doi: 10.1007/s00417-014-2800-6, 12. (2006) 354:148996. official website and that any information you provide is encrypted A variety of additional signs and symptoms have been reported in individuals with COL4A1/A2-related disorders including childhood-onset epilepsy, hemolytic anemia (a condition characterized by low levels of circulating red blood cells due to their premature destruction leading to fatigue, weakness, lightheadedness, dizziness, irritability, headaches, and pale skin color), mitral valve prolapse (flaps of the valve located between the upper and lower left heart chambers bulge or collapse during contraction allowing leakage of blood back into the left atrium). Since fewer than 100 families have been reported, the exact prevalence of COL4A1-related disorders is not well-established. The information on this site should not be used as a substitute for professional medical care or advice. doi: 10.1212/WNL.0000000000001309, 8. Unauthorized use of these marks is strictly prohibited. PV and VW followed the children at the Neuropediatrics clinic of the same hospital. doi: 10.1056/NEJMoa053727, 7. Axenfeld-Rieger is a collection of abnormalities affecting the front of the eye including the iris (colored part of the eye) and cornea (abnormally small corneas called microcornea), which is the transparent membrane that covers the eyes. Type IV collagen molecules attach to each other to form complex protein networks. 13 and so Gould Syndrome is considered Autosomal and should affect males and females in equal numbers. Unable to load your collection due to an error, Unable to load your delegates due to an error. 2011 Cephalic Disorders Fact Sheet. Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. Written informed consent was obtained from the patient and the patient's parents for publication of this case report. This is called genotype-phenotype correlation. Research in mice with Col4a1 mutations suggests that the position of the mutation is very important. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. 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%). This group rarely survives beyond 2 years. Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, et al. Am J Neuroradiol. Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain. HANAC syndrome is a rare condition, although the exact prevalence is unknown. Neurology. Bookshelf Am J Med Genet. Depending on the cell type that acquires the mutation and when the mutation arises, the individual may have many or few cells with the mutation. (D) III- 3Brain MRI showed small asymptomatic lesions in white matter. Comparison of Clinical, Radiographic, and Histological Features in COL4A1 Syndrome Compared With Other Single Gene Disorders Causing SVD. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. COL4A1 and COL4A2 are on Chr. This variant highlights that the COL4A1 mutation should be sought in cases of familial ophthalmologic pathologies associated with congenital porencephaly or early onset leukoencephalopathy. Abnormal blood vessels in the brain are a major consequence of COL4A1 and COL4A2 gene mutations. In most people, small vessel disease in the brain does not cause symptoms. Molecular analysis was performed on a gDNA level by means of PCR amplification of all the coding exons and the flanking intron region. In people with HANAC syndrome, the vasculature and other tissues within the kidneys, brain, muscles, eyes, and throughout the body weaken. Neuropediatrics. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. Neurology. 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 . Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. Molecular Dynamics Investigation on the Effects of Protonation and Lysyl Hydroxylation on Sulfilimine Cross-links in Collagen IV. (For more information on this disorder, choose cadasil as your search term in the Rare Disease Database. This condition causes mutations in genes that produce a specific type of collagen. GeneReviews. Suite 500 However, it is also very likely that basement membrane defects also contribute to abnormal signaling and function of cells that form blood vessels in the brain and elsewhere. 2012;54:569-574. https://www.ncbi.nlm.nih.gov/pubmed/22574627, Lanfranconi S, Markus HS. The variant was found in IV-3 and IV-5 and not in asymptomatic relatives (III-4, IV-1, IV-4). If the mutation arises after fertilization, then some cells will carry the mutation and others will not this is called mosaicism. Neurology. We believe that the variant p.Gly743Val is likely pathogenic for several reasons. Sci Rep. 2016;6:18602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, Rannikmae K, Davies G, Thomson PA, et al. The severity of the condition varies greatly among affected individuals. 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. He would separate the two halves of her brain by Disease Overview. [Hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC): a new basement membrane-disease associated with mutations of the COL4A1 gene]. Sibon I, Coupry I, Menegon P, Bouchet JP, Gorry P, Burgelin I, Calvas P, doi: 10.1002/ana.23736, 4. It looks like nothing was found at this location. In the eye, patients may have retinal arteriolar tortuosities and retinal hemorrhages or anterior segment dysgenesis. If individuals have muscle cramps, blood tests can reveal elevated levels creatine kinase, which is a muscle enzyme. III-3 was informed of the genetic diagnosis and is now regularly followed and screened for cataracts and brain aneurysms. Supporting children in their development to reduce handicaps and combining their follow-up with parent counseling could be considered as an ideal approach. I cannot describe the feeling of seeing your child healed. Phone: 202-588-5700. Endovascular therapy is a minimally-invasive procedure in which a long, thin tube called a catheter is passed into the blood vessel to repair or strengthen the blood vessel. COL4A1 is an essential component for basal membrane stability. functional hemispherectomy. doi: 10.1038/gim.2015.30, 21. PS: wrote thi paper and performed the review of the literature under the supervision of GN. Antiinflammatory therapy with canakinumab for atherosclerotic disease. Phone: 202-588-5700. Lanfranconi S, Markus HS. Mutated patients develop a diffuse small vessel disease of the brain as shown by a diffuse leukoencephalopathy on MRI. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. Washington, DC 20036 Surgery may be necessary for individuals with severe cataracts. J Neurol Sci. 1779 Massachusetts Avenue Phone: 617-249-7300, Danbury, CT office 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. 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. In the front of the eye, patients can have abnormally small eyes (microphthalmia), cataracts (cloudy lenses), and anterior segment dysgenesis (Axenfeld-Rieger). Zenteno JC, Cresp J, Buentello-Volante B, Buil JA, Bassaganyas F, Vela-Segarra JI, et al. At least six affected families have been described in the scientific literature. Suite 310 What is the prognosis of a genetic condition? Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. Years published: 2019. (2007) 357:268795. 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. Genet Med. 2015;17:843-853. https://www.nature.com/articles/gim2014210, Yoneda Y, Haginoya K, Kato M, et al. 30. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. CADASIL is an acronym that stands for: (C)erebral relating to the brain (A)utosomal (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 arteries (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. Our review highlights that COL4A1 mutations can present for the first time in adult life with features of cerebral SVD, including subcortical hemorrhage and ischemic stroke, . September 2003. Autosomal Dominant Familial Porencephaly Type I. The variant was confirmed by bidirectional fluorescence DNA sequencing (Sanger method). The site is secure. Mutations in COL4A3, COL4A4 and COL4A5 were found in the early 1990's in patients with Alport Syndrome. 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. Breedveld G, De Coo IF, Lequin MH, Arts WFM, Heutink P, Gould DB, et al. The extents to which intracellular and/or extracellular insults contribute to pathology remain an open question. Some people with COL4A1-related brain small-vessel disease have an eye abnormality called Axenfeld-Rieger anomaly. Contact a health care provider if you have questions about your health. NCI CPTC Antibody Characterization Program. Affected individuals may have no observable symptoms or only isolated migraines with aura. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. doi: 10.1007/s10897-008-9169-9, 16. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. 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. Berg R, Aleck A, Kaplan A. Familial porencephaly. Recent findings: 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). Many patients with COL4A1 and COL4A2 mutations have additional signs and symptoms that do not include the cerebral vasculature. COL4A1 -related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. Suite 310 Type IV Collagens and Basement Membrane Diseases: Cell Biology and Pathogenic Mechanisms. Mutations in the gene have been linked to diseases of the brain, muscle, kidney, eye, and cardiovascular system. Eur J Paediatr Neurol. A similar term, variable expressivity, describes when affected individuals have widely varying signs and symptoms. A dominantly inherited mutation in collagen IV A1 (COL4A1) causing childhood onset stroke without porencephaly. Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. 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. No use, distribution or reproduction is permitted which does not comply with these terms. The COL4A1 gene has 52 exons and most of the pathogenic variants are distributed across exons 10 to 47 in the triple-helix domain. Ultrasound in utero from IV-6 (A). (2011) 42:13. 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 http://www.centerwatch.com/, For information about clinical trials conducted in Europe, contact: Curr Med Chem. 2009;73:1873-1882. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/, Mao, M, Alavi MV, Labelle-Dumais, C, Gould DB. Individuals with HANAC syndrome also experience a variety of eye problems. Firstly, it segregates within the family with the phenotype. Teaching families how to advocate for their loved ones and access medical information. She was struggling to advance both cognitively and physically because of uncontrolled epilepsy. It is ubiquitously expressed in many tissues and cell types. BMC Med Genet. Yoneda Y, Haginoya K, Kato M, Osaka H, Yokochi K, Arai H, et al. doi: 10.1002/ajmg.10452, 18. 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. These types of correlations can be difficult to detect in patients because of the broad genetic variability in humans. Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. The COL4A1 gene mutations that cause HANAC syndrome result in the production of a protein that disrupts the structure of type IV collagen. In people with COL4A1-related brain small-vessel disease, the vasculature in the brain weakens, which can lead to blood vessel breakage and stroke. IV-6 was born at 35 weeks after a pregnancy marked by gestational diabetes. IV-3 was diagnosed with ventriculomegaly in utero. Still other individuals may not develop any symptoms until well into adulthood. Am J Med Genet A. Copyright 2020 Scoppettuolo, Ligot, Wermenbol, Van Bogaert and Naeije. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Neurovascular Alterations in Vascular Dementia: Emphasis on Risk Factors. cutting tissue called the corpus callosum, then make some additional delicate 2022 Mar 24;3:100140. doi: 10.1016/j.cccb.2022.100140. Going from having seizures every day for six years to having no seizures is nothing short of a miracle. Interpretation of variant significance was done according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines (20). Probands' father had severe hypermetropia and bilateral cataracts. Eur J Med Genet. J Perinatol. Muscle cramps can be spontaneous or triggered by exercise. Science. Gould Syndrome is an ultra rare genetic, multi-system disorder. Axenfeld-Rieger anomaly involves underdevelopment and eventual tearing of the colored part of the eye (iris) and a pupil that is not in the center of the eye. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. Neurol. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues, including the brain. https://www.ncbi.nlm.nih.gov/pubmed/26610912. It is important to discuss these concepts with a genetic counselor and understand their implications. In her first six years of life, Zeeva spent hundreds of nights in the hospital, had 13 operations and countless procedures, (from eye surgeries to Achilles heel, a shunt placed in her brain, and spine surgery). 2022 Oct 26;7(44):39680-39689. doi: 10.1021/acsomega.2c03360. The first reports of human COL4A1 mutations were in patients with autosomal dominant porencephaly and a more recent study found that COL4A1 mutations were found in ~16% of patients with porencephaly. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1-related disorders. This raises questions about what tests Liliane has a lot to be grateful for this holiday season. 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). Accessibility The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and review of the literature. COL4A1 Syndrome CADASIL This variant p.Gly743Val combines hypermetropia in all heterozygotic patients and highly penetrant antenatal porencephaly (associated with motor and intellectual deficits). Ten months later, the left hemiparesis was observed with a lack of voluntary prehension on his left side without spasticity. Stroke. Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. (2013) 73:4857. eCollection 2022. When a mutation occurs in one of these genes, the rope does not wind up properly and it stays inside the cell. Jeanne M, Gould DB. The surgery Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity. (E,F) IV-3Brain MRI showed left frontotemporal dilatation and diffusion tensor imaging (DTI) sequences demonstrated no left corticospinal tract (cranio-caudal fibers, indigo, with arrows). Symptoms of the following disorders can be similar to those of COL4A1/A2-related disorders. Shah S, Kumar Y, McLean B, Churchill A, Stoodley N, Rankin J, et al. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. 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. Available online at: https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3 (accessed March 20, 2020). This condition causes mutations in genes that produce a specific type of collagen. mutations: a novel genetic multisystem disease. Children inherit a full complement of chromosomes from each of their parent and so we carry two copies of each gene. 2017 Jan;66:100-103. doi: 10.1016/j.pediatrneurol.2016.04.010. 2014 Mar;261(3):500-3. doi: 10.1007/s00415-013-7224-4. COL4A1/A2-related disorders can also be associated with a variety of abnormalities affecting the front or back of the eyes. Fragile or damaged blood vessels or basement membranes in the kidneys can lead to blood in the urine (hematuria). People with this condition may have a bulge in one or multiple blood vessels in the brain (intracranial aneurysms). January 31, 2019 Neurology. *Correspondence: Pasquale Scoppettuolo, Pasquale.scoppettuolo@gmail.com, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3, Creative Commons Attribution License (CC BY). When these ropes are secreted, they assemble into net-like structures outside the cells. Resource(s) for Medical Professionals and Scientists on This Disease: Staals J, Makin SDJ, Doubal FN, Dennis MS, Wardlaw JM. Slavotinek AM, Garcia ST, Chandratillake G, Bardakjian T, Ullah E, Wu D, et al. doi: 10.1126/science.1109418, 5. How are genetic conditions treated or managed? Some individuals do not have any observable symptoms (asymptomatic); others can develop severe, even life-threatening complications. A Podcast For The Rare Disease Community, Policy Statements & Letters to Policymakers. Danbury, CT 06810 Jeanne M, Gould DB. The disorder causes many symptoms, not the least of which are strokes and epilepsy. Early intervention is important in ensuring that children with reach their highest potential. It is not uncommon for an unaffected parent to have a severely affected child. doi: 10.1212/WNL.0000000000006567, PubMed Abstract | CrossRef Full Text | Google Scholar, 2. Molecular genetic testing can detect variations in the COL4A1 and COL4A2 genes that cause these disorders, but is available only as a diagnostic service at specialized laboratories. 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). percent confident in Dr. Madsen and the epilepsy team. 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). The heterozygous variant c.2228G>T [NM_001845.4(COL4A1):c.2228G>T (p.Gly743Val)] was identified in exon 30 of the COL4A1 gene. Ronco P. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Fax: 203-263-9938, Washington, DC Office COL4A1 brain small-vessel disease is an autosomal dominant condition resulting from a mutation to the COL4A1 gene, located on the long arm of chromosome 13, that normally encodes for the alpha-1 chain of type IV collagen 1-6. seizure activity. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. 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 muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1 -related disorders. Here we report a family in which three siblings presented severe hypermetropia and porencephaly. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. 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. COL4A1/A2-related disorders are caused by dominant mutations in the COL4A1 or COL4A2 genes. (2010). NORD strives to open new assistance programs as funding allows. Progressive cerebral atrophies in three children with COL4A1 mutations. doi: 10.1186/s12881-014-0097-2, 11. Epub 2022 Apr 14. 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. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. One patient (IV-3) was treated for spasticity and seizures with valproic acid. small vessel disease: a systematic review. Dev Med Child Neurol. For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. The https:// ensures that you are connecting to the Neurology. doi: 10.1212/01.WNL.0000123113.46672.68, 25. At the age of 12, IV-3 underwent cerebral palsy quality of life (CPQoL) questionnaires in which they expressed a satisfactory quality of life and a good relationship with other children. 2011 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. Rarely, new mutations in the gene occur in people with no history of the disorder in their family. Focke JK, Veltkamp R, Bauer P, Kraemer M. J Neurol. 2008 May;192(5):971-84; discussion 984-6. The disorder causes many symptoms, not the least of which are strokes and epilepsy. 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. 2010 Aug;41(8):e513-8. COL4A1 disorder is probably largely underestimated because of its multisystem and variable phenotype. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. Developmental defects to the front of the eye, which also includes the ocular drainage structures between the iris and cornea, can lead to increased pressure in the eye (elevated intraocular pressure, or IOP). HHS Vulnerability Disclosure, Help J Med Genet. PS and NL: followed III-3 at the Erasme Neurology outpatients clinic. Matrix Biol. Phone: 203-263-9938 Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Paques M, Ronco P. Am J Med Genet A. To date, over 50 pathogenic or likely pathogenic variants have been described in the COL4A1 gene, most of them missense (2). Clin Genet. (2014) 15:16. Colin E, Sentilhes L, Sarfati A, Mine M, Guichet A, Ploton C, et al. (2005) 308:116771. In the brain, intracerebral hemorrhage is the most frequent phenotype. 2010 Collagen alpha-1(IV) chain (COL4A1) is a protein that in humans is encoded by the COL4A1 gene on chromosome 13. (No doctor had ever taken a call on their lunch break to speak with me). 1. 2018;91:e2078-e2088. With genetic disorders, the type of mutation, or its location in the gene can sometimes be associated with varying outcomes.
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