I cannot describe the feeling of seeing your child healed. A similar term, variable expressivity, describes when affected individuals have widely varying signs and symptoms. III-3 was asymptomatic but for severe hypermetropia and bilateral cataracts. The variability and severity of symptoms is significant and how COL4A1/A2-related disorders will potentially affect an individual can be unique. Gould Syndrome is often 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. 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. Contact a health care provider if you have questions about your health. 13 and so Gould Syndrome is considered Autosomal and should affect males and females in equal numbers. 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. doi: 10.1001/archophthalmol.2010.42, 10. Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. Suite 310 Mosaicism can contribute to both reduced penetrance or variable expressivity but other factors do as well. Other phenotypes include intracranial aneurysms, porencephaly, infantile hemiparesis, muscle cramps, optic nerve dysgenesis and secondary glaucoma. . 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. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1 -related disorders. She had seizures every day, couldnt gain weight, sleep right, or generally enjoy her life. Berg R, Aleck A, Kaplan A. Familial porencephaly. If either parent also carries the mutation, it is considered inherited. small vessel disease: a systematic review. 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. Collagen type IV alpha 1 (COL4A1) silence hampers the invasion, migration and epithelial-mesenchymal transition (EMT) of gastric cancer cells through blocking Hedgehog signaling pathway. The strengths of our study are the extensive systemic work-up, the 5-year neurological follow-up, and the pluridisciplinary approach. 2012;322:25-30. https://www.ncbi.nlm.nih.gov/pubmed/22868088, Shah S, Ellard S, Kneen R, et al. After the COL4A1 mutation was found, systemic manifestations of COL4A1 mutations were investigated. doi: 10.1212/WNL.0000000000006567, PubMed Abstract | CrossRef Full Text | Google Scholar, 2. But she is learning to read, enjoys swimming, horseback riding, and is a glass jewelry and pottery artist. Federal government websites often end in .gov or .mil. Epub 2014 Jan 5. A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family. Genet Med. Facebook: https://www.facebook.com/Col4A1Foundation Please Note 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. N Engl J Med. We provide education, advocacy, and resources for families and individuals affected. Careers. Type IV collagen networks play an important role in the basement membranes in virtually all tissues throughout the body, particularly the basement membranes surrounding the body's blood vessels (vasculature). sharing sensitive information, make sure youre on a federal Please note that NORD provides this information for the benefit of the rare disease community. Am J Med Genet. Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies. Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. The expressivity of the disease is highly variable with high intra- and inter-familial variability (2). The signs and symptoms can manifest at almost any age from before birth to old age. Matrix Biol. (2007) 357:268795. TTY: (866) 411-1010 Front. doi: 10.1002/ana.23736, 4. Clipboard, Search History, and several other advanced features are temporarily unavailable. Written informed consent was obtained from the patient and the patient's parents for publication of this case report. Various muscles can be affected and muscle strength can become weakened. Unable to load your collection due to an error, Unable to load your delegates due to an error. Aneurysms are bulges or enlargements of a blood vessel caused by weakening of the wall of the blood vessel. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. came with risks and was the hardest decision we had ever faced, yet we felt 100 To use the sharing features on this page, please enable JavaScript. Illumina's Sequencing by Synthesis (SBS) technology (MiSeq Personal Sequencer, Illumina) analyzed the generated amplicons. doi: 10.1007/s00417-014-2800-6, 12. 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 doctor had ever taken a call on their lunch break to speak with me). PV and VW followed the children at the Neuropediatrics clinic of the same hospital. The type IV collagens are encoded by six different genes (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5 and COL4A6). In most cases, an affected person has one parent with the condition. While muscle cramps may begin in childhood, many of the other symptoms do not appear until later in life. Until just this year, her 16-year-old daughter Emily, who #1 Ranked Childrens Hospital by U. S. News & World Report. Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Paques M, Ronco P. Am J Med Genet A. COL4A1/A2-related disorders are caused by dominant mutations in the COL4A1 or COL4A2 genes. Advanced imaging techniques can include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). (2015) 88:46873. This is not specific to COL4A1/A2-related disorders, and is a sign of many different types of muscle disease. Type IV collagen is an important component of basement membranes in many tissues, especially blood vessels 1-6. Hum Mol Genet. Aguglia U, Gambardella A, Breedveld GJ, Oliveri RL, Le Piane E, Messina D, et al. At 2 years old, IV-6 presented obvious left hemiparesis but could move without help. ACS Omega. Neuropediatrics. doi: 10.1038/gim.2015.30, 21. *Correspondence: Pasquale Scoppettuolo, Pasquale.scoppettuolo@gmail.com, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3, Creative Commons Attribution License (CC BY). Epub 2022 Apr 14. Given the variable expressivity of these mutations, COL4A1/A2-related disorders are likely under diagnosed and the exact number of people who have these disorders is unknown. All authors contributed to the article and approved the submitted version. 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). One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. Aura refers to additional neurological symptoms that occur with, or sometimes before, the development of the migraine headache. Slavotinek AM, Garcia ST, Chandratillake G, Bardakjian T, Ullah E, Wu D, et al. Phone: 203-263-9938 Gunda B, Mine M, Kovcs T, Hornyk C, Bereczki D, Vrallyay G, Rudas G, Audrezet MP, Tournier-Lasserve E. J Neurol. COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. Some of these patients have been described as having HANAC syndrome, which is an acronym for hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. What are the different ways a genetic condition can be inherited? 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 ( 2 - 4 ), hemorrhage ( 2, 5 - 7) and aneurysms ( 8 )], ophthalmological Additional features include poor or absent speech development, facial paralysis (paresis), involuntary muscle spasms (spasticity) that result in slow, stiff, rigid movements, visual field defects, and hydrocephalus, a condition in which accumulation of excessive cerebrospinal fluid in the skull causes pressure on the tissues of the brain, resulting in a variety of symptoms. PMC 2017;155:45-57. https://www.ncbi.nlm.nih.gov/pubmed/28254515, Alavi MV, Mao M, Pawlikowski BT, et al. Phone: 203-263-9938 IV-3 and IV-6 are closely followed by a neuropediatrician (VW). Coupry I, Sibon I, Mortemousque B, Rouanet F, Mine M GC. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. We therefore began our analysis of mutant Col4a1 G498V mice by examining the retinal vascular network at three and nine months of age. Drugs that prevent irregular heartbeats (anti-arrhythmic medications) are used to treat supraventricular arrythmia. 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. Some people with COL4A1-related brain small-vessel disease have an eye abnormality called Axenfeld-Rieger anomaly. https://www.ncbi.nlm.nih.gov/pubmed/26610912. my mom suggested we call Boston Childrens Hospital. (For more information on this disorder, choose cadasil as your search term in the Rare Disease Database. The reference sequences were NM_001845.4 (NP_001836.2) for COL4A1 and NM_001846.2 (NP_001837.2) for COL4A2. doi: 10.1111/cge.12543. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.). 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. Ten months later, the left hemiparesis was observed with a lack of voluntary prehension on his left side without spasticity. However, there are exceptions that depend on precisely when and where the mutation arose. doi: The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. 2012;21:R97-R110. Gould Syndrome is diagnosed following a genetic test revealing a mutation in COL4A1 or COL4A2. Jeanne M, Gould DB. III-3 was informed of the genetic diagnosis and is now regularly followed and screened for cataracts and brain aneurysms. This study clearly demonstrates that COL4A1 and COL4A2 mutations cause clinically variable cerebrovascular disease that includes characteristic features of cerebral small vessel disease. Shah S, Kumar Y, McLean B, Churchill A, Stoodley N, Rankin J, et al. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/. Cesarean delivery for pregnancies with fetus at risk for a COL4A1-related disorder is recommended to prevent brain vascular injury attributable to birth trauma during delivery (6). doi: 10.1038/jp.2013.135, 29. 2009 Jun 25 [Updated 2016 Jul 7]. Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability. Fax: 203-263-9938, Washington, DC Office COL4A1/A2-related disorders are rare, genetic, multi-system disorders. Teaching families how to advocate for their loved ones and access medical information. COL4A1 may be a candidate gene in unexplained familial syndromes with autosomal dominant hematuria, cystic kidney disease, intracranial aneurysms, and muscle cramps. Phone: 617-249-7300, Danbury, CT office basement membranes surrounding the body's blood vessels, Genetic Testing Registry: Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps, National Organization for Rare Disorders (NORD), ANGIOPATHY, HEREDITARY, WITH NEPHROPATHY, ANEURYSMS, AND MUSCLE CRAMPS. Childhood presentation of COL4A1 mutations. Suite 500 Neuropsychological tests disclosed language delay and learning difficulties requiring speech therapy at the age of 9 years. 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. GeneReviews. The size and location of cerebral cavities contributes to clinical variability. It affects mainly young adults, children and more typically neonates. Gould Syndrome Foundation (COL4a1/COL4A2) seeks to educate the community on the rare disease COL4A1 and it's subcategorical diagnosis'. If individuals have muscle cramps, blood tests can reveal elevated levels creatine kinase, which is a muscle enzyme. Molecular analysis was performed on a gDNA level by means of PCR amplification of all the coding exons and the flanking intron region. (2017) 5758:2944. HANAC syndrome is caused by genetic changes in the COL4A1 gene. Some affected individuals may develop weakness or paralysis of one side of the body (hemiparesis or hemiplegia) and have seizures. Type IV collagen molecules attach to each other to form complex protein networks. Ophthalmological features associated with COL4A1 mutations. The risk is the same for males and females. Orignac I, Dousset V, Lacombe D, Orgogozo JM, Arveiler B, Goizet C. COL4A1 A dashed arrow indicates secondary atrophy in the left cerebral peduncle. BMC Med Genet. J Genet Couns. 2014 Mar;261(3):500-3. doi: 10.1007/s00415-013-7224-4. The timeline for the clinical examination and ancillary tests performed is illustrated in Figure 2. 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.