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Glioblastoma (GBM), similar to most cancers, is dependent on fermentation metabolism for the synthesis of biomass and energy (ATP) regardless of the cellular or genetic heterogeneity seen within the tumor. The transition from respiration to fermentation arises from the documented defects in the number, the structure, and the function of mitochondria and mitochondrial-associated membranes in GBM tissue. Glucose and glutamine are the major fermentable fuels that drive GBM growth. The major waste products of GBM cell fermentation (lactic acid, glutamic acid, and succinic acid) will acidify the microenvironment and are largely responsible for drug resistance, enhanced invasion, immunosuppression, and metastasis. Besides surgical debulking, therapies used for GBM management (radiation, chemotherapy, and steroids) enhance microenvironment acidification and, although often providing a time-limited disease control, will thus favor tumor recurrence and complications. The simultaneous restriction of glucose and glutamine, while elevating non-fermentable, anti-inflammatory ketone bodies, can help restore the pH balance of the microenvironment while, at the same time, providing a non-toxic therapeutic strategy for killing most of the neoplastic cells.
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Objective: Krabbe disease is a fatal leukodystrophy caused by deficiency in galactocerebrosidase enzyme activity. The only currently available therapy is hematopoietic stem cell transplantation with bone marrow or umbilical cord blood (UCBT), which leads to increased lifespan and functional abilities when performed in the preclinical stage. While stabilization of white matter disease has been seen on serial MRI studies, neuropathological changes following transplantation have not been documented so far. Materials and Methods: We report the first postmortem examination of a 15-year-old female patient with infantile Krabbe disease after UCBT in infancy. Results: In contrast to an untreated Krabbe disease brain, which showed severe myelin and oligodendrocyte loss with occasional globoid cells, the transplanted brain displayed markedly improved myelin preservation, but not reaching normal myelination levels. Consistent with the transplanted patient's clinical presentation of pronounced deficits in gross motor skills, corticospinal tracts were most severely affected. No globoid cells or evidence of active demyelination were observed in the central nervous system, indicative of at least partially successful functional restoration. This was corroborated by the identification of male donor-derived cells in the brain by in situ hybridization. Unlike the observed disease stabilization in the central nervous system, the patient experienced progressive peripheral neuropathy. While diminished macrophage infiltration was seen postmortem, peripheral nerves exhibited edema, myelin and axon loss and persistent Schwann cell ultrastructural inclusions. Conclusion: Umbilical cord blood transplantation was able to alter the natural disease progression in the central but less so in the peripheral nervous system, possibly due to limited cross-correction of Schwann cells.
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Background: Successful treatment of glioblastoma (GBM) remains futile despite decades of intense research. GBM is similar to most other malignant cancers in requiring glucose and glutamine for growth, regardless of histological or genetic heterogeneity. Ketogenic metabolic therapy (KMT) is a non-toxic nutritional intervention for cancer management. We report the case of a 32-year-old man who presented in 2014 with seizures and a right frontal lobe tumor on MRI. The tumor cells were immunoreactive with antibodies to the IDH1 (R132H) mutation, P53 (patchy), MIB-1 index (4-6%), and absent ATRX protein expression. DNA analysis showed no evidence of methylation of the MGMT gene promoter. The presence of prominent microvascular proliferation and areas of necrosis were consistent with an IDH-mutant glioblastoma (WHO Grade 4). Methods: The patient refused standard of care (SOC) and steroid medication after initial diagnosis, but was knowledgeable and self-motivated enough to consume a low-carbohydrate ketogenic diet consisting mostly of saturated fats, minimal vegetables, and a variety of meats. The patient used the glucose ketone index calculator to maintain his Glucose Ketone Index (GKI) near 2.0 without body weight loss. Results: The tumor continued to grow slowly without expected vasogenic edema until 2017, when the patient opted for surgical debulking. The enhancing area, centered in the inferior frontal gyrus, was surgically excised. The pathology specimen confirmed IDH1-mutant GBM. Following surgery, the patient continued with a self-administered ketogenic diet to maintain low GKI values, indicative of therapeutic ketosis. At the time of this report (May 2021), the patient remains alive with a good quality of life, except for occasional seizures. MRI continues to show slow interval progression of the tumor. Conclusion: This is the first report of confirmed IDH1-mutant GBM treated with KMT and surgical debulking without chemo- or radiotherapy. The long-term survival of this patient, now at 80 months, could be due in part to a therapeutic metabolic synergy between KMT and the IDH1 mutation that simultaneously target the glycolysis and glutaminolysis pathways that are essential for GBM growth. Further studies are needed to determine if this non-toxic therapeutic strategy could be effective in providing long-term management for other GBM patients with or without IDH mutations.
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In abusive head trauma victims, optic nerves and optic sheath hemorrhages are commonly associated with retinal hemorrhages. Until now, optic nerve and optic nerve sheath hemorrhages related to abusive head trauma have been identified by exenteration and soft-tissue sectioning during postmortem examination. In 2013, we proposed the use of tailored high-resolution susceptibility-weighted imaging (SWI) MRI sequences to depict retinal hemorrhages in lieu of the gold standard dilated fundus exam, in select patients, and in 2017 we showed how the same high-resolution sequences used in the coronal plane can depict ruptured bridging veins in abusive head trauma. This paper describes the new potential diagnostic application of high-resolution axial and coronal SWI in the diagnosis of optic nerve and optic sheath hemorrhages.
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Maltrato a los Niños , Traumatismos Craneocerebrales , Niño , Humanos , Lactante , Imagen por Resonancia Magnética , Nervio Óptico/diagnóstico por imagen , Hemorragia Retiniana/diagnóstico por imagenRESUMEN
Abusive head trauma (AHT) is the leading cause of fatal head injuries in children younger than 2 years. An intracranial pathology can exist even in the setting of a normal physical exam. A delay in the diagnosis of AHT can have serious life-threatening consequences for the child and increases the potential the child will be abused again. In this article, we review the traumatic subdural hematoma as well as various morpho-structural patterns of shearing injuries and thrombosis of intracranial bridging veins. This work serves as a summary of patterns of imaging features of intracranial venous injury in AHT, as described in the literature, to facilitate familiarity and early detection of abusive head trauma in the pediatric population. Essentially, in AHT there is a traumatic injury to the bridging vein with either partial or complete tear. This can secondarily result in thrombosis at the terminal end of the bridging vein with blood clots adjacent to the bridging vein.
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Maltrato a los Niños , Traumatismos Craneocerebrales , Lesiones del Sistema Vascular , Niño , Maltrato a los Niños/diagnóstico , Traumatismos Craneocerebrales/diagnóstico por imagen , Hematoma Subdural/diagnóstico por imagen , Humanos , Lactante , Estudios RetrospectivosRESUMEN
The use of the ketogenic diet (KD) as an adjuvant therapy in high-grade gliomas (HGG) is supported by preclinical studies, but clinical data on its effects on metabolism are currently lacking. In this study, we describe the effects of a KD on glucose profile, ketonemia, energy metabolism, and nutritional status, in adults affected by HGG. This was a single-arm prospective study. An isocaloric 3:1 KD was administered for 1 mo. Glucose profile was assessed by using fasting glycemia, insulin, and glycated hemoglobin. To evaluate ketonemia changes, a hand-held ketone meter was used from home. Energy metabolism was assessed by indirect calorimetry. Nutritional status was evaluated through changes in body composition and in lipid and hepatic profile. No changes in fasting glycemia were observed; however, insulinemia dropped to half of baseline levels. The KD shifted the metabolism, rising ketonemia and decreasing glucose oxidation rate to a quarter of the initial values. Moreover, the KD was generally safe. One-month intervention with the KD was able to act upon key metabolic substrates potentially involved in HGG metabolism. The lack of a significant reduction in fasting glycemia should be investigated in future studies.
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Dieta Cetogénica , Glioma , Adulto , Glucosa , Humanos , Insulina , Estudios ProspectivosRESUMEN
Retinal hemorrhages are an integral part of the evaluation of abusive head trauma (AHT). Timely detection of retinal hemorrhage not only facilitates the diagnosis of AHT, but has the potential to prevent further abuse to the child and the siblings and to identify the abuser. The gold standard for diagnosing retinal hemorrhage is a dilated fundoscopy exam, which requires pharmacological dilation. As such, there is a small percentage of patients for whom the dilated fundoscopy exam might be delayed. Evolving literature suggests that MRI, specifically susceptibility-weighted imaging (SWI), of the orbits might provide an alternative diagnostic tool for noninvasively detecting retinal hemorrhages, particularly when there is a delay in administering the dilated fundoscopy exam. In this paper we review the utility of SWI for detecting retinal hemorrhages in abusive head trauma, including discussion of diagnostic limitations and future research.
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Maltrato a los Niños , Traumatismos Craneocerebrales , Niño , Maltrato a los Niños/diagnóstico , Traumatismos Craneocerebrales/complicaciones , Traumatismos Craneocerebrales/diagnóstico por imagen , Humanos , Lactante , Imagen por Resonancia Magnética , Neuroimagen , Hemorragia Retiniana/diagnóstico por imagenRESUMEN
PURPOSE: Until now, the diagnosis of optic nerves hemorrhages in abusive head trauma (AHT) has been obtained only in the postmortem setting. The aim of the IRB-approved study was to assess the presence of optic nerves hemorrhages in AHT patients using 3D-SWI. METHODS: Thirteen children with a final confirmed multidisciplinary diagnosis of AHT underwent coronal and axial 3D-SWI imaging of the orbits. The presence of optic nerve sheath (ONS) hemorrhages was defined by thickening and marked 3D-SWI hypointensity of the ONS, resulting in mass effect upon the CSF space. Optic nerve (ON) hemorrhages were defined by areas of susceptibility artifacts in the ON parenchyma. Superficial siderosis was defined by susceptibility artifact coating the ON. Furthermore, data about post-traumatic deformity of the ONS at the head of the optic nerve were collected. RESULTS: The average age of the population was 7.9 ± 5.9 months old. The average GCS was 11.8 ± 4.5. The male to female ratio was 7:6. ONS hemorrhages were identified in 69.2% of cases. Superficial siderosis and ON hemorrhages were identified in 38.5 and 76.9% of cases, respectively. 3D-SWI also depicted traumatic deformity of the ONS at the level of the optic nerve head in 10 cases (76.9%). No statistical correlations were identified between RetCam findings and 3D-SWI findings or GCS and ON hemorrhages. CONCLUSION: This research shows that dedicated MRI with volumetric SWI of the orbits can depict hemorrhages in the ON, ONS, and ONS injury, in AHT victims.
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Maltrato a los Niños , Traumatismos Craneocerebrales , Niño , Traumatismos Craneocerebrales/complicaciones , Traumatismos Craneocerebrales/diagnóstico por imagen , Femenino , Humanos , Lactante , Masculino , Nervio Óptico/diagnóstico por imagen , Proyectos Piloto , Hemorragia Retiniana/diagnóstico por imagen , Hemorragia Retiniana/etiologíaRESUMEN
INTRODUCTION: Glioblastoma (GBM) has poor survival with standard treatment. Experimental data suggest potential for metabolic treatment with low carbohydrate ketogenic diet (KD). Few human studies of KD in GBM have been done, limited by difficulty and variability of the diet, compliance, and feasibility issues. We have developed a novel KD approach of total meal replacement (TMR) program using standardized recipes with ready-made meals. This pilot study evaluated feasibility, safety, tolerability, and efficacy of GBM treatment using TMR program with "classic" 4:1 KD. METHOD: GBM patients were treated in an open-label study for 6 months with 4:1 [fat]:[protein + carbohydrate] ratio by weight, 10 g CH/day, 1600 kcal/day TMR. Patients were either newly diagnosed (group 1) and treated adjunctively to radiation and temozolomide or had recurrent GBM (group 2). Patients checked blood glucose and blood and urine ketone levels twice daily and had regular MRIs. Primary outcome measures included retention, treatment-emergent adverse events (TEAEs), and TEAE-related discontinuation. Secondary outcome measures were survival time from treatment initiation and time to MRI progression. RESULTS: Recruitment was slow, resulting in early termination of the study. Eight patients participated, 4 in group 1 and 4 in group 2. Five (62.5%) subjects completed the 6 months of treatment, 4/4 subjects in group 1 and 1/4 in group 2. Three subjects stopped KD early: 2 (25%) because of GBM progression and one (12.5%) because of diet restrictiveness. Four subjects, all group 1, continued KD on their own, three until shortly before death, for total of 26, 19.3, and 7 months, one ongoing. The diet was well tolerated. TEAEs, all mild and transient, included weight loss and hunger (n = 6) which resolved with caloric increase, nausea (n = 2), dizziness (n = 2), fatigue, and constipation (n = 1 each). No one discontinued KD because of TEAEs. Seven patients died. For these, mean (range) survival time from diet initiation was 20 months for group 1 (9.5-27) and 12.8 months for group 2 (6.3-19.9). Mean survival time from diagnosis was 21.8 months for group 1 (11-29.2) and 25.4 months for group 2 ( 13.9-38.7). One patient with recurrent GBM and progression on bevacizumab experienced a remarkable symptom reversal, tumor shrinkage, and edema resolution 6-8 weeks after KD initiation and survival for 20 months after starting KD. CONCLUSION: Treatment of GBM patients with 4:1 KD using total meal replacement program with standardized recipes was well tolerated. The small sample size limits efficacy conclusions. TRIAL REGISTRATION: NCT01865162 registered 30 May 2013, and NCT02302235 registered 26 November 2014, https://clinicaltrials.gov/.
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Rationale and Objectives: To compare cerebral pulsed arterial spin labeling (PASL) perfusion among controls, hypoxic ischemic encephalopathy (HIE) neonates with normal conventional MRI(HIE/MRIâ), and HIE neonates with abnormal conventional MRI(HIE/MRIâ). To create a predictive machine learning model of neurodevelopmental outcomes using cerebral PASL perfusion. Materials and Methods: A total of 73 full-term neonates were evaluated. The cerebral perfusion values were compared by permutation test to identify brain regions with significant perfusion changes among 18 controls, 40 HIE/MRIâ patients, and 15 HIE/MRIâ patients. A machine learning model was developed to predict neurodevelopmental outcomes using the averaged perfusion in those identified brain regions. Results: Significantly decreased PASL perfusion in HIE/MRIâ group, when compared with controls, were found in the anterior corona radiata, caudate, superior frontal gyrus, precentral gyrus. Both significantly increased and decreased cerebral perfusion changes were detected in HIE/MRIâ group, when compared with HIE/MRIâ group. There were no significant perfusion differences in the cerebellum, brainstem and deep structures of thalamus, putamen, and globus pallidus among the three groups. The machine learning model demonstrated significant correlation (p < 0.05) in predicting language(r = 0.48) and motor(r = 0.57) outcomes in HIE/MRIâ patients, and predicting language(r = 0.76), and motor(r = 0.53) outcomes in an additional group combining HIE/MRIâ and HIE/MRIâ. Conclusion: Perfusion MRI can play an essential role in detecting HIE regardless of findings on conventional MRI and predicting language and motor outcomes in HIE survivors. The perfusion changes may also reveal important insights into the reperfusion response and intrinsic autoregulatory mechanisms. Our results suggest that perfusion imaging may be a useful adjunct to conventional MRI in the evaluation of HIE in clinical practice.
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OBJECTIVES: To evaluate the incidence of anemia in patients with abusive head trauma (AHT), noninflicted traumatic brain injury (TBI), and physical abuse without AHT and the effect of anemia on outcome. STUDY DESIGN: In a retrospective, single-center cohort study, we included children under the age of 3 years diagnosed with either AHT (n = 75), noninflicted TBI (n = 77), or physical abuse without AHT (n = 60) between January 1, 2014, and December 31, 2016. Neuroimaging was prospectively analyzed by pediatric neuroradiologists. Primary outcome was anemia at hospital presentation. Secondary outcomes included unfavorable outcome at hospital discharge, defined as a Glasgow Outcome Scale between 1 and 3, and intracranial hemorrhage (ICH) volume. RESULTS: Patients with AHT had a higher rate of anemia on presentation (47.3%) vs noninflicted TBI (15.6%) and physical abuse without AHT (10%) (P < .001). Patients with AHT had larger ICH volumes (33.3 mL [10.1-76.4 mL] vs 1.5 mL [0.6-5.2 mL] ; P < .001) and greater ICH/total brain volume percentages than patients with noninflicted TBI (4.6% [1.4-8.2 %] vs 0.2% [0.1-0.7%]; P < .001). Anemia was associated with AHT (OR, 4.7; 95% CI, 2.2-10.2) and larger ICH/total brain volume percentage (OR, 1.1; 95% CI, 1.1-1.2) in univariate analysis. Unfavorable outcome at hospital discharge was associated with anemia (OR, 4.4; 95% CI, 1.6-12.6) in univariate analysis, but not after controlling for covariates. CONCLUSIONS: Patients with AHT were more likely to present to the hospital with anemia and increased traumatic ICH volume than patients with noninflicted TBI or physical abuse without AHT. Children with anemia and AHT may be at increased risk for an unfavorable outcome.
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Anemia/epidemiología , Traumatismos Craneocerebrales/complicaciones , Hemorragias Intracraneales/complicaciones , Abuso Físico , Medición de Riesgo/métodos , Traumatismos Craneocerebrales/diagnóstico , Femenino , Humanos , Incidencia , Lactante , Hemorragias Intracraneales/diagnóstico , Masculino , Pennsylvania/epidemiología , Estudios Retrospectivos , Factores de RiesgoRESUMEN
The neurodiagnostic criteria of Leigh syndrome have not yet been clearly redefined based on the expanding of molecular etiologies. We aimed to analyze 20 years of clinical, genetic, and magnetic resonance studies from our Leigh syndrome cohort to provide a detailed description of central nervous system lesions in Leigh syndrome and their biological evolution in view of their genetic and clinical findings. Our study adds new neurodiagnostic insights to the current knowledge of Leigh syndrome, including association with overlapping syndromes, and the correlation of pathogenic genetic variants with neuroimaging phenotypes. ANN NEUROL 2020;88:218-232.
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ADN Mitocondrial/genética , Variación Genética/genética , Enfermedad de Leigh/diagnóstico por imagen , Enfermedad de Leigh/genética , Imagen por Resonancia Magnética/métodos , Niño , Femenino , Estudios de Seguimiento , Humanos , Masculino , Neuroimagen/métodos , Estudios RetrospectivosRESUMEN
INTRODUCTION: Spontaneous third ventriculostomies have been reported in relation to obstructive hydrocephalus and increased intracranial pressure and are most commonly seen as disruption of the floor of the third ventricle. Hydrocephalus has been reported in patients with Krabbe disease; however, it is clinically difficult to monitor for hydrocephalus in patients with Krabbe disease as symptoms of increased intracranial pressure may overlap with symptoms of Krabbe disease. We describe a case series of spontaneous third ventriculostomy and hydrocephalus, likely in response to increased intracranial pressure, in patients with infantile Krabbe disease. METHODS: Brain magnetic resonance images of patients with infantile Krabbe disease were retrospectively analyzed to assess for ventricular size and presence of spontaneous third ventriculostomies. A brain atlas was used to standardize the calculation of ventricular size. Mid-sagittal, T2-weighted images around the third ventricle were assessed for spontaneous third ventriculostomies. Developmental outcomes were measured with a series of standardized and validated tests. RESULTS: Seventy-five patients with infantile Krabbe disease were evaluated. Twelve cases of spontaneous third ventriculostomies were identified. Head circumference (SE = 8.07; P < 0.001) and average ventricular volume were greater (left: SE = 1.47, P < 0.001) in patients with spontaneous third ventriculostomies when compared with patients without spontaneous third ventriculostomies. Patients with spontaneous third ventriculostomies also had more delayed development in adaptive (difference = 0.2, P < 0.01), gross motor (difference = 0.0, P < 0.01), and fine motor (difference = 0.1, P < 0.001) function. CONCLUSIONS: Spontaneous third ventriculostomies, likely in the context of increased intracranial pressure, were identified in patients with Krabbe disease. Although difficult to assess, our study highlights the importance of monitoring for increased intracranial pressure, which can result in spontaneous third ventriculostomies, in patients with infantile Krabbe disease.
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Hidrocefalia/etiología , Hipertensión Intracraneal/etiología , Leucodistrofia de Células Globoides/complicaciones , Tercer Ventrículo/patología , Adolescente , Niño , Preescolar , Femenino , Humanos , Hidrocefalia/diagnóstico , Lactante , Hipertensión Intracraneal/diagnóstico , Imagen por Resonancia Magnética , Masculino , Tercer Ventrículo/diagnóstico por imagenRESUMEN
RASopathy is caused by dysfunction in the MAPK pathway, and include syndromes like Noonan syndrome (NS), NS with multiple lentigines (formerly known as Leopard syndrome), cardiofaciocutaneous (CFC), Legius syndrome, capillary malformation-arteriovenous malformation, neurofibromatosis type 1, and Costello syndrome. When counted together, RASopathies affect 1/1000 live births, and are characterized by cardiovascular manifestations, short stature, developmental delay, renal, urogenital, skin/skeletal abnormalities, and dysmorphic appearance. NS-one of the most common RASopathies-occurs in 1/1000 to 1/2500 live births. On the other hand, the frequency of CFC is unknown, but it is one of the rarest RASopathies, with estimates of only a few hundred cases worldwide. However, its phenotype overlaps with that of NS. In this case series, we describe 5 patients with a clinical and genetic diagnosis of RASopathy-either NS or CFC-all of whom were also diagnosed with isolated sagittal synostosis (ISS). Medical records from ophthalmology, cardiology, plastic surgery, medical genetics, cleft craniofacial, and neurosurgery were used to determine patient history. In our cohort, late presentation of ISS was the predominant form of ISS presentation. We hope this report further characterizes the burgeoning relationship between RASopathy and ISS. Furthermore, these findings support including sagittal synostosis among the presenting features in the clinical phenotype of RASopathies. Ethical approval was obtained from the university's institutional review board.
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BACKGROUND: We report the incidence of Chiari malformation I (CMI) in a cohort of 377 patients with isolated sagittal synostosis (ISS), which is to the best of our knowledge the largest such series reported to date. METHODS: A retrospective review of patients seen at a single institution from 2007 to 2017 was completed. ISS, Chiari malformations (CMI and CMII) and hydrocephalus were diagnosed by a senior neuroradiologist (G.Z.). Patients who met the inclusion criteria were divided into early (group A) and late (group B) presenting groups, as well as operated (group I) and unoperated (group II) groups. The patients were further subdivided into group AI (early operated), group AII (early unoperated), group BI (late operated), and group BII (late unoperated). Once identified, patient notes were examined for the following data sets: date of birth, age of presentation, age at last follow-up, other systemic conditions as well as molecular testing results. Surgical interventions, ophthalmological, and other relevant data were recorded. Statistical analysis was run in the form of a chi-square test to identify a significant difference between each subgroup. A literature review of the incidence of Chiari malformations in patients with ISS was conducted. RESULTS: Three hundred seventy-seven patients constitute the study's total cohort (272 were males and 105 females). This cohort was divided into patients who underwent surgical repair of ISS (group 1: n = 200), and patients who did not (group 2: n = 177). The entire cohort was also divided into early (group A: n = 161) and late (group B: n = 216) presenting craniosynostosis. In the total cohort, 22/377 (5.8%) patients with CMI were identified. CMI was found in 14/200 (7.0%) patients in group I, and 8/177 (4.5%) patients in group II. CMI was found in 2/161 (1%) patients in group A, and 20/216 (9.2%) patients in group B. The incidence of CMI in group AI (early operated) was 2/151 (1.3%), in group AII (early unoperated) was 0/10, in group BI (late operated) was 11/49 (21%), and in group BII (late unoperated) was 9/167 (5.4%). Chi-square analysis revealed a significant difference between the incidence of CMI in the early-presenting (group A) and late-presenting (group B) groups (P = 0.001) and between the late-presenting operated (BI) and late-presenting unoperated (BII) groups (P = 0.001). The incidence of hydrocephalus was 1.6% (6/377) in the total cohort. However, all patients diagnosed with hydrocephalus came from group II (no surgical ISS correction). The incidence of hydrocephalus in group II was 3.3% (6/177). The incidence of hydrocephalus in group BII (late unoperated ISS) was 3.0% (5/167). The incidence of hydrocephalus in group AII (early unoperated ISS) was 9.0% (1/11). CONCLUSIONS: We noted the highest incidence of CMI-21%-in group BI (late-presenting operated). We noted hydrocephalus in group II (nonoperated), with the highest incidence of hydrocephalus found in the group BII (late-presenting unoperated) subgroup. We therefore recommend patients with ISS receive funduscopic examination to screen for raised intracranial pressure (ICP) associated with CMI and hydrocephalus, especially patients with late-presenting ISS.
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BACKGROUND: Mutations in AIMP1, which plays an important role in the development and maintenance of axon-cytoskeleton integrity and regulating neurofilaments, cause neurodegeneration of variable severity and white matter abnormalities. METHODS: From the patient records we analyzed the clinical evaluation, molecular genetics, neurodiagnostic, and neuroradiological investigations. RESULTS: We describe six members of a large consanguineous family with a phenotype of severe neurodegeneration in the form of developmental delays, progressive microcephaly, epilepsy, and failure to thrive. MRI showed callosal atrophy and T2 hyperintensity in the superficial white matter. The periventricular and deep white matter structures were, however, preserved. MR spectroscopy demonstrated N-acetylaspartate preservation without evidence of neuroinflammation. Exome sequencing showed a novel homozygous mutation of the AIMP1 gene in all individuals: c.917A>G (p.(Asp306Gly)). CONCLUSIONS: This novel homozygous mutation of the AIMP1 gene is characterized by preserved development of the periventricular and deep white matter structures as demonstrated by MRI and MR spectroscopy correlation.
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Ácido Aspártico/análogos & derivados , Citocinas/genética , Proteínas de Neoplasias/genética , Enfermedades Neurodegenerativas , Proteínas de Unión al ARN/genética , Sustancia Blanca/patología , Adolescente , Adulto , Ácido Aspártico/metabolismo , Niño , Consanguinidad , Discapacidades del Desarrollo/etiología , Discapacidades del Desarrollo/genética , Epilepsia/etiología , Epilepsia/genética , Insuficiencia de Crecimiento/etiología , Insuficiencia de Crecimiento/genética , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Microcefalia/etiología , Microcefalia/genética , Mutación , Enfermedades Neurodegenerativas/complicaciones , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Linaje , Fenotipo , Sustancia Blanca/diagnóstico por imagen , Adulto JovenRESUMEN
Reports of systemic associations in patients with Isolated Sagittal Synostosis (ISS) are sparse. Craniofacial surgeons, and other providers, should be aware that a significant proportion of patients with ISS may have syndromic or systemic involvement. This study investigates the incidence of systemic disease and syndromic diagnosis in a cohort of patients presenting with ISS (ie, patients with sagittal synostosis without other sutural involvement). METHODS: This study consists of a retrospective review of patients diagnosed with ISS between 2007 and 2017 at a single institution. Patients were divided according to onset (early <1 year, late >1 year) of ISS. Patient notes were examined for congenital anomalies, systemic conditions, and molecular testing. Only patients with isolated sagittal fusion-meaning, patients with sagittal synostosis and no other sutural involvement-were included. RESULTS: Three hundred seventy-seven patients met the inclusion criteria: systemic conditions were identified in 188/377 (50%) of them. One hundred sixty-one patients with early onset (Group A), and 216 patients with late onset ISS (Group B) were identified. Systemic involvement was identified in 38% of Group A and 60% of Group B, which was statistically significant (P < 0.001). Forty-eight of 377 (13%) of patients had a syndromic diagnosis, and 79% of these were confirmed via genetic testing. Thirty-five percent of patients were diagnosed with central nervous system anomalies and 16% had craniofacial anomalies. CONCLUSIONS: Nearly 50% of the patients initially diagnosed with ISS were found to have some form of systemic involvement. This supports affording full pediatric and genetic evaluation with molecular testing to these children.