Years published: 2019. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.). 2013;73:48-57. https://www.ncbi.nlm.nih.gov/pubmed/23225343, Kuo DS, Labelle-Dumais C, Gould DB. Dr. Madsen suggested Zeeva have an operation called a 10.1161/STROKEAHA.110.581918. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. Molecular analysis was performed on a gDNA level by means of PCR amplification of all the coding exons and the flanking intron region. https://www.ncbi.nlm.nih.gov/pubmed/20558831, Alamowitch S, Plaisier E, Favrole P, et al. ), A variety of rare genetic disorders may have symptoms similar to those found in COL4A1/A2-related disorders. (2017) 5758:2944. MedlinePlus also links to health information from non-government Web sites. 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. The strengths of our study are the extensive systemic work-up, the 5-year neurological follow-up, and the pluridisciplinary approach. When our 8-year-old daughter, Zeeva, giggles and runs in her walker to the swing set, its like watching pure childhood joy. The COL4A1 and COL4A2 genes were screened in proband IV-6. Mutations in the gene have been linked to diseases of the brain, muscle, kidney, eye, and cardiovascular system. The management of COL4A1/A2-related disorders may require the coordinated efforts of a team of specialists. 2017;57-58:29-44. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328961/, Sondergaard CB, Nielsen JE, Hansen CK, Christensen H. Hereditary cerebral small vessel disease and stroke. Children inherit a full complement of chromosomes from each of their parent and so we carry two copies of each gene. Disease Overview. 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: This group rarely survives beyond 2 years. doi: 10.1001/archophthalmol.2010.42, 10. The prevalence of HANAC syndrome (hereditary angiopathy-nephropathy-aneurysms-muscle cramps syndrome) is not available, but at least six affected families have been reported worldwide to date. 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). Treatment Berg R, Aleck A, Kaplan A. Familial porencephaly. official website and that any information you provide is encrypted Seattle, WA: University of Washington, Seattle; 1993-. 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). Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. Exon mutations of the COL4A1 genes are responsible for a broad spectrum of cerebral, ocular, and systemic manifestations. After the COL4A1 mutation was found, systemic manifestations of COL4A1 mutations were investigated. (2009) 73:187382. Firstly, it segregates within the family with the phenotype. 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). Cysts can also form in one or both kidneys, and the cysts may grow larger over time. NORD is a registered 501(c)(3) charity organization. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. The number of genes implicated in epilepsy has grown rapidly in the past decade. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. The limitations include the limited number of tested members (only two generations) due to a large family spread over Europe and not fully accessible. Please note that NORD provides this information for the benefit of the rare disease community. About half of people with this condition 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). Thats not to say Zeeva hasnt had to work hard since the surgery. 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. Urine analysis to test for blood or excess protein can be used to evaluate renal function and identify if the kidneys might be affected. (18) and Staals et al. 2022 Oct 26;7(44):39680-39689. doi: 10.1021/acsomega.2c03360. eCollection 2021. (2013) 73:4857. There is in addition a specific phenotype called HANAC with constant nephropathy, muscle cramps and frequent intracranial aneurysms. Copyright 2020 Scoppettuolo, Ligot, Wermenbol, Van Bogaert and Naeije. These aneurysms have the potential to burst, causing bleeding within the brain (hemorrhagic stroke). 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. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. COL4A1/COL4A2 gene mutations description, symptoms and the sub-diagnosis. Clin Neurol Neurosurg. 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. Other phenotypes include intracranial aneurysms, porencephaly, infantile hemiparesis, muscle cramps, optic nerve dysgenesis and secondary glaucoma. Disclaimer. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. The site is secure. Volonghi I, Pezzini A, Del Zotto E, Giossi A, Costa P, Ferrari D, Padovani A. In most cases, an affected person has one parent with the condition. Sibon I, Coupry I, Menegon P, Bouchet JP, Gorry P, Burgelin I, Calvas P, Compared to other COL4A1-related disorders, the brain is only mildly affected in HANAC syndrome. Berg's criteria was used for porencephaly (16, 17) and white matter hyperintensities were characterized as in Fazekas et al. 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). Lenses corrected for hypermetropia. It affects mainly young adults, children and more typically neonates. 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). (2014) 252:178994. percent confident in Dr. Madsen and the epilepsy team. Suite 500 Symptoms of the following disorders can be similar to those of COL4A1/A2-related disorders. 11:827. doi: 10.3389/fneur.2020.00827. http://www.centerwatch.com/, For information about clinical trials conducted in Europe, contact: 1A-B). 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. Phone: 202-588-5700. We recently described hereditary angiopathy with nephropathy, aneurysm, and muscle cramps (HANAC) syndrome in 3 families with closely localized COL4A1 mutations. Illumina's Sequencing by Synthesis (SBS) technology (MiSeq Personal Sequencer, Illumina) analyzed the generated amplicons. 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. 1900 Crown Colony Drive A variety of additional signs and symptoms have been reported in individuals with COL4A1/A2-related disorders including childhood-onset epilepsy, hemolytic anemia (a condition characterized by low levels of circulating red blood cells due to their premature destruction leading to fatigue, weakness, lightheadedness, dizziness, irritability, headaches, and pale skin color), mitral valve prolapse (flaps of the valve located between the upper and lower left heart chambers bulge or collapse during contraction allowing leakage of blood back into the left atrium). 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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/, Federico A, Di Donato I, Bianchi S, et al. 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. (No doctor had ever taken a call on their lunch break to speak with me). government site. Nearly half of these participants were diagnosed with infantile spasms. The conditions in this group have a range of signs and symptoms that involve fragile 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. 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. We therefore began our analysis of mutant Col4a1 G498V mice by examining the retinal vascular network at three and nine months of age. 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). Brain magnetic resonance imaging (MRI) scans were carried out on a three Tesla Brain MRI (Achieva, Ingenia; Philips Healthcare, Best, The Netherlands). What is the prognosis of a genetic condition? We each inherit a full complement on autosomes from each of our parents giving us two copies of each gene. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet Accessed January 28, 2019. doi: 10.1056/NEJMoa071906, 14. Bull Acad Natl Med. 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). Zagaglia Selch C, Nisevic JR, et al. 2015;17:843-853. https://www.nature.com/articles/gim2014210, Yoneda Y, Haginoya K, Kato M, et al. COL4A1/A2-related disorders are caused by dominant mutations in the COL4A1 or COL4A2 genes. (1987) 8:4216. 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). The proportion of cases caused by a de novopathogenic variant is estimated to be at least 27%. The variant was found in IV-3 and IV-5 and not in asymptomatic relatives (III-4, IV-1, IV-4). Slavotinek AM, Garcia ST, Chandratillake G, Bardakjian T, Ullah E, Wu D, et al.