Cerebral Amyloid Angiopathy (ORPHA:85458)
A rare genetic cerebral small vessel disease characterized by amyloid deposition in the cerebral blood vessels leading to predominantly hemorrhagic strokes, focal neurological deficits, and progressive cognitive decline eventually leading to dementia.
Epidemiology
The prevalence is unknown. HCHWA has been described in several families from all over the world. The estimated number of affected patients is between 300 and 400.
Clinical description
Unlike sporadic forms of cerebral amyloid angiopathy (CAA), HCHWA usually presents in younger patients (<55 years of age) and has more severe manifestations. Clinical features depend on the HCHWA disease type, with 7 discovered to date: Icelandic, Dutch, Arctic, Piedmont, Iowa, Flemish and Italian (see these terms). In general, patients present with either a stroke (with headache, nausea, vomiting, focal neurological deficits, and alterations in consciousness) or progressive dementia of the Alzheimer type. Transient neurological symptoms lasting a few minutes to a few hours, and seizures can also occur. Microbleeds and hemorrhages can occur throughout the brain, and are caused by involvement of the vessels in the cerebral cortex and the meninges. Hemorrhages tend to recur. Cognitive decline is progressive and can lead to dementia, either in a stepwise fashion or slowly progressive as in Alzheimer's disease.
Etiology
Most forms of HCHWA (Dutch, Arctic, Piedmont, Iowa, Flemish and Italian) are due to a point-mutation in the APP gene on chromosome 21q21.2, which encodes the beta-amyloid precursor protein. This mutation causes increased accumulation of amyloid-beta protein in the walls of cerebral arteries and capillaries. This can lead to rupture or narrowing of the blood vessels, leading to hemorrhagic or non-hemorrhagic stroke. Sometimes the affected blood vessels show signs of inflammation (CAA-angiitis). Only one form of HCHWA, Icelandic type, is due to a mutation in the CST3 gene on chromosome 20p11.2, encoding the precursor protein cystatin C.
Diagnostic methods
For a probable diagnosis of HCHWA a detailed family history, and (preferably) a magnetic resonance imaging (MRI) scan should be performed. Typically, the MRI shows multiple lobar (cortical, subcortical) hemorrhages and leukoencephalopathy. In the presence of otherwise unexplained lobar hemorrhages and a typical family history, the finding of a causative mutation is sufficient for a definite diagnosis of HCHWA in vivo. At postmortem examination severe CAA, and cortical, lobar or subcortical hemorrhages are found.
Differential diagnosis
Differential diagnoses include all other conditions that could cause lobar intracerebral hemorrhage such as coagulopathies, vasculitis, intravascular large B-cell lymphoma (see these terms), CNS neoplasms, cavernous malformations, cerebral vascular malformation and antecedent trauma
Antenatal diagnosis
Antenatal diagnosis is possible but is rarely performed.
Genetic counseling
The presently known types of HCHWA are inherited in an autosomal dominant manner. Screening of family members of patients with HCHWA is recommended, because of the possibility of genetic counseling. Presymptomatic genetic testing is offered.
Management and treatment
There is no known acute or preventive treatment for cerebral hemorrhages in HCHWA. Antihypertensive therapy is recommended, even in cases of mild to moderate hypertension, but its efficacy is not evidence-based. Corticosteroids can ameliorate symptoms caused by CAA-related inflammation. Patients experiencing seizures should be given antiepileptic drugs. Surgical hematoma evacuation is rarely performed for HCHWA because of the poor outcome associated with severe neurological deficits.
Prognosis
The prognosis is often poor.

                            Last update: 
                            February 2013


                            - Expert reviewer(s): 
                            Dr Joost HAAN  - Pr G.M. [Gisela] TERWINDT