Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is disease of the arteries in the brain, which causes tissue loss in the subcortical region of the brain and the destruction of

myelin Myelin Sheath ( ) is a lipid-rich material that in most vertebrates surrounds the axons of neurons to insulate them and increase the rate at which electrical impulses (called action potentials) pass along the axon. The myelinated axon can be lik ...

in the CNS. CARASIL is characterized by symptoms such as gait disturbances, hair loss, low back pain,

dementia Dementia is a syndrome associated with many neurodegenerative diseases, characterized by a general decline in cognitive abilities that affects a person's ability to perform activities of daily living, everyday activities. This typically invo ...

, and

stroke Stroke is a medical condition in which poor cerebral circulation, blood flow to a part of the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemor ...

. CARASIL is a

rare disease A rare disease is any disease that affects a small percentage of the population. In some parts of the world, the term orphan disease describes a rare disease whose rarity results in little or no funding or research for treatments, without financi ...

, having only been diagnosed in about 50 patients, of which ten have been genetically confirmed. Most cases have been reported in Japan,Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy. (2011). Retrieved 1/28, 2015 but Chinese and caucasian individuals have also been diagnosed with the disease.Carasil. (2013). Retrieved 1/28, 2015, from http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=EN&Expert=199354 CARASIL is inherited in an

autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...

pattern. There is currently no cure for CARASIL.Fukutake, T. (2010). Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL): From discovery to gene identification. Journal of Stroke and Cerebrovascular Diseases, 20(2), 85-86,87,88,89,90,91. Other names for CARASIL include familial young-adult-onset arteriosclerotic leukoencephalopathy with alopecia and lumbago without arterial hypertension, Nemoto disease and Maeda syndrome.

Signs and symptoms

Symptoms of CARASIL may include spondylosis deformans,

lumbago Low back pain or lumbago is a common disorder involving the muscles, nerves, and bones of the back, in between the lower edge of the ribs and the lower fold of the buttocks. Pain can vary from a dull constant ache to a sudden sharp feeling. ...

(lower back pain) due to herniated disks,

alopecia Hair loss, also known as alopecia or baldness, refers to a loss of hair from part of the head or body. Typically at least the head is involved. The severity of hair loss can vary from a small area to the entire body. Inflammation or scarring ...

, spasticity in the limbs leading to gait disturbances,

dysarthria Dysarthria is a speech sound disorder resulting from neurological injury of the motor component of the motor–speech system and is characterized by poor articulation of phonemes. It is a condition in which problems effectively occur with the ...

, urinary incontinence, pseudobulbular signs,

arteriosclerosis Arteriosclerosis, literally meaning "hardening of the arteries", is an umbrella term for a vascular disorder characterized by abnormal thickening, hardening, and loss of elasticity of the walls of arteries; this process gradually restricts th ...

of cerebral arteries, mood changes,

, and

. Individuals with CARASIL may experience

spondylosis Spondylosis is the degeneration of the vertebral column from any cause. In the more narrow sense, it refers to spinal osteoarthritis, the age-related degeneration of the spinal column, which is the most common cause of spondylosis. The degener ...

and

beginning in their teens, although alopecia is not seen in all patients. Other signs of the disease, particularly neurological abnormalities, may present from ages 20–40 with symptoms worsening over time. About 50% of affected patients present with stroke, and most strokes experienced by patients are lacunar infarcts. Many patients experience some form of mood changes, personality disorders, and/or dementia over time.

Cause

CARASIL is caused by mutation of the '' HTRA1'' gene which encodes the HtrA serine peptidase 1 protein (HTRA1). ''HTRA1'' is located on chromosome 10 and encodes an enzyme that regulates signaling by the

TGF-β Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other ...

family of proteins. TGF-β protein family plays an important role in cellular functions, especially in

angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and ...

. Individuals with CARASIL have mutations in ''HTRA1'' which leads to a reduced amount of HTRA1 protein or no HTRA1 protein at all. The mutant proteins are unable to suppress TGF-β activity. Increase in TGF-β1 activity has been seen in the

tunica media The tunica media (Neo-Latin "middle coat"), or media for short, is the middle tunica (layer) of an artery or vein. It lies between the internal elastic lamina of the tunica intima on the inside and the tunica externa on the outside. Artery The ...

of affected small arteries. CARASIL is an

disease, meaning that both parents must be a carrier for the

allele An allele is a variant of the sequence of nucleotides at a particular location, or Locus (genetics), locus, on a DNA molecule. Alleles can differ at a single position through Single-nucleotide polymorphism, single nucleotide polymorphisms (SNP), ...

in order for the disease to be passed on to the child. As with other autosomal recessive diseases, the likelihood of receiving a

recessive allele In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and ...

from both parents increases if the parents are closely related to each other (

consanguineous Consanguinity (from Latin '' consanguinitas'' 'blood relationship') is the characteristic of having a kinship with a relative who is descended from a common ancestor. Many jurisdictions have laws prohibiting people who are closely related by blo ...

). This trend has been observed for CARASIL.

Pathophysiology

A few different types of mutations to the ''HTRA1'' gene have been observed in CARASIL patients.

Nonsense mutation In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a ''nonsense codon'', or a premature stop codon in the transcribed mRNA, and leads to a truncated, incomplete, and possibly nonfunctional protein product. No ...

s have been shown to cause no HTRA1 protein to be produced, while

missense mutation In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Missense mutations change amino acids, which in turn alt ...

s have been shown to produce some HTRA1 protein, but with reduced activity. Regardless of whether or not HTRA1 protein is produced, or its activity is greatly reduced, the normal regulatory activity of the HTRA1 protein is lost. This means that

(transforming growth factor beta) signaling cannot be repressed as normal. When

activity goes unchecked, it alters the structure of the small blood vessels in the brain, increasing an individual's risk of

and other neurological abnormalities. Abnormally increased TGF-β activity is also suspected to be involved in the

and

seen in CARASIL patients, but that has not been confirmed and the mechanism is not yet known. CARASIL is a disease characterized by damage to the small blood vessels of the brain. When blood vessels in the brain are damaged, blood flow can be reduced or stopped leading to stroke. It can also lead to a variety of different symptoms depending on what area of the brain has lost its blood supply. This is what causes the spasticity in the limbs, slurred speech, urinary incontinence, and

seen in some patients. Progressive damage to and loss of the white matter, or

ated areas, in the brain leads to some of the other neurological symptoms, such as forgetfulness progressing to

, mood changes, confusion, and apathy.

Diagnosis

CARASIL can be tentatively diagnosed by a thorough medical history, examination of symptoms, differential diagnoses, and

MRI Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to generate pictures of the anatomy and the physiological processes inside the body. MRI scanners use strong magnetic fields, magnetic field gradients, and rad ...

scans of the brain. Diffuse white matter changes (

leukoencephalopathy Leukoencephalopathy ( leukodystrophy-like diseases) is a term that describes all of the brain white matter diseases, whether their molecular cause is known or unknown. It can refer specifically to any of these diseases: * Progressive multifocal le ...

) and multiple lacunar infarcts in the

basal ganglia The basal ganglia (BG) or basal nuclei are a group of subcortical Nucleus (neuroanatomy), nuclei found in the brains of vertebrates. In humans and other primates, differences exist, primarily in the division of the globus pallidus into externa ...

of the

thalamus The thalamus (: thalami; from Greek language, Greek Wikt:θάλαμος, θάλαμος, "chamber") is a large mass of gray matter on the lateral wall of the third ventricle forming the wikt:dorsal, dorsal part of the diencephalon (a division of ...

are usually determining factors seen on

scans of affected individuals. Further

genetic testing Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...

must be used to confirm the diagnosis. It is suspected that there are many cases of CARASIL that have not been diagnosed because of the similarities with other neurological disorders. Several disease that are frequently used for differential diagnoses include

Binswanger's disease Binswanger's disease, also known as subcortical leukoencephalopathy and subcortical arteriosclerotic encephalopathy, is a form of small-vessel vascular dementia caused by damage to the white brain matter. White matter atrophy can be caused by ma ...

CADASIL CADASIL or CADASIL syndrome, involving cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, is the most common form of hereditary stroke disorder and is thought to be caused by mutations of the '' NOTCH3'' gen ...

Nasu-Hakola disease Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy also known as Nasu–Hakola disease is a rare disease characterised by early-onset dementia and multifocal bone cysts. It is caused by autosomal recessive loss of functio ...

, and chronic progressive

multiple sclerosis Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelinthe insulating covers of nerve cellsin the brain and spinal cord. As a demyelinating disease, MS disrupts the nervous system's ability to Action potential, transmit ...

Treatment

There is currently no treatment or cure for CARASIL. Most frequently, a combination of supportive care and medications to prevent the occurrence of

are recommended. Counseling or other forms of emotional support may be beneficial to both patients and family members. Medications or therapies may be used to treat specific symptoms of the disease.

Tizanidine Tizanidine, sold under the brand name Zanaflex among others, is an alpha-2 (α2) adrenergic receptor agonist, similar to clonidine, that is used to treat muscle spasticity due to spinal cord injury, multiple sclerosis, and spastic cerebral ...

and

baclofen Baclofen, sold under the brand name Lioresal among others, is a medication used to treat muscle spasticity, such as from a spinal cord injury or multiple sclerosis. It may also be used for hiccups and muscle spasms near the end of life, and ...

may be used to treat the spasticity of the limbs. A walker or cane may be used to assist individuals with gait disturbances.

Anxiolytic An anxiolytic (; also antipanic or anti-anxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxie ...

s may be prescribed for mood changes.

Prognosis

The prognosis for individuals with CARASIL is progressive neurological decline over the course of 10–20 years after the onset of symptoms, ultimately ending in death. CARASIL is a degenerative disease, and most patients live only 10 years past symptom onset, although some may live for 20–30 more years.

Epidemiology

Of the approximately 50 cases worldwide, the majority were found in Japan, with a few cases in China, Spain, Portugal, and Romania. CARASIL appears to affect males more often than females. A ratio of 7.5 males to 1 female was observed in Japan.

Research

Research consists primarily of case studies reporting observed cases of CARASIL, one study suggests that a possible future treatment option may be inhibition of TGF-β signaling by an angiotensin I receptor agonist, due to the fact that an excess of TGF-β signaling is involved in causing CARASIL. This approach has been used in Marfan syndrome, which also involves excessive TGF-β signaling. This suggestion has not yet been tested. A study examining the MRI scans of seven CARASIL patients in Japan found a characteristic "arc sign" in advanced cases. This may be used in the future to determine which patients should undergo genetic testing for CARASIL. The connection with vascular diseases of the heart is unclear.

References

External links

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