For example, treatment may include physical therapy, speech therapy, anti-convulsant medications for seizures, and a shunt to treat hydrocephalus by draining excess fluid from the skull. This group rarely survives beyond 2 years. Neurology. doi: 10.1002/ana.23736, 4. Mutated patients develop a diffuse small vessel disease of the brain as shown by a diffuse leukoencephalopathy on MRI. NORD gratefully acknowledges Douglas Gould, PhD, Professor, Director of Research, Denise B. Evans Endowed Chair in Ophthalmology, Departments of Ophthalmology and Anatomy, Institute for Human Genetics, University of California San Francisco School of Medicine, and the COL4A1 Foundation, for assistance in the preparation of this report. Your support helps to ensure everyones free access to NORDs rare disease reports. The p.Gly743Val variant is a conservative substitution that occurs in a position highly conserved across species (SIFT analysis: DeleteriousScore 0, median: 4.22, highly conserved nucleotide and amino acid, up to Tetraodon considering 11 species) and affects a crucial and abundant residue within the triple-helix-forming collagenous domain of the protein, which consist of long stretches of Gly-X-Y repeats. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology Sue. Neurol. Slavotinek AM, Garcia ST, Chandratillake G, Bardakjian T, Ullah E, Wu D, et al. Collagen type IV alpha 1 (COL4A1) silence hampers the invasion, migration and epithelial-mesenchymal transition (EMT) of gastric cancer cells through blocking Hedgehog signaling pathway. Changing lives of those with rare disease. If individuals have muscle cramps, blood tests can reveal elevated levels creatine kinase, which is a muscle enzyme. Most individuals diagnosed with a COL4A1-related disorder have an affected parent. The main symptom is single or repeated bleeding inside the skull (intracranial hemorrhaging) that can occur without cause (spontaneously), after trauma, or when taking drugs that slow blood clotting (anticoagulants). https://nord1dev.wpengine.com/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/, For information about clinical trials sponsored by private sources, contact: The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. This is not specific to COL4A1/A2-related disorders, and is a sign of many different types of muscle disease. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. Paques M, Ronco P. Novel COL4A1 mutations associated with HANAC syndrome: a role functional hemispherectomy. The COL4A1 stroke syndrome. Gould Syndrome is often characterized by abnormal blood vessels in the brain (cerebral vasculature defects), eye development defects (ocular dysgenesis), muscle disease (myopathy), and kidney abnormalities (renal pathology); however, many other aspects of the syndrome including abnormalities affecting the structure of the brain (cerebral cortical abnormalities) and lung (pulmonary) abnormalities continue to emerge and the full spectrum is still uncharacterized. Stroke. Fetal origin of brain damage in 2 infants with a COL4A1 mutation: fetal and neonatal MRI. N Engl J Med. This condition causes mutations in genes that produce a specific type of collagen. doi: 10.1212/WNL.0000000000001309, 8. Disclaimer. COL4A1 mutations are responsible for a wide range of abnormalities affecting mainly the brain and the retinal vasculature, the anterior and posterior ocular structures and the renal glomerules. Here we report a family in which three siblings presented severe hypermetropia and porencephaly. cuts under the microscope. September 2003. A dashed arrow indicates secondary atrophy in the left cerebral peduncle. January 31, 2019 COL4A1 -related brain small-vessel disease is part of a group of conditions called the COL4A1 -related disorders. The COL4A1 gene mutations that cause COL4A1-related brain small-vessel disease result in the production of a protein that disrupts the structure of type IV collagen. Plaisier E, Ronco P. COL4A1-Related Disorders. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden. Clin Neurol Neurosurg. Acute urinary retention due to a novel collagen COL4A1 mutation. When this enzyme is elevated, it is a sign of muscle damage. (1982) 40:5679. 2011 2018;91:e2078-e2088. 2010 Aug;41(8):e513-8. In people with HANAC syndrome, angiopathy affects several parts of the body. Summary: Oral expression was reduced and neuropsychological testing revealed language delay with a prominent expression deficit. There is in addition a specific phenotype called HANAC with constant nephropathy, muscle cramps and frequent intracranial aneurysms. Given the variable expressivity of these mutations, COL4A1/A2-related disorders are likely under diagnosed and the exact number of people who have these disorders is unknown. Rarely, affected individuals will have a condition called Raynaud phenomenon in which the blood vessels in the fingers and toes temporarily narrow, restricting blood flow to the fingertips and the ends of the toes. (2008) 23:17. (2010) 14:1827. There are no standardized treatment protocols or guidelines for affected individuals. 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. Some affected individuals may develop weakness or paralysis of one side of the body (hemiparesis or hemiplegia) and have seizures. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. Gould Syndrome is an ultra rare genetic, multi-system disorder. 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. Drugs that prevent irregular heartbeats (anti-arrhythmic medications) are used to treat supraventricular arrythmia. He underwent at birth neurosonography for axial hypotonia that revealed ventricular asymmetry and right frontotemporal dilatation (Figure 3). Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. Science. Ultrasound in utero from IV-6 (A). COL4A1 Mutations as a Monogenic Cause of Cerebral Small Vessel - Stroke COL4A1 is an essential component for basal membrane stability and exon mutations of COL4A1 gene mutations are responsible for a broad spectrum of systemic manifestations characterized by small vessel involvement of variable severity, including neurological (1) [porencephaly (24), hemorrhage (2, 57) and aneurysms (8)], ophthalmological (912) (retinal artery tortuosity, Axenfeld Rieger anomalies, cataracts, and severe hypermetropia), renal (13) (renal cysts, and microscopic hematuria), and systemic (13) findings (cramps with a high creatine kinase level [CK], Raynaud's phenomenon, and arrhythmias). https://www.ncbi.nlm.nih.gov/pubmed/20558831, Alamowitch S, Plaisier E, Favrole P, et al. The information on this site should not be used as a substitute for professional medical care or advice. By continuing to use this website, you agree to the Terms of Service & Privacy Policy, A Podcast For The Rare Disease Community, Policy Statements & Letters to Policymakers. Some of the patient advocacy organizations listed in the Resources section below provide support and information to affected individuals and their families. Contact a health care provider if you have questions about your health. For example, Type I collagen mutations cause Osteogenesis Imperfecta (brittle bone disease), Type II collagen mutations cause chondrodysplasias (defects of cartilage) and mutations in Type III collagen cause a form of Ehlers-Danlos Syndrome. ACS Omega. IV-6 was born at 35 weeks after a pregnancy marked by gestational diabetes. Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors. Dev Med Child Neurol. What is Gould Syndrome? - Gould Syndrome Foundation Dr. Joseph Madsen was as wonderful in person as he had been on the phone. Cerebral small vessel disease with hemorrhage is likely milder continuum from porencephaly and exhibits many of the same symptoms (with the exception of the brain cavities). What does it mean to have a COL4A1 - Little Braveheart | Facebook Arch Neurol. (2009) 73:187382. Neurology. This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. These exceptions are nuanced and should be discussed with a genetic counselor. People with COL4A1-related brain small vessel disease also have leukoencephalopathy, which is a change in a type of brain tissue called white matter that can be seen with magnetic resonance imaging (MRI). (2007) 357:268795. COL4A1/COL4A2 gene mutations description, symptoms and the sub-diagnosis. It is passed through families in a autosomal dominant fashion. (2012) 54:56974. Understanding what it has taken to get her to this point, though, is close to unimaginable. Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORDs mission. 2012;54:569-574. https://www.ncbi.nlm.nih.gov/pubmed/22574627, Lanfranconi S, Markus HS. 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. Fazekas F, Chawluk JB, Alavi A. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. Gunda B, Mine M, Kovcs T, Hornyk C, Bereczki D, Vrallyay G, Rudas G, Audrezet MP, Tournier-Lasserve E. J Neurol. Breedveld G, De Coo IF, Lequin MH, Arts WFM, Heutink P, Gould DB, et al. Suggestive evidence for linkage to chromosome 13qter for autosomal dominant type 1 porencephaly. 2015;17:843-853. https://www.nature.com/articles/gim2014210, Yoneda Y, Haginoya K, Kato M, et al. She was struggling to advance both cognitively and physically because of uncontrolled epilepsy. At 1 month of age, a neuropediatric examination disclosed normal neck muscle tonus, normal Moro reflex, bilateral placing reaction, and open hands. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Type IV collagen is an important component of basement membranes in many tissues, especially blood vessels 1-6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/. He smiled, caught it, and asked Zeeva if he could throw it back. doi: 10.1111/j.1469-8749.2011.04198.x, 26. IV-3 and IV-6 are closely followed by a neuropediatrician (VW). In addition to providing strength and support to tissues, basement membranes provide instructional cues to cells. Clinically, COL4A1 mutations are responsible for different overlapping phenotypes including porencephaly (24), brain small vessel disease (2, 57) with or without ocular anomalies, HANAC (13) (hereditary angiopathy with nephropathy, aneurysms, and muscle cramps) syndrome, ophthalmological abnormalities (912), and non-syndromic autosomal dominant congenital cataracts (10). Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, et al. Neurology. (2005) 308:116771. The effects of the disorder range from subtle or mild to severe, depending on associated brain abnormalities. . 2017;57-58:29-44. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328961/, Sondergaard CB, Nielsen JE, Hansen CK, Christensen H. Hereditary cerebral small vessel disease and stroke. Childhood presentation of COL4A1 mutations. Shah S, Ellard S, Kneen R, Lim M, Osborne N, Rankin J, et al. 2018;61:765-772. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. doi: 10.1136/jmg.2005.035584, 15. When a mutation occurs in one of these genes, the rope does not wind up properly and it stays inside the cell. PS: wrote thi paper and performed the review of the literature under the supervision of GN. Symptoms that may occur in individuals with autosomal dominant type I porencephaly include migraines, weakness or paralysis of one side of the body (hemiparesis or hemiplegia), seizures, stroke, and dystonia, a group of neurological disorders characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions. Powered by NORD, the IAMRARE Registry Platform is driving transformative change in the study of rare disease. Received: 06 January 2020; Accepted: 01 July 2020; Published: 11 September 2020. Gould Syndrome is a rare, genetic, multi-system disorder. Bethesda, MD 20894, Web Policies Role of COL4A1 in small-vessel disease and hemorrhagic stroke. Systemic work-up including renal function, CK levels, urinary sediment test, and renal ultrasound proved unremarkable. NORD is not a medical provider or health care facility and thus can neither diagnose any disease or disorder nor endorse or recommend any specific medical treatments. The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. Purpose of review: HHS Vulnerability Disclosure, Help A Podcast For The Rare Disease Community, Policy Statements & Letters to Policymakers. Dev Med Child Neurol. Zeeva woke up after a ten-hour procedure, opened her eyes, and it felt like we were seeing her for the first time. It is important to discuss these concepts with a genetic counselor and understand their implications. Last updated: Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. Neurovascular Alterations in Vascular Dementia: Emphasis on Risk Factors. Focke JK, Veltkamp R, Bauer P, Kraemer M. J Neurol. 2022 Sep;269(9):5153-5156. doi: 10.1007/s00415-022-11111-0. Cereb Circ Cogn Behav. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1-related disorders. He would separate the two halves of her brain by https://www.clinicaltrialsregister.eu/, JOURNAL ARTICLES Various muscles can be affected and muscle strength can become weakened. Still other individuals may not develop any symptoms until well into adulthood. Nat Methods. Some people with COL4A1-related brain small-vessel disease have an eye abnormality called Axenfeld-Rieger anomaly. 2009;73:1873-1882. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/, Mao, M, Alavi MV, Labelle-Dumais, C, Gould DB. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) Frontiers | p.Gly743Val Mutation in COL4A1 Is Responsible for Familial Prenatal clinical manifestations in individuals with COL4A1/2 variants. Subsequently, it has been recognized that autosomal dominant COL4A1 and COL4A2 mutations cause a broad spectrum of cerebrovascular disease, whose onset occurs from fetal life onward and whose severity may range from small-vessel disease to fatal intraparenchymal hemorrhage.,, While epilepsy is known to be a clinical feature of porencephaly, the The COL4A1 and COL4A2 genes were screened in proband IV-6. Cataracts, which are a clouding of the lenses of the eyes, are often present from birth (congenital) and may be one of the first identifiable signs of the syndrome. COL4A1 is an essential component for basal membrane stability and exon mutations of COL4A1 gene mutations are responsible for a broad spectrum of systemic manifestations characterized by small vessel involvement of variable severity, including neurological ( 1) [porencephaly ( 2 - 4 ), hemorrhage ( 2, 5 - 7) and aneurysms ( 8 )], ophthalmological Some of these patients have been described as having HANAC syndrome, which is an acronym for hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.). The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. We describe, here, the phenotype of a likely pathologic variant (p.Gly743Val) in exon 30 of the COL4A1 gene, responsible for an oculo-cerebral phenotype characterized by severe hypermetropia and highly penetrant porencephaly in absence of other systemic complications. The latest research shows that insufficient COL4A1/A2 in basement membranes damages different tissues in very different ways. In some people, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. Our data testing the effects of established mutations on collagen biosynthesis suggest that the intracellular retention of mutant COL4A1 proteins at the expense of their secretion appears to be a common effect of many COL4A1 mutations. Epub 2022 Apr 14. By continuing to use this website, you agree to the Terms of Service & Privacy Policy. Abnormal retinal arteries are prone to rupture causing bleeding associated with temporary loss of vision or even retinal detachments that can cause permanent vision loss. Axenfeld-Rieger anomaly and cataract can cause impaired vision. Sibon I, Coupry I, Menegon P, Bouchet JP, Gorry P, Burgelin I, Calvas P, Here, we report a patient with schizencephaly, detected by fetal ultrasonography and fetal magnetic resonance imaging, with a de novo novel mutation in COL4A1 (c.2645_2646delinsAA, p.Gly882Glu). In the brain, intracerebral hemorrhage is the most frequent phenotype. Rarely, new mutations in the gene occur in people with no history of the disorder in their family. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Teaching families how to advocate for their loved ones and access medical information. These proteins have very restricted expression and Alport Syndrome primarily affects the kidneys with variable involvement of the eye and cochlea (hearing). Colin E, Sentilhes L, Sarfati A, Mine M, Guichet A, Ploton C, et al. (2002) 112:198202. Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, et al. Each child of an individual with a COL4A1-related disorder has a 50% chance of inheriting the pathogenic variant. (1987) 8:4216. After the COL4A1 mutation was found, systemic manifestations of COL4A1 mutations were investigated. 2017 Jan;66:100-103. doi: 10.1016/j.pediatrneurol.2016.04.010. Yet, five siblings, showing mild phenotype even in the second generation support a Mendelian transmission with variable expressivity and no other mechanism. The type IV collagens are encoded by six different genes (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5 and COL4A6). Clin Genet. However, these findings can be observed independently or in combinations, in many patients with COL4A1 and COL4A2 mutations. The brain MRI of IV-6 disclosed a large right-sided frontoparietal cavity (Figure 3B) with communication to the lateral ventricle, isosignal to CFS. Bone. Autosomal Dominant Familial Porencephaly Type I. (2006) 354:148996. Mosaicism can contribute to both reduced penetrance or variable expressivity but other factors do as well. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome So far, it appears as though mutations in COL4A1 and COL4A2 lead to identical disease, however, for reasons that are not yet understood, mutations in COL4A2 are much less frequent than those in COL4A1. Neurology. Zagaglia S, Selch C, Nisevic JR, Mei D, Michalak Z, Hernandez-Hernandez L, et al. 10.2174/092986710790936293. We each inherit a full complement on autosomes from each of our parents giving us two copies of each gene. The blood vessels as well as thin sheet-like structures called basement membranes that separate and support cells are weakened and more susceptible to breakage. Stroke is often the first symptom of this condition, typically occurring in mid-adulthood. and transmitted securely. Zagaglia Selch C, Nisevic JR, et al. What are the different ways a genetic condition can be inherited? COL4A1/A2-related disorders are believed to affect females and males in equal numbers. 8600 Rockville Pike She had seizures every day, couldnt gain weight, sleep right, or generally enjoy her life. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. At 2 years old, IV-6 presented obvious left hemiparesis but could move without help. Painful muscle cramps can occur and can develop before three years of age. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. This blood vessel abnormality can cause episodes of bleeding within the eyes following any minor trauma to the eyes, leading to temporary vision loss. This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Some individuals with COL4A1-related brain small-vessel disease do not have any signs or symptoms of the condition. 1. They are typically characterized by abnormal blood vessels in the brain (cerebral vasculature defects), eye development defects (ocular dysgenesis), muscle disease (myopathy), and kidney abnormalities (renal pathology); however, many other aspects of the syndrome including abnormalities affecting the structure of the brain (cerebral cortical abnormalities) and lung (pulmonary) abnormalities continue to emerge and the full spectrum is still uncharacterized. This condition causes mutations in genes that produce a specific type of collagen. What does it mean to have a COL4A1 gene mutation: The COL4A1 gene provides instructions for making one component of type IV collagen, which is a flexible protein important in the structure of many. The non-working gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual (called sporadic or de novo). Copyright 2020 Scoppettuolo, Ligot, Wermenbol, Van Bogaert and Naeije. 2022 Oct 26;7(44):39680-39689. doi: 10.1021/acsomega.2c03360. As the name suggests, mutations in the COL4A1 gene cause COL4A1-related brain small vessel disease. Mutations in the COL4A1 gene cause HANAC syndrome. IV-5 had microcephaly without motor deficits, a language delay, a mental retardation (IQ of 62) that required adapted schooling, and severe hypermetropia. When our 8-year-old daughter, Zeeva, giggles and runs in her walker to the swing set, its like watching pure childhood joy. Hereditary angiopathy with nephropathy, aneurysms, and - MedlinePlus PS and NL: followed III-3 at the Erasme Neurology outpatients clinic. There are notable differences in the specific signs and symptoms (clinical heterogeneity), and different organs are affected to different degrees between patients even among members of a family who carry the same gene mutation. View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. Internet. (2015) 88:46873. doi: 10.1016/j.ejpn.2009.04.010, 27. COL4A1 is a subunit of the type IV collagen and plays a role in angiogenesis. The strengths of our study are the extensive systemic work-up, the 5-year neurological follow-up, and the pluridisciplinary approach. Additional features include poor or absent speech development, facial paralysis (paresis), involuntary muscle spasms (spasticity) that result in slow, stiff, rigid movements, visual field defects, and hydrocephalus, a condition in which accumulation of excessive cerebrospinal fluid in the skull causes pressure on the tissues of the brain, resulting in a variety of symptoms. Neurology. N Engl J Med. People with HANAC syndrome develop kidney disease (nephropathy). 2008 May;192(5):971-84; discussion 984-6. Aguglia U, Gambardella A, Breedveld GJ, Oliveri RL, Le Piane E, Messina D, et al. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Individuals with this condition are at increased risk of having more than one stroke in their lifetime. Curr Opin Neurol. COL4A1 collagen type IV alpha 1 chain [ (human)] - National Center for All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. Novel COL4A1 mutation in a fetus with early prenatal onset of - Nature [Hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC): a new basement membrane-disease associated with mutations of the COL4A1 gene]. This can occur if the carrier is a mosaic which means that some cells carry the mutation while other cells do not. doi: 10.1038/jp.2013.135, 29. I cannot describe the feeling of seeing your child healed. 4 Both . doi: 10.1007/s10897-008-9169-9, 16. The proportion of cases caused by a de novopathogenic variant is estimated to be at least 27%. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. With genetic disorders, the type of mutation, or its location in the gene can sometimes be associated with varying outcomes. A diagnosis of COL4A1/A2-related disorders is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests including advanced imaging techniques. Zeeva is one of fewer than 150 people in the world with a rare disease called Gould Syndrome or COL4A1/A2. Mutations in COL4A3, COL4A4 and COL4A5 were found in the early 1990's in patients with Alport Syndrome. People listened to us and to Zeeva in a very different and proactive way. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and review of the literature. We are a registered 501(c)3 Nonprofit dedicated to providing hope and help to children and adults with Gould Syndrome; affecting COL4A1 and COL4A2 genes. Liu X, Yang Q, Tang L, He J, Tian D, Wang B, Xie L, Li C, Fan D. Front Neurol. It is not uncommon for an unaffected parent to have a severely affected child. Contact a health care provider if you have questions about your health. For example, the position of the mutation along the length of the protein can influence the severity of cerebrovascular disease and mutations in functional subdomains can influence the likelihood of tissue-specific involvement (for example, muscle). Collagen, type IV, alpha 1 - Wikipedia Phone: 202-588-5700. The degree of mosaicism is highly variable ranging from only a small percent of cells with the mutation to nearly all cells carrying the mutation and depends on the stage during development that the mutation occurred. All authors contributed to the article and approved the submitted version. The site is secure. It is ubiquitously expressed in many tissues and cell types. Resource(s) for Medical Professionals and Scientists on This Disease: While muscle cramps may begin in childhood, many of the other symptoms do not appear until later in life. (2017) 377:111931. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Paques M, Ronco P. Am J Med Genet A. Careers. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes or factors influencing the disorder make it challenging to develop a complete picture of associated symptoms and prognosis. These aneurysms have the potential to burst, causing bleeding within the brain (hemorrhagic stroke). Quincy, MA 02169 doi: 10.1212/WNL.0b013e3181eee440, 28.