Genetic central nervous system and retinal vascular disease
-Rare genetic disease
Rare central nervous system and retinal vascular disease
-Rare neurologic disease
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. ... 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 it was a syndrome comprising 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. - 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.
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 (602194.0002-602194.0005) on chromosome 10q25. The mutant proteins ... 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 (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.
CARASIL should be suspected in persons with the following [Fukutake & Hirayama 1995, Hara et al 2009]:...
DiagnosisClinical Diagnosis CARASIL should be suspected in persons with the following [Fukutake & Hirayama 1995, Hara et al 2009]:Early-onset leukoaraiosis (changes in deep white matter in the brain, observed on MRI or CT). Leukoaraiosis may precede neurologic symptoms. The neurologic finding is usually slowly progressive gait disturbance with spasticity in the lower extremities [Fukutake & Hirayama 1995, Hara et al 2009]. Alopecia in the teens Note: Alopecia is variable: a sib with leukoaraiosis without alopecia has been reported [Yanagawa et al 2002, Hara et al 2009]. Acute mid to lower back pain (lumbago) between the ages 20 and 40 years. MRI and/or X-rays show spondylosis and disk degeneration with osteophyte formation in the cervical and/or lumbar spine. A family history consistent with autosomal recessive inheritanceBrain imaging. Brain magnetic resonance imaging (MRI) resembles that of CADASIL (cerebral autosomal dominant ateriopathy with subcortical infarcts and leukoencephalopathy). Findings in symptomatic individuals: White matter hyperintensities are symmetrically distributed and located in the periventricular and deep white matter [Fukutake & Hirayama 1995], suggesting that the white matter changes precede the onset of neurologic symptoms, including gait disturbance, character change, and cognitive decline.T2-signal abnormalities in the white matter of the cerebellum, brain stem, middle cerebellar peduncle and in the external capsule, characteristics of CARASIL, are sometimes observed. Relative preservation of U-fibers is observed.Lacunar infarcts (linearly arranged groups of rounded and circumscribed lesions with signal intensity identical to that of cerebrospinal fluid) are sometimes found in basal ganglia and subcortical white matter.The progression of MRI changes is not well documented in CARASIL; thus, it is not clear if the white matter changes in the anterior temporal poles and external capsule, which are characteristic early signs in CADASIL, are also observed in early stages of CARASIL. Pathology. Arteriosclerosis associated with intimal thickening and dense collagen fibers, loss of vascular smooth muscle cells, and hyaline degeneration of the media were observed in cerebral small arteries. These pathologic findings resemble those observed in persons with non-hereditary ischemic cerebral small-vessel disease [Maeda et al 1976, Zhang & Olsson 1997, Tanoi et al 2000, Yanagawa et al 2002, Okeda et al 2004, Oide et al 2008]. These changes are relatively limited in cerebral small arteries; therefore, skin biopsy is not useful for diagnosis. Note: Granular osmiophilic material within the vascular media close to smooth muscle cells, a pathologic hallmark for CADASIL, is never observed in CARASIL. Molecular Genetic Testing Gene. HTRA1 is the only gene in which mutation is known to be associated with CARASIL.Clinical testing Sequence analysis of entire coding and flanking intronic regions. HTRA1 is a serine protease; its protease domain exists in exons 3-6 [Hara et al 2009]. Of the four causative mutations in HTRA1 identified to date, two are nonsense mutations and two are missense mutations in exon 3 and 4. Table 1. Summary of Molecular Genetic Testing Used in CARASILView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityHTRA1Sequence analysisSequence variants 2Unknown 3Clinical1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. Hara et al [2009]Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing Strategy To confirm/establish the diagnosis in a probandThe diagnosis is suggested by: young-adult onset of spasticity, emotional lability, alopecia, white changes on MRI, and pedigree compatible with autosomal recessive inheritance. The diagnosis is confirmed by HTRA1 molecular genetic testing, which should begin with exons 3-6, followed by complete sequencing of HTRA1.Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) Disorders No other phenotypes are known to be associated with mutations in HTRA1.A SNP (rs11200638: -512G>A) at the promoter region of HTRA1 for which homozygosity for the AA genotype increased risk of wet age-related macular degeneration has been identified as age-related macular degeneration 7 (ARMD7) (OMIM 610149).
Alopecia is frequently recognized in the teen years (not all). Scalp alopecia is diffuse, not confined to the frontal or parietal regions. There is no obvious body hair loss....
Natural History Alopecia is frequently recognized in the teen years (not all). Scalp alopecia is diffuse, not confined to the frontal or parietal regions. There is no obvious body hair loss.Neurologic symptoms begin between ages 20 and 50 years. The most frequent initial symptom is slowly progressive gait disturbance from spasticity and pyramidal signs in the lower extremities beginning between ages 20 and 30 years. Mood change (depression and irritability) and cognitive dysfunction begin between ages 30 and 50 years. Pseudobulbar palsy also begins between ages 30 and 50 years. About 50% of affected individuals have a lacunar stroke-like episode before age 40 years. The disease progresses slowly over five to 20 years following the onset of neurologic symptoms. In the advanced stage, emotional incontinence, abulia, and akinetic mutism develop. Spondylosis (disk degeneration with osteophyte formation) results in acute lower and mid back pain (lumbago) and lower limb pain beginning between ages 20 and 30 years. MRI may show disc herniations, degeneration of vertebral bodies, and nodular thickening of the posterior longitudinal ligament [Zheng et al 2009]. Also reported on radiography are severe spondylitis deformans with osteoporosis in the lumbar spine and deformity and formation of osseous specula in the knee joints [Yanagawa et al 2002].
No strong genotype-phenotype correlations exist in CARASIL. ...
Genotype-Phenotype Correlations No strong genotype-phenotype correlations exist in CARASIL. Individuals homozygous for the p.Arg370X mutation who make no protein as a result of nonsense-mediated mRNA decay cannot be clinically distinguished from individuals homozygous for the missense mutation who have some residual enzyme activity [Hara et al 2009]. Siblings who share the same genotype may have variable clinical course.
Inherited disorders that cause leukoaraiosis in adulthood are summarized in Table 2. They can be distinguished from CARASIL by clinical signs, MRI findings, mode of inheritance, and appropriate laboratory investigations. ...
Differential DiagnosisInherited disorders that cause leukoaraiosis in adulthood are summarized in Table 2. They can be distinguished from CARASIL by clinical signs, MRI findings, mode of inheritance, and appropriate laboratory investigations. Table 2. Inherited Disorders that Cause Leukoaraiosis in AdulthoodView in own windowDiseaseInheritanceGeneUnique Clinical FeaturesCADASIL 1AD NOTCH3Isolated T2 hyperintensities involving the temporal poles; skin biopsy can be evaluated for NOTCH3 protein expression and granular osmophilic material (GOM) by EM HERNS (hereditary endotheliopathy with retinopathy, nephropathy, and stroke) 2AD TREX1 Retinal artery abnormalities (macular capillary dropout, tortuous telangiectasia); progressive visual loss; Raynaud phenomenon, migraine, contrast-enhancing lesion, mimicking tumor; proteinuria and hematuriaHANAC (hereditary angiopathy with nephropathy, aneurysms and muscle cramps) 3 AD COL4A1 Renal abnormalities (hematuria, cystic kidney), intracranial aneurysm, muscle cramp, retinal arteriolar tortuosity (retinal hemorrhages)Fabry diseaseXRGLAPeriodic severe pain in the extremities, angiokeratoma, renal insufficiency, hypohidrosis, left ventricular hypertrophy, corneal opacitiesFamilial cerebral amyloid angiopathy AD APP Lobar hemorrhage, multiple microbleedsFamilial British dementia 4 AD ITM2BAtaxia and spasticityFamilial SVD-Portuguese-French type 5 AD Unknown Swedish hereditary multi-infarct dementia 6 AD Unknown EM= electron microscopy1. Chabriat et al [2009]2. Jen et al [1997], Terwindt et al [1998]3. Plaisier et al [2007]4. Mead et al [2000]5. Verreault et al [2006]6. Low et al [2007]The differential diagnosis of CARASIL includes sporadic small vessel diseases including Binswanger disease, hereditary small vessel diseases (SVDs), and primary angiitis of the nervous system. The clinical characteristics and MRI abnormalities in these conditions may resemble those of CARASIL. Binswanger disease can be distinguished from CARASIL by the presence of hypertension. CARASIL should also be considered in any young person who has alopecia in conjunction with multiple white matter lesions on MRI.
To establish the extent of disease in an individual diagnosed with CARASIL, the following evaluations are recommended:...
Management Evaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with CARASIL, the following evaluations are recommended:Neurologic evaluationStandard brain MRI (FLAIR sequence) to check the involvement of cerebral white matter. Spine MRI to check the degenerative change in lumbar or cervical spine Treatment of ManifestationsSupportive care in the form of practical help, emotional support, and counseling are appropriate for affected individuals and their families. Gait disturbance from spasticity and pyramidal signs in the lower extremities may require walking aids or medication such as baclofen or tizanidine.Character change may require anxiolytic medication.Dementia has no specific treatmentPrevention of Secondary ComplicationsAlthough anti-platelet therapy and anti-hypertension therapy may be recommended, there is no evidence for their effectiveness.SurveillanceThe interval at which persons with CARASIL are followed depends on the severity and type of symptoms and the needs of the individuals and their care givers.Agents/Circumstances to AvoidSmoking and a high-salt diet, which may hasten the progression of arteriosclerosis, should be avoided. Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. CARASIL: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDHTRA110q26.13Serine protease HTRA1HTRA1 homepage - Mendelian genesHTRA1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for CARASIL (View All in OMIM) View in own window 600142CEREBRAL AUTOSOMAL RECESSIVE ARTERIOPATHY WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY; CARASIL 602194HTRA SERINE PEPTIDASE 1; HTRA1Normal allelic variants. HTRA1 has nine exons and a transcript 2138 bp in length.Pathologic allelic variants. Two missense mutations in exons 3 and 4 and two nonsense mutations have been reported (Table 3). Table 3. HTRA1 Allelic Variants View in own windowClass of Variant AlleleDNA Nucleotide Change (Alias 1) Protein Amino Acid ChangeReference SequencesNormalc.102C>T (230C>T)p.Ala34AlaNM_002775.4 NP_002766.1c.108G>C (236G>C)p.Gly36Glyc.108G>T (236G>T)p.Gly36GlyPathologicc. 754G>Ap.Ala252Thrc. 889G>Ap.Val297Metc. 904C>Tp.Arg302X c.1108C>Tp.Arg370XSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). 1. Variant designation that does not conform to current naming conventionsNormal gene product. HTRA1, a 480-amino acid protein, belongs to the HTRA protein family, the members of which have dual activities as chaperones and serine proteases [Clausen et al 2002]. Members of the HTRA family serve as stress sensors for unfolded proteins and repress transforming growth factor-beta (TGF-β) family signaling [Clausen et al 2002, Oka et al 2004]. HTRA1 is a serine protease; its protease domain is encoded in exons 3-6 [Hara et al 2009].Abnormal gene product. Biochemical and functional studies of mutant HTRA1 with CARASIL revealed the loss of protease activity and consequent dysinhibition of TGF-β family signaling of mutant HTRA1 [Hara et al 2009].