Angiopathy, Hereditary, with Nephropathy, Aneurysms, and Muscle Cramps Clinical CharacteristicsOcular Features: Tortuosity of second and third order arterioles is usually present bilaterally but does not involve first order branches. Intraretinal hemorrhages may also be seen and are sometimes associated with minor stress and trauma. No fluorescein leakage is present. Vision usually remains good but transient vision loss may be reported if the retinal hemorrhages involve the fovea and parafoveal areas. Systemic Features: Nail bed capillaries may appear tortuous. Aneurysms of the internal carotid and middle cerebral arteries can be present and cerebrovascular accidents sometimes occur. Brain imaging may show degrees of leukoencephalopathy. Large renal cysts, mild hematuria both microscopic and gross, and mild renal failure are sometimes seen. Some patients experience Raynaud phenomena. Muscle cramps lasting seconds to hours are not uncommon. Some patients have supraventricular cardiac arrhythmias. Alterations in basement membrane morphology can be seen on electron microscopy in many areas of the body but that of the glomeruli is normal even though the filtration rate is decreased. GeneticsThis is an autosomal dominant condition as the result of heterozygous mutations in COL4A1 (13q34). Mutations in the same gene have also been found in a simpler autosomal dominant disease known as Retinal Arteriolar Tortuosity (180000). The latter may be an allelic condition or the same disorder. Pedigree: Autosomal dominantTreatmentTreatment Options: No treatment is available for the underlying disease although symptomatic relief for cramps, arrhythmias, and renal failure may be beneficial. ReferencesArticle Title: Col4a1 mutations cause progressive retinal neovascular defects and retinopathy Alavi MV, Mao M, Pawlikowski BT, Kvezereli M, Duncan JL, Libby RT, John SW, Gould DB. Col4a1 mutations cause progressive retinal neovascular defects and retinopathy. Sci Rep. 2016 Jan 27;6:18602. doi: 10.1038/srep18602. PubMed ID: 26813606 Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Paques M, Ronco P. Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain. Am J Med Genet A. 2010 Oct;152A(10):2550-5. PubMed ID: 20818663 Autosomal-dominant familial hematuria with retinal arteriolar tortuosity and contractures: a novel syndrome Plaisier E, Alamowitch S, Gribouval O, Mougenot B, Gaudric A, Antignac C, Roullet E, Ronco P. Autosomal-dominant familial hematuria with retinal arteriolar tortuosity and contractures: a novel syndrome. Kidney Int. 2005 Jun;67(6):2354-60. PubMed ID: 15882279 Read more about Angiopathy, Hereditary, with Nephropathy, Aneurysms, and Muscle Cramps
Col4a1 mutations cause progressive retinal neovascular defects and retinopathy Alavi MV, Mao M, Pawlikowski BT, Kvezereli M, Duncan JL, Libby RT, John SW, Gould DB. Col4a1 mutations cause progressive retinal neovascular defects and retinopathy. Sci Rep. 2016 Jan 27;6:18602. doi: 10.1038/srep18602. PubMed ID: 26813606
Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Paques M, Ronco P. Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain. Am J Med Genet A. 2010 Oct;152A(10):2550-5. PubMed ID: 20818663
Autosomal-dominant familial hematuria with retinal arteriolar tortuosity and contractures: a novel syndrome Plaisier E, Alamowitch S, Gribouval O, Mougenot B, Gaudric A, Antignac C, Roullet E, Ronco P. Autosomal-dominant familial hematuria with retinal arteriolar tortuosity and contractures: a novel syndrome. Kidney Int. 2005 Jun;67(6):2354-60. PubMed ID: 15882279
Retinal Arteriolar Tortuosity Clinical CharacteristicsOcular Features: The diameter of retinal arterioles and their degree of tortuosity are continuous metrics without specific endpoints. However, examination of the retinal vasculature can identify a set of patients in which the arterioles are strikingly tortuous. It is most evident in second and third order vessels. In such individuals retinal hemorrhages may occur following mild trauma and exercise. They are usually located in the posterior pole and may account for reported episodes of temporary vision loss if located in the foveal and parafoveal areas. No vascular leakage is seen on fluorescein angiography. The retinal hemorrhages usually resolve without permanent damage. The vascular tortuosity seems to have its onset in the first two decades of life and has been described as progressive. Systemic Features: Increased tortuosity of capillaries in the nail beds can be seen and some individuals have hematuria. The phenotype in this condition is variable and seems to be specific to individual families. There are families in which extraocular disease has been ruled out whereas in other families there may be small vessel disease in the brain, and yet other families in which nephropathy, muscle cramps, and aneurysms occur with the retinal arteriolar tortuosity. Patients with systemic vascular disease frequently have evidence of leukoencephalopathy on brain scans. There is a significant risk of major vascular accidents in the central nervous system. GeneticsHeterozygous mutations in the COL4A1 gene (13q34) have been identified in families with simple retinal arteriolar tortuosity. The gene product is a component of type IV collagen which is found in basement membranes throughout the body, including blood vessels. Mutations in COL4A1 have also been found in the multisystem disease known as HANAC (Hereditary Angiopathy with Nephropathy, Aneurysm and Cramps) (611773) in which tortuosity of the retinal arterioles is also seen. Vascular tortuosity is also a feature of Fabry disease (301500) and Williams syndrome (194050). Pedigree: Autosomal dominantTreatmentTreatment Options: No treatment is known but patients should avoid strenuous excercise. ReferencesArticle Title: Col4a1 mutations cause progressive retinal neovascular defects and retinopathy Alavi MV, Mao M, Pawlikowski BT, Kvezereli M, Duncan JL, Libby RT, John SW, Gould DB. Col4a1 mutations cause progressive retinal neovascular defects and retinopathy. Sci Rep. 2016 Jan 27;6:18602. doi: 10.1038/srep18602. PubMed ID: 26813606 Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity Zenteno JC, Crespi J, Buentello-Volante B, Buil JA, Bassaganyas F, Vela-Segarra JI, Diaz-Cascajosa J, Marieges MT. Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity. Graefes Arch Clin Exp Ophthalmol. 2014 Sep 17. [Epub ahead of print]. PubMed ID: 25228067 Progressive inherited retinal arteriolar tortuosity with spontaneous retinal hemorrhages Wells CG, Kalina RE. Progressive inherited retinal arteriolar tortuosity with spontaneous retinal hemorrhages. Ophthalmology. 1985 Aug;92(8):1015-24. PubMed ID: 4047598 Familial retinal arteriolar tortuosity with retinal hemorrhage Goldberg, M. F., Pollack, I. P., Green, W. R. Familial retinal arteriolar tortuosity with retinal hemorrhage. Am. J. Ophthal. 73: 183-191, 1972. Read more about Retinal Arteriolar Tortuosity
Col4a1 mutations cause progressive retinal neovascular defects and retinopathy Alavi MV, Mao M, Pawlikowski BT, Kvezereli M, Duncan JL, Libby RT, John SW, Gould DB. Col4a1 mutations cause progressive retinal neovascular defects and retinopathy. Sci Rep. 2016 Jan 27;6:18602. doi: 10.1038/srep18602. PubMed ID: 26813606
Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity Zenteno JC, Crespi J, Buentello-Volante B, Buil JA, Bassaganyas F, Vela-Segarra JI, Diaz-Cascajosa J, Marieges MT. Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity. Graefes Arch Clin Exp Ophthalmol. 2014 Sep 17. [Epub ahead of print]. PubMed ID: 25228067
Progressive inherited retinal arteriolar tortuosity with spontaneous retinal hemorrhages Wells CG, Kalina RE. Progressive inherited retinal arteriolar tortuosity with spontaneous retinal hemorrhages. Ophthalmology. 1985 Aug;92(8):1015-24. PubMed ID: 4047598
Familial retinal arteriolar tortuosity with retinal hemorrhage Goldberg, M. F., Pollack, I. P., Green, W. R. Familial retinal arteriolar tortuosity with retinal hemorrhage. Am. J. Ophthal. 73: 183-191, 1972.