Cerebral autosomal recessive arteriopathy-subcortical infarcts-leukoencephalopathy (ORPHA:199354)
CARASIL is a hereditary cerebral small vessel disease characterized by early-onset gait disturbances, premature scalp alopecia, ischemic stroke, acute mid to lower back pain and progressive cognitive disturbances leading to severe dementia.
Epidemiology
The prevalence is unknown. Less than 10 genetically proven cases have been reported, with most of them occurring in Japan where no founder haplotypes have yet been found, indicating the likely existence of unreported cases. The additional familial cases have been reported from Spain and China.
Clinical description
CARASIL has a slight male predominance. Onset varies but usually the first signs of the disease are diffuse alopecia (not always present) and gait disturbances that can often present before 30 years of age. Attacks of severe lower and mid back pain usually occur between the ages of 20-45. Some may suffer from disk herniations, nodular thickening, and severe spondylitis deformans with osteoporosis. Several cases have shown lumbago without any radiological abnormalities. Half of patients suffer from a typical lacunar stroke while the other half experiences a stepwise deterioration in brain function. Neurological symptoms include pseudobulbar palsy, hyperreflexia, vestibular symptoms, and ophthalmoplegia. Cognitive deficits begin to appear around the age of 30-40 with the first manifestation being forgetfulness. Other manifestations include emotional incontinence, personality changes (lability and irritability), disorientation to time and eventually apallic syndrome. In advanced stages emotional incontinence, abulia and akinetic mutism develop. Patients are usually bedridden 10 years after disease onset but can live for 20-30 years with the illness.
Etiology
CARASIL is caused by a mutation in the HTRA1 gene, encoding the HtrA serine peptidase 1 protein (HTRA1) which represses signaling by transforming growth factor (TGF)-beta family members. Patients with a mutation have reduced or no amounts of HTRA1 which leads to increased signaling by the (TGF)-beta family and consequently to the manifestations seen in CARASIL.
Diagnostic methods
Diagnosis is based on the presence of characteristic clinical and brain magnetic resonance (MRI) imaging findings. MRI findings are similar to those seen in CADASIL syndrome (see this term) including symmetrical distribution of white matter hypersensitivities. White matter high-signal intensity lesions and multiple lacunar infarctions are observed and are most often located in the periventricular and deep white matter. Dilation of cerebral sulci and lateral ventricles is noted in some individuals. Pathological findings show arteriosclerosis in the cerebral small arteries. Genetic testing can confirm diagnosis with a mutation in the HTRA1 gene.
Differential diagnosis
Differential diagnoses include primary angiitis of the central nervous system, Binswanger disease, CADASIL, Nasu-Hakola disease, chronic progressive multiple sclerosis and adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (see these terms). As Hutchinson-Gilford progeria syndrome and Werner syndrome (see these terms) also feature premature baldness and arteriosclerosis, they must also be excluded.
Antenatal diagnosis
Antenatal diagnosis is possible for at-risk pregnancies, where one parent has a known disease-causing mutation in the family.
Genetic counseling
CARASIL is inherited autosomal recessively. Genetic counseling is recommended in families where a mutation in the HTRA1 gene has been identified.
Management and treatment
There is no cure for CARASIL syndrome. Emotional support and counseling for patients and their families is recommended. Canes or a wheelchair may be needed due to gait problems and medications such as tizanidine and baclofen may relieve spasticity. Anxiolytic medication may be prescribed for character changes. A high-salt diet and smoking should be avoided due to arteriosclerosis.
Prognosis
The prognosis is poor with the average duration of illness lasting 10 years.

                            Last update: 
                            May 2013


                            - Expert reviewer(s): 
                            Pr Osamu ONODERA