(2015) 17:40524. 2018;61:765-772. Congenital Cephalic Disorders Combinations of the in silico tool MutationTaster (21) and the Alamut software (ALAMUT package, http://www.interactivebiosoftware.com, France) predicted the variant to be pathogenic as it likely alters the protein structure/function due to a detrimental effect on 112 heterotrimers formation and type IV collagen stability. COL4A1 codes for extracellular matrix proteins that form heterotrimers that are major components of nearly all organ basal membranes. In addition the whole spectrum of the phenotype is not yet known and there are many asymptomatic patients. (D) III- 3Brain MRI showed small asymptomatic lesions in white matter. 30. In addition to the effects of a clear COL4A1 or COL4A2 mutation, large genetic studies reported associations for COL4A1/A2 with intracranial aneurysms, myocardial infarction, arterial calcification, arterial stiffness, deep intracerebral hemorrhages, lacunar ischemic stroke, reduced white matter volume and vascular leukoencephalopathy. COL4A1 Mutation in a Neonate With Intrauterine Stroke and Anterior Segment Dysgenesis. percent confident in Dr. Madsen and the epilepsy team. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/, Federico A, Di Donato I, Bianchi S, et al. Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden. The https:// ensures that you are connecting to the COL4A1 and COL4A2 are on Chr. The heterozygous variant c.2228G>T [NM_001845.4(COL4A1):c.2228G>T (p.Gly743Val)] was identified in exon 30 of the COL4A1 gene. Raynaud phenomenon is typically triggered by changes in temperature and usually causes no long term damage. Painful muscle cramps can occur and can develop before three years of age. Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, et al. 2017 Jan;66:100-103. doi: 10.1016/j.pediatrneurol.2016.04.010. Suite 500 The .gov means its official. 2015;84:918-926. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, Meuwissen ME, Halley DJ, Smit LS, et al. How are genetic conditions treated or managed? GeneReviews. The COL4A1 and COL4A2 genes were screened in proband IV-6. 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. The disorder causes many symptoms, not the least of which are strokes and epilepsy. (2014) 34:757. This review dsecribes the clinical spectrum of a newly identified disorder related to COL4A1 gene mutations. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Powered by NORD, the IAMRARE Registry Platform is driving transformative change in the study of rare disease. Accessibility Cysts can also form in one or both kidneys, and the cysts may grow larger over time. 2013;73:48-57. https://www.ncbi.nlm.nih.gov/pubmed/23225343, Kuo DS, Labelle-Dumais C, Gould DB. This variant highlights that the COL4A1 mutation should be sought in cases of familial ophthalmologic pathologies associated with congenital porencephaly or early onset leukoencephalopathy. Cereb Circ Cogn Behav. The prevalence of HANAC syndrome (hereditary angiopathy-nephropathy-aneurysms-muscle cramps syndrome) is not available, but at least six affected families have been reported worldwide to date. This can manifest as porencephaly if the vessels rupture in utero, hemorrhagic stroke postnatally or in adults, or even small cerebral microbleeds that might go unnoticed except on MRI. COL4A1/A2-related disorders are caused by dominant mutations in the COL4A1 or COL4A2 genes. 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. doi: 10.1111/cge.12379, 13. 2009 Dec 1;73(22):1873-82. doi: 10.1212/WNL.0b013e3181c3fd12. Some individuals with COL4A1-related brain small-vessel disease do not have any signs or symptoms of the condition. COL4A1 is an essential component for basal membrane stability. There are 28 different types of collagen in your body and mutations in the genes that encode these proteins lead to multiple, highly diverse diseases. Berg R, Aleck A, Kaplan A. Familial porencephaly. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. Type IV collagen molecules attach to each other to form complex protein networks. COL4A1 disorder is probably largely underestimated because of its multisystem and variable phenotype. 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. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. MedlinePlus also links to health information from non-government Web sites. This study clearly demonstrates that COL4A1 and COL4A2 mutations cause clinically variable cerebrovascular disease that includes characteristic features of cerebral small vessel disease. However, there are exceptions that depend on precisely when and where the mutation arose. 2009;73:1873-1882. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/, Mao, M, Alavi MV, Labelle-Dumais, C, Gould DB. doi: 10.1055/s-0031-1275343, 24. The human phenotypes are extremely variable between patients and between families, with disease onset as early as in the fetal period. The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. There is in addition a specific phenotype called HANAC with constant nephropathy, muscle cramps and frequent intracranial aneurysms. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. doi: 10.1007/s00417-014-2800-6, 12. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. Genet Med. Phone: 202-588-5700. doi: 10.1056/NEJMoa1707914, 6. Stroke. (2015) 88:46873. The two genes that code for these proteins are tightly linked on chromosome 13 and dominant COL4A1 and COL4A2 gene mutations cause a highly variable, multisystem disorder. A dominantly inherited mutation in collagen IV A1 (COL4A1) causing childhood onset stroke without porencephaly. The cells of the retina trigger nerve impulses that run from the optic nerve to the brain to form sight. 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. Muscle cramps can be spontaneous or triggered by exercise. With genetic disorders, the type of mutation, or its location in the gene can sometimes be associated with varying outcomes. mutation in Axenfeld-Rieger anomaly with leukoencephalopathy and stroke. As the name suggests, mutations in the COL4A1 gene cause COL4A1-related brain small vessel disease. 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. Vilain C, Van Regemorter N, Verloes A, David P, Van Bogaert P. Neuroimaging fails to identify asymptomatic carriers of familial porencephaly. 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). Services that may be beneficial for some affected individuals include medical, social, and/or vocational services such as special remedial education. Each child of an individual with a COL4A1-related disorder has a 50% chance of inheriting the pathogenic variant. These protein networks are the main component of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. Neurovascular Alterations in Vascular Dementia: Emphasis on Risk Factors. TTY: (866) 411-1010 Fax: 203-263-9938, Washington, DC Office 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. (2002) 112:198202. HANAC syndrome is a rare condition, although the exact prevalence is unknown. Lanfranconi S, Markus HS. Stroke is a leading cause of death and serious long-term disability in developed nations. Pediatr Neurol. COL4A1 Syndrome CADASIL Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) In people with HANAC syndrome, the vasculature and other tissues within the kidneys, brain, muscles, eyes, and throughout the body weaken. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. Zeeva woke up after a ten-hour procedure, opened her eyes, and it felt like we were seeing her for the first time. II-2 had a limp since childhood attributed to forceps delivery. 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. When we didnt feel we had any options left for treatment, IV-6 was born at 35 weeks after a pregnancy marked by gestational diabetes. (2020). Individuals with this condition are at increased risk of having more than one stroke in their lifetime. In some people, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. IV-5Brain MRI revealing porencephalic cyst of frontal horn of lateral right ventricle (C). We described the phenotype associated to a likely pathogenic variant of the COL4A1 gene (c.2228G>T, p.Gly743Val) responsible for severe hypermetropia and familial porencephaly. National Taiwan University Hospital, Taiwan, Kaohsiung Chang Gung Memorial Hospital, Taiwan, Carrera de Medicina, Universidad Cientfica del Sur, Peru, Federal University of Rio Grande do Sul, Brazil. Pathology. Molecular analysis was performed on a gDNA level by means of PCR amplification of all the coding exons and the flanking intron region. In the back of the eye, affected individuals have also twisting or distortion (tortuosity) of arteries in the retina (bilateral retinal arterial tortuosity) as part of the syndrome or as an isolated finding. (2008) 17:42433. doi: 10.1038/gim.2014.210, 3. COL4A1/A2-related disorders can also be associated with a variety of abnormalities affecting the front or back of the eyes. 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. [Hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC): a new basement membrane-disease associated with mutations of the COL4A1 gene]. These disorders include autosomal dominant retinal vasculopathy with cerebral leukodystrophy (RVCL), hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukodystrophy (CARASIL), mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), Fabry disease, and a variety of leukodystrophies, rare progressive metabolic disorders that affect the brain, spinal cord and often the peripheral nerves. COL4A1/A2-related disorders are believed to affect females and males in equal numbers. HHS Vulnerability Disclosure, Help Clinical case reports suggest a syndrome with characteristic core findings; however, much about the disorder is not fully understood. In the brain, intracerebral hemorrhage is the most frequent phenotype. Matrix Biol. In the brain, intracerebral hemorrhage is the most frequent phenotype. The proportion of cases caused by a de novopathogenic variant is estimated to be at least 27%. sharing sensitive information, make sure youre on a federal Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1-related disorders. Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity. 2022 May 27;13:827165. doi: 10.3389/fneur.2022.827165. COL4A1 mutations as a monogenic cause of cerebral Aura refers to additional neurological symptoms that occur with, or sometimes before, the development of the migraine headache. Still other individuals may not develop any symptoms until well into adulthood. Antiinflammatory therapy with canakinumab for atherosclerotic disease. 1. One patient (IV-3) was treated for spasticity and seizures with valproic acid. Eur J Med Genet. 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. HANAC syndrome is caused by genetic changes in the COL4A1 gene. Washington, DC 20036 Some affected individuals may develop weakness or paralysis of one side of the body (hemiparesis or hemiplegia) and have seizures. 2014 Mar;261(3):500-3. doi: 10.1007/s00415-013-7224-4. Am J Neuroradiol. Aguglia U, Gambardella A, Breedveld GJ, Oliveri RL, Le Piane E, Messina D, et al. Stroke. Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. mutations: a novel genetic multisystem disease. While muscle cramps may begin in childhood, many of the other symptoms do not appear until later in life. Additionally, consultation with a genetic counselor is strongly recommended for affected individuals and their families and psychosocial support for the entire family is essential. By continuing to use this website, you agree to the Terms of Service & Privacy Policy. When this enzyme is elevated, it is a sign of muscle damage. 2022 Oct 26;7(44):39680-39689. doi: 10.1021/acsomega.2c03360. NCI CPTC Antibody Characterization Program. Gould Syndrome is an ultra rare genetic, multi-system disorder. National Library of Medicine 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. (For more information on this disorder, choose cadasil as your search term in the Rare Disease Database. Ultrasound in utero from IV-6 (A). The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. eCollection 2021. In a retrospective study of 52 patients with COL4A1 mutations, stroke occurred in 17.3% of subjects and MRI showed white matter abnormalities (63.5%), subcortical microbleeds (52.9%), porencephaly (46%), enlarged spaces around blood vessels, (19.2%), and small infarctions (13.5%). Progressive cerebral atrophies in three children with COL4A1 mutations. All authors contributed to the article and approved the submitted version. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Children inherit a full complement of chromosomes from each of their parent and so we carry two copies of each gene. Dr. Joseph Madsen was as wonderful in person as he had been on the phone. Mutated patients develop a diffuse small vessel disease of the brain as shown by a diffuse leukoencephalopathy on MRI. For example, if the mutation arises during the formation of the sperm or the egg, then all of the cells that make up the child will carry the mutation. Bethesda, MD 20894, Web Policies Advanced imaging techniques can include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). Exome sequencing in 32 patients with anophthalmia/microphthalmia and developmental eye defects. Your support helps to ensure everyones free access to NORDs rare disease reports. In addition to providing strength and support to tissues, basement membranes provide instructional cues to cells. Secondly, the p.Gly743Val variant is a missense mutation that shares features with other missense pathogenic mutations that occur in the COL4A1 gene exon 30: congenital porencephaly, epilepsy, and neuropsychological anomalies in p.Gly749Ser (23, 24), ophthalmologic defects and neuropsychological deficits in absence of systemic signs in variant p.Gly755Arg (2527), and antenatal fetal intracerebral hemorrhage, ocular anomalies associated to cerebral leukoencephalopathy in variant p.Gly773Arg (12, 28, 29). Prenatal clinical manifestations in individuals with COL4A1/2 variants. Ann Resource(s) for Medical Professionals and Scientists on This Disease: ), A variety of rare genetic disorders may have symptoms similar to those found in COL4A1/A2-related disorders. COL4A1/COL4A2 gene mutations description, symptoms and the sub-diagnosis. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. (2009) 73:187382. Aicardi-Goutieres syndrome - About the Disease - Genetic and Rare Diseases Information Center National Center for Advancing Translational Sciences Browse by Disease About GARD Contact Us We recently launched the new GARD website and are still developing specific pages. (2006) 43:4905. Interestingly, COL4A1 and COL4A2 mutations appear to lead to generally similar outcomes although COL4A2 mutations occur less frequently. In most cases, an affected person has one parent with the condition. Collagen alpha-1(IV) chain (COL4A1) is a protein that in humans is encoded by the COL4A1 gene on chromosome 13. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. Danbury, CT 06810 Clinical Testing and Workup Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, Marro B, What are the different ways a genetic condition can be inherited? Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. 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. 10.1161/STROKEAHA.110.581918. Neurology. (2010) 14:1827. 2010;41:e513-518. PMC All individuals with this condition have arteries that twist and turn abnormally within the light-sensitive tissue at the back of the eyes (arterial retinal tortuosity). Some people with COL4A1-related brain small-vessel disease have an eye abnormality called Axenfeld-Rieger anomaly. Vermeulen RJ, Peeters-Scholte C, Van Vugt JJMG, Barkhof F, Rizzu P, Van der Schoor SRD, et al. Jeanne M, Gould DB. The first time he came to meet us, Zeeva threw a sock at him. IV-5 had microcephaly without motor deficits, a language delay, a mental retardation (IQ of 62) that required adapted schooling, and severe hypermetropia. This report highlights both the broad spectrum of COL4A1 mutations and the yield of testing the COL4A1 gene in familial ophthalmological and brain disorders. At least 50 individuals with this condition have been described in the scientific literature. As a result, the skin around the affected area may turn white or blue for a brief period of time and the area may tingle or throb. Image showed ventricular asymmetry and brain MRI confirmed right frontotemporal dilatation (B). Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. Participants with epilepsy frequently reported developmental delays (88.6%), stroke (60.0%), cerebral palsy (65.7%), and constipation (57.1%). Many patients with COL4A1 and COL4A2 mutations have additional signs and symptoms that do not include the cerebral vasculature. (2017) 377:111931. For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. 1900 Crown Colony Drive Focke JK, Veltkamp R, Bauer P, Kraemer M. J Neurol. The retina is the light-sensitive membrane that lines the inside of the eyes. National Institute of Neurological Disorders and Stroke. J Neurol Sci. Eur J Paediatr Neurol. Dr. Madsen suggested Zeeva have an operation called a Various treatments have been reported in the medical literature as part of single case reports or small series of patients. In people with HANAC syndrome, angiopathy affects several parts of the body. Doctors and researchers to bring research and medical therapeutic options to those affected. doi: 10.1212/WNL.0000000000006567, PubMed Abstract | CrossRef Full Text | Google Scholar, 2. This group rarely survives beyond 2 years. (1987) 8:4216. These proteins have very restricted expression and Alport Syndrome primarily affects the kidneys with variable involvement of the eye and cochlea (hearing). Written informed consent was obtained from the patient and the patient's parents for publication of this case report. Keywords: COL4A1, Type IV collagen, familial porencephaly, ocular malformations, variable expressivity, Citation: Scoppettuolo P, Ligot N, Wermenbol V, Van Bogaert P and Naeije G (2020) p.Gly743Val Mutation in COL4A1 Is Responsible for Familial Porencephaly and Severe Hypermetropia. Exon mutations of the COL4A1 genes are responsible for a broad spectrum of cerebral, ocular, and systemic manifestations. the basement membranes surrounding the body's blood vessels, National Organization for Rare Disorders (NORD), BRAIN SMALL VESSEL DISEASE 1 WITH OR WITHOUT OCULAR ANOMALIES. 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. 11:827. doi: 10.3389/fneur.2020.00827. See our, COL4A1-related brain small-vessel disease, URL of this page: https://medlineplus.gov/genetics/condition/col4a1-related-brain-small-vessel-disease/. After the COL4A1 mutation was found, systemic manifestations of COL4A1 mutations were investigated. Neurology. MedlinePlus also links to health information from non-government Web sites. Cavalin M, Mine M, Philbert M, et al. Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. (1982) 40:5679. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. Figure 3. PS: wrote thi paper and performed the review of the literature under the supervision of GN. 2012;54:569-574. https://www.ncbi.nlm.nih.gov/pubmed/22574627, Lanfranconi S, Markus HS. Thirdly, bioinformatic tools and ACMG (20) classify p.Gly743Val as likely pathogenic due to the combination of the following criteria: (i) the p.Gly743Val variant is located in a mutational hotspot/or critical and well-established functional domain, (ii) the p.Gly743Val variant is absent from controls in the Exome Sequencing Project as reported by GeneDx (30), (iii) the p.Gly743Val variant is a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease, (iv) the variant p.Gly743Val has been previously reported, without phenotypic description in one other report [GeneDx Accession: SCV000531635.4 Submitted: (January 29, 2019)] and from one likely pathogenic [Undiagnosed Diseases Network, NIH Accession: SCV000926981.1 Submitted: (February 21, 2019)], and (v) which multiple lines of computational evidence support a deleterious effect on the gene product (see the Bioinfromatic Interpretation of Results). Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet Accessed January 28, 2019. 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). We describe here the phenotype of a likely pathogenic gene variant, p.Gly743Val, which is responsible for a missense mutation in the COL4A1 gene exon 30 in a three generation family with severe hypermetropia and highly penetrant porencephaly in the absence of systemic manifestations. (2014) 252:178994. Affected individuals may have no observable symptoms or only isolated migraines with aura. A dashed arrow indicates secondary atrophy in the left cerebral peduncle. Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors. If either parent also carries the mutation, it is considered inherited. (2008) 23:17. Unable to load your collection due to an error, Unable to load your delegates due to an error. She, then, developed seizures which were controlled by valproic acid. Internet. Type IV collagen networks play an important role in the basement membranes in virtually all tissues throughout the body, particularly the basement membranes surrounding the body's blood vessels (vasculature). Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. 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. The management of COL4A1/A2-related disorders may require the coordinated efforts of a team of specialists. and transmitted securely. 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. Bone. Only one copy of COL4A1 or COL4A2 needs to acquire a mutation in order to cause disease which means the mutations are Dominant thus, Gould Syndrome is considered Autosomal Dominant. Mutations in the COL4A1 gene cause HANAC syndrome. Mutations in COL4A1 or COL4A2 cause Gould Syndrome and, because these two proteins are found in almost all tissues; nearly any organ can be affected. Mosaicism can contribute to both reduced penetrance or variable expressivity but other factors do as well. 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. Hum Mol Genet. To use the sharing features on this page, please enable JavaScript. This condition causes mutations in genes that produce a specific type of collagen. If individuals have muscle cramps, blood tests can reveal elevated levels creatine kinase, which is a muscle enzyme. Rarely, new mutations in the gene occur in people with no history of the disorder in their family.
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