Image showed ventricular asymmetry and brain MRI confirmed right frontotemporal dilatation (B). 55 Kenosia Avenue Neurology. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) The pathogenic mechanisms of COL4A1 mutations are not fully elucidated and may vary according to the mutation type, the affected exon (mutations responsible for systemic HANAC syndrome cluster at exon 24 and 25), the position of the mutation within the triple-helix domain, and the mutation location. (2010). 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. Interestingly, COL4A1 and COL4A2 mutations appear to lead to generally similar outcomes although COL4A2 mutations occur less frequently. What are the different ways a genetic condition can be inherited? Prenatal clinical manifestations in individuals with COL4A1/2 variants. Disease Overview. 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. 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). Phone: 617-249-7300, Danbury, CT office PS and NL: followed III-3 at the Erasme Neurology outpatients clinic. Epub 2016 Apr 24. 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). U.S. Department of Health and Human Services, Autosomal dominant familial hematuria, retinal arteriolar tortuosity, contractures, Hereditary angiopathy with nephropathy, aneurysm, and muscle cramps syndrome. 2018;91:e2078-e2088. Dr. Madsen suggested Zeeva have an operation called a Not only did Dr. Madsen, help heal Zeevas brain, but he was instrumental in supporting us as we founded the Gould Syndrome Foundation, a 501(c)(3) non-profit that promotes education, advocacy, and medical advancements in Gould Syndrome, COL4A1/COL4A2 diseases. 2011 Each child of an individual with a COL4A1-related disorder has a 50% chance of inheriting the pathogenic variant. The outcomes are highly variable ranging from brain hemorrhage before birth (in utero) leading to cavities in the brain (porencephaly) to mild age-related brain abnormalities that can only be observed on a specialized x-ray called magnetic resonance imaging (MRI). Stroke is a leading cause of death and serious long-term disability in developed nations. Last updated: 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. N Engl J Med. Deml B, Reis LM, Maheshwari M, Griffis C, Bick D, Semina E. Whole exome analysis identifies dominant COL4A1 mutations in patients with complex ocular phenotypes involving microphthalmia. These types of correlations can be difficult to detect in patients because of the broad genetic variability in humans. COL4A1 -related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. 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). Childhood presentation of COL4A1 mutations. 2011 Meuwissen MEC, Halley DJJ, Smit LS, Lequin MH, Cobben JM, De Coo R, et al. The COL4A2 test was negative. 55 Kenosia Avenue A diagnosis of COL4A1/A2-related disorders is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests including advanced imaging techniques. In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. Aguglia U, Gambardella A, Breedveld GJ, Oliveri RL, Le Piane E, Messina D, et al. Other causes of porencephaly were ruled out [maternal alloimmunization, trauma, peri-natal cerebral ischemia (normal Apgar scores at birth), and negative TORCH complex tests]. doi: 10.1212/WNL.0000000000001309, 8. Stroke. 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. She had seizures every day, couldnt gain weight, sleep right, or generally enjoy her life. Ann Neurol. Ultrasound in utero from IV-6 (A). Summary. Cereb Circ Cogn Behav. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. How can gene variants affect health and development? 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. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. Fragile or damaged blood vessels or basement membranes in the kidneys can lead to blood in the urine (hematuria). Exome sequencing in 32 patients with anophthalmia/microphthalmia and developmental eye defects. ), A variety of rare genetic disorders may have symptoms similar to those found in COL4A1/A2-related disorders. (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). Facebook: https://www.facebook.com/Col4A1Foundation Please Note In most cases, an affected person has one parent with the condition. Science. doi: 10.1016/j.ejpn.2009.04.010, 27. Novel heterozygous COL4A2 variant c.2572A>G, p.(I858V) mimicking Sneddon's and Divry van Bogaert Syndrome. In affected individuals, stroke is usually caused by bleeding in the brain (hemorrhagic stroke) rather than a lack of blood flow in the brain (ischemic stroke), although either type can occur. Ann Neurol. Genetic counseling will be proposed when IV-3 and IV-6 intend to start a family as there is a 50% risk of mutation transmission to the next generation and potential obstetrical complications. 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. 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. doi: 10.1212/WNL.0b013e3181eee440, 28. These protein networks are the main components of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. Firstly, it segregates within the family with the phenotype. 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. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. Surgery may be necessary for individuals with severe cataracts. 2022 Sep;269(9):5153-5156. doi: 10.1007/s00415-022-11111-0. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. IV-3 had a left hemisphere porencephalic cyst and the lack of evidence of a left corticospinal tract on tractography (Figures 3E,F), IV-5 had a porencephalic cyst on the right lateral ventricle (Figure 3C), and III-3 had leukoencephalopathy (Figure 3D). Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity. doi: 10.1212/WNL.0000000000000837, 20. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, et al. 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. 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). Phone: 617-249-7300, Danbury, CT office 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). Symptoms of the following disorders can be similar to those of COL4A1/A2-related disorders. 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. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. INTERNET 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, . Gould Syndrome is diagnosed following a genetic test revealing a mutation in COL4A1 or COL4A2. Molecular analysis was performed on a gDNA level by means of PCR amplification of all the coding exons and the flanking intron region. Paques M, Ronco P. Novel COL4A1 mutations associated with HANAC syndrome: a role doi: 10.1002/ana.23736, 4. So far, it appears as though mutations in COL4A1 and COL4A2 lead to identical disease, however, for reasons that are not yet understood, mutations in COL4A2 are much less frequent than those in COL4A1. (2006) 354:148996. Some people with COL4A1-related brain small-vessel disease have an eye abnormality called Axenfeld-Rieger anomaly. my mom suggested we call Boston Childrens Hospital. MedlinePlus also links to health information from non-government Web sites. A dashed arrow indicates secondary atrophy in the left cerebral peduncle. 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. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1 -related disorders. The information on this site should not be used as a substitute for professional medical care or advice. How are genetic conditions treated or managed? In people with HANAC syndrome, the vasculature and other tissues within the kidneys, brain, muscles, eyes, and throughout the body weaken. (1982) 40:5679. doi: 10.1038/nmeth.2890, 22. Years published: 2019. There are no standardized treatment protocols or guidelines for affected individuals. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/. These exceptions are nuanced and should be discussed with a genetic counselor. Neurology. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Comparisons may be useful for a differential diagnosis: CADASIL is a rare genetic disorder affecting the small blood vessels in the brain. [Hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC): a new basement membrane-disease associated with mutations of the COL4A1 gene]. Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain. Fax: 203-263-9938, Washington, DC Office doi: 10.1186/s12881-014-0097-2, 11. Phone: 202-588-5700. J Med Genet. Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability. Zagaglia Selch C, Nisevic JR, et al. All authors contributed to the article and approved the submitted version. 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. By continuing to use this website, you agree to the Terms of Service & Privacy Policy. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/, Federico A, Di Donato I, Bianchi S, et al. percent confident in Dr. Madsen and the epilepsy team. With input from doctors, researchers, and the US Food & Drug Administration, NORD has created IAMRARE to facilitate patient-powered natural history studies to shape rare disease research and treatments. Some affected individuals may develop weakness or paralysis of one side of the body (hemiparesis or hemiplegia) and have seizures. Suite 500 This review dsecribes the clinical spectrum of a newly identified disorder related to COL4A1 gene mutations. (2010) 75:7479. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. In the brain, intracerebral hemorrhage is the most frequent phenotype. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. 2009 Dec 1;73(22):1873-82. doi: 10.1212/WNL.0b013e3181c3fd12. Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies. National Institute of Neurological Disorders and Stroke. HANAC syndrome is caused by genetic changes in the COL4A1 gene. Curr Med Chem. Mosaic individuals are likely less severely affected, or even asymptomatic, because they have many cells that secrete COL4A1 normally and that can compensate for those cells that cannot. Migraines can occur with or without aura. We therefore began our analysis of mutant Col4a1 G498V mice by examining the retinal vascular network at three and nine months 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. Individuals with COL4A1/A2-related disorders have characteristic patterns of brain disease when viewed under advanced imaging techniques. Born at term after a 39-week pregnancy, IV-3 had an unremarkable first clinical evaluation at 3 months. Yoneda Y, Haginoya K, Kato M, Osaka H, Yokochi K, Arai H, et al. (2004) 62:16135. Neuropsychological tests disclosed language delay and learning difficulties requiring speech therapy at the age of 9 years. A similar term, variable expressivity, describes when affected individuals have widely varying signs and symptoms. 2018;61:765-772. He also wanted to remove a shunt that was implanted in When our 8-year-old daughter, Zeeva, giggles and runs in her walker to the swing set, its like watching pure childhood joy. Acute or chronic IOP elevation can lead to glaucoma where the increased pressure damages the optic nerve causing progressive and irreversible vision loss. Am J Med Genet A. This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder. Am J Med Genet. Mice with Col4a1 and Col4a2 gene mutations have pathology in many organs and the presence and severity of pathology in a given organ appears to depend on the location of the mutation, genetic context, and environmental interactions. ACS Omega. (2014) 252:178994. She also showed severe hypermetropia. Jeanne M, Gould DB. Autosomal Dominant Brain Small Vessel Disease. Neuropediatrics. Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. Neurology. 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). This variant p.Gly743Val combines hypermetropia in all heterozygotic patients and highly penetrant antenatal porencephaly (associated with motor and intellectual deficits). The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Affected individuals have kidney disease (nephropathy) causing blood in the urine (hematuria) that can either be seen by the naked eye (gross hematuria) or only visible when tested (microscopic hematuria). Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. No ophthalmological surgery was planned on annual control for any member, but only positive lens correction prescribed. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. Staals J, Makin SDJ, Doubal FN, Dennis MS, Wardlaw JM. COL4A1 disorder is probably largely underestimated because of its multisystem and variable phenotype. Zeevas brain to treat a cyst in her brain caused by porencephaly. Resource(s) for Medical Professionals and Scientists on This Disease: 2021 Sep 10;13:727590. doi: 10.3389/fnagi.2021.727590. Urine analysis to test for blood or excess protein can be used to evaluate renal function and identify if the kidneys might be affected. doi: 10.1056/NEJMoa053727, 7. Children with the most severe brain malformations may have: Intellectual impairment Seizures Hydrocephalus Spasticity People who have a disorder of the corpus callosum typically have: eCollection 2022. Suite 500 Orignac I, Dousset V, Lacombe D, Orgogozo JM, Arveiler B, Goizet C. COL4A1 This is not specific to COL4A1/A2-related disorders, and is a sign of many different types of muscle disease. 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. Contact a health care provider if you have questions about your health. 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. 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. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. doi: 10.1212/WNL.0b013e3181c3fd12, 9. Jeanne M, Gould DB. The retina was collected and immunolabeled with an anti-collagen IV antibody, for reconstruction of the entire vascular network (Fig. COL4A1-related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. Sci Rep. 2016;6:18602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, Rannikmae K, Davies G, Thomson PA, et al. Cysts can also form in one or both kidneys, and the cysts may grow larger over time. Background: COL4A1 mutations cause familial porencephaly, infantile hemiplegia, cerebral small vessel disease (CSVD), and hemorrhagic stroke. Mutated patients develop a diffuse small vessel disease of the brain as shown by a diffuse leukoencephalopathy on MRI. While muscle cramps may begin in childhood, many of the other symptoms do not appear until later in life. 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. 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. FOIA Maybe try a search? COL4A1 mutations as a monogenic cause of cerebral 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. In the brain, intracerebral hemorrhage is the most frequent phenotype. Lanfranconi S, Markus HS. Sibon I, Coupry I, Menegon P, Bouchet JP, Gorry P, Burgelin I, Calvas P, Shah S, Kumar Y, McLean B, Churchill A, Stoodley N, Rankin J, et al. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet Accessed January 28, 2019. 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. 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. Slavotinek AM, Garcia ST, Chandratillake G, Bardakjian T, Ullah E, Wu D, et al. Epub 2010 Jun 17. doi: 10.1212/WNL.0000000000006567, PubMed Abstract | CrossRef Full Text | Google Scholar, 2. mutations: a novel genetic multisystem disease. Gould Syndrome is a rare, genetic, multi-system disorder. Your support helps to ensure everyones free access to NORDs rare disease reports. BMC Med Genet. One patient (IV-3) was treated for spasticity and seizures with valproic acid. Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. The size and location of cerebral cavities contributes to clinical variability. 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%). Some individuals develop cysts on the kidney. Some may only develop specific symptoms such as isolated migraines or strokes in childhood or adulthood. doi: 10.1056/NEJMoa071906, 14. Therapies are based on the specific symptoms in each individual. 8600 Rockville Pike A Podcast For The Rare Disease Community, Policy Statements & Letters to Policymakers. All patients suffering from HANAC syndrome display retinal arteriolar tortuosity and occasional retinal hemorrhages. Berg's criteria was used for porencephaly (16, 17) and white matter hyperintensities were characterized as in Fazekas et al. Bookshelf 2017;155:45-57. https://www.ncbi.nlm.nih.gov/pubmed/28254515, Alavi MV, Mao M, Pawlikowski BT, et al. I cannot describe the feeling of seeing your child healed. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. Matrix Biol. If individuals have muscle cramps, blood tests can reveal elevated levels creatine kinase, which is a muscle enzyme. Yet, five siblings, showing mild phenotype even in the second generation support a Mendelian transmission with variable expressivity and no other mechanism. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. The .gov means its official. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Congenital Cephalic Disorders COL4A1/A2-related disorders follow an autosomal dominant pattern of inheritance. In some people, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. These protein networks are the main component of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. Any muscle may be affected, and cramps usually last from a few seconds to a few minutes, although in some cases they can last for several hours. Many patients with COL4A1 and COL4A2 mutations have additional signs and symptoms that do not include the cerebral vasculature. (2014) 34:757. Bethesda, MD 20894, Web Policies Phone: 203-263-9938 The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Disclaimer. IV-5 had microcephaly without motor deficits, a language delay, a mental retardation (IQ of 62) that required adapted schooling, and severe hypermetropia. government site. 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. 30. Fetal origin of brain damage in 2 infants with a COL4A1 mutation: fetal and neonatal MRI. Danbury, CT 06810 A diagnosis can be confirmed through molecular genetic testing. Curr Opin Neurol. When an individual tests positive for a mutation but does not manifest the effects, it is referred to as having incomplete or reduced penetrance. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. for the triple helical CB3[IV] domain. Early intervention is important in ensuring that children with reach their highest potential. The expressivity of the disease is highly variable with high intra- and inter-familial variability (2). It is ubiquitously expressed in many tissues and cell types. 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. What does it mean if a disorder seems to run in my family? Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies, https://nord1dev.wpengine.com/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328961/, https://www.ncbi.nlm.nih.gov/pubmed/28254515, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, https://www.nature.com/articles/gim2014210, https://www.ncbi.nlm.nih.gov/pubmed/23225343, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/, https://www.ncbi.nlm.nih.gov/pubmed/22868088, https://www.ncbi.nlm.nih.gov/pubmed/22574627, https://www.ncbi.nlm.nih.gov/pubmed/20558831, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/, https://www.ncbi.nlm.nih.gov/pubmed/26610912, https://www.ncbi.nlm.nih.gov/books/NBK7046/, https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet, https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/, https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/, https://rarediseases.org/patient-assistance-programs/caregiver-respite/, Learn more about Patient Assistance Programs >, Arginine: Glycine Amidinotransferase Deficiency, https://rarediseases.org/non-member-patient/epilepsy-foundation/, Gould Syndrome Foundation (COL4a1/COL4A2), https://rarediseases.org/non-member-patient/gould-syndrome-foundation-col4a1-col4a2/, https://rarediseases.org/non-member-patient/national-kidney-foundation/, https://rarediseases.org/non-member-patient/nih-national-eye-institute/, NIH/National Institute of Neurological Disorders and Stroke, Aromatic L-Amino Acid Decarboxylase Deficiency, https://rarediseases.org/non-member-patient/nih-national-institute-of-neurological-disorders-and-stroke/, https://rarediseases.org/non-member-patient/the-arc/, Learn more about Patient Organization & Membership >, HANAC: hereditary angiopathy, nephropathy and cramps syndrome (OMIM #611773), POREN1: autosomal dominant type 1 porencephaly; porencephaly with infantile hemiplegia (OMIM #175780, RATOR: retinal arterial tortuosity (OMIM #180000), BSVD: brain small vessel disease with or without ocular anomalies (OMIM #607595), ICH: susceptibility to intracerebral hemorrhage (OMIM #614519).
