HTRA1-Related Autosomal Dominant Cerebral Small Vessel Disease
Cerebral small vessel disease (CSVD) represents a group of disorders affecting the small arteries, arterioles, capillaries, and venules of the brain. Among the genetic forms of CSVD, cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) has been well-characterized. CARASIL is caused by biallelic mutations in the high temperature requirement serine peptidase A1 (HTRA1) gene, leading to severe neurological and systemic manifestations. However, recent evidence has emerged suggesting that heterozygous mutations in HTRA1 can also cause CSVD, but with a distinct autosomal dominant inheritance pattern and a milder clinical phenotype. This article provides a comprehensive overview of HTRA1-related autosomal dominant CSVD, based on a study that analyzed the genetic and clinical characteristics of this condition.
Background and Introduction
HTRA1 encodes a serine protease that plays a critical role in vascular integrity, skeletal development, and osteogenesis. Initially, HTRA1 mutations were identified as the cause of CARASIL, a severe autosomal recessive disorder characterized by young-adult-onset non-hypertensive cerebral small vessel arteriopathy, alopecia, and spondylosis. However, studies have since revealed that heterozygous HTRA1 mutations can also lead to CSVD, albeit with a milder phenotype and later onset. This discovery has expanded the spectrum of HTRA1-related diseases and highlighted the importance of genetic testing in diagnosing hereditary CSVD.
Clinical Characteristics of HTRA1-Related Autosomal Dominant CSVD
The study analyzed 44 probands with HTRA1-related autosomal dominant CSVD and compared their clinical features with 22 probands of typical CARASIL. The findings revealed significant differences between the two groups. Patients with heterozygous HTRA1 mutations had a later age of onset, with a median age of 53.5 years, compared to 28 years in CARASIL patients. Additionally, HTRA1-related autosomal dominant CSVD probands exhibited a higher prevalence of vascular risk factors, such as hypertension and diabetes, which were rare in CARASIL cases.
The clinical presentation of HTRA1-related autosomal dominant CSVD was milder than that of CARASIL. While ischemic events were a common initial symptom in 59.1% of heterozygous HTRA1 mutation carriers, 25% of patients presented with chronic progressive symptoms without acute cerebrovascular events. Cognitive impairment was less severe in HTRA1-related autosomal dominant CSVD patients at the time of diagnosis, despite their older age. Extraneurological signs, such as alopecia and spondylosis, were also less prevalent in heterozygous HTRA1 mutation carriers compared to CARASIL patients.
Genetic Characteristics of HTRA1 Mutations
The study identified 35 heterozygous HTRA1 mutations in 44 probands, including 29 missense mutations, four nonsense mutations, one inframe mutation, and one truncating mutation. The majority of these mutations were located in the trypsin-like serine protease domain (54.3%) and the Kazal-type serine protease domain (20%). Notably, amino acids near positions 250–300 and 150–200 were the most frequently affected regions in heterozygous HTRA1 mutations. These regions are critical for the trimerization and activation of HTRA1, suggesting that mutations in these areas may disrupt the protease’s function and lead to disease.
In contrast, CARASIL patients predominantly harbored mutations in the trypsin-like serine protease domain, with fewer mutations preceding the 200th amino acid. No mutations were reported in the Kazal-type serine protease domain in CARASIL patients, highlighting a distinct genetic profile between the two conditions.
Pathogenesis and Molecular Mechanisms
The pathogenesis of HTRA1-related autosomal dominant CSVD is not fully understood, but several mechanisms have been proposed. Heterozygous HTRA1 mutations may exert a dominant-negative effect, where the mutant protein interferes with the function of the wild-type protein. This is particularly relevant for HTRA1, which functions as a homotrimer. Mutations that disrupt trimerization or activation domains can impair the protease activity of HTRA1, leading to vascular dysfunction and CSVD.
However, not all heterozygous HTRA1 mutations exhibit a dominant-negative effect. Some mutations may result in haploinsufficiency, where the reduced levels of functional HTRA1 protein are insufficient to maintain vascular integrity. Additionally, the degree of protease activity impairment may influence the severity and penetrance of the disease, as patients with mutations causing a dominant-negative effect tend to have more severe leukoencephalopathy.
Case Reports
The study presented three new Chinese cases of HTRA1-related autosomal dominant CSVD, each with unique clinical and genetic features.
Patient 1 was a 40-year-old female with recurrent ischemic strokes, progressive memory decline, and mood disturbances. MRI revealed diffuse white matter abnormalities and multiple lacunar infarcts. Genetic testing identified a heterozygous missense mutation (p.N324T) in the HTRA1 gene, classified as likely pathogenic.
Patient 2 was a 38-year-old female with multiple ischemic strokes, cognitive decline, and spondylosis. MRI showed diffuse leukoencephalopathy and microbleeds. A heterozygous missense mutation (p.R166C) in HTRA1 was identified, classified as likely pathogenic.
Patient 3 was a 54-year-old male with hypertension, diabetes, and recurrent ischemic strokes. MRI revealed progressive white matter hyperintensity and microbleeds. Genetic testing identified a heterozygous missense mutation (p.V175M) in HTRA1, classified as uncertain significance due to the inability to perform co-segregation analysis.
Discussion and Conclusions
HTRA1-related autosomal dominant CSVD represents a milder phenotype of CARASIL, characterized by a later onset, slower progression, and less severe cognitive impairment. The presence of vascular risk factors and the absence of extraneurological signs in many patients make this condition clinically distinct from CARASIL. Genetic testing for HTRA1 mutations should be considered in patients with unexplained CSVD, particularly those with a family history of the disease.
The study highlighted the importance of specific regions in the HTRA1 protein, particularly amino acids 250–300 and 150–200, as hotspots for pathogenic mutations. These regions are critical for the protease’s function, and mutations in these areas may disrupt trimerization and activation, leading to disease. Further research is needed to elucidate the molecular mechanisms underlying HTRA1-related autosomal dominant CSVD and to develop targeted therapies for this condition.
In conclusion, HTRA1-related autosomal dominant CSVD is a distinct genetic disorder with unique clinical and genetic characteristics. The identification of heterozygous HTRA1 mutations has expanded the spectrum of hereditary CSVD and underscores the importance of genetic testing in diagnosing and managing this condition.
doi.org/10.1097/CM9.0000000000001176
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