Heterozygous Pathogenic and Likely Pathogenic Symptomatic HTRA1 Variant Carriers in Cerebral Small Vessel Disease.

High temperature requirement serine peptidase A1 (HTRA1) related cerebral small vessel disease (CSVD) includes both symptomatic heterozygous HTRA1 variant carrier and cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) patients. Presently, most reported symptomatic heterozygous HTRA1 variant carrier cases are sporadic family reports with a lack of specific characteristics. Additionally, the molecular mechanism of heterozygous HTRA1 gene variants is unclear. We conducted this review to collect symptomatic carriers of heterozygous HTRA1 gene variants reported as of 2022, analyzed all pathogenicity according to American College of Medical Genetics and Genomics (ACMG) variant classification, and summarized the cases with pathogenic and likely pathogenic HTRA1 variants gender characteristics, age of onset, geographical distribution, initial symptoms, clinical manifestations, imaging signs, HTRA1 gene variant information and to speculate its underlying pathogenic mechanisms. In this review, we summarized the following characteristics of pathogenic and likely pathogenic symptomatic HTRA1 variant carriers: to date, the majority of reported symptomatic HTRA1 carriers are in European and Asian countries, particularly in China which was found to have the highest number of reported cases. The age of first onset is mostly concentrated in the fourth and fifth decades. The heterozygous HTRA1 gene variants were mostly missense variants. The two variant sites, 166-182 aa and 274-302 aa, were the most concentrated. Clinicians need to pay attention to de novo data and functional data, which may affect the pathogenicity analysis. The decrease in HtrA1 protease activity is currently the most important explanation for the genetic pathogenesis.

Type II Alexander disease with fragile X mental retardation 1 gene mutation.

Alexander disease (AxD) is a rare, autosomal dominant genetic disorder with an incidence of approximately 1 in 27,00.000. It is caused by a missense mutation in the GFAP gene encoding the glial fibrillary acidic protein. Fragile X-associated tremor/ataxia syndrome (FXTAS) is an X-linked dominant genetic disease, usually caused by a pre-mutation: an unmethylated expansion in the range of 50-200 CGG repeats in the fragile X mental retardation 1 (FMR1) gene. The clinical manifestations of these two diseases are complex and have some similarities. Both type II AxD and FXTAS may have ataxia as the first symptom. Here, we describe a case of type II AxD with ataxia as the first symptom accompanying a hemizygous mutation in the FMR1 gene (NM_001185081, exon13, c 0.1256C>T, p.T419M, g 0.147026507C>T). A sporadic genetic mutation led us to misdiagnose the patient with FXTAS initially. Whole-genome sequencing confirmed a heterozygous mutation in the GFAP gene (NM_002055.5, exon4, c 0.1158C>A, p.N386K, g 0.6310C>A). This report indicates that when the patient's clinical manifestation is ataxia, and imaging results suggest that the midbrain, medulla oblongata, and other subcerebellar structures are atrophied, AxD should be considered. Whole-genome sequencing is thus feasible to avoid missed diagnoses and misdiagnoses.