The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders.

Inherited glycosylphosphatidylinositol deficiency disorders (IGDs) are a group of rare multisystem disorders arising from pathogenic variants in glycosylphosphatidylinositol anchor pathway (GPI-AP) genes. Despite associating 24 of at least 31 GPI-AP genes with human neurogenetic disease, prior reports are limited to single genes without consideration of the GPI-AP as a whole and with limited natural history data. In this multinational retrospective observational study, we systematically analyse the molecular spectrum, phenotypic characteristics and natural history of 83 individuals from 75 unique families with IGDs, including 70 newly reported individuals; the largest single cohort to date. Core clinical features were developmental delay or intellectual disability (DD/ID, 90%), seizures (83%), hypotonia (72%) and motor symptoms (64%). Prognostic and biologically significant neuroimaging features included cerebral atrophy (75%), cerebellar atrophy (60%), callosal anomalies (57%) and symmetric restricted diffusion of the central tegmental tracts (60%). Sixty-one individuals had multisystem involvement including gastrointestinal (66%), cardiac (19%) and renal (14%) anomalies. Though dysmorphic features were appreciated in 82%, no single dysmorphic feature had a prevalence >30%, indicating substantial phenotypic heterogeneity. Follow-up data were available for all individuals, 15 of whom were deceased at the time of writing. Median age at seizure onset was 6 months. Individuals with variants in synthesis stage genes of the GPI-AP exhibited a significantly shorter time to seizure onset than individuals with variants in transamidase and remodelling stage genes of the GPI-AP (P = 0.046). Forty individuals had intractable epilepsy. The majority of individuals experienced delayed or absent speech (95%), motor delay with non-ambulance (64%), and severe-to-profound DD/ID (59%). Individuals with a developmental epileptic encephalopathy (51%) were at greater risk of intractable epilepsy (P = 0.003), non-ambulance (P = 0.035), ongoing enteral feeds (P < 0.001) and cortical visual impairment (P = 0.007). Serial neuroimaging showed progressive cerebral volume loss in 87.5% and progressive cerebellar atrophy in 70.8%, indicating a neurodegenerative process. Genetic analyses identified 93 unique variants (106 total), including 22 novel variants. Exploratory analyses of genotype-phenotype correlations using unsupervised hierarchical clustering identified novel genotypic predictors of clinical phenotype and long-term outcome with meaningful implications for management. In summary, we expand both the mild and severe phenotypic extremities of the IGDs, provide insights into their neurological basis, and vitally, enable meaningful genetic counselling for affected individuals and their families.

Primary endovascular treatment for acute ischemic stroke in teenage patients: a short case series.

PURPOSE: To analyze the safety and efficacy of primary endovascular treatment (EVT) for acute ischemic stroke (AIS) in patients younger than 18 years of age. METHODS: Review of 4 patients < 18 years of age with AIS, prospectively enrolled in an electronic database registry for acute ischemic stroke patients who underwent thrombectomy at tertiary centers, from January 2011 to February 2017. Clinical and imaging data were analyzed. RESULTS: All patients were female. Patients 1 to 4 were 14, 13, 16, and 13 years old, respectively. Patients 1 and 3 had left middle cerebral artery occlusion, patient 2 basilar occlusion, and patient 4 right tandem occlusion. Mean NIHSS score was 13 (7-19) on arrival and 4 (0-5) at 24 h. Patient 2 had Osler-Weber-Rendu disease and patient 4 a previously surgically repaired complete atrioventricular canal. All patients presented with clinical-radiological mismatch. CT/CTA was used in patients 1 and 4 and MRI/MRA in patients 2 and 3. Stent retriever was used in 3 patients (patients 1, 3, and 4) and direct aspiration first-pass technique in 1 (patient 2). All 4 procedures resulted in successful recanalization and 3-month functional independence. CONCLUSION: Primary EVT is reported in patients 13 to 16 years of age with AIS due to large vessel occlusion and clinical-radiological mismatch. Procedures were safe and effective with prompt recanalization and good clinical outcome.

Diagnostic challenge in children with an acquired demyelinating syndrome: an illustrative case report.

The clinical-radiological and biological overlap of the spectrum of pediatric demyelinating disorders makes the diagnostic process of a child with an acquired demyelinating syndrome truly challenging. We present a 9-year-old girl with subacute symptoms of severe decrease in bilateral visual acuity and gait ataxia. An urgent MRI showed inflammatory-demyelinating lesions affecting the periaqueductal gray matter, the cerebellar hemispheres, the area postrema as well as both optic nerves and chiasm. Likewise, multisegmental involvement of the cervical and dorsal spinal cord was found, with short and peripheral lesions. Anti myelin oligodendrocyte glycoprotein (MOG) antibodies (Abs) were positive in cerebrospinal fluid (CSF) and weakly in serum. Oligoclonal bands (OB) were positive in CSF. Based on all this, the diagnosis of MOG antibody disease (MOGAD) with a neuromyelitis optica spectrum disorder (NMOSD)-like picture was made. Given the good clinical and radiological recovery after the acute phase treatment, and that anti MOG Abs became negative, it was decided to keep the patient without specific treatment. However, during follow-up, while the patient was asymptomatic, a control brain MRI showed the appearance of new lesions with morphology and topography suggestive of multiple sclerosis (MS). This, added to the presence of OB, made the diagnosis of pediatric-onset MS (POMS) likely. Immunosuppressive treatment was restarted with a good response since then. Unlike adult-onset MS, children with POMS may usually not have entirely typical clinical and radiological features at presentation. In many cases, the time factor and close clinical and radiological monitoring could be critical to make an accurate diagnosis.

Brain paraneoplastic syndromes in a patient with mediastinal ganglioneuroma.

Paraneoplastic neurologic syndromes are a rare and heterogeneous group of immune-mediated syndromes caused by underlying solid and nonsolid tumors. We present a case of 8-year-old female with long history of mild headaches and central instability who presented multiple poorly defined signal abnormalities at the subcortical white matter of both cerebral hemispheres and cerebellar atrophy on brain magnetic resonance imaging. Further studies revealed a posterior mediastinum ganglioneuroma derived from a mature ganglioneuroblastoma that was treated with surgery. Two paraneoplastic neurologic syndromes were considered: Anti-N-Methyl-D-Aspartate Receptor (NMDAR) encephalitis due to the resolution of subcortical signal abnormalities after mediastinal mass resection and opsoclonus-myoclonus-ataxia syndrome due to cerebellar atrophy. Intertnational guideline established the criteria for definite diagnosis of paraneoplastic neurologic syndromes and detection of onconeural antibodies is not mandatory for their diagnosis. Paraneoplastic neurologic syndromes may appear several years before the tumor is detected.

Tumor neuroectodérmico primitivo supratentorial / No disponible

No disponible