.
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Predisposición Genética a la Enfermedad , Factores de Intercambio de Guanina Nucleótido/genética , Enfermedad de la Neurona Motora/genética , Adolescente , Adulto , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/patología , Niño , Preescolar , Codón sin Sentido/genética , Femenino , Mutación del Sistema de Lectura/genética , Estudios de Asociación Genética , Humanos , Lactante , Masculino , Enfermedad de la Neurona Motora/clasificación , Enfermedad de la Neurona Motora/patología , Neuronas Motoras/metabolismo , Neuronas Motoras/patología , Paraplejía Espástica Hereditaria/genética , Paraplejía Espástica Hereditaria/patología , Adulto JovenRESUMEN
Mutations in the cytoplasmic dynein 1 heavy chain gene (DYNC1H1) have been identified in rare neuromuscular (NMD) and neurodevelopmental (NDD) disorders such as spinal muscular atrophy with lower extremity dominance (SMALED) and autosomal dominant mental retardation syndrome 13 (MRD13). Phenotypes and genotypes of ten pediatric patients with pathogenic DYNC1H1 variants were analyzed in a multi-center study. Data mining of large-scale genomic variant databases was used to investigate domain-specific vulnerability and conservation of DYNC1H1. We identified ten patients with nine novel mutations in the DYNC1H1 gene. These patients exhibit a broad spectrum of clinical findings, suggesting an overlapping disease manifestation with intermixed phenotypes ranging from neuropathy (peripheral nervous system, PNS) to severe intellectual disability (central nervous system, CNS). Genomic profiling of healthy and patient variant datasets underlines the domain-specific effects of genetic variation in DYNC1H1, specifically on toleration towards missense variants in the linker domain. A retrospective analysis of all published mutations revealed domain-specific genotype-phenotype correlations, i.e., mutations in the dimerization domain with reductions in lower limb strength in DYNC1H1-NMD and motor domain with cerebral malformations in DYNC1H1-NDD. We highlight that the current classification into distinct disease entities does not sufficiently reflect the clinical disease manifestation that clinicians face in the diagnostic work-up of DYNC1H1-related disorders. We propose a novel clinical classification for DYNC1H1-related disorders encompassing a spectrum from DYNC1H1-NMD with an exclusive PNS phenotype to DYNC1H1-NDD with concomitant CNS involvement.
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Encéfalo/diagnóstico por imagen , Dineínas Citoplasmáticas/genética , Genómica , Atrofia Muscular Espinal/genética , Encéfalo/anomalías , Encéfalo/patología , Análisis Mutacional de ADN , Femenino , Humanos , Lactante , Extremidad Inferior/diagnóstico por imagen , Extremidad Inferior/patología , Deformidades Congénitas de las Extremidades Inferiores/diagnóstico por imagen , Deformidades Congénitas de las Extremidades Inferiores/genética , Deformidades Congénitas de las Extremidades Inferiores/patología , Masculino , Atrofia Muscular Espinal/clasificación , Atrofia Muscular Espinal/diagnóstico por imagen , Atrofia Muscular Espinal/patología , Mutación Missense/genética , FenotipoRESUMEN
Rapid progress has recently been made in the elucidation of the genetic basis of childhood-onset inherited generalized dystonia (IGD) due to the implementation of genomic sequencing methodologies. We identified four patients with childhood-onset IGD harboring novel disease-causing mutations in lysine-specific histone methyltransferase 2B gene (KMT2B) by whole-exome sequencing. The main focus of this paper is to gain novel pathophysiological insights through understanding the molecular consequences of these mutations.The disease course is mostly progressive, evolving from lower limbs into generalized dystonia, which could be associated with dysarthria, dysphonia, intellectual disability, orofacial dyskinesia, and sometimes distinct dysmorphic facial features. In two patients, motor performances improved after bilateral implantation of deep brain stimulation in the globus pallidus internus (GPi-DBS). Pharmacotherapy with trihexyphenidyl reduced dystonia in two patients.We discovered three novel KMT2B mutations. Our analyses revealed that the mutation in patient 1 (c.7463 A > G, p.Y2488C) is localized in the highly conserved FYRC domain of KMT2B. This mutation holds the potential to alter the inter-domain FYR interactions, which could lead to KMT2B instability. The mutations in patients 2 and 3 (c.3602dupC, p.M1202Dfs*22; c.4229delA, p.Q1410Rfs*12) lead to predicted unstable transcripts, likely to be subject to degradation by non-sense mediated decay.Childhood-onset progressive dystonia with orofacial involvement is one of the main clinical manifestations of KMT2B mutations. In all, 26% (18/69) of the reported cases have T2 signal alterations of the globus pallidus internus, mostly at a younger age. Anticholinergic medication and GPi-DBS are promising treatment options and shall be considered early.An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Rapid progress has recently been made in the elucidation of the genetic basis of childhood-onset inherited generalized dystonia (IGD) due to the implementation of genomic sequencing methodologies. We identified four patients with childhood-onset IGD harboring novel disease-causing mutations in lysine-specific histone methyltransferase 2B gene (KMT2B) by whole-exome sequencing. The main focus of this paper is to gain novel pathophysiological insights through understanding the molecular consequences of these mutations. The disease course is mostly progressive, evolving from lower limbs into generalized dystonia, which could be associated with dysarthria, dysphonia, intellectual disability, orofacial dyskinesia, and sometimes distinct dysmorphic facial features. In two patients, motor performances improved after bilateral implantation of deep brain stimulation in the globus pallidus internus (GPi-DBS). Pharmacotherapy with trihexyphenidyl reduced dystonia in two patients. We discovered three novel KMT2B mutations. Our analyses revealed that the mutation in patient 1 (c.7463A > G, p.Y2488C) is localized in the highly conserved FYRC domain of KMT2B. This mutation holds the potential to alter the inter-domain FYR interactions, which could lead to KMT2B instability. The mutations in patients 2 and 3 (c.3596_3697insC, p.M1202Dfs*22; c.4229delA, p.Q1410Rfs*12) lead to predicted unstable transcripts, likely to be subject to degradation by non-sense-mediated decay. Childhood-onset progressive dystonia with orofacial involvement is one of the main clinical manifestations of KMT2B mutations. In all, 26% (18/69) of the reported cases have T2 signal alterations of the globus pallidus internus, mostly at a younger age. Anticholinergic medication and GPi-DBS are promising treatment options and shall be considered early.
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Distonía/diagnóstico , Distonía/etiología , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , N-Metiltransferasa de Histona-Lisina/genética , Mutación , Fenotipo , Edad de Inicio , Alelos , Niño , Preescolar , Progresión de la Enfermedad , Distonía/terapia , Femenino , Estudios de Asociación Genética/métodos , Genómica/métodos , Genotipo , N-Metiltransferasa de Histona-Lisina/química , Humanos , Masculino , Modelos Moleculares , Neuroimagen/métodos , Linaje , Conformación Proteica , Relación Estructura-Actividad , Evaluación de Síntomas , Secuenciación Completa del GenomaRESUMEN
Single gene (Mendelian) disorders are one of the leading causes of neonatal morbidity and mortality. However, in the setting of preterm birth phenotypic features of genetic diseases are often undifferentiated and are clinically very difficult to interpret based on the wide range of differential diagnoses. We report an extremely low birth weight infant (ELBW) born prematurely at 23 + 0 gestational weeks after twin pregnancy with a novel clinical manifestation with persistent hyperglycaemia as well as the known manifestations of disease-associated hypokinesia, renal salt wasting, and multifocal atrial tachycardia. The patient died of heart failure on the 72nd day of life. Whole exome sequencing (WES) revealed a previously well established, disease-causing heterozygous likely pathogenic variant in the Harvey rat sarcoma viral oncogene homolog (HRAS)-gene (c.35Gâ¯>â¯C, p. G12A, rs104894230), which implied the clinical diagnosis of Costello syndrome (CS; OMIM#190020.0004). The twin brother merely had complications related to preterm birth and did not show any CS symptoms. In conclusion, our case illustrated that CS should be considered in ELBW infants showing a life-threatening combination of complex cardiac arrhythmia and hypokinesia. If a syndromic disorder is suspected in the neonatal intensive care unit (NICU) setting, rapid WES is a useful, non-invasive diagnostic tool in critically ill ELBW infants.
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Secuenciación del Exoma/métodos , Embarazo Gemelar/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Resultado Fatal , Femenino , Humanos , Recien Nacido con Peso al Nacer Extremadamente Bajo/sangre , Recién Nacido , Recien Nacido Prematuro/sangre , Unidades de Cuidado Intensivo Neonatal , Masculino , Polimorfismo de Nucleótido Simple , EmbarazoAsunto(s)
Dineínas Citoplasmáticas/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Variación Genética , Neuronas/metabolismo , Fenotipo , Estudios de Asociación Genética/métodos , Humanos , Trastornos del Neurodesarrollo/diagnóstico , Trastornos del Neurodesarrollo/genética , Enfermedades Neuromusculares/diagnóstico , Enfermedades Neuromusculares/genéticaRESUMEN
Goldberg-Shprintzen megacolon syndrome (GOSHS) (OMIM 609460) is characterized by a combination of learning difficulties, characteristic dysmorphic features and Hirschsprung's disease. Variable clinical features include iris coloboma, congenital heart defects and central nervous system abnormalities, in particular polymicrogyria. GOSHS has been attributed to recessive mutations in KIAA1279, encoding kinesin family member (KIF)-binding protein (KBP) with a crucial role in neuronal microtubule dynamics. Here we report on a 7-year-old girl with GOSHS as a result of a homozygous deletion of exons 5 and 6 of the KIAA1279 gene. She had been referred with the suspicion of an underlying neuromuscular disorder before the genetic diagnosis was established, prompted by the findings of motor developmental delay, hypotonia, ptosis and absent reflexes. Neurophysiological studies revealed unequivocal evidence of a peripheral axonal sensory motor neuropathy. We hypothesize that an axonal sensory motor neuropathy may be part of the phenotypical spectrum of KIAA1279-related GOSHS, probably reflecting the effects of reduced KBP protein expression on peripheral neuronal function.
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Secuencia de Bases , Anomalías Craneofaciales/genética , Neuropatía Hereditaria Motora y Sensorial/genética , Enfermedad de Hirschsprung/genética , Proteínas del Tejido Nervioso/genética , Eliminación de Secuencia , Niño , Anomalías Craneofaciales/metabolismo , Anomalías Craneofaciales/patología , Exones , Femenino , Expresión Génica , Neuropatía Hereditaria Motora y Sensorial/metabolismo , Neuropatía Hereditaria Motora y Sensorial/patología , Enfermedad de Hirschsprung/metabolismo , Enfermedad de Hirschsprung/patología , Humanos , Datos de Secuencia Molecular , Proteínas del Tejido Nervioso/deficiencia , Células Receptoras Sensoriales/metabolismo , Células Receptoras Sensoriales/patologíaRESUMEN
SARS-CoV-2 infection causes transient cardiorespiratory and neurological disorders, and severe acute illness is rare among children. Post COVID-19 condition (PCC) may cause profound, persistent phenotypes with increasing prevalence. Its manifestation and risk factors remain elusive. In this monocentric study, we hypothesized that atopy, the tendency to produce an exaggerated immunoglobulin E (IgE) immune response, is a risk factor for the manifestation of pediatric PCC. We present a patient cohort (n = 28) from an early pandemic period (2021-2022) with comprehensive evaluations of phenotypes, pulmonary function, and molecular investigations. PCC predominantly affected adolescents and presented with fatigue, dyspnea, and post-exertional malaise. Sensitizations to aeroallergens were found in 93% of cases. We observed elevated IgE levels (mean 174.2 kU/L, reference < 100 kU/L) regardless of disease severity. Concurrent Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) was found in 29% of patients that also faced challenges in school attendance. ME/CFS manifestation was significantly associated with elevated immunoglobulin G subclasses IgG3 (p < 0.05) and IgG4 (p < 0.05). A total of 57% of patients showed self-limiting disease courses with mean recovery at 12.7 months (range 5-25 months), 29% at 19.2 months (range 12-30 months), and the rest demonstrated overall improvement. These findings offer additional insights into immune dysregulation as a risk factor for pediatric PCC.
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Biallelic variants in the Golgi SNAP receptor complex member 2 gene (GOSR2) have been reported in progressive myoclonus epilepsy with neurodegeneration. Typical clinical features include ataxia and areflexia during early childhood, followed by seizures, scoliosis, dysarthria, and myoclonus. Here, we report two novel patients from unrelated families with a GOSR2-related disorder and novel genetic and clinical findings. The first patient, a male compound heterozygous for the GOSR2 splice site variant c.336+1G>A and the novel c.364G>A,p.Glu122Lys missense variant showed global developmental delay and seizures at the age of 2 years, followed by myoclonus at the age of 8 years with partial response to clonazepam. The second patient, a female homozygous for the GOSR2 founder variant p.Gly144Trp, showed only mild fine motor developmental delay and generalized tonic-clonic seizures triggered by infections during adolescence, with seizure remission on levetiracetam. The associated movement disorder progressed atypically slowly during adolescence compared to its usual speed, from initial intention tremor and myoclonus to ataxia, hyporeflexia, dysmetria, and dystonia. These findings expand the genotype-phenotype spectrum of GOSR2-related disorders and suggest that GOSR2 should be included in the consideration of monogenetic causes of dystonia, global developmental delay, and seizures.
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Distonía , Trastornos Distónicos , Epilepsias Mioclónicas Progresivas , Mioclonía , Adolescente , Niño , Preescolar , Femenino , Humanos , Masculino , Ataxia/genética , Mutación , Epilepsias Mioclónicas Progresivas/genética , Proteínas Qb-SNARE/genética , ConvulsionesRESUMEN
PURPOSE: This study aims to present a family with two children with MSS who presented with different ophthalmic features. We also aim to review MSS patients' ocular manifestations to provide a basis for future clinical trials and improve MSS patients' ophthalmologic care. CASE DESCRIPTION: Both patients presented with global developmental delay, microcephaly, cerebellar ataxia, and myopathy. The older sibling had developed bilateral cataracts at the age of six. Her 2 years younger sister interestingly showed bilateral hyperopic refractive error without cataracts yet. Mendeliome sequencing unraveled a novel homozygous frameshift mutation in the SIL1 gene (SIL1, NM_022464.5, c.1042dupG, p.E348Gfs*4), causing MSS. A systematic literature review revealed that cataracts appear in 96% of MSS cases with a mean onset at 3.2 years. Additional frequent ocular features were strabismus (51.6%) and nystagmus (45.2%). CONCLUSION: SIL1-related MSS is associated with marked clinical variability. Cataracts can develop later than neuromuscular features and cognitive signs. Since cataract is a relatively late finding, patients may refer to ophthalmologists for other reasons such as refractive errors, strabismus, or nystagmus. Molecular genetic testing for SIL1 is essential to facilitate early diagnosis in patients with suspected MSS.
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Catarata , Degeneraciones Espinocerebelosas , Estrabismo , Catarata/complicaciones , Catarata/diagnóstico , Catarata/genética , Femenino , Estudios de Asociación Genética , Factores de Intercambio de Guanina Nucleótido/genética , Humanos , Degeneraciones Espinocerebelosas/complicaciones , Degeneraciones Espinocerebelosas/genética , Estrabismo/diagnóstico , Estrabismo/genéticaRESUMEN
OBJECTIVE: Intracellular signaling networks rely on proper membrane organization to control an array of cellular processes such as metabolism, proliferation, apoptosis, and macroautophagy in eukaryotic cells and organisms. Phosphatidylinositol 4-phosphate (PI4P) emerged as an essential regulatory lipid within organelle membranes that defines their lipid composition and signaling properties. PI4P is generated by four distinct phosphatidylinositol 4-kinases (PI4K) in mammalian cells: PI4KA, PI4KB, PI4K2A, PI4K2B. Animal models and human genetic studies suggest vital roles of PI4K enzymes in development and function of various organs, including the nervous system. Bi-allelic variants in PI4KA were recently associated with neurodevelopmental disorders (NDD), brain malformations, leukodystrophy, primary immunodeficiency, and inflammatory bowel disease. Here, we describe patients from two unrelated consanguineous families with PI4K2A deficiency and functionally explored the pathogenic mechanism. METHODS: Two patients with PI4K2A deficiency were identified by exome sequencing, presenting with developmental and epileptic-dyskinetic encephalopathy. Neuroimaging showed corpus callosum dysgenesis, diffuse white matter volume loss, and hypoplastic vermis. In addition to NDD, we observed recurrent infections and death at toddler age. We further explored identified variants with cellular assays. RESULTS: This clinical presentation overlaps with what was previously reported in two affected siblings with homozygous nonsense PI4K2A variant. Cellular studies analyzing these human variants confirmed their deleterious effect on PI4K2A activity and, together with the central role of PI4K2A in Rab7-associated vesicular trafficking, establish a link between late endosome-lysosome defects and NDD. INTERPRETATION: Our study establishes the genotype-phenotype spectrum of PI4K-associated NDD and highlights several commonalities with other innate errors of intracellular trafficking.
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Epilepsia Generalizada , Antígenos de Histocompatibilidad Menor , Malformaciones del Sistema Nervioso , Trastornos del Neurodesarrollo , Fosfotransferasas (Aceptor de Grupo Alcohol) , Epilepsia Generalizada/genética , Homocigoto , Humanos , Antígenos de Histocompatibilidad Menor/genética , Malformaciones del Sistema Nervioso/genética , Trastornos del Neurodesarrollo/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/genéticaRESUMEN
Apraxia is a common cognitive deficit after left hemisphere (LH) stroke. It has been suggested that a disturbed representation of the human body underlies apraxic imitation deficits. Thus, we here tested the hypothesis that a deficient body structural description (BSD), i.e., a deficient representation of a body part's position (relative to a standard human body), contributes to apraxic end-position errors in imitation, while controlling for deficits in the semantic representation of the human body (body image, BI) and naming deficits. A quantitative pointing task to assess putative BSD deficits and an apraxia assessment, including imitation and pantomime tasks, were applied to 27 patients with LH stroke and 19 healthy subjects. While LH stroke patients without apraxia (n=15) did not differ from control subjects in their pointing performance, patients suffering from imitation apraxia (n=10) showed a differential deficit when pointing to body parts of other humans compared to object parts. Voxel-based lesion symptom mapping (VLSM) revealed an association of these differential pointing deficits (indicating a deficient BSD) with lesions in the angular gyrus of the left inferior parietal cortex. This first quantitative group study of BSD deficits in LH stroke patients supports the notion that apraxic end-position errors in imitation are - at least in part - due to a deficient coding of the position of human body parts.
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Apraxias/fisiopatología , Encéfalo/fisiopatología , Conducta Imitativa/fisiología , Accidente Cerebrovascular/fisiopatología , Adulto , Anciano , Anciano de 80 o más Años , Apraxias/diagnóstico por imagen , Apraxias/etiología , Encéfalo/diagnóstico por imagen , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Lóbulo Parietal/diagnóstico por imagen , Lóbulo Parietal/fisiopatología , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/diagnóstico por imagenRESUMEN
Congenital myopathies (CM) form a genetically heterogeneous group of disorders characterized by perinatal muscle weakness. Here, we report an 11-year old male offspring of consanguineous parents of Lebanese origin. He presented with proximal weakness including Gower's sign, and skeletal muscle biopsy revealed myopathic changes with core-like structures. Whole exome sequencing of this index patient lead to the discovery of a novel genetically defined CM subtype based on bi-allelic mutations in the uncoordinated mutant number-45 myosin chaperone B (UNC45B) NM_173167:c.2261G > A, p.Arg754Gln. The mutation is conserved in evolution and co-segregates within the pedigree with the phenotype, and located in the myosin binding armadillo repeat domain 3 (ARM3), and has a CADD Score of 35. On a multimeric level, UNC45B aggregates to a chain which serves as an assembly line and functions as a "template" defining the geometry, regularity, and periodicity of myosin arranged into muscle thick filaments. Our discovery is in line with the previously described myopathological phenotypes in C. elegans and in vertebrate mutants and knockdown-models. In conclusion, we here report for the first time a patient with an UNC45B mutation causing a novel genetically defined congenital myopathy disease entity.
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Alelos , Chaperonas Moleculares/genética , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/genética , Mutación/genética , Secuencia de Aminoácidos , Niño , Humanos , Masculino , LinajeRESUMEN
Infants suffering from life-threatening apnea, stridor, cyanosis, and increased muscle tone may often be misdiagnosed with infantile seizures and inappropriately treated because of lack and delay in genetic diagnosis. Here, we report a patient with increased muscle tone after birth and hypertonic attacks with life-threatening apnea but no epileptiform patterns in EEG recordings. We identified novel compound heterozygous variants in SLC6A5 (NM_004211.4:c.[1429T > C];[1430delC]) by trio whole-exome sequencing, containing a base deletion inherited by the asymptomatic mother leading to a frameshift (c.1430delC, p.Ser477PhefsTer9) and a de novo base exchange leading to an amino acid change (c.1429T > C, p.Ser477Pro). To date, there are four known disease-associated genes for primary hyperekplexia, all of which are involved in the functioning of glycinergic synapses. SLC6A5 encodes the sodium- and chloride-dependent glycine transporter 2 (GlyT2), which recaptures glycine, a major inhibitory transmitter in the brainstem and spinal cord. The diagnosis altered the patient's medical care to his benefit because SLC6A5 mutations with rather benign courses of hyperekplexia may be spared of needless pharmacotherapy. Symptoms eventually decreased in frequency until about once in 2 mo at 2 yr age. We present the first report of halting hyperekplexia episodes by maternal soothing in multiple instances. We highlight the importance of clarifying the genetic diagnosis by rapid next-generation sequencing techniques in this group of infantile apneic attacks with hyperekplexia due to the broad differential diagnoses.
Asunto(s)
Proteínas de Transporte de Glicina en la Membrana Plasmática/genética , Hiperekplexia/genética , Apnea/genética , Preescolar , Proteínas de Transporte de Glicina en la Membrana Plasmática/metabolismo , Humanos , Hiperekplexia/terapia , Lactante , Masculino , Mutación , Secuenciación del Exoma/métodosRESUMEN
Aim: Initiated by students, this pilot study examines how obtaining medical students' perspectives via a structured online survey may prove useful for curriculum deliberation. Methods: In 2012, 747 students of 32 medical faculties in Germany assessed disciplines specified in the Medical Licensure Act (AÄpprO) thereby concerning the allocation of teaching time, perceived usefulness regarding preparation for state examination and medical practice, their interest and motivation for studying as well as consideration for future work. Results: Internal medicine, surgery, paediatrics, gynaecology/obstetrics and general medicine rank amongst the upper third regarding allocation of teaching time and perceived usefulness for future medical practice. Concerning both preparation for state examination and medical practice internal medicine ranks second, while surgery only 22nd and 28th of 32, respectively. Some clinical-theoretical disciplines (e.g. pharmacology) are in the top ten regarding perceived preparation for state examination, too. Students who consider choosing internal medicine for future work rate associated disciplines significantly higher regarding usefulness for clinical practice (e.g. pharmacology) or motivation for studying (e.g. microbiology) than other students do. Conclusion: A simple survey reveals interesting data on students' perceptions and ideas of medical studies. Though the data are plausible, interpretations should be done with caution. Nonetheless, data like these should give rise to further questions and discussions, e.g. as part of curriculum deliberation.