Angiopathy, Hereditary, with Nephropathy, Aneurysms, and Muscle Cramps

Clinical Characteristics
Ocular 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.


This 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.

Treatment Options: 

No treatment is available for the underlying disease although symptomatic relief for cramps, arrhythmias, and renal failure may be beneficial.

Article Title: 


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. 

PubMedID: 26813606

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.

PubMedID: 20818663

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.

PubMedID: 15882279