Front. Treatment 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. Affected individuals may have no observable symptoms or only isolated migraines with aura. Supporting children in their development to reduce handicaps and combining their follow-up with parent counseling could be considered as an ideal approach. Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. The latest research shows that insufficient COL4A1/A2 in basement membranes damages different tissues in very different ways. 2010;41:e513-518. In people with COL4A1-related brain small-vessel disease, the vasculature in the brain weakens, which can lead to blood vessel breakage and stroke. This is not specific to COL4A1/A2-related disorders, and is a sign of many different types of muscle disease. Yoneda Y, Haginoya K, Kato M, Osaka H, Yokochi K, Arai H, et al. 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. *Correspondence: Pasquale Scoppettuolo, Pasquale.scoppettuolo@gmail.com, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3, Creative Commons Attribution License (CC BY). 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. After the COL4A1 mutation was found, systemic manifestations of COL4A1 mutations were investigated. Another limitation is the systemic work-up based on described phenotypes and supposed affected organs. In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. The .gov means its official. September 2003. She had seizures every day, couldnt gain weight, sleep right, or generally enjoy her life. Unauthorized use of these marks is strictly prohibited. can also contribute. COL4A1 codes for extracellular matrix proteins that form heterotrimers that are major components of nearly all organ basal membranes. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. The disorder causes many symptoms, not the least of which are strokes and epilepsy. These exceptions are nuanced and should be discussed with a genetic counselor. Suite 310 Shah S, Ellard S, Kneen R, Lim M, Osborne N, Rankin J, et al. What is the prognosis of a genetic condition? It is possible that insufficient collagen in the basement membrane predisposes blood vessels in the brain to leak or rupture. Ronco P. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. 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. Other eye problems experienced by people with COL4A1-related brain small-vessel disease include clouding of the lens of the eye (cataract) and the presence of arteries that twist and turn abnormally within the light-sensitive tissue at the back of the eye (arterial retinal tortuosity). We therefore began our analysis of mutant Col4a1 G498V mice by examining the retinal vascular network at three and nine months of age. Understanding what it has taken to get her to this point, though, is close to unimaginable. Zagaglia S, Selch C, Nisevic JR, Mei D, Michalak Z, Hernandez-Hernandez L, et al. Many patients with COL4A1 and COL4A2 mutations have additional signs and symptoms that do not include the cerebral vasculature. Sci Rep. 2016;6:18602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, Rannikmae K, Davies G, Thomson PA, et al. (2015) 17:84353. The size and location of cerebral cavities contributes to clinical variability. 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 people with HANAC syndrome, the vasculature and other tissues within the kidneys, brain, muscles, eyes, and throughout the body weaken. Mosaicism can contribute to both reduced penetrance or variable expressivity but other factors do as well. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. One patient (IV-3) was treated for spasticity and seizures with valproic acid. However, there are exceptions that depend on precisely when and where the mutation arose. MeSH Neurology. doi: 10.1212/WNL.0000000000001309, 8. Doctors and researchers to bring research and medical therapeutic options to those affected. A diagnosis can be confirmed through molecular genetic testing. 2022 Mar 24;3:100140. doi: 10.1016/j.cccb.2022.100140. Zagaglia Selch C, Nisevic JR, et al. Hereditary cerebral small vessel diseases: a review. What is the prognosis of a genetic condition? View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. Dev Med Child Neurol. Colin E, Sentilhes L, Sarfati A, Mine M, Guichet A, Ploton C, et al. 1900 Crown Colony Drive Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. We connect and coordinate our families with researchers and medical professionals to get our disease and management coordination into the medical realm. Congenital Cephalic Disorders Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Epub 2016 Apr 24. COL4A1/A2-related disorders are dominant genetic disorders. Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. 1. The brain MRI of IV-6 disclosed a large right-sided frontoparietal cavity (Figure 3B) with communication to the lateral ventricle, isosignal to CFS. What are the different ways a genetic condition can be inherited? (2014) 83:122834. doi: 10.1038/gim.2015.30, 21. National Center for Biotechnology Information. More info about Gould Syndrome is available at https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. Early intervention is important in ensuring that children with reach their highest potential. 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). Sibon I, Coupry I, Menegon P, Bouchet JP, Gorry P, Burgelin I, Calvas P, The human phenotypes are extremely variable between patients and between families, with disease onset as early as in the fetal period. 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. (2002) 112:198202. Please note that NORD provides this information for the benefit of the rare disease community. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. (2007) 357:268795. 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. 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). The variant was confirmed by bidirectional fluorescence DNA sequencing (Sanger method). COL4A1-related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. Gould Syndrome - COL4A1 - COL4A2 genes - Gould Syndrome Foundation Gould Syndrome Foundation 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. If the mutation arises after fertilization, then some cells will carry the mutation and others will not this is called mosaicism. 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. Axenfeld-Rieger anomaly and cataract can cause impaired vision. Focke JK, Veltkamp R, Bauer P, Kraemer M. J Neurol. This condition causes mutations in genes that produce a specific type of collagen. The https:// ensures that you are connecting to the Some individuals do not have any observable symptoms (asymptomatic); others can develop severe, even life-threatening complications. Hum Mol Genet. (D) III- 3Brain MRI showed small asymptomatic lesions in white matter. Going from having seizures every day for six years to having no seizures is nothing short of a miracle. Probands' father had severe hypermetropia and bilateral cataracts. Individuals with HANAC syndrome also experience a variety of eye problems. 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. Meuwissen MEC, Halley DJJ, Smit LS, Lequin MH, Cobben JM, De Coo R, et al. Ann HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. 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. 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. 8600 Rockville Pike Vermeulen RJ, Peeters-Scholte C, Van Vugt JJMG, Barkhof F, Rizzu P, Van der Schoor SRD, et al. Raynaud phenomenon is typically triggered by changes in temperature and usually causes no long term damage. Standardized (15) familiar pedigree is showed in Figure 1. 1779 Massachusetts Avenue I cannot describe the feeling of seeing your child healed. 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. Type IV collagen molecules attach to each other to form complex protein networks. Ultrasound in utero from IV-6 (A). Six alpha chains of type IV. Dr. Joseph Madsen was as wonderful in person as he had been on the phone. 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. He also wanted to remove a shunt that was implanted in Unable to load your collection due to an error, Unable to load your delegates due to an error. Nat Methods. Born at term after a 39-week pregnancy, IV-3 had an unremarkable first clinical evaluation at 3 months. Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability. COL4A1 encodes type IV collagen 1 chain, a crucial component of nearly all basement membrane including vasculature, renal glomerule and ocular structures. People with this condition may have a bulge in one or multiple blood vessels in the brain (intracranial aneurysms). The ultimate goal of IAMRARE is to unite patients and research communities in the improvement of care and drug development. IV-5 had microcephaly without motor deficits, a language delay, a mental retardation (IQ of 62) that required adapted schooling, and severe hypermetropia. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, (2006) 43:4905. 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. Bethesda, MD 20894, Web Policies No patient had cramps, cardiac symptoms, or abnormalities or Raynaud phenomenon. doi: 10.1038/gim.2014.210, 3. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. In some people, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. III-3 was informed of the genetic diagnosis and is now regularly followed and screened for cataracts and brain aneurysms. Teaching families how to advocate for their loved ones and access medical information. Molecular Dynamics Investigation on the Effects of Protonation and Lysyl Hydroxylation on Sulfilimine Cross-links in Collagen IV. All authors contributed to the article and approved the submitted version. 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. Antiinflammatory therapy with canakinumab for atherosclerotic disease. Lenses corrected for hypermetropia. Systemic work-up including renal function, CK levels, urinary sediment test, and renal ultrasound proved unremarkable. He underwent at birth neurosonography for axial hypotonia that revealed ventricular asymmetry and right frontotemporal dilatation (Figure 3).
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