COL4A1

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.

Genetics

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.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

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

References
Article Title: 

Retinal Arteriolar Tortuosity

Clinical Characteristics
Ocular 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.

Genetics

Heterozygous 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 dominant
Treatment
Treatment Options: 

No treatment is known but patients should avoid strenuous excercise.

References
Article Title: 
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