Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy

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Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy
Other namesMaeda syndrome
Autosomal recessive - en.svg
CARASIL is autosomal recessive.

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 in the CNS. [1] CARASIL is characterized by symptoms such as gait disturbances, hair loss, low back pain, dementia, and stroke. [2] CARASIL is a rare disease, having only been diagnosed in about 50 patients, of which ten have been genetically confirmed. [3] Most cases have been reported in Japan, [4] [5] but Chinese and caucasian individuals have also been diagnosed with the disease. [6] [1] [3] CARASIL is inherited in an autosomal recessive pattern. [7] There is currently no cure for CARASIL. [8] Other names for CARASIL include familial young-adult-onset arteriosclerotic leukoencephalopathy with alopecia and lumbago without arterial hypertension, [4] Nemoto disease [4] and Maeda syndrome. [1]

Contents

Signs and symptoms

Symptoms of CARASIL may include spondylosis deformans, lumbago (lower back pain) due to herniated disks, alopecia, spasticity in the limbs leading to gait disturbances, dysarthria, urinary incontinence, pseudobulbular signs, arteriosclerosis of cerebral arteries, mood changes, stroke, and dementia. [3] [7] [8] [9]

Individuals with CARASIL may experience spondylosis and alopecia beginning in their teens, [1] [5] although alopecia is not seen in all patients. [9] 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. [8] Many patients experience some form of mood changes, personality disorders, and/or dementia over time. [7] [5]

Cause

CARASIL is caused by mutation of the HTRA1 gene which encodes the HtrA serine peptidase 1 protein (HTRA1). [3] [5] HTRA1 is located on chromosome 10 [10] and encodes an enzyme that regulates signaling by the TGF-β family of proteins. [3] [2] TGF-β protein family plays an important role in cellular functions, especially in angiogenesis. [4] [5] 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. [3] [10] [2] Increase in TGF-β1 activity has been seen in the tunica media of affected small arteries. [2]

CARASIL is an autosomal recessive disease, meaning that both parents must be a carrier for the allele in order for the disease to be passed on to the child. [11] As with other autosomal recessive diseases, the likelihood of receiving a recessive allele from both parents increases if the parents are closely related to each other (consanguineous). [1] [10] This trend has been observed for CARASIL. [1] [10]

Pathophysiology

A few different types of mutations to the HTRA1 gene have been observed in CARASIL patients. [12] Nonsense mutations have been shown to cause no HTRA1 protein to be produced, while missense mutations have been shown to produce some HTRA1 protein, but with reduced activity. [9] 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 TGF-β (transforming growth factor beta) signaling cannot be repressed as normal. When TGF-β activity goes unchecked, it alters the structure of the small blood vessels in the brain, increasing an individual's risk of stroke and other neurological abnormalities. [4] Abnormally increased TGF-β activity is also suspected to be involved in the alopecia and lumbago seen in CARASIL patients, but that has not been confirmed and the mechanism is not yet known. [4]

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 dysarthria seen in some patients. [1]

Progressive damage to and loss of the white matter, or myelinated areas, in the brain leads to some of the other neurological symptoms, such as forgetfulness progressing to dementia, mood changes, confusion, and apathy. [1]

Diagnosis

CARASIL can be tentatively diagnosed by a thorough medical history, examination of symptoms, differential diagnoses, and MRI scans of the brain. [11] [7] Diffuse white matter changes (leukoencephalopathy) and multiple lacunar infarcts in the basal ganglia of the thalamus are usually determining factors seen on MRI scans of affected individuals. [3] [8] Further genetic testing must be used to confirm the diagnosis. [3] [1]

It is suspected that there are many cases of CARASIL that have not been diagnosed because of the similarities with other neurological disorders. [1] Several disease that are frequently used for differential diagnoses include Binswanger's disease, CADASIL, Nasu-Hakula disease, and chronic progressive multiple sclerosis. [3] [1]

Treatment

There is currently no treatment or cure for CARASIL. [3] [1] Most frequently, a combination of supportive care and medications to prevent the occurrence of stroke are recommended. [1] [8] Counseling or other forms of emotional support may be beneficial to both patients and family members. [3] Medications or therapies may be used to treat specific symptoms of the disease. Tizanidine and baclofen may be used to treat the spasticity of the limbs. [3] A walker or cane may be used to assist individuals with gait disturbances. [3] [9] Anxiolytics may be prescribed for mood changes. [3] [9]

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, [3] although some may live for 20–30 more years. [2]

Epidemiology

Of the approximately 50 cases worldwide, the majority were found in Japan, with a few cases in China, Spain, Portugal, and Romania. [6] CARASIL appears to affect males more often than females. A ratio of 7.5 males to 1 female was observed in Japan. [10] [13]

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. [14]

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. [15]

See also

Related Research Articles

Vascular dementia (VaD) is dementia caused by problems in the blood supply to the brain, resulting from a cerebrovascular disease. Restricted blood supply (ischemia) leads to cell and tissue death in the affected region, known as an infarct. The three types of vascular dementia are subcortical vascular dementia, multi-infarct dementia, and stroke related dementia. Subcortical vascular dementia is brought about by damage to the small blood vessels in the brain. Multi-infarct dementia is brought about by a series of mini-strokes where many regions have been affected. The third type is stroke related where more serious damage may result. Such damage leads to varying levels of cognitive decline. When caused by mini-strokes, the decline in cognition is gradual. When due to a stroke, the cognitive decline can be traced back to the event.

<span class="mw-page-title-main">Binswanger's disease</span> Medical condition

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 many circumstances including chronic hypertension as well as old age. This disease is characterized by loss of memory and intellectual function and by changes in mood. These changes encompass what are known as executive functions of the brain. It usually presents between 54 and 66 years of age, and the first symptoms are usually mental deterioration or stroke.

<span class="mw-page-title-main">Cerebrovascular disease</span> Condition that affects the arteries that supply the brain

Cerebrovascular disease includes a variety of medical conditions that affect the blood vessels of the brain and the cerebral circulation. Arteries supplying oxygen and nutrients to the brain are often damaged or deformed in these disorders. The most common presentation of cerebrovascular disease is an ischemic stroke or mini-stroke and sometimes a hemorrhagic stroke. Hypertension is the most important contributing risk factor for stroke and cerebrovascular diseases as it can change the structure of blood vessels and result in atherosclerosis. Atherosclerosis narrows blood vessels in the brain, resulting in decreased cerebral perfusion. Other risk factors that contribute to stroke include smoking and diabetes. Narrowed cerebral arteries can lead to ischemic stroke, but continually elevated blood pressure can also cause tearing of vessels, leading to a hemorrhagic stroke.

<span class="mw-page-title-main">CADASIL</span> Medical condition

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 Notch 3 gene on chromosome 19. The disease belongs to a family of disorders called the leukodystrophies. The most common clinical manifestations are migraine headaches and transient ischemic attacks or strokes, which usually occur between 40 and 50 years of age, although MRI is able to detect signs of the disease years prior to clinical manifestation of disease.

Bilateral frontoparietal polymicrogyria is a genetic disorder with autosomal recessive inheritance that causes a cortical malformation. Our brain has folds in the cortex to increase surface area called gyri and patients with polymicrogyria have an increase number of folds and smaller folds than usual. Polymicrogyria is defined as a cerebral malformation of cortical development in which the normal gyral pattern of the surface of the brain is replaced by an excessive number of small, fused gyri separated by shallow sulci and abnormal cortical lamination. From ongoing research, mutation in GPR56, a member of the adhesion G protein-coupled receptor (GPCR) family, results in BFPP. These mutations are located in different regions of the protein without any evidence of a relationship between the position of the mutation and phenotypic severity. It is also found that GPR56 plays a role in cortical pattering.

<span class="mw-page-title-main">Perivascular space</span>

A perivascular space, also known as a Virchow–Robin space, is a fluid-filled space surrounding certain blood vessels in several organs, including the brain, potentially having an immunological function, but more broadly a dispersive role for neural and blood-derived messengers. The brain pia mater is reflected from the surface of the brain onto the surface of blood vessels in the subarachnoid space. In the brain, perivascular cuffs are regions of leukocyte aggregation in the perivascular spaces, usually found in patients with viral encephalitis.

Pseudobulbar palsy is a medical condition characterized by the inability to control facial movements and caused by a variety of neurological disorders. Patients experience difficulty chewing and swallowing, have increased reflexes and spasticity in tongue and the bulbar region, and demonstrate slurred speech, sometimes also demonstrating uncontrolled emotional outbursts.

<span class="mw-page-title-main">NOTCH3</span> Protein-coding gene in the species Homo sapiens

Neurogenic locus notch homolog protein 3(Notch 3) is a protein that in humans is encoded by the NOTCH3 gene.

<span class="mw-page-title-main">Leukoencephalopathy with vanishing white matter</span> Neurological disease

Leukoencephalopathy with vanishing white matter is an autosomal recessive neurological disease. The cause of the disease are mutations in any of the 5 genes encoding subunits of the translation initiation factor eIF2B: EIF2B1, EIF2B2, EIF2B3, EIF2B4, or EIF2B5. The disease belongs to a family of conditions called the Leukodystrophies.

Progressive Myoclonic Epilepsies (PME) are a rare group of inherited neurodegenerative diseases characterized by myoclonus, resistance to treatment, and neurological deterioration. The cause of PME depends largely on the type of PME. Most PMEs are caused by autosomal dominant or recessive and mitochondrial mutations. The location of the mutation also affects the inheritance and treatment of PME. Diagnosing PME is difficult due to their genetic heterogeneity and the lack of a genetic mutation identified in some patients. The prognosis depends largely on the worsening symptoms and failure to respond to treatment. There is no current cure for PME and treatment focuses on managing myoclonus and seizures through antiepileptic medication (AED).

<span class="mw-page-title-main">HTRA1</span> Protein-coding gene in the species Homo sapiens

Serine protease HTRA1 is an enzyme that in humans is encoded by the HTRA1 gene. The HTRA1 protein is composed of four distinct protein domains. They are from amino-terminus to carboxyl-terminus an Insulin-like growth factor binding domain, a kazal domain, a trypsin-like peptidase domain and a PDZ domain.

Leukoencephalopathy with neuroaxonal spheroids (LENAS) is an extremely rare kind of leukoencephalopathy and is classified as a neurodegenerative disease. LENAS is a cause of severe and subacute dementia that results from damage to certain areas of the brain. This damage is to a type of brain tissue called white matter and axon damage due to swellings which are termed spheroids.

Megalencephalic leukoencephalopathy with subcortical cysts is a form of hereditary CNS demyelinating disease. It belongs to a group of disorders called leukodystrophies. It is characterized by early-onset enlargement of the head (macrocephaly) as well as delayed-onset neurological deterioration to include spasticity, epilepsy, and lack of muscular coordination. MLC does not appear to be a disease that is fatal at birth or early in life despite its symptoms, although the number of patients throughout history known to have the disease is fairly limited.

<span class="mw-page-title-main">Kufor–Rakeb syndrome</span> Medical condition

Kufor–Rakeb syndrome (KRS) is an autosomal recessive disorder of juvenile onset also known as Parkinson disease-9 (PARK9). It is named after Kufr Rakeb in Irbid, Jordan. Kufor–Rakeb syndrome was first identified in this region in Jordan with a Jordanian couple's 5 children who had rigidity, mask-like face, and bradykinesia. The disease was first described in 1994 by Najim Al-Din et al. The OMIM number is 606693.

A silent stroke is a stroke that does not have any outward symptoms associated with stroke, and the patient is typically unaware they have suffered a stroke. Despite not causing identifiable symptoms, a silent stroke still causes damage to the brain and places the patient at increased risk for both transient ischemic attack and major stroke in the future. In a broad study in 1998, more than 11 million people were estimated to have experienced a stroke in the United States. Approximately 770,000 of these strokes were symptomatic and 11 million were first-ever silent MRI infarcts or hemorrhages. Silent strokes typically cause lesions which are detected via the use of neuroimaging such as MRI. The risk of silent stroke increases with age but may also affect younger adults. Women appear to be at increased risk for silent stroke, with hypertension and current cigarette smoking being amongst the predisposing factors.

Grinker's myelinopathy, also known as anoxic leukoencephalopathy, is a rare disease of the central nervous system. The disease is characterized by a delayed leukoencephalopathy after a hypoxic episode. It is typically, though not necessarily, related to carbon monoxide poisoning or heroin overdose. It occurs in roughly 2.8% of those who experience an acute hypoxic/anoxic episode. Because of the wide range of symptoms and the delay in onset, it is often misdiagnosed as other neuropathologies. Grinker's myelinopathy was originally characterized by Roy R. Grinker in 1925 or 1926, depending on the source.

<span class="mw-page-title-main">Hereditary diffuse leukoencephalopathy with spheroids</span> Medical condition

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a rare adult onset autosomal dominant disorder characterized by cerebral white matter degeneration with demyelination and axonal spheroids leading to progressive cognitive and motor dysfunction. Spheroids are axonal swellings with discontinuous or absence of myelin sheaths. It is believed that the disease arises from primary microglial dysfunction that leads to secondary disruption of axonal integrity, neuroaxonal damage, and focal axonal spheroids leading to demyelination. Spheroids in HDLS resemble to some extent those produced by shear stress in a closed head injury with damage to axons, causing them to swell due to blockage of axoplasmic transport. In addition to trauma, axonal spheroids can be found in aged brain, stroke, and in other degenerative diseases. In HDLS, it is uncertain whether demyelination occurs prior to the axonal spheroids or what triggers neurodegeneration after apparently normal brain and white matter development, although genetic deficits suggest that demyelination and axonal pathology may be secondary to microglial dysfunction. The clinical syndrome in patients with HDLS is not specific and it can be mistaken for Alzheimer's disease, frontotemporal dementia, atypical Parkinsonism, multiple sclerosis, or corticobasal degeneration.

Élisabeth Tournier-Lasserve is a French neurologist, medical geneticist, university professor and hospital practitioner in genetics. Together with three colleagues, she was the co-recipient of the Brain Prize in 2019, the world's largest brain research prize.

Anne Joutel is a French neurologist and neuroscientist who is Research Director at the Institute of Psychiatry and Neurosciences of Paris. In 2019, together with three colleagues, she was awarded the Brain Prize, the largest prize awarded for brain research.

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