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OBJECTIVE: GNAO1-related disorders (OMIM #615473 and #617493), caused by variants in the GNAO1 gene, are characterized by developmental delay or intellectual disability, hypotonia, movement disorders, and epilepsy. Neither a genotype-phenotype correlation nor a clear severity score have been established for this disorder. The objective of this prospective and retrospective observational study was to develop a severity score for GNAO1-related disorders, and to delineate the correlation between the underlying molecular mechanisms and clinical severity. METHODS: A total of 16 individuals with GNAO1-related disorders harboring 12 distinct missense variants, including four novel variants (p.K46R, p.T48I, p.R209P, and p.L235P), were examined with repeated clinical assessments, video-electroencephalogram monitoring, and brain magnetic resonance imaging. The molecular pathology of each variant was delineated using a molecular deconvoluting platform. RESULTS: The patients displayed a wide variability in the severity of their symptoms. This heterogeneity was well represented in the GNAO1-related disorders severity score, with a broad range of results. Patients with the same variant had comparable severity scores, indicating that differences in disease profiles are not due to interpatient variability, but rather, to unique disease mechanisms. Moreover, we found a significant correlation between clinical severity scores and molecular mechanisms. INTERPRETATION: The clinical score proposed here provides further insight into the correlation between pathophysiology and phenotypic severity in GNAO1-related disorders. We found that each variant has a unique profile of clinical phenotypes and pathological molecular mechanisms. These findings will contribute to better understanding GNAO1-related disorders. Additionally, the severity score will facilitate standardization of patients categorization and assessment of response to therapies in development. ANN NEUROL 2023;94:987-1004.
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Epilepsia , Trastornos del Movimiento , Humanos , Estudios Prospectivos , Trastornos del Movimiento/genética , Epilepsia/diagnóstico por imagen , Epilepsia/genética , Mutación Missense , Proteínas de Unión al GTP/genética , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/genética , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/metabolismoRESUMEN
Hypothalamic hamartomas (HHs) are rare congenital lesions formed by heterotopic neuronal and glial cells attached to the mammillary bodies, tuber cinereum, and hypothalamus.They often present with an intractable epilepsy typically characterized by gelastic seizures but commonly associated with other types of refractory seizures. The clinical course is progressive in most of the cases, starting with gelastic seizures in infancy and deteriorating into complex seizure disorders that result in catastrophic epilepsy associated with cognitive decline and behavioral disturbances.Hamartomas are known to be intrinsically epileptogenic and the site of origin for the gelastic seizures. As antiepileptic drugs are typically ineffective in controlling HH-related epilepsy, different surgical options have been proposed as a treatment to achieve seizure control. Resection or complete disconnection of the hamartoma from the mammillothalamic tract has proved to achieve a long-lasting control of the epileptic syndrome.Usually, symptoms and their severity are typically related to the size, localization, and type of attachment. Precocious puberty appears mostly in the pedunculated type, while epileptic syndrome and behavioral decline are frequently related to the sessile type. For this reason, different classifications of HHs have been developed based on their size, extension, and type of attachment to the hypothalamus.The bigger and more complex hypothalamic hamartomas typically present with severe refractory epilepsy, behavioral disturbances, and progressive cognitive decline posing a formidable challenge for the control of these symptoms.We present here our experience with the multimodal treatment for complex hypothalamic hamartomas. After an in-depth review of the literature, we systematize our approach for the different types of hypothalamic hamartomas.
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Epilepsia Refractaria , Epilepsias Parciales , Síndromes Epilépticos , Hamartoma , Enfermedades Hipotalámicas , Humanos , Hamartoma/complicaciones , Terapia CombinadaRESUMEN
Low-grade gliomas, especially glioneuronal tumors, are a common cause of epilepsy in children. Seizures associated with low-grade pediatric tumors are medically refractory and present a significant burden to patients. Often, morbidity and patients´ quality of life are determined rather by the control of seizures than the oncological process itself and the resolution of epilepsy represents an important part in the treatment of LGGs. The pathogenesis of tumor-related seizures in focal LGG tumors is multifactorial, and mechanisms differ probably among patients and tumor types. Pediatric low-grade tumors associated with epilepsy include a series of neoplasms that have a pure astrocytic or glioneuronal lineage. They are usually benign tumors with a neocortical localization typically in the temporal lobes, but also in other supratentorial locations. Gangliogliomas and dysembryoplastic neuroepithelial tumors (DNET) are the most common entities together with astrocytic gliomas (pilocytic astrocytomas and pleomorphic xanthoastrocytoma) and angiocentric gliomas, and dual pathology is found in up to 40% of glioneuronal tumors. The treatment of low-grade gliomas and associated epilepsy is based mainly on resection and the extent of surgery is the main predictor of postoperative seizure control in patients with a LGG. Long-term epilepsy-associated tumors (LEATs) tend to be well-circumscribed, and therefore, the chances for a complete resection and epilepsy control with a safe approach are very high. New treatments have emerged as alternatives to open microsurgical approaches, including laser thermal ablation or the use of BRAF inhibitors. Future advances in identifying seizure-related biomarkers and molecular tumor pathways will facilitate targeted treatment strategies that will have a deep impact both in oncologic and epilepsy outcomes.
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The number of genes implicated in neurodevelopmental conditions is rapidly growing. Recently, variants in PPP2R1A have been associated with syndromic intellectual disability and a consistent, but still expanding, phenotype. The PPP2R1A gene encodes a protein subunit of the serine/threonine protein phosphatase 2A enzyme, which plays a critical role in cellular function. We report an individual showing pontocerebellar hypoplasia (PCH), microcephaly, optic and peripheral nerve abnormalities, and an absence of typical features like epilepsy and an abnormal corpus callosum. He bears an unreported variant in an atypical region of PPP2R1A. In silico studies, functional analysis using immunofluorescence, and super-resolution microscopy techniques were performed to investigate the pathogenicity of the variant. This analysis involved a comparative analysis of the patient's fibroblasts with both healthy control cells and cells from an individual with the previously described phenotype. The results showed reduced expression of PPP2R1A and the presence of aberrant protein aggregates in the patient's fibroblasts, supporting the pathogenicity of the variant. These findings suggest a potential association between PPP2R1A variants and PCH, expanding the clinical spectrum of PPP2R1A-related neurodevelopmental disorder. Further studies and descriptions of additional patients are needed to fully understand the genotype-phenotype correlation and the underlying mechanisms of this novel phenotype.
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Discapacidad Intelectual , Microscopía , Humanos , Masculino , Ojo , Fibroblastos , Proteína Fosfatasa 2/genética , Factores de TranscripciónRESUMEN
Signal sequence receptor protein 4 (SSR4) is a subunit of the translocon-associated protein complex, which participates in the translocation of proteins across the endoplasmic reticulum membrane, enhancing the efficiency of N-linked glycosylation. Pathogenic variants in SSR4 cause a congenital disorder of glycosylation: SSR4-congenital disorders of glycosylation (CDG). We describe three SSR4-CDG boys and review the previously reported. All subjects presented with hypotonia, failure to thrive, developmental delay, and dysmorphic traits and showed a type 1 serum sialotransferrin profile, facilitating the diagnosis. Genetic confirmation of this X-linked CDG revealed one de novo hemizygous deletion, one maternally inherited deletion, and one de novo nonsense mutation of SSR4. The present subjects highlight the similarities with a connective tissue disorder (redundant skin, joint laxity, blue sclerae, and vascular tortuosity). The connective tissue problems are relevant, and require preventive rehabilitation measures. As an X-linked disorder, genetic counseling is essential.
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Proteínas de Unión al Calcio , Trastornos Congénitos de Glicosilación , Glicoproteínas de Membrana , Receptores Citoplasmáticos y Nucleares , Receptores de Péptidos , Proteínas de Unión al Calcio/genética , Trastornos Congénitos de Glicosilación/diagnóstico , Trastornos Congénitos de Glicosilación/genética , Trastornos Congénitos de Glicosilación/patología , Tejido Conectivo/patología , Glicosilación , Humanos , Masculino , Glicoproteínas de Membrana/genética , Fenotipo , Receptores Citoplasmáticos y Nucleares/genética , Receptores de Péptidos/genéticaRESUMEN
BACKGROUND: Mitochondrial diseases (MD) are genetic metabolic disorders that impair normal mitochondrial structure or function. The aim of this study was to investigate the status of circulating cell-free mitochondrial DNA (ccfmtDNA) in cerebrospinal fluid (CSF), together with other biomarkers (growth differentiation factor-15 [GDF-15], alanine, and lactate), in a cohort of 25 patients with a molecular diagnosis of MD. METHODS: Measurement of ccfmtDNA was performed by using droplet digital PCR. RESULTS: The mean copy number of ccfmtDNA was approximately 6 times higher in the MD cohort compared to the control group; patients with mitochondrial deletion and depletion syndromes (MDD) had the higher levels. We also detected the presence of both wild-type mtDNA and mtDNA deletions in CSF samples of patients with single deletions. Patients with MDD with single deletions had significantly higher concentrations of GDF-15 in CSF than controls, whereas patients with point mutations in mitochondrial DNA presented no statistically significant differences. Additionally, we found a significant positive correlation between ccfmtDNA levels and GDF-15 concentrations (r = 0.59, P = 0.016). CONCLUSION: CSF ccfmtDNA levels are significantly higher in patients with MD in comparison to controls and, thus, they can be used as a novel biomarker for MD research. Our results could also be valuable to support the clinical outcome assessment of MD patients.
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Ácidos Nucleicos Libres de Células , Enfermedades Mitocondriales , Biomarcadores/líquido cefalorraquídeo , Ácidos Nucleicos Libres de Células/genética , ADN Mitocondrial/genética , Humanos , Mitocondrias/genética , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/genéticaRESUMEN
Early-onset severe spinocerebellar ataxia 42 with neurodevelopmental deficits (SCA42ND, MIM#604065) is an ultrarare autosomal dominant syndrome related to de novo CACNA1G gain-of-function pathogenic variants. All patients with SCA42ND show cerebellar atrophy and/or hypoplasia on neuroimaging and share common features such as dysmorphic features, global developmental delay, and axial hypotonia, all manifesting within the first year of life. To date, only 10 patients with SCA42ND have been reported with functionally confirmed gain-of-function variants, bearing either of two recurrent pathogenic variants. We describe a girl with congenital ataxia, without epilepsy, and a de novo p.Ala961Thr pathogenic variant in CACNA1G. We review the published subjects with the aim of better characterizing the dysmorphic features that may be crucial for clinical recognition of SCA42ND. Cerebellar atrophy, together with digital anomalies, particularly broad thumbs and/or halluces, should lead to clinical suspicion of this disease. We describe the first pharmacological attempt to treat a patient with SCA42ND using zonisamide, an antiepileptic drug with T-type channel blocker activity, in an off-label indication using an itemized study protocol. No efficacy was observed at the dose tested. However, without pharmacological treatment, she showed a positive evolution in neurodevelopment during the follow-up.
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Canales de Calcio Tipo T/genética , Epilepsia/genética , Hipotonía Muscular/genética , Ataxias Espinocerebelosas/genética , Edad de Inicio , Alelos , Preescolar , Epilepsia/complicaciones , Epilepsia/diagnóstico por imagen , Epilepsia/tratamiento farmacológico , Femenino , Mutación con Ganancia de Función/genética , Humanos , Lactante , Masculino , Hipotonía Muscular/complicaciones , Hipotonía Muscular/diagnóstico por imagen , Hipotonía Muscular/tratamiento farmacológico , Mutación , Linaje , Fenotipo , Ataxias Espinocerebelosas/complicaciones , Ataxias Espinocerebelosas/diagnóstico por imagen , Ataxias Espinocerebelosas/tratamiento farmacológico , Zonisamida/administración & dosificaciónRESUMEN
PURPOSE: Pediatric low-grade gliomas are the most frequent brain tumors in children. The standard approach for symptomatic unresectable tumors is chemotherapy. Recently, key molecular alterations/pathways have been identified and targeted drugs developed and tested in clinical trials. We describe our institutional experience with MAPK pathway targeted therapy. METHODS: We retrospectively reviewed the medical reports of 23 patients diagnosed with PLGG and treated with either trametinib or dabrafenib at Hospital Sant Joan de Dèu (Barcelona, Spain). Patients with neurofibromatosis were excluded. Objective response rate (ORR) and disease control rate (DCR) were determined using the Response Assessment in Pediatric Neuro-Oncology criteria in low-grade glioma. ORR was defined as the proportion of patients with the best overall response including complete remission (CR) or partial remission (PR). DCR was the sum of the CR, PR, and stable disease (SD) rates. RESULTS: ORR with trametinib was 0% (95% CI, 0%-23.2%) and DCR was 78.6% (95% CI, 49.2%-95.3%). Eleven patients had SD and three patients presented PD. ORR with dabrafenib was 41.7% (95% CI, 16.5%-71.4%), including four CR and one patient with PR. DCR with dabrafenib was 100% (95% CI, 73.5%-100%); there were seven SD and none PD. Treatment was well tolerated. Only three patients, on trametinib, presented grade 3 adverse effects: leukocytoclastic vasculitis, cheilitis, and bone infection. CONCLUSIONS: Our experience adds to the growing data about the efficacy and tolerability of targeted therapy in patients with PLGG. When present, toxicity is mainly mild-moderate and transient. Ongoing prospective clinical trials are trying to address if its use should be advanced to first-line therapy.
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Neoplasias Encefálicas , Glioma , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Encefálicas/tratamiento farmacológico , Niño , Glioma/tratamiento farmacológico , Humanos , Estudios Prospectivos , Estudios Retrospectivos , EspañaRESUMEN
BACKGROUND: Li-Fraumeni Syndrome (LFS) is a cancer predisposition syndrome characterized by the early-onset of multiple primary cancers which can occur at different moments (metachronous onset) or, more rarely, coincidentally (synchronous onset). Here we describe a previously unreported patient with presentation of synchronous Wilms tumor and Choroid plexus papilloma, leading to the diagnosis of a Li-Fraumeni Syndrome (LFS). CASE PRESENTATION: A 6-year-old girl without previous complains presented with abdominal pain. Abdominal US and MRI showed a left renal tumor with subcapsular hematoma. Due to mild headaches, the diagnostic workup included a brain MRI that unexpectedly identified a large left parietal lobe tumor. Histopathological analysis determined the diagnosis of classic Wilms tumor and choroid-plexus papilloma (CPP), respectively. Both neoplasms showed intense nuclear p53 immunostaining associated with the pathogenic TP53 mutation c.844C > T (p.Arg282Trp). Our patient and her father shared the same heterozygous germline TP53 mutation, confirming the diagnosis of familiar Li-Fraumeni syndrome in the girl. The treatment was tailored to simultaneous tumor presentations. CONCLUSIONS: LFS has been associated with Choroid plexus carcinoma (CPC), but rarely with CPP as in our patient. That suggests that it may be advisable to consider the possibility of analyzing TP53 mutation, not only in all patients with CPC, but also in some patients with CPP, especially when histological or clinical evidences point out to perform this study. The dissimilar presentation of LFS among our patient's father, not having so far any neoplasia diagnosed, while her daughter presented precociously with two simultaneous different tumors, could be related to possible effects of modifier genes on the underlying mutant p53 genotype.
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The CACNA1A gene encodes the pore-forming α1A subunit of the voltage-gated CaV2.1 Ca2+ channel, essential in neurotransmission, especially in Purkinje cells. Mutations in CACNA1A result in great clinical heterogeneity with progressive symptoms, paroxysmal events or both. During infancy, clinical and neuroimaging findings may be unspecific, and no dysmorphic features have been reported. We present the clinical, radiological and evolutionary features of three patients with congenital ataxia, one of them carrying a new variant. We report the structural localization of variants and their expected functional consequences. There was an improvement in cerebellar syndrome over time despite a cerebellar atrophy progression, inconsistent response to acetazolamide and positive response to methylphenidate. The patients shared distinctive facial gestalt: oval face, prominent forehead, hypertelorism, downslanting palpebral fissures and narrow nasal bridge. The two α1A affected residues are fully conserved throughout evolution and among the whole human CaV channel family. They contribute to the channel pore and the voltage sensor segment. According to structural data analysis and available functional characterization, they are expected to exert gain- (F1394L) and loss-of-function (R1664Q/R1669Q) effect, respectively. Among the CACNA1A-related phenotypes, our results suggest that non-progressive congenital ataxia is associated with developmental delay and dysmorphic features, constituting a recognizable syndromic neurodevelopmental disorder.
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Ataxia/patología , Canales de Calcio/genética , Mutación , Adulto , Secuencia de Aminoácidos , Ataxia/congénito , Ataxia/etiología , Ataxia/metabolismo , Canales de Calcio/química , Canales de Calcio/metabolismo , Niño , Femenino , Humanos , Masculino , Neuroimagen , Fenotipo , Conformación Proteica , Homología de Secuencia , Relación Estructura-Actividad , Adulto JovenRESUMEN
Okur-Chung neurodevelopmental syndrome (OCNS, MIM#617062) is a rare autosomal dominant syndrome related to CSNK2A1 mutations. It is characterized by intellectual disability, hypotonia, feeding and speech difficulties, dysmorphic features, and multisystem involvement. To date, less than 30 patients with OCNS have been described in detail in the literature, primarily in Asian populations. Here, we report a 5-year-old Spanish female with OCNS arising from a novel CSNK2A1 mutation c.149A>G, p.Tyr50Cys. Although her clinical features were compatible with OCNS syndrome, magnetic resonance imaging unexpectedly showed a duplication of the pituitary gland, a clinical finding not previously related to any known genetic condition. Other novel signs were an absence of the olfactory bulbs and multiple duplications of cervical vertebrae. We suggest that the midline abnormalities may be a significant part of this condition and lead to diagnostic suspicion. However, further descriptions are needed.
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Discapacidad Intelectual/genética , Anomalías Musculoesqueléticas/genética , Trastornos del Neurodesarrollo/genética , Quinasa de la Caseína II/genética , Preescolar , Femenino , Humanos , Discapacidad Intelectual/diagnóstico , Anomalías Musculoesqueléticas/diagnóstico , Anomalías Musculoesqueléticas/patología , Mutación/genética , Trastornos del Neurodesarrollo/diagnóstico , Trastornos del Neurodesarrollo/patología , Bulbo Olfatorio/patología , Hipófisis/patologíaRESUMEN
OBJECTIVE: To delineate the epileptic phenotype of LAMA2-related muscular dystrophy (MD) and correlate it with the neuroradiological and muscle biopsy findings, as well as the functional motor phenotype. METHODS: Clinical, electrophysiological, neuroradiological, and histopathological data of 25 patients with diagnosis of LAMA2-related MD were analyzed. RESULTS: Epilepsy occurred in 36% of patients with LAMA2-related MD. Mean age at first seizure was 8 years. The most common presenting seizure type was focal-onset seizures with or without impaired awareness. Visual aura and autonomic signs, including vomiting, were frequently reported. Despite a certain degree of variability, bilateral occipital or temporo-occipital epileptiform abnormalities were by far the most commonly observed. Refractory epilepsy was found in 75% of these patients. Epilepsy in LAMA2-related MD was significantly more prevalent in those patients in whom the cortical malformations were more extensive. In contrast, the occurrence of epilepsy was not found to be associated with the patients' motor ability, the size of their white matter abnormalities, or the amount of residual merosin expressed on muscle. SIGNIFICANCE: The epileptic phenotype of LAMA2-related MD is characterized by focal seizures with prominent visual and autonomic features associated with EEG abnormalities that predominate in the posterior quadrants. A consistent correlation between epileptic phenotype and neuroimaging was identified, suggesting that the extension of the polymicrogyria may serve as a predictor of epilepsy occurrence.
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Distrofias Musculares/congénito , Adolescente , Edad de Inicio , Anticonvulsivantes/uso terapéutico , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Encéfalo/fisiopatología , Niño , Preescolar , Electroencefalografía , Electromiografía , Femenino , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Distrofias Musculares/diagnóstico por imagen , Distrofias Musculares/tratamiento farmacológico , Distrofias Musculares/fisiopatología , Neuroimagen , Fenotipo , Adulto JovenRESUMEN
INTRODUCTION: Phosphomannomutase-2 deficiency (PMM2-CDG) is associated with a recognisable facial pattern. There are no early severity predictors for this disorder and no phenotype-genotype correlation. We performed a detailed dysmorphology evaluation to describe facial gestalt and its changes over time, to train digital recognition facial analysis tools and to identify early severity predictors. METHODS: Paediatric PMM2-CDG patients were evaluated and compared with controls. A computer-assisted recognition tool was trained. Through the evaluation of dysmorphic features (DFs), a simple categorisation was created and correlated with clinical and neurological scores, and neuroimaging. RESULTS: Dysmorphology analysis of 31 patients (4-19 years of age) identified eight major DFs (strabismus, upslanted eyes, long fingers, lipodystrophy, wide mouth, inverted nipples, long philtrum and joint laxity) with predictive value using receiver operating characteristic (ROC) curveanalysis (p<0.001). Dysmorphology categorisation using lipodystrophy and inverted nipples was employed to divide patients into three groups that are correlated with global clinical and neurological scores, and neuroimaging (p=0.005, 0.003 and 0.002, respectively). After Face2Gene training, PMM2-CDG patients were correctly identified at different ages. CONCLUSIONS: PMM2-CDG patients' DFs are consistent and inform about clinical severity when no clear phenotype-genotype correlation is known. We propose a classification of DFs into major and minor with diagnostic risk implications. At present, Face2Gene is useful to suggest PMM2-CDG. Regarding the prognostic value of DFs, we elaborated a simple severity dysmorphology categorisation with predictive value, and we identified five major DFs associated with clinical severity. Both dysmorphology and digital analysis may help physicians to diagnose PMM2-CDG sooner.
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Trastornos Congénitos de Glicosilación/diagnóstico , Trastornos Congénitos de Glicosilación/genética , Facies , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Fenotipo , Fosfotransferasas (Fosfomutasas)/deficiencia , Adolescente , Niño , Preescolar , Femenino , Pruebas Genéticas , Humanos , Masculino , Fosfotransferasas (Fosfomutasas)/genética , Curva ROC , España , Adulto JovenRESUMEN
PURPOSE: Real-time MRI-guided laser interstitial thermal therapy (LITT) is a challenging procedure due to its technical complexity, as well as the need for efficient multidisciplinary teamwork and transfer of an anesthetized patient between operating room (OR) and magnetic resonance (MR). A highly realistic simulation was developed to design the safest process before being applied to real patients. In this report, authors address the description of the methodology used for this simulation and its purposefulness. METHODS: The entire image planning, anesthetic, and surgical process were performed on a modified pediatric simulation mannequin with a brain made of medical grade silicone including a hypothalamic hamartoma. Preoperative CT and MR were acquired. Stereotactic insertion of the optical fiber was assisted by the Neuromate® stereotactic robot. Laser ablation was performed with the Medtronic Visualase® MRI-guided system in a 3T Phillips Ingenia® MR scanner. All the stages of the process, participants, and equipment were the same as planned for a real surgery. RESULTS: No critical errors were found in the process design that prevented the procedure from being performed with adequate safety. Specific proposals for team positioning and interaction in patient transfers and in MR room were validated. Some specific elements that could improve safety were identified. CONCLUSION: Highly realistic simulation has been an extremely useful tool for safely planning LITT, because professionals were able to take actions in the workflow based not on ideas but on lived experiences. It contributed definitively to build a well-coordinated surgical team that worked safely and more efficiently.
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Enfermedades Hipotalámicas , Terapia por Láser , Robótica , Niño , Hamartoma , Humanos , Enfermedades Hipotalámicas/cirugía , Rayos Láser , Imagen por Resonancia MagnéticaRESUMEN
Choroid plexus tumors (CPT) can present in the baseline magnetic resonance imaging (MRI) with lesions compatible with leptomeningeal dissemination. Therapeutic strategy in this condition is controversial. We present a case of an infant with CPP and significant diffuse leptomeningeal contrast enhancement at diagnosis, which spontaneously resolved after removal of the primary tumor. In these challenging cases, several aspects, such as histopathological/molecular diagnosis and close radiological follow-up, should be taken into account to avoid unnecessary treatments.
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Neoplasias Meníngeas/diagnóstico por imagen , Papiloma del Plexo Coroideo/diagnóstico por imagen , Plexo Coroideo/diagnóstico por imagen , Plexo Coroideo/patología , Diagnóstico Diferencial , Femenino , Humanos , Lactante , Imagen por Resonancia Magnética , Meninges/diagnóstico por imagen , Meninges/patología , Papiloma del Plexo Coroideo/patología , Papiloma del Plexo Coroideo/cirugíaRESUMEN
Stroke-like episodes (SLE) occur in phosphomannomutase deficiency (PMM2-CDG), and may complicate the course of channelopathies related to Familial Hemiplegic Migraine (FHM) caused by mutations in CACNA1A (encoding CaV2.1 channel). The underlying pathomechanisms are unknown. We analyze clinical variables to detect risk factors for SLE in a series of 43 PMM2-CDG patients. We explore the hypothesis of abnormal CaV2.1 function due to aberrant N-glycosylation as a potential novel pathomechanism of SLE and ataxia in PMM2-CDG by using whole-cell patch-clamp, N-glycosylation blockade and mutagenesis. Nine SLE were identified. Neuroimages showed no signs of stroke. Comparison of characteristics between SLE positive versus negative patients' group showed no differences. Acute and chronic phenotypes of patients with PMM2-CDG or CACNA1A channelopathies show similarities. Hypoglycosylation of both CaV2.1 subunits (α1A and α2α) induced gain-of-function effects on channel gating that mirrored those reported for pathogenic CACNA1A mutations linked to FHM and ataxia. Unoccupied N-glycosylation site N283 at α1A contributes to a gain-of-function by lessening CaV2.1 inactivation. Hypoglycosylation of the α2δ subunit also participates in the gain-of-function effect by promoting voltage-dependent opening of the CaV2.1 channel. CaV2.1 hypoglycosylation may cause ataxia and SLEs in PMM2-CDG patients. Aberrant CaV2.1 N-glycosylation as a novel pathomechanism in PMM2-CDG opens new therapeutic possibilities.
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Enfermedades Cerebelosas/complicaciones , Canalopatías/complicaciones , Fosfotransferasas (Fosfomutasas)/deficiencia , Accidente Cerebrovascular/complicaciones , Adolescente , Secuencia de Aminoácidos , Canales de Calcio/genética , Enfermedades Cerebelosas/diagnóstico por imagen , Canalopatías/diagnóstico por imagen , Niño , Preescolar , Electroencefalografía , Femenino , Glicosilación , Células HEK293 , Humanos , Activación del Canal Iónico/efectos de los fármacos , Imagen por Resonancia Magnética , Masculino , Mutación/genética , Fosfotransferasas (Fosfomutasas)/química , Fosfotransferasas (Fosfomutasas)/metabolismo , Accidente Cerebrovascular/diagnóstico por imagen , Tunicamicina/farmacologíaRESUMEN
OBJECTIVE: We aim to delineate the progression of cerebellar atrophy (the primary neuroimaging finding) in children with phosphomannomutase-deficiency (PMM2-CDG) by analyzing longitudinal MRI studies and performing cerebellar volumetric analysis and a 2D cerebellar measurement. METHODS: Statistical analysis was used to compare MRI measurements [midsagittal vermis relative diameter (MVRD) and volume] of children with PMM2-CDG and sex- and age-matched controls, and to determine the rate of progression of cerebellar atrophy at different ages. RESULTS: Fifty MRI studies of 33 PMM2-CDG patients were used for 2D evaluation, and 19 MRI studies were available for volumetric analysis. Results from a linear regression model showed that patients have a significantly lower MVRD and cerebellar volume compared to controls (p < 0.001 and p < 0.001 respectively). There was a significant negative correlation between age and MVRD for patients (p = 0.014). The rate of cerebellar atrophy measured by the loss of MVRD and cerebellar volume per year was higher at early ages (r = -0.578, p = 0.012 and r = -0.323, p = 0.48 respectively), particularly in patients under 11 years (p = 0.004). There was a significant positive correlation between MVRD and cerebellar volume in PMM2-CDG patients (r = 0.669, p = 0.001). CONCLUSIONS: Our study quantifies a progression of cerebellar atrophy in PMM2-CDG patients, particularly during the first decade of life, and suggests a simple and reliable measure, the MVRD, to monitor cerebellar atrophy. Quantitative measurement of MVRD and cerebellar volume are essential for correlation with phenotype and outcome, natural follow-up, and monitoring in view of potential therapies in children with PMM2-CDG.