Epub 2022 Apr 23. The neuropsychiatric manifestations of CADASIL include mood and behavior disturbances and various . HHS Vulnerability Disclosure, Help (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database. Myelin is a covering or "sheath" that coats, protects, and insulates nerve fibers. Hallmark symptoms of CADASIL may include: 1) recurrent strokes, 2) cognitive impairment, 3) migraine with aura, and 4) psychiatric disturbances. Research suggests that the disorder often goes undiagnosed or misdiagnosed making it difficult to determine the true frequency of CADASIL in the general population. The main symptoms of CADASIL are stroke, cognitive impairment, migraine with aura and psychiatric disturbances. With age, continued cognitive decline may result in dementia, a progressive loss of memory and decline in intellectual abilities that interferes with performing routine tasks of daily life. The brain ends up lacking oxygen. 2022 Aug 10;13:909131. doi: 10.3389/fgene.2022.909131. [citation needed], Ischemic strokes are the most frequent presentation of CADASIL, with approximately 85% of symptomatic individuals developing transient ischemic attacks or stroke(s). This medication is usually used in patients with acute stroke within the first three hours. Diagnostic criteria of vascular dementia in CADASIL. Feuer DS, Handberg EM, Mehrad B, Wei J, Bairey Merz CN, Pepine CJ, Keeley EC. [13][14], No specific treatment for CADASIL is available. Joutel A, Vahedi K, Corpechot C, et al. Rarely, seizures (fits) occur as part of CADASIL. Keywords: Totowa, New Jersey. 2003;82:251-256. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1500/ Accessed July 8, 2019. There are also self-pay options. Zea-Sevilla MA, Bermejo-Velasco P, Serrano-Heranz R, Calero M. J Alzheimers Dis. [2][3], The condition was identified and named by French researchers Marie-Germaine Bousser and Elisabeth Tournier-Lasserve in the 1990s. Vomiting. In individuals with CADASIL, abnormal feelings or warning signs called aura often precede these headaches. Careers. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) associated with a novel C82R mutation in the NOTCH3 gene. 2022 Sep;135(9):1059-1068. doi: 10.1016/j.amjmed.2022.04.006. Joshi S, Yau W, Kermode A. CADASIL mimicking multiple sclerosis: The importance of clinical and MRI red flags. The dominant form of the condition may be caused by a change in the NOTCH3 gene, which is involved in the functioning of muscles cells that make up walls of blood vessels, but may also be due to changes in genes that remain to be identified. Before Disclaimer, National Library of Medicine The patients . Please enable it to take advantage of the complete set of features! Most CADASIL patients are diagnosed by the time they are 40; most CARASIL patients are diagnosed by the time they are 30. sharing sensitive information, make sure youre on a federal CADASIL is a rare genetic disorder affecting the small blood vessels in the brain. ThinkGenetic does not provide medical advice, diagnosis or treatment. These lesions are concentrated around the basal ganglia, peri-ventricular white matter, and the pons, and are similar to those seen in Binswanger disease. The "aura" symptoms may occur just before a migraine develops. A classic lacunar syndrome occurs in at least two-thirds of affected patients while hemispheric strokes are much less common. Medications such as anti-hypertensive, anti-convulsants, and anti-depressants may be used for prevention of migraines in CADASIL patients. NOTE: It does not mean patients with CADASIL can not have also large vessel disease - carotid artery plaque or cardioembolic type of stroke - when a blood clot forms in carotid artery plaque or the heart, goes to the brain and . Mutations in the NOTCH3 gene result in abnormal accumulation of this protein at the surface of smooth muscle cells. The term CADASIL was first coined in 1993. CADASIL is suspected based on symptoms, family history, and brain MRI lesions compatible with the disease. TIAs result in similar symptoms as strokes but resolve in less than 24 hours. Autosomal dominant mutations in the Notch 3 gene (on the long arm of chromosome 19) cause an abnormal accumulation of Notch 3 at the cytoplasmic membrane of vascular smooth muscle cells both in cerebral and extracerebral vessels,[8] seen as granular osmiophilic deposits on electron microscopy. The genetic test for CADASIL was not available until the year 2000. 2017;145:79-114. Patients may be instructed to take aspirin daily to help lower their risk of a heart attack or stroke. Lancet Neurol. Strokes are characterized by a number of neurological symptoms including paralysis, loss of sensation, problems walking, slurred speech or other speech problems, etc. government site. This service is provided by ThinkGenetic and is free. However, it is increasingly recognized that individual symptom types, onset, and disease severity span a wide spectrum, even among individuals in the same family. BMC Med. [26] And James Dewar, best known as vocalist for Robin Trower, died age 59 from complications of CADASIL. These additional symptoms usually affect vision and may consist of the sudden appearance of a bright light in the center of the field of vision (scintillating scotoma) or, less frequently, disturbances in all or part of the field of vision. Therefore, skin biopsies are often used for the diagnosis. If people with CADASIL become anxious, they may notice the following signs; feeling very worried most of the day being restless or feeling 'on edge' becoming tired very quickly having muscle tension In some cases, anti- anxiety medication may be helpful. Information on Clinical Trials and Research Studies, 5 Myths About Orphan Drugs and the Orphan Drug Act, https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/, NIH/National Institute of Neurological Disorders and Stroke, https://www.ncbi.nlm.nih.gov/books/NBK1500/, https://www.ninds.nih.gov/Disorders/All-Disorders/CADASIL-Information-Page, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=136, cerebral autosomal dominant arteriopathy w/subcortical infarcts & leukoencephalopathy. CADASIL is characterized by migraine headaches and multiple strokes progressing to dementia. Stroke or transient ischemic attack was an initial symptom in 45 patients, with a mean age of onset of 41.29.2 years. Acta Neurol Scand. The main symptoms of CADASIL are stroke, cognitive impairment, migraine with aura and psychiatric disturbances. Would you like email updates of new search results? Several hundred mutations in NOTCH3 have been described worldwide in CADASIL, and virtually all of these mutations alter the cysteine content of the extracellular NOTCH3 gene product. [21], In one small study, around 1/3 of patients with CADASIL were found to have cerebral microhemorrhages (tiny areas of old blood) on MRI. Donepezil in patients with subcortical vascular cognitive impairment: a randomized double-blind trial in CADASIL. [24], Recent research into the illness of philosopher Friedrich Nietzsche has suggested that his mental illness and death may have been caused by CADASIL rather than tertiary syphilis. During a consultation, the genetic counselor will answer your questions and take you through a comprehensive discussion to determine what steps and/or genetic tests would be appropriate for you. In his first novel, 'The Chain Diaries', published in 2022, Steve Scarlett has given his protagonist the disease to increase awareness after his wife was diagnosed with CADASIL after a stroke in 2011. This site needs JavaScript to work properly. and transmitted securely. More details are available from Genome Medical. [18] In this regard, the advent of the "Ditans" such as Lasmiditan, lacking vasoconstrictive effect, and the "Gepants" such as Ubrogepant and Rimegepant, are attractive alternatives, albeit not yet field-tested in this condition. INTRODUCTION. The https:// ensures that you are connecting to the Migraine headaches and seizures associated with CADASIL may be treated using medications. COSTS AND INSURANCE COVERAGE: The actual consultation is provided by our partner, Genome Medical. Any other diseases that look a lot like CADASIL? Consultations are available anywhere in the U.S. by phone or video. A mutation in the Notch3 gene alters the muscular walls in these . [9] Leukoencephalopathy follows. The only way to positively diagnose either condition is through genetic testing. Epub 2020 May 13. Thanks for contacting us. The mean age of onset of ischemic episodes is approximately 46 years (range 3070). Stroke. For patients with a hereditary condition, genetic counseling, available through the Cedars-Sinai Medical Genetics Institute, can help identify families at risk and provide referrals to specialized health care providers. Review. CADASIL coma: an underdiagnosed acute encephalopathy. If you're located outside of the United States, click here. Epub 2020 Jan 4. 2004:687-692. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy. This resulted in the famous libel trial that resulted in a jury's awarding Whistler one farthing damages. symptom prevalence #17 Most reported #13 Most indicative. The reported cases have affected more men than women. CADASIL affects males and females in equal numbers. 2022 Jul 1;14(7):e26495. Myocardial infarction in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). There is no cure for CADASIL or CARASIL. Dichgans M. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy. [15] Short-term use of atorvastatin, a statin-type cholesterol-lowering medication, has not been shown to be beneficial in CADASIL patients' cerebral hemodynamic parameters,[17] although treatment of comorbidities such as high cholesterol is recommended. 2010.Dec;23(4):269-76. doi: 10.1177/0891988710383570. Call 877-688-4791 to make an appointment over the phone or request a call back at a time convenient to you. We've partnered with Genome Medical to provide you with access to trained and licensed genetic experts in all 50 states. It is not uncommon for CADASIL patients to have evidence of stroke on MRI without any history of stroke-like symptoms (silent strokes). Someone from ThinkGenetic will be in touch within 48 hours. The pathological hall-mark of CADASIL is a granular osmiophilic material (GOM) within the basal membranes of smooth muscle cells of cerebral [3] and extracerebral arterioles [4]. A variety of rare genetic disorders may have symptoms similar to those found in CADASIL. The specific symptoms and severity of the disorder can vary greatly among affected individuals, even among members of the same family. Because CADASIL is a rare disorder, many people are misdiagnosed before the correct diagnosis is made. CADASIL, on the other hand, affects men and women equally. What are the less common symptoms of CADASIL? The inflammatory attacks that produce the characteristic scarring (plaques or patches) of the myelin sheath occur randomly at multiple sites and vary in intensity. Symptoms may include slowly progressive difficulty with concentration, deficits in attention span or memory dysfunction, difficulty making decisions or solving problems, and general loss of interest (apathy). For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office: Toll free: (800) 411-1222 TTY: (866) 411-1010 Email: [emailprotected], Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/, For information about clinical trials sponsored by private sources, contact: www.centerwatch.com For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/. Encephalopathy is a general term for disease of the brain. People will begin to have difficulty with everyday tasks and their daily routines. Strokes occur because blood flow to the brain is blocked or slowed. MeSH ObjectiveCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebral small vessel disease caused by mutations in the NOTCH3 gene. doi: 10.1016/j.jstrokecerebrovasdis.2016.05.013. To find out more about our partnership, click here. Damage to the blood vessels in the brain can lead to the brain tissues receiving too little blood to survive. The disease is responsible for migraine with aura at onset, for transient ischemic attacks and stroke during mid-adulthood, and can lead progressively to dementia. Imaging tests may also be used to help diagnose the condition and better understand the patient's symptoms. The course of the disease may advance, relapse, remit, or stabilize. Seattle (WA): University of Washington, Seattle; 1993-2019. Patients who have CADASIL or CARASIL in their family are at an increased risk of developing the condition. All Rights Reserved. As abnormal muscle cells surrounding the blood vessels gradually die off, the blood vessels themselves are damaged (arteriopathy). Humana Press. As such, the CADASIL diagnosis can only be confirmed by DNA testing of blood samples for characteristic mutations in the NOTCH3 gene or by identifying granular osmiophilic material (GOM) inclusions on a skin biopsy. CADASIL may be mistaken for more common, better known disorders like multiple sclerosis or Alzheimer's disease. [] peripheral nerves, typically causing numbness or weakness (neuropathy) Muscular weakness due to a muscular disease (myopathy) Confusion, fever and coma (CADASIL coma) Acute vestibular syndrome ( rapid onset (over seconds to hours) of vertigo, nausea/vomiting [rarediseases.info.nih.gov] These sorrel formulations may cause nausea . The genetic cause of many cases remain to be discovered. Rimoin D, Connor JM, Pyeritz RP, Korf BR. The presenting symptoms, age at onset, and disease progression in CADASIL are variable, both between and within families. Further in vivo studies as well as data aggregation and mult CADASIL is characterized by migraine headaches and multiple strokes progressing to dementia. Microvascular Dysfunction as a Systemic Disease: A Review of the Evidence. L-Arginine was proposed as potential treatment after some benefit was seen on the cerebral circulation in subjects with CADASIL; limitations of the study preclude translating these results to the clinical practice with great accuracy. These disorders include cerebral autosomal dominant arteriopathy with subcortical infarcts and leukodystrophy (CADASIL), mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), Fabry disease, and some of the leukodystrophies, which are a rare group of progressive metabolic disorders that affect the brain, spinal cord . CADASIL is a life-threatening and disabling disease. In this trial, researchers were not able to establish efficacy of this potential therapy. CADASIL is caused by changes (mutations) in the NOTCH3 gene. Symptoms of the following disorders can be similar to those of CADASIL. This service is available for free, but remember that our counselors can't give medical advice. eCollection 2022. Medicine. It is worthy of note that ischemic strokes typically occur in the absence of traditional cardiovascular risk factors. The most common symptoms specific to CADASIL are migraine headaches and repeated strokes that progress to dementia. The initial session typically lasts for 30 minutes. Cerebral small-vessel disease is a prevalent condition that is strongly associated with ischemic stroke and dementia. Please consider sharing your experience on social media to help your friends and family start their genetic journeys. The recessive form of the condition may be caused by a change in the HTRA1 gene, which is involved in the formation of new blood vessels, but again, some cases arise from undiscovered gene mutations. Your password has been reset successfully. Cureus. Bookshelf In the event of an acute stroke-like episode, patients with CADASIL should not be treated with a thrombolytic agent (clot dissolving medication). By continuing to browse this site, you are agreeing to our use of cookies. 2009;10:905-910. Although strokes are the most common symptom associated with CADASIL, some affected individuals never have strokes. Other symptoms may include: Other symptoms that are associated with CARASIL, which are sometimes dismissed at first, are: Symptoms of CARASIL may progress more rapidly than those of CADASIL. For example, some people do not develop migraines or do not develop psychiatric symptoms. strokes or stroke-like episodes, major psychiatric symptoms and dementia. There are several disorders that have signs and symptoms that overlap with CADASIL. 2008;118:291-295. Sporadic small vessel disease can also resemble CADASIL. Labauge P. CADASIL. While most treatments for CADASIL patients' symptoms including migraine and stroke are similar to those without CADASIL, these treatments are almost exclusively empiric, as data regarding their benefit to CADASIL patients are limited. Migraine was also a common initial symptom, reported by 42 patients at a younger mean age of 28.311.7 years. Mini-strokes called transient . Seizures (epilepsy) is an infrequent finding in CADASIL, but can occur, usually following a stroke. Chen MJ, Zhang Y, Luo WJ, Dong HL, Wei Q, Zhang J, Ruan QQ, Ni W, Li HF. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominantly inherited angiopathy caused by pathogenic variants in the NOTCH3 gene on chromosome 19 [].CADASIL is now recognized as an important cause of stroke in the young [].Stroke and vascular cognitive impairment remain the main causes of morbidity and mortality . His sister, Fanny Mendelssohn, was similarly affected. Stroke: pathophysiology, diagnosis, and management. [1] The disease belongs to a family of disorders called the leukodystrophies. The randomness of the location of plaques or patches causes a wide range of neurological symptoms, which may vary from person to person. In: Paul RH, Cohen R, Ott BR, Sal S, eds. Migraine with aura refers to migraine headaches that occur with "aura", which are additional symptoms such as flashes of light, blind spots or tingling of the hands or face. This is true even for members of the same family. [4][5] Together with two other researchers, Hugues Chabriat and Anne Joutel, they received the 2019 Brain Prize for their research into the condition. 2008;39:838-844. Psychological support is often essential, and genetic counseling is recommended for affected individuals and their families. Angiitis is inflammation of the walls of small blood vessels. Bethesda, MD 20894, Web Policies NORD strives to open new assistance programs as funding allows. Patients must rely on the personal and individualized medical advice of their qualified health care professionals before seeking any information related to their particular diagnosis, cure or treatment of a condition or disorder. Patients with CADASIL have an increased risk of bleeding in . A 501(c)(3) non-profit organization. ), Multiple sclerosis is a prevalent chronic neuroimmune (both the nervous system and the immunological system are involved) disorder of the central nervous system involving the brain, spinal cord and optic nerves. CARASIL is so rare that only 50 cases have been identified, and most of these have been in Japan and China. CADASIL is an acronym that stands for: (D)ominant a form of inheritance in which one copy of an abnormal gene is necessary for the development of a disorder, (A)rteriopathy disease of the arteries (blood vessels that carry blood away from the heart), (S)ubcortical relating to specific areas of the brain supplied by deep small blood vessels, (I)nfarcts tissue loss in the brain caused by lack of blood flow to the brain, which occurs when circulation through the small arteries is severely reduced or interrupted, (L)eukoencephalopathy lesions in the brain white matter caused by the disease and observed on MRI. The disease belongs to a family of disorders called the leukodystrophies. [7], The underlying pathology of CADASIL is progressive hypertrophy of the smooth muscle cells in blood vessels. Benisty S, Hernandez K, Viswanathan A, et al. CARASIL requires both parents be carriers of the condition in order for symptoms to be present. Sporadic small vessel disease includes Binswanger's disease, a rare disorder in which thickening and narrowing of the arteries in the brain causes damage to the brain eventually leading to dementia. Stroke-like Symptoms as a Symptom in CADASIL. Having the CADASIL gene does not mean you are at high risk if you are well and do not have symptoms. 2002:3210-3212. doi: 10.7759/cureus.26495. 2018:STROKEAHA-118. episodes (TIA or stroke), cognitive deficits, migraine with aura and psychiatric symptoms [2]. CADASIL Information Page. J Stroke Cerebrovasc Dis. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) as a model of small vessel disease: update on clinical, diagnostic, and management aspects. [18] Stopping oral contraceptive pills may be recommended. However, as this is quite expensive and CADASIL is a systemic arteriopathy, evidence of the mutation can be found in small and medium-size arteries. The .gov means its official. 2003;74:249-252. A New NOTCH3 Gene Mutation Associated With a CADASIL (Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy) Diagnosis. If you'd prefer, you can also submit questions to a Genetic Counselor by email. New York, NY. Clipboard, Search History, and several other advanced features are temporarily unavailable. [16] Control of high blood pressure is particularly important in CADASIL patients. Not surprisingly, depression is very frequent after any type of stroke and usually improves with time, although treatment may be necessary. As in CADASIL, patients can experience progressive memory loss, deterioration of intellectual abilities and loss of balance with a progressive worsening of these symptoms, but symptoms are usually less severe and occur later in life. 2015;43(2):363-7. doi: 10.3233/JAD-141218. The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. 2000-2022 The StayWell Company, LLC. 1997;350:1511-1515. These symptoms are caused by damage to small blood vessels, especially those within the brain. Cognitive impairment eventually develops in many affected individuals on average between the ages of 50-60, although the progression of the disease will vary. Choose a doctor and schedule an appointment. The Cerebral Autosomal-Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL) Scale: a screening tool to select patients for NOTCH3 gene analysis. PMC NORD is a registered 501(c)(3) charity organization. Click here for more information. Use this form to send an email to one of our trained, licensed experts in the field of genetics. Algahtani H, Shirah B, Alharbi SY, Al-Qahtani MH, Abdulkareem AA, Naseer MI. Churchill Livingstone. 2022 Cedars-Sinai. [2][11] These white matter lesions are also seen in asymptomatic individuals with the mutated gene. Stroke-like symptoms is a sometimes reported symptom in the CADASIL community, and is also an indicative symptom of CADASIL. 2017;15(1):41. 2017;35:75-7. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. eCollection 2022. Individuals with CADASIL can suffer from anxiety or depression. [15] Antiplatelet agents such as aspirin, dipyridamole, or clopidogrel might help prevent strokes; however, anticoagulation may be inadvisable given the propensity for microhemorrhages. Clinically and primarily CADASIL is characterized by migraine, stroke, mood disturbances and cognitive declines. We have sent a confirmation email to "". Patients should be treated for factors that can further damage blood vessels, such as hypertension, and should be encouraged to abstain from smoking. Migraines are severe headaches that often cause excruciating pain and can be disabling. Stroke. Symptoms can include headaches, confusion, and hallucinations. A Novel Heterozygous Variant in Exon 19 of NOTCH3 in a Saudi Family with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy. CADASIL and CARASIL are both caused by a gene mutation. 1-3 It is estimated that >10% of patients with stroke and white . 8600 Rockville Pike J Biol Chem. Cognitive function is a person's ability to process thoughts and reason. [27], In the movie The Sea Inside, one of the characters is stated to have CADASIL.[28]. NORD gratefully acknowledges Karen Orjuela, MD, Vascular Neurologist, Assistant Professor of Neurology, University of Colorado, Michael Wang, MD, PhD, Assistant Professor of Neurology, University of Michigan Health System, and cureCADASIL Association, for assistance in the preparation of this report. Some patients suffer from severe attacks with unusual symptoms such as confusion, fever or coma in very rare situations. In: Mohr JP, Choi DW, Grotta JC, eds. These symptoms might improve rapidly (so-called transient ischemic attacks (TIAs)) or lead to more persistent losses (completed stroke). Stroke. The patient should assume that all stroke symptoms signal an emergency and should not wait to see if they go away. https://www.ncbi.nlm.nih.gov/books/NBK1500/, https://rarediseases.org/rare-diseases/cadasil/, https://www.uptodate.com/contents/cerebral-autosomal-dominant-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy-cadasil, https://ghr.nlm.nih.gov/condition/cerebral-autosomal-dominant-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy#genes, http://www.uptodate.com/contents/cerebral-autosomal-dominant-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy-cadasil, https://www.genomemedical.com/advancedcare-billing/. JOURNAL ARTICLES Herv D, Chabriat H. CADASIL. A case of CADASIL presenting as schizophreniform organic psychosis has been reported. Drug therapy for depression or other psychiatric abnormalities are sometimes needed. 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