Muscle cramps can be spontaneous or triggered by exercise. 2010 Aug;41(8):e513-8. Slavotinek AM, Garcia ST, Chandratillake G, Bardakjian T, Ullah E, Wu D, et al. Gould Syndrome Foundation (COL4a1/COL4A2) seeks to educate the community on the rare disease COL4A1 and it's subcategorical diagnosis'. It is possible that insufficient collagen in the basement membrane predisposes blood vessels in the brain to leak or rupture. NCI CPTC Antibody Characterization Program. (2020). If neither parent carries the mutation, it is considered de novo which means that the mutation is a new occurrence. COL4A1 Mutations and Hereditary Angiopathy, Nephropathy, Aneurysms, and Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. 2021 Sep 10;13:727590. doi: 10.3389/fnagi.2021.727590. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) The team may eventually include pediatric neurologists (diagnose and treat disorders of the brain, nerves and nervous system in children); ophthalmologists (who specialize in eye disorders) hematologists (who specialize in blood disorders); cardiologists (who specialize in heart disorders, nephrologists (who specialize in kidney disorders) and other healthcare professionals may need to systematically and comprehensively plan treatment. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. 1. One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. doi: 10.1111/cge.12543. doi: 10.1136/jmg.2005.035584, 15. In people with COL4A1-related brain small-vessel disease, the vasculature in the brain weakens, which can lead to blood vessel breakage and stroke. doi: 10.2214/ajr.149.2.351, 19. Front Aging Neurosci. The effects of the disorder range from subtle or mild to severe, depending on associated brain abnormalities. Novel COL4A1 mutation in a fetus with early prenatal onset of - Nature No microbleeds or cystic cavities were found. Lenses corrected for hypermetropia. 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. II-2 had a limp since childhood attributed to forceps delivery. Jeanne M, Gould DB. Progressive cerebral atrophies in three children with COL4A1 mutations. Individuals with this condition are at increased risk of having more than one stroke in their lifetime. Affected individuals may have no observable symptoms or only isolated migraines with aura. 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). Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden. Bull Acad Natl Med. doi: 10.1002/ajmg.10452, 18. For asymptomatic patients, cerebral and vessel imaging for aneurysm screening and ophthalmologic follow-up are indicated (2). doi: 10.1001/archneur.1983.04050080067013, 17. 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. We each inherit a full complement on autosomes from each of our parents giving us two copies of each gene. Supporting children in their development to reduce handicaps and combining their follow-up with parent counseling could be considered as an ideal approach. Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. 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. Disease Overview. 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. 2008 May;192(5):971-84; discussion 984-6. Understanding what it has taken to get her to this point, though, is close to unimaginable. Some of the patient advocacy organizations listed in the Resources section below provide support and information to affected individuals and their families. 128:4839. 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. Drugs that prevent irregular heartbeats (anti-arrhythmic medications) are used to treat supraventricular arrythmia. 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). 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: Individuals with COL4A1 or COL4A2 mutations can also develop formation of clefts or slits in the two halves of the brain (schizencephaly) in which cerebral hemispheres are missing and replaced with sacs filled with cerebrospinal fluid (hydranencephaly), abnormal folds in the brain surface (polymicrogyria) or abnormalities in the normal laying of the neuronal cells in the brain (cortical lamination defects). Many patients with COL4A1 and COL4A2 mutations have additional signs and symptoms that do not include the cerebral vasculature. MedlinePlus also links to health information from non-government Web sites. Quincy, MA 02169 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. Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. Rouaud T, Labauge P, Lasserve ET, Mine M, Coustans M, Deburghgraeve V, et al. (2015) 88:46873. Graefe's Arch Clin Exp Ophthalmol. 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. Zeevas brain to treat a cyst in her brain caused by porencephaly. Rarely, new mutations in the gene occur in people with no history of the disorder in their family. 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). Suite 310 Muscle cramps experienced by most people with HANAC syndrome typically begin in early childhood. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, Marro B, (2018) 91:e207888. eCollection 2022. 2015;17:843-853. https://www.nature.com/articles/gim2014210, Yoneda Y, Haginoya K, Kato M, et al. (2006) 354:148996. Acute or chronic IOP elevation can lead to glaucoma where the increased pressure damages the optic nerve causing progressive and irreversible vision loss. Berg's criteria was used for porencephaly (16, 17) and white matter hyperintensities were characterized as in Fazekas et al. 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. Neurology. (2011) 42:13. N Engl J Med. Most individuals diagnosed with a COL4A1-related disorder have an affected parent. COL4A1 Mutation in a Neonate With Intrauterine Stroke and Anterior Segment Dysgenesis. COL4A1 brain small-vessel disease - Radiopaedia How are genetic conditions treated or managed? COL4A1/A2-related disorders are rare, genetic, multi-system disorders. seizure activity. If individuals have muscle cramps, blood tests can reveal elevated levels creatine kinase, which is a muscle enzyme. NORD strives to open new assistance programs as funding allows. Years published: 2019. doi: 10.1056/NEJMoa053727, 7. 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. Hum Mol Genet. The human phenotypes are extremely variable between patients and between families, with disease onset as early as in the fetal period. The proportion of cases caused by a de novopathogenic variant is estimated to be at least 27%. 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. can also contribute. U.S. Department of Health and Human Services, Brain small-vessel disease with hemorrhage. doi: View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. It affects mainly young adults, children and more typically neonates. HANAC syndrome is caused by genetic changes in the COL4A1 gene. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. Some individuals develop cysts on the kidney. Some may only develop specific symptoms such as isolated migraines or strokes in childhood or adulthood. doi: 10.1007/s00417-014-2800-6, 12. No patient had cramps, cardiac symptoms, or abnormalities or Raynaud phenomenon. Gould Syndrome is a rare, genetic, multi-system disorder. Zeeva woke up after a ten-hour procedure, opened her eyes, and it felt like we were seeing her for the first time. Gould Syndrome is diagnosed following a genetic test revealing a mutation in COL4A1 or COL4A2. When we didnt feel we had any options left for treatment, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/, Federico A, Di Donato I, Bianchi S, et al. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/. Neurol. ACS Omega. Liu X, Yang Q, Tang L, He J, Tian D, Wang B, Xie L, Li C, Fan D. Front Neurol. All patients suffering from HANAC syndrome display retinal arteriolar tortuosity and occasional retinal hemorrhages. 2022 May 27;13:827165. doi: 10.3389/fneur.2022.827165. Phone: 617-249-7300, Danbury, CT office Phone: 203-263-9938 doi: 10.1038/gim.2014.210, 3. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies. PV and VW followed the children at the Neuropediatrics clinic of the same hospital. This review dsecribes the clinical spectrum of a newly identified disorder related to COL4A1 gene mutations. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues, including the brain. 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. 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. This can lead to problems 1) if too much of the misfolded protein accumulates within cells, 2) if not enough of the protein exits the cells to form networks, and 3) occasionally, the presence of the mutant proteins outside the cells can interfere with the structure of the network. Painful muscle cramps can occur and can develop before three years of age. 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. Am J Med Genet. Cereb Circ Cogn Behav. In the front of the eye, patients can have abnormally small eyes (microphthalmia), cataracts (cloudy lenses), and anterior segment dysgenesis (Axenfeld-Rieger). As the name suggests, mutations in the COL4A1 gene cause COL4A1-related brain small vessel disease. GeneReviews. Since fewer than 100 families have been reported, the exact prevalence of COL4A1-related disorders is not well-established. Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain.
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