Hereditary cystatin C amyloid angiopathy

Crystal structure of human cystatin C monomer

Hereditary Cystatin C Amyloid Angiopathy (HCCAA), also known as Hereditary Cerebral Hemorrhage with Amyloidosis of Icelandic type (HCHWA-I), is a rare genetic disorder characterized by the deposition of amyloid in the walls of the cerebral arteries. This condition leads to cerebral hemorrhage, stroke, and progressive brain damage. It is caused by mutations in the CST3 gene, which encodes the cystatin C protein, a potent inhibitor of cysteine proteases.

Genetics

HCCAA is inherited in an autosomal dominant pattern, meaning that only one copy of the altered gene is necessary to cause the disorder. The mutation responsible for HCCAA leads to the production of a variant of cystatin C that is prone to forming amyloid fibrils. These fibrils accumulate in the cerebral arteries, causing the walls of these vessels to become brittle and prone to rupture.

Symptoms

The primary symptom of HCCAA is recurrent cerebral hemorrhage, which typically begins in adulthood, although the age of onset can vary. Other symptoms may include headache, confusion, seizures, and neurological deficits such as paralysis or loss of sensation, depending on the location and severity of the hemorrhages. Over time, the accumulation of amyloid can lead to cognitive decline and dementia.

Diagnosis

Diagnosis of HCCAA is based on clinical presentation, family history, and radiological findings. Magnetic resonance imaging (MRI) can reveal cerebral hemorrhages and the characteristic patterns of amyloid deposition. Genetic testing can confirm the diagnosis by identifying the specific mutation in the CST3 gene.

Treatment

There is currently no cure for HCCAA, and treatment focuses on managing symptoms and preventing further cerebral hemorrhages. This may include antihypertensive medication to control blood pressure, as well as measures to avoid anticoagulants, which can increase the risk of bleeding. In some cases, surgical intervention may be necessary to remove large hemorrhages.

Prognosis

The prognosis for individuals with HCCAA varies depending on the frequency and severity of cerebral hemorrhages. With careful management, some individuals may maintain a relatively high quality of life for many years. However, the risk of recurrent hemorrhage and progressive neurological decline remains a significant concern.

Epidemiology

HCCAA is most commonly reported in individuals of Icelandic descent, where it is a significant cause of stroke and dementia. However, cases have been identified in other populations, suggesting that the condition may be underdiagnosed.