col4a1 syndrome life expectancy col4a1 syndrome life expectancy

doi: 10.1136/jmg.2005.035584, 15. For example, an individual may carry genetic variants elsewhere in their genome that confers protection or susceptibly to the mutation and environmental experiences (trauma, anticoagulant use, physical exertion etc.) Neurology. If individuals have muscle cramps, blood tests can reveal elevated levels creatine kinase, which is a muscle enzyme. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and review of the literature. Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. Migraines can occur with or without aura. Dr. Joseph Madsen was as wonderful in person as he had been on the phone. An official website of the United States government. Various muscles can be affected and muscle strength can become weakened. Cereb Circ Cogn Behav. Collagen type IV alpha 1 (COL4A1) and 2 (COL4A2) are extracellular matrix proteins that together constitute a major component of nearly all basement membranes. doi: 10.1212/WNL.0000000000006567, PubMed Abstract | CrossRef Full Text | Google Scholar, 2. 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. Neurology. 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. Our experience with Boston Childrens was very different from the other places we had been for epilepsy and neurology treatment. Figure 3. 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. 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%). Many patients with COL4A1 and COL4A2 mutations have additional signs and symptoms that do not include the cerebral vasculature. Danbury, CT 06810 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 . 2022 May 27;13:827165. doi: 10.3389/fneur.2022.827165. The severity of the condition varies greatly among affected individuals. Type IV Collagens and Basement Membrane Diseases: Cell Biology and Pathogenic Mechanisms. Unable to load your collection due to an error, Unable to load your delegates due to an error. Neurology. These aneurysms have the potential to burst, causing bleeding within the brain (hemorrhagic stroke). HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. The ultimate goal of IAMRARE is to unite patients and research communities in the improvement of care and drug development. It affects mainly young adults, children and more typically neonates. No use, distribution or reproduction is permitted which does not comply with these terms. Axenfeld-Rieger anomaly is associated with various other eye abnormalities, including underdevelopment and eventual tearing of the colored part of the eye (iris), and a pupil that is not in the center of the eye. Washington, DC 20036 doi: 10.2214/ajr.149.2.351, 19. Facebook: https://www.facebook.com/Col4A1Foundation Please Note 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. Aguglia U, Gambardella A, Breedveld GJ, Oliveri RL, Le Piane E, Messina D, et al. Some of these patients have been described as having HANAC syndrome, which is an acronym for hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. doi: 10.1007/s10897-008-9169-9, 16. September 2003. Novel heterozygous COL4A2 variant c.2572A>G, p.(I858V) mimicking Sneddon's and Divry van Bogaert Syndrome. Mutations in COL4A3, COL4A4 and COL4A5 were found in the early 1990's in patients with Alport Syndrome. 2018;91:e2078-e2088. 2012;54:569-574. https://www.ncbi.nlm.nih.gov/pubmed/22574627, Lanfranconi S, Markus HS. Progressive cerebral atrophies in three children with COL4A1 mutations. 2009 Dec 1;73(22):1873-82. doi: 10.1212/WNL.0b013e3181c3fd12. In addition the whole spectrum of the phenotype is not yet known and there are many asymptomatic patients. Cysts can also form in one or both kidneys, and the cysts may grow larger over time. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Some affected individuals may develop weakness or paralysis of one side of the body (hemiparesis or hemiplegia) and have seizures. Rouaud T, Labauge P, Lasserve ET, Mine M, Coustans M, Deburghgraeve V, et al. Treatment trials will be critical to determine the long-term safety and effectiveness of specific medications and treatments for individuals with COL4A1/A2-related disorders. He underwent at birth neurosonography for axial hypotonia that revealed ventricular asymmetry and right frontotemporal dilatation (Figure 3). For the nucleotide numbering, the HVGS terms (www.hgvs.org) were applied with the nucleotide A of the ATG startcodon = c.1. Compared to other COL4A1-related disorders, the brain is only mildly affected in HANAC syndrome. COL4A1/A2-related disorders are caused by dominant mutations in the COL4A1 or COL4A2 genes. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. Fax: 203-263-9938, Washington, DC Office 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). FOIA (2005) 308:116771. Early intervention is important in ensuring that children with reach their highest potential. Fetal intracerebral hemorrhage and cataract: think COL4A1. We each inherit a full complement on autosomes from each of our parents giving us two copies of each gene. Some individuals with COL4A1-related brain small-vessel disease do not have any signs or symptoms of the condition. 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, . IV-3 goes to a normal school, but special schooling is required for IV-6. For instance, retinal arteriolar tortuosity relates to mutations in the amino-terminal one-third of the protein while mutations causing cataracts and ocular morphologic alterations are more likely to occur, closer to the carboxy terminus (22), like the variant we report. 2013;73:48-57. https://www.ncbi.nlm.nih.gov/pubmed/23225343, Kuo DS, Labelle-Dumais C, Gould DB. The .gov means its official. Aura refers to additional neurological symptoms that occur with, or sometimes before, the development of the migraine headache. (2014) 11:3612. 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). COL4A1/A2-related disorders are rare, genetic, multi-system disorders. Neurol. Over 100 families have been identified with these disorders in the medical literature and many more cases are known that are not in the published literature. Accessibility Until just this year, her 16-year-old daughter Emily, who #1 Ranked Childrens Hospital by U. S. News & World Report. A similar term, variable expressivity, describes when affected individuals have widely varying signs and symptoms. (2015) 17:40524. If neither parent carries the mutation, it is considered de novo which means that the mutation is a new occurrence. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, et al. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. cutting tissue called the corpus callosum, then make some additional delicate (2014) 83:122834. January 31, 2019 Dr. Madsen suggested Zeeva have an operation called a II-2 had a limp since childhood attributed to forceps delivery. doi: 10.1038/gim.2015.30, 21. 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. . No ophthalmological surgery was planned on annual control for any member, but only positive lens correction prescribed. doi: 10.1016/j.matbio.2016.10.003, 23. 2014 Mar;261(3):500-3. doi: 10.1007/s00415-013-7224-4. Yet, as for all COL4A1 mutations, no specific treatment is currently available, and, due to the variable penetrance, adapted follow-up is challenging. 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. The management of COL4A1/A2-related disorders may require the coordinated efforts of a team of specialists. Xia XY, Li N, Cao X, Wu QY, Li TF, Zhang C, et al. COL4A1 is a subunit of the type IV collagen and plays a role in angiogenesis. Matrix Biol. In the brain, intracerebral hemorrhage is the most frequent phenotype. To better define pathology caused by Col4a1 mutations, we characterized myopathy in two different Col4a1 mutant mouse strainsCol4a1 ex41 and Col4a1 G394V.We selected these strains from an allelic series of Col4a1 mutant mice because they showed the most severe myopathy according to NPN quantification in quadriceps while having different effects on [1(IV)] 2 2(IV) secretion. The signs and symptoms can manifest at almost any age from before birth to old age. This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder. 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). Interestingly, COL4A1 and COL4A2 mutations appear to lead to generally similar outcomes although COL4A2 mutations occur less frequently. Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. After a normal neonatal period, those affected develop a rapidly progressive course involving irritability, hyperaesthesia, visual and hearing loss, severe cognitive and motor deterioration, and seizures. 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).