Do heterozygous HTRA1 mutations carriers form a distinct clinical entity?

Dear Editor,

I read with interest the recent study of heterozygous mutations of HTRA1 gene in patients with late onset familial cerebral small vessel disease (SVD) by Di Donato and colleagues.1 This large Italian cohort confirms the so‐called weak phenocopy of CARASIL heterozygous patients, including a later onset of stroke and dementia, lack of spondylosis/alopecia, or leukoencephalopathy, which has been recently described by Nozaki2 and Verdura3. In above studies, both genetic modifiers and environmental factors—even so far unknown—may play an essential role in the nuance of clinical phenotype and white matter changes among these patients.

Di Donato and colleagues suggested: “This is a novel familial condition, which overlaps clinically among sporadic SVD and other adult rare monogenic cerebrovascular disorders, such as CADASIL and CARASIL.” However, the authors did not prove a possible genotype‐phenotype correlation. As regards to the mild phenotypic expression in heterozygous HTRA1 mutations, Di Donato agreed with Nozaki about the dominant‐negative effect. Nevertheless, the dominant‐negative effect may not be indispensable for every heterozygous HTRA1 mutation to cause SVD.4

Di Donato and colleagues could contribute significantly to phenotypic diversity, if they had shown a unique phenotype of their cohort. To quantify this contribution, an accurate method to identify and phenotype carriers is needed. A distinct gene expression phenotype should differ among carriers on the basis of HTRA1 mutant protein; however, Verdura and colleagues showed a complete loss of protease activity only in five of seven pathogenic variants described, and Nozaki and colleagues presented HTRA1 mutant with no reduction in protease activity. Given that impaired HTRA1 protease function seems to be a core feature of HTRA1‐related autosomal dominant SVD, high‐quality methods for proteomics are needed as valuable tools for phenotyping by measurement of expression levels of protease.

Although up to 5% of hereditary SVD in the European population was attributed to heterozygous HTRA1 mutations, the true prevalence remains underestimated.2 A possible explanation is that it is difficult to discriminate SVD patients with or without a heterozygous HTRA1 mutation. A recent study by Lee and colleagues4 is the largest one among the four SVD cohorts investigating heterozygous HTRA1 mutations.1, 2, 3, 4 Although intracerebral hemorrhage has never been reported in patients with a heterozygous HTRA1 mutation before, three patients in this study have both ischemic and hemorrhagic strokes. Except for more familial cases, the clinical (presence of alopecia/spondylosis or not) and neuroimaging characteristics (white matter hyperintensity with anterior temporal pole lesions on brain magnetic resonance) of SVD caused by a heterozygous HTRA1 mutation resemble those of other patients with SVD (including those with unknown molecular status). Therefore, these features are not reliable clues to differentiate these patients.

Moreover, there is a lack of large histopathological studies to evaluate the heterozygous HTRA1 carriers. So far, only two autopsy reports with heterozygous HTRA1 mutations, have been published, develop chronic SVD through underlying mechanisms similar to those of CARASIL.2, 5 The autopsied case described by Ito et al5 showed no change of small vessels in the visceral organs and skin compared to patients with CARASIL. Ito et al noticed that “These histological characteristics of the extracranial vessels appear to be quite different from those of intracranial small vessels. Furthermore, it seems unlikely that these features are clearly distinct from athero‐ and arteriolosclerosis.” Future pathologic studies should clarify the variability of the vascular changes in the histogenesis of leukoencephalopathy in patients with heterozygous HTRA1 mutations and whether there is a genotype–phenotype correlation.

In conclusion, even though there are many unanswered issues, overall the efforts of Di Donato’s and the others SVD cohorts are of great importance by identifying an important contributor to SVD. The exact molecular mechanism of mutant HTRA1‐dependent SVD in heterozygous individuals is still not fully understood. Noticeably, Uemura and colleagues showed the clinical spread of CARASIL.6 According to the authors, the clinical features of SVD resulting from an heterozygous HTRA1 mutation extend to patients with chronic SVD alone or to those with dominantly inherited SVD. It seems more correct to use the term of spectrum of HTRA1‐related SVD instead of a novel condition, but it remains unproved the genotype–phenotype correlation. Lowering the cost of next‐generation sequencing technology may allow prompt diagnosis of these rare causes of SVD, by identifying others unknown disease‐causing variants.

CONFLICT OF INTEREST

The author declare no conflict of interest.