Cerebral Arteriopathy, Autosomal Recessive, With Subcortical Infarcts And Leukoencephalopathy

A number sign (#) is used with this entry because of evidence that autosomal recessive cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is caused by homozygous or compound heterozygous mutation in the HTRA1 gene (602194) on chromosome 10q26.

Description

Autosomal recessive cerebral arteriopathy with subcortical infarcts and leukoencephalopathy is a nonhypertensive cerebral small vessel arteriopathy characterized by alopecia, spondylosis, and progressive motor dysfunction and dementia. Onset is usually in the second or third decade (summary by Hara et al., 2009).

Clinical Features

Maeda et al. (1976) reported 2 Japanese brothers, born of consanguineous parents, with young adult-onset progressive encephalopathy characterized by extrapyramidal features and dementia. Clinical features included generalized rigidity, spastic ataxia, hyperreflexia, extensor plantar responses, pseudobulbar symptoms, and dementia. The encephalopathy resembled Binswanger encephalopathy, but blood pressure was normal. Both brothers had alopecia, and 1 brother had back pain with lumbar disc herniation. Onset was in the third decade and death occurred within 10 years after a rapidly progressive course.

Fukutake et al. (1985) reported 3 affected brothers and proposed that the syndrome comprised encephalopathy, alopecia, and lumbago.

Yamamura et al. (1987) described progressive subcortical vascular encephalopathy without hypertension or other known causes of vasculopathy in a 30-year-old Japanese man who was born of consanguineous parents. They reviewed the literature and found similar cases with onset at ages 25 to 30. Affected individuals had a diffuse alopecia since youth and spondylitis deformans with early onset.

Fukutake and Hirayama (1995) stated that 17 patients with CARASIL had been reported; all were Japanese. Age at onset of encephalopathy ranged from 20 to 44 years, with the majority in the late twenties. Alopecia developed prior to neurologic symptoms in most cases. The male to female ratio was 7.5:1. The inheritance pattern was autosomal recessive. Common clinical features included progressive dementia, pseudobulbar palsy, pyramidal signs, spondylosis deformans, and acute lumbago with lumbar disc herniation. About half of the patients experienced acute strokes. Less common features included muscle rigidity, ataxia, brainstem signs, and ophthalmoplegia. Six of 7 deceased patients had died within 10 years of onset. None of the patients had chronic arterial hypertension or significant vascular risk factors. Brain imaging showed diffuse white matter abnormalities with small foci of lacunae similar to that observed in classic Binswanger encephalopathy. Findings compatible with arteriosclerosis were observed in 6 of 12 patients who underwent cerebral angiography.

Yanagawa et al. (2002) reported 2 affected sisters of first-cousin parents. The older sister presented at age 40 with a 6-year history of knee pain and unsteady gait, with progression to unilateral hemiparesis, dysarthria, emotional instability, and urinary incontinence, and death at age 51. The younger sister presented at age 38 with sudden-onset diplopia and right hemiparesis. She reported knee and lower back pain since her teens. Brain imaging showed diffuse cerebral white matter lesions, and spine radiography showed severe spondylitis deformans with osteoporosis. She required the use of a wheelchair at age 48. Neither patient had alopecia. Yanagawa et al. (2002) emphasized that CARASIL is a hereditary cerebrovascular disease with accompanying extracranial symptoms.

Hara et al. (2009) reported 6 consanguineous Japanese families with classic CARASIL. Onset of initial symptoms was in the second of life (range, 14 to 18 years), and the most common initial feature was alopecia. Other features included spondylosis, progressive dementia, gait disturbance with pyramidal signs, and white matter changes on brain MRI.

Mendioroz et al. (2010) reported a Caucasian man of Spanish descent who presented at age 34 years with unsteady gait, urinary urgency, and slurred speech, and had alopecia since before age 18 years. Physical examination showed dysarthria, dysphagia, emotional instability, spastic gait, and extensor plantar responses. The disorder was progressive, and he developed cognitive impairment with dysexecutive syndrome, pseudobulbar syndrome, and tetraparesis. Brain MRI showed a diffuse leukoencephalopathy involving periventricular and deep white matter, including anterior temporal lobes and external capsules, as well as multiple microbleeds and multiple lacunar infarcts throughout the brain. In addition, there were multilevel degenerative changes in the cervical spinal cord. Genetic analysis identified a homozygous mutation in the HTRA1 gene (G295R; 602194.0006). The patient's mother, who was heterozygous for the mutation, had nonhypertensive leukoencephalopathy.

Bianchi et al. (2014) reported a 29-year-old Romanian woman with CARASIL. She had chronic lumbar and cervical pain since age 14, and 2 ischemic strokes in her twenties resulted in hemiparesis and dysarthria. Physical examination showed ataxia, gaze-evoked nystagmus, dysmetria, and hypoactive reflexes. Cognition was normal, and she did not have alopecia. Brain imaging showed severe diffuse leukoencephalopathy, including subcortical infarcts and evidence of microbleeds. Brain imaging of her parents showed mild supratentorial leukoencephalopathy in her father and diffuse infra- and supratentorial leukoencephalopathy in her mother; however, both parents were neurologically normal. These findings suggested that the carrier condition may be paucisymptomatic.

Neuropathologic Features

Neuropathologic examination of the patients reported by Maeda et al. (1976) showed diffuse and focal demyelination with sparing of U fibers and severe arteriosclerotic changes of meningeal arteries and 100- to 400-micron diameter arteries in the cerebral white matter. There was fibrous intimal proliferation, severe hyalinosis, and splitting of the intima and/or the internal elastic membrane.

Yokoi and Nakayama (1985) performed autopsies on 4 individuals with this syndrome, demonstrating arteriosclerosis in the small arteries of the heart, spleen, kidneys, and brain. There was diffuse demyelination of the cerebral white matter with some preservation of U fibers and small cystic foci in the white matter and the basal ganglia. The degeneration of the white matter was caused by arteriosclerotic changes of the small arteries: fibrous intimal proliferation and hyaline degeneration with splitting of the internal elastic membrane.

Yanagawa et al. (2002) reported postmortem findings in a patient with CARASIL. There were prominent arteriosclerotic changes in the small arteries of the white matter and basal ganglia, with fibrous intimal proliferation, hyaline degeneration, splitting of the internal elastic lamina, and a concentrically narrowed lumen. There was no evidence of neurodegenerative disease. No serious vascular changes were observed in the heart or kidney, and no sclerotic changes were seen in quadriceps muscle biopsy.

Molecular Genetics

By linkage analysis and fine mapping, followed by candidate gene sequencing, in 6 consanguineous Japanese families with CARASIL, Hara et al. (2009) identified 45 different homozygous mutations in the HTRA1 gene (see, e.g., 602194.0002-602194.0005) on chromosome 10q25. The mutant proteins were unable to suppress TGF-beta (TGFB1; 190180) activity, and increased expression TGFB1 was observed in the tunica media of affected small arteries. These findings indicated that CARASIL is a disease associated with dysregulation of TGF-beta signaling.

In a 29-year-old Romanian woman with CARASIL, Bianchi et al. (2014) identified compound heterozygous mutations in the HTRA1 gene (602194.0007 and 602194.0008). Functional studies of the variants were not performed.

Nomenclature

Bowler and Hachinski (1994) noted the similarity of this disorder to CADASIL (125310), autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy, and proposed that the disorder be called CARASIL for cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy.