Clinical Guidance

No strong genotype-phenotype correlations for HTRA1 have been identified in classic CARASIL . Those who have a heterozygous HTRA1 missense variant that either leads to defective trimerization or is located in the LD or L3 domain may have a more severe phenotype than those who have a heterozygous HTRA1 loss-of-function variant .

Source: GeneReviews — "HTRA1 Disorder"

Diagnostic Criteria

Clinical diagnostic criteria for HTRA1 disorder, including the classic CARASIL phenotype ("classic CARASIL"), have not been published.

Suggestive Findings

HTRA1 disorder should be suspected in individuals with the following clinical, neuroimaging, and family history findings. Clinical features. Individuals presenting before age 55 years with the following:

• Slowly progressive dementia

• Mood changes, such as apathy and irritability

• Slowly progressive gait disturbance with spasticity in the lower extremities

Note: Those with a heterozygous HTRA1 pathogenic variant (HTRA1 cerebral small vessel disease) may present with these features after age 55 years. Additional young adult-onset findings in those with biallelic pathogenic variants in HTRA1 (classic CARASIL):

Source: GeneReviews — "HTRA1 Disorder"

Differential Diagnosis

Other inherited disorders that cause leukoaraiosis in adulthood are summarized in . They can be distinguished from HTRA1 disorder by clinical signs, MRI findings, and appropriate laboratory investigations. Note: Classic CARASIL should be considered in any young person who has alopecia in conjunction with multiple white matter lesions on MRI.

Table 2.

Inherited Disorders with Adult-Onset Leukoaraiosis to Consider in the Differential Diagnosis of HTRA1 Disorder

Gene(s) | Disorder | MOI | Clinical Description

COL4A1, COL4A2 | COL4A1- COL4A2-related small vessel disease (See COL4A1-Related Disorders.) | AD | • Intracranial aneurysm

• Renal abnormalities (hematuria, cystic kidney)

• Muscle cramps

• Retinal arteriolar tortuosity (retinal hemorrhages)

CTSA | CARASAL | AD | Therapy-resistant hypertension1

Source: GeneReviews — "HTRA1 Disorder"

Management Guidelines

Consensus clinical management guidelines for HTRA1 disorder, including classic CARASIL, have not been published. Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with HTRA1 disorder, the evaluations summarized in Table (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 3. Recommended Evaluations Following Initial Diagnosis in Individuals with HTRA1 Disorder

Source: GeneReviews — "HTRA1 Disorder"

Clinical Guidance

Smoking and a high-salt diet, which may hasten the progression of arteriosclerosis, should be avoided.

Source: GeneReviews — "HTRA1 Disorder"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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.

Source: GeneReviews — "HTRA1 Disorder"

Surveillance Guidelines

The interval at which a person with HTRA1 disorder is followed depends on the severity and type of symptoms and the needs of the affected individual and caregivers.

Source: GeneReviews — "HTRA1 Disorder"