scholarly journals Expanding the phenotype of SPARC-related osteogenesis imperfecta: clinical findings in two patients with pathogenic variants in SPARC and literature review

2021 ◽  
pp. jmedgenet-2021-107942
Author(s):  
Anna Durkin ◽  
Catherine DeVile ◽  
Paul Arundel ◽  
Mary Bull ◽  
Jennifer Walsh ◽  
...  
Keyword(s):  
White Matter ◽  
Osteogenesis Imperfecta ◽  
Motor Development ◽  
Bone Fractures ◽  
Brain Mri ◽  
Subcortical White Matter ◽  
Clinical Findings ◽  
Long Bone ◽  
Vertebral Compression Fractures ◽  
Multiple Fractures

BackgroundSecreted protein, acidic, cysteine rich (SPARC)-related osteogenesis imperfecta (OI), also referred to as OI type XVII, was first described in 2015, since then there has been only one further report of this form of OI. SPARC is located on chromosome 5 between bands q31 and q33. The encoded protein is necessary for calcification of the collagen in bone, synthesis of extracellular matrix and the promotion of changes to cell shape.MethodsWe describe a further two patients with previously unreported homozygous SPARC variants with OI: one splice site; one nonsense pathogenic variant. We present detailed information on the clinical and radiological phenotype and correlate this with their genotype. There are only two previous reports by Mendozo-Londono et al and Hayat et al with clinical descriptions of patients with SPARC variants.ResultsFrom the data we have obtained, common clinical features in individuals with OI type XVII caused by SPARC variants include scoliosis (5/5), vertebral compression fractures (5/5), multiple long bone fractures (5/5) and delayed motor development (3/3). Interestingly, 2/4 patients also had abnormal brain MRI, including high subcortical white matter changes, abnormal fluid-attenuated inversion in the para-atrial white matter and a large spinal canal from T10 to L1. Of significance, both patients reported here presented with significant neuromuscular weakness prompting early workup.ConclusionCommon phenotypic expressions include delayed motor development with neuromuscular weakness, scoliosis and multiple fractures. The data presented here broaden the phenotypic spectrum establishing similar patterns of neuromuscular presentation with a presumed diagnosis of ‘myopathy’.

Intrauterine transplantation of human fetal mesenchymal stem cells from first-trimester blood repairs bone and reduces fractures in osteogenesis imperfecta mice

Blood ◽  
2008 ◽  
Vol 111 (3) ◽  
pp. 1717-1725 ◽  
Author(s):  
Pascale V. Guillot ◽  
Oyebode Abass ◽  
J. H. Duncan Bassett ◽  
Sandra J. Shefelbine ◽  
George Bou-Gharios ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Osteogenesis Imperfecta ◽  
Bone Fractures ◽  
First Trimester ◽  
Long Bone ◽  
Structural Protein ◽  
Plate Height ◽  
Multiple Fractures ◽  
Donor Cells

Abstract The inherited skeletal dysplasia osteogenesis imperfecta (OI) results in multiple fractures and is currently treated empirically. We transplanted human first-trimester fetal blood mesenchymal stem cells (MSCs) into homozygous oim mice in utero. This resulted in a two-thirds reduction in long bone fractures (P < .01), with fewer fractures per mouse (median 1, range 0-2 in mice that received transplants vs median 3, range 1-5 in mice that did not receive transplants by 12 weeks, P < .01). Nearly all mice that did not receive transplants had fractures (47 [97.9%] of 48), in contrast to 17 (58.6%) of 29 4- to 12-week-old mice that received transplants (P < .01). Transplantation was associated with increased bone strength (P < .01), thickness (P < .01), and length (P < .01), and normalization/reduction of growth plate height in 4- to 12-week-old oim was reduced in mice that underwent transplantion (P < .001). More donor cells were found in bone tissues compared with other organs (P < .001), with cells clustered in areas of active bone formation and remodeling, and at sites of fracture healing. Donor cells found in the bone expressed osteoblast lineage genes, and produced the extracellular bone structural protein osteopontin. Finally, MSC transplantation decreased bone hydroxyproline content. In conclusion, intrauterine transplantation of fetal MSCs markedly reduced fracture rates and skeletal abnormalities in a mouse model of the intermediate severity type III OI, suggesting a scientific basis for MSC treatment of affected human fetuses.

Bone density and bone health alteration in boys with Duchenne Muscular Dystrophy: a prospective observational study

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Renu Suthar ◽  
B. V. Chaithanya Reddy ◽  
Manisha Malviya ◽  
Titiksha Sirari ◽  
Savita Verma Attri ◽  
...  
Keyword(s):  
Lumbar Spine ◽  
Bone Health ◽  
Prospective Observational Study ◽  
Bone Fractures ◽  
Long Bone ◽  
Vertebral Compression Fractures ◽  
Serum Osteocalcin ◽  
Z Score ◽  
X Ray ◽  
Compression Fractures

Abstract Objectives Boys with Duchenne Muscular Dystrophy (DMD) are at increased risk for compromised bone health, manifesting as low-impact trauma long bone fractures and vertebral compression fractures. Methods In a prospective observational study, we studied bone health parameters in North Indian boys with DMD. We consecutively enrolled ambulatory boys with DMD on glucocorticoid therapy. Bone health was evaluated with X-ray spine, Dual-energy X-ray absorptiometry (DXA), serum calcium, vitamin D3 (25[OH]D), 1,25-dihyroxyvitamin D3 (1,25[OH]2D3), serum osteocalcin, osteopontin, and N terminal telopeptide of type 1 collagen (Ntx) levels. Results A total of 76 boys with DMD were enrolled. The median age was 8.5 (interquartile range [IQR] 7.04–10.77) years. Among these, seven (9.2%) boys had long bone fractures, and four (5.3%) had vertebral compression fractures. Fifty-four (71%) boys underwent DXA scan, and among these 31 (57%) had low bone mineral density (BMD, ≤−2 z-score) at the lumbar spine. The mean BMD z-score at the lumbar spine was −2.3 (95% confidence interval [CI] = −1.8, −2.8), and at the femoral neck was −2.5 (95% CI = −2, −2.9). 25(OH)D levels were deficient in 68 (89.5%, n=76) boys, and 1,25(OH)2D3 levels were deficient in all. Mean serum osteocalcin levels were 0.68 ± 0.38 ng/mL (n=54), serum osteopontin levels were 8.6 ± 4.6 pg/mL (n=54) and serum Ntx levels were 891 ± 476 nmol/L (n=54). Boys with low BMD received glucocorticoids for longer duration, in comparison to those with normal BMD (median, IQR [16.9 (6–34) months vs. 7.8 (4.8–13.4) months]; p=0.04). Conclusions Bone health is compromised in North Indian boys with DMD. BMD at the lumbar spine is reduced in more than half of boys with DMD and nearly all had vitamin D deficiency on regular vitamin D supplements. Longer duration of glucocorticoid therapy is a risk factor for low BMD in our cohort.

Abstract WP253: Diagnostic Evaluation and Outcome of Cerebral Fat Embolism: Single Center Retrospective Review

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Breana L Taylor ◽  
Arielle P Davis ◽  
Steven R Peters ◽  
Allison Kunze ◽  
Amita Singh ◽  
...  
Keyword(s):  
Orthopedic Surgery ◽  
Bone Fractures ◽  
Brain Mri ◽  
Diagnostic Testing ◽  
Retrospective Chart Review ◽  
Altered Mental Status ◽  
Fat Embolism ◽  
Long Bone ◽  
Mri Findings ◽  
Diffusion Restriction

Introduction: Cerebral Fat Embolism (CFE) is an underappreciated complication of trauma and orthopedic surgery whose diagnosis is mostly based on clinical suspicion. The utility of diagnostic testing is poorly defined. Methods: Using discharge diagnosis codes and a stroke database at a Level 1 Trauma Center, we performed a retrospective chart review of diagnostic workup and outcome for CFE from 2005 to 2019. Among those with a diagnosis of systemic fat emboli syndrome after long-bone fracture, cerebral involvement was established based on altered mental status, retinal findings, brain MRI findings or a combination of these. This report focuses on those who had MRI, all of which had findings of CFE. Results: Forty patients with CFE were identified, comprising 0.3% of all patients admitted with long-bone fractures. Of these patients, the average age was 39 years (SD 22), 30 (75%) were men, 28 (70%) had hypoxemia, 2 (5%) had petechial rash, and 29 (73%) were comatose, including 16 (40%) following orthopedic surgery. Brain MRI findings of CFE included scattered diffusion-restriction (60%), confluent white-matter edema (33%) and diffuse petechial hemorrhage (30%), with 27% having multiple findings of CFE. Ophthalmologic evaluation revealed exudates or hemorrhage suggestive of Purtscher-like retinopathy in 20 (91%) of 22 patients examined. Transcranial doppler microembolic signals (MES) were detected in 17 (53%) of 32 patients examined and were associated with scattered diffusion-restriction on MRI (chi square, p =0.01). Twelve patients (30%) died before discharge, 15 (38%) were discharged to a nursing facility, 12 (30%) to a rehabilitation facility and 1 (3%) to home. After a mean of 5.4 months, 1 patient had died, 11 had severe disability and 16 had moderate disability or better. Conclusion: The diagnosis of CFE is complicated by unknown sensitivity of diagnostic modalities. Nonetheless, typical MRI and ophthalmologic findings can assist in diagnosis. MES are associated with scattered infarction on MRI, suggesting active disease. The outcome of patients with CFE is highly variable, and a better understanding of this potentially devastating disease will require studies with larger numbers of cases collected in a standard fashion at multiple trauma centers.

Sclerostin antibody reduces long bone fractures in the oim/oim model of osteogenesis imperfecta

Bone ◽  
2019 ◽  
Vol 124 ◽  
pp. 137-147 ◽  
Author(s):  
Mickaël Cardinal ◽  
Janne Tys ◽  
Thomas Roels ◽  
Sébastien Lafont ◽  
Michael S. Ominsky ◽  
...  
Keyword(s):  
Osteogenesis Imperfecta ◽  
Bone Fractures ◽  
Long Bone ◽  
Long Bone Fractures ◽  
Sclerostin Antibody

Occipital epilepsy with subcortical atrophy in celiac disease

2020 ◽  
pp. 10.1212/CPJ.0000000000000942
Author(s):  
Alionka Bostan ◽  
Chiara Mabiglia ◽  
Adraa Nouini ◽  
Hélène Visée ◽  
Bernard Dan ◽  
...  
Keyword(s):  
Celiac Disease ◽  
White Matter ◽  
Brain Mri ◽  
Occipital Lobe ◽  
Subcortical White Matter ◽  
Gluten Free Diet ◽  
Epileptic Focus ◽  
Gluten Free ◽  
Lobe Atrophy

We report a 50-year-old man with celiac disease who presented with occipital epilepsy. Brain MRI showed right occipital subcortical white matter hyperintensities, consistent with the posterior epileptic focus suggested by the clinical features of the seizures and documented on EEG. Shortly after the introduction of gluten free diet the white matter abnormalities resolved. The patient went on to develop simultagnosia. Follow-up MRI showed right occipital lobe atrophy. This report emphasizes the importance of recognizing gluten associated neurologic manifestations and usefulness of gluten free diet.

scholarly journals Fingolimod-associated PML with mild IRIS in MS

2017 ◽  
Vol 5 (1) ◽  
pp. e415 ◽  
Author(s):  
Shuhei Nishiyama ◽  
Tatsuro Misu ◽  
Yukiko Shishido-Hara ◽  
Kazuo Nakamichi ◽  
Masayuki Saijo ◽  
...  
Keyword(s):  
White Matter ◽  
Immune Reconstitution ◽  
Jc Virus ◽  
Brain Mri ◽  
Subcortical White Matter ◽  
Precentral Gyrus ◽  
Fluid Attenuated Inversion Recovery ◽  
Viral Inclusions ◽  
Inflammatory Syndrome

Objective:To clarify the clinical, neuropathologic, and virologic characteristics of progressive multifocal leukoencephalopathy (PML) and its immune reconstitution inflammatory syndrome (IRIS) in a patient with fingolimod-treated MS.Methods:A case study.Results:A 34-year-old patient with MS using fingolimod for 4 years had a gradual progression of right hemiparesis and aphasia with a new subcortical white matter lesion in the precentral gyrus by initial MRI. Blood tests were normal, except for lymphopenia (160 cells/μL). One month after the cessation of fingolimod, brain MRI depicted a diffusely exacerbated hyperintensity on fluid-attenuated inversion recovery and diffusion-weighed imaging in the white matter with punctate gadolinium enhancement, suggesting PML-IRIS. A very low level of JC virus (JCV)-DNA (15 copies/mL) was detected in the CSF as judged by quantitative PCR. Brain tissues were biopsied from the left frontal lesion, which showed some small demyelinated foci with predominant loss of myelin-associated glycoprotein with infiltrations of lymphocytes and macrophages, but clear viral inclusion was not observed with hematoxylin-eosin staining. JCV-DNA was uniquely detectable in an active inflammatory demyelinating lesion by in situ hybridization, possibly suggesting an early phase of PML. DNA extracted from the brain sample was positive for JCV-DNA (151 copies/cell). It took 3 months to normalize the blood lymphocyte count. The patient was treated with 1 g of IV methylprednisolone for 3 days and a weekly oral dose (375 mg) of mefloquine, and her symptoms gradually improved.Conclusion:Low CSF JCV-DNA and unfound viral inclusions initially made her diagnosis difficult. The clinical course of fingolimod-associated PML may be associated with mild immune reconstitution.

scholarly journals Cognitive Impact of Lacunar Infarcts and White Matter Hyperintensity Volume

2015 ◽  
Vol 5 (1) ◽  
pp. 170-175 ◽  
Author(s):  
Matthew W. Warren ◽  
Myron F. Weiner ◽  
Heidi C. Rossetti ◽  
Roderick McColl ◽  
Ron Peshock ◽  
...  
Keyword(s):  
White Matter ◽  
Brain Mri ◽  
Population Based ◽  
Clinical Findings ◽  
Community Dwelling ◽  
White Matter Hyperintensity ◽  
Cognitive Screening ◽  
Lacunar Infarcts ◽  
Automated Method ◽  
Moca Score

Background: Subcortical lacunar infarcts and white matter hyperintensities (WMH) are common neuroradiological findings, but few studies associate between these insults and cognition in a community-dwelling population. Methods: The Dallas Heart Study is a population-based initiative whose assessments included demographic and clinical findings including brain MRI and the Montreal Cognitive Assessment (MoCA). The presence and number of lacunes in subjects aged over 55 years were assessed by study physicians. The WMH volume was measured by an automated method. The association between the presence and number of lacunar infarcts and of WMH volume with the total MoCA score and subdomains was assessed using linear regression with adjustment for age, gender and self-reported ethnicity. Results: In 609 subjects with valid data, both the presence and the increasing number of lacunes were associated with lower MoCA scores, even after adjusting for demographic variables. The presence of lacunes was also associated with lower scores in the memory, executive and attention subdomains. The WMH volume was not significantly associated with the MoCA score. Conclusion: The presence and increasing number of lacunes in midlife is associated with a lower performance in multiple domains of a cognitive screening measure after adjusting for demographic factors.

scholarly journals Post‐traumatic cerebral fat embolism syndrome with a favourable outcome: a case report

BMC Neurology ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Wei Wang ◽  
Weibi Chen ◽  
Yan Zhang ◽  
Yingying Su ◽  
Yuping Wang
Keyword(s):  
Bone Fractures ◽  
Fat Embolism ◽  
Long Bone ◽  
Cerebellar Hemisphere ◽  
Field Pattern ◽  
Acute Chest Syndrome ◽  
Multiple Fractures ◽  
Cognitive Changes ◽  
Fat Embolism Syndrome ◽  
Embolism Syndrome

Abstract Background Fat embolism syndrome (FES) is a change in physiology resulting from mechanical causes, trauma, or sepsis. Neurological manifestations of FES can vary from mild cognitive changes to coma and even cerebral oedema and brain death. Here, we present an unusual case of cerebral fat emboli that occurred in the absence of acute chest syndrome or right-to-left shunt. Case presentation A previously healthy 57-year-old right-handed male was admitted to our department because of unconsciousness after a car accident for 3 days. He suffered from multiple fractures of the bilateral lower extremities and pelvis. This patient had severe anaemia and thrombocytopenia. Head MRI showed multiple small lesions in the whole brain consistent with a “star field” pattern, including high signals on T2-weighted (T2w) and fluid-attenuated inversion recovery (FLAIR) images in the bilateral centrum semiovale; both frontal, parietal and occipital lobes; and brainstem, cerebellar hemisphere, and deep and subcortical white matter. Intravenous methylprednisolone, heparin, mannitol, antibiotics and nutritional support were used. Although this patient had severe symptoms at first, the outcome was favourable. Conclusions When patients have long bone and pelvic fractures, multiple bone fractures and deteriorated neurological status, cerebral fat embolism (CFE) should be considered. Additionally, CFE may occur without an intracardiac shunt. The early diagnosis and appropriate management of FES are important, and prior to and following surgery, patients should be monitored comprehensively in the intensive care unit. With appropriate treatment, CFE patients may achieve good results.

scholarly journals Methadone-Induced Delayed Posthypoxic Encephalopathy: Clinical, Radiological, and Pathological Findings

2010 ◽  
Vol 2010 ◽  
pp. 1-4 ◽  
Author(s):  
Manoj Mittal ◽  
Yunxia Wang ◽  
Alan Reeves ◽  
Kathy Newell
Keyword(s):  
White Matter ◽  
Psychiatric Symptoms ◽  
Brain Mri ◽  
Brain Biopsy ◽  
Autoimmune Disorder ◽  
Subcortical White Matter ◽  
Pathological Findings ◽  
Elevated Liver Enzymes ◽  
Work Up

Objective. To describe the clinical, radiological and pathological findings in a patient with methadone-induced delayed posthypoxic encephalopathy (DPHE).Case Report. A Thirty-eight-year-old man was found unconscious for an unknown duration after methadone and diazepam ingestion. His initial vitals were temperature 104 degree Fahrenheit, heart rate 148/minute, respiratory rate 50/minute, and blood pressure 107/72 mmhg. He developed renal failure, rhabdomyolysis, and elevated liver enzymes which resolved completely in 6 days. After 2 weeks from discharge he had progressive deterioration of his cognitive, behavioral and neurological function. Brain MRI showed diffuse abnormal T2 signal in the corona radiata, centrum semiovale, and subcortical white matter throughout all lobes. Extensive work up was negative for any metabolic, infectious or autoimmune disorder. Brain biopsy showed significant axonal injury in the white matter. He was treated successfully with combination of steroids and antioxidants. Follow up at 2 year showed no residual deficits.Conclusion. Our observation suggests that patients on methadone therapy should be monitored for any neurological or psychiatric symptoms, and in suspected cases MRI brain may help to make the diagnosis of DPHE. A trial of steroids and antioxidants may be considered in these patients.

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