Clinical characteristics.

HTRA1 disorder is a phenotypic spectrum in which some individuals have few to no symptoms and others manifest with the more severe CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy) phenotype. Those who have a heterozygous HTRA1 pathogenic variant may have mild neurologic findings (sometimes identified only on neuroimaging) or mild-to-moderate neurologic signs and symptoms of CARASIL. In this chapter, the term "classic CARASIL" refers to the more severe phenotype associated with biallelic pathogenic variants, and "HTRA1 cerebral small vessel disease" (HTRA1-CSVD) refers to the milder phenotype associated with a heterozygous HTRA1 pathogenic variant.

• Classic CARASIL is characterized by early-onset changes in the deep white matter of the brain observed on MRI, and associated neurologic findings. The most frequent initial symptom is gait disturbance from spasticity beginning between ages 20 and 40 years. Forty-four percent of affected individuals have stroke-like episodes before age 40 years. Mood changes (apathy and irritability), pseudobulbar palsy, and cognitive dysfunction begin between ages 20 and 50 years. The disease progresses slowly following the onset of neurologic symptoms. Scalp alopecia and acute mid- to lower-back pain (lumbago) before age 30 years are characteristic.
• The most frequent initial symptom in individuals with HTRA1-CSVD is slowly progressive gait disturbance after age 40 years, which may be followed by the development of mood changes and cognitive dysfunction. A majority of affected individuals have a stroke-like episode after age 40 years. Spondylosis and alopecia are seen in a minority of individuals with HTRA1-CSVD.

Diagnosis/testing.

The diagnosis of HTRA1 disorder is established in a proband by identification of either a heterozygous or biallelic pathogenic variant(s) in HTRA1 on molecular genetic testing.

Management.

Treatment of manifestations: Consideration of anti-platelet therapy and anti-hypertensive therapy for those with cerebral microbleeds; physical therapy, walking aids, and home adaptations for those with gait disturbance; consideration of medication (baclofen or tizanidine) for spasticity; wig or hairpiece for those with alopecia; standard treatment for spinal spondylosis and mood disorder; supportive care including emotional support and counseling for affected individuals and their families.

Surveillance: Follow-up intervals are based on the severity and type of symptoms and the needs of the individuals and their caregivers.

Agents/circumstances to avoid: Smoking and a high-salt diet, which may hasten the progression of arteriosclerosis.

Genetic counseling.

HTRA1 disorder caused by biallelic pathogenic variants (i.e., the classic CARASIL phenotype) is inherited in an autosomal recessive manner. HTRA1 disorder caused by heterozygous pathogenic variants is inherited in an autosomal dominant manner.

• Autosomal recessive inheritance. At conception, each sib of an affected individual has a 25% chance of inheriting both HTRA1 pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being heterozygous, and a 25% chance of inheriting neither pathogenic variant and not being at risk for HTRA1 disorder.
• Autosomal dominant inheritance. Each sib of an affected individual has a 50% risk of inheriting the pathogenic variant from their affected parent.

Once the HTRA1 pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for HTRA1 disorder are possible.

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 [Fukutake & Hirayama 1995, Fukutake 2011, Nozaki et al 2014]

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):

• Spondylosis deformans. Acute mid- to lower-back pain (lumbago) associated with spondylosis and disk degeneration with osteophyte formation in the lumbar spine
• Alopecia. Typically seen before age 30 years
  Note: Alopecia is variable; affected individuals with biallelic HTRA1 pathogenic variants without alopecia have been reported [Nishimoto et al 2011, Nozaki et al 2014].

Neuroimaging. Extended white matter lesions and external capsule lesions:

• Early-onset leukoaraiosis (changes in deep white matter in the brain, observed on MRI or CT). Leukoaraiosis may precede neurologic symptoms [Fukutake 2011, Nozaki et al 2015].
• Brain MRI resembling that of CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). Findings in symptomatic individuals may include the following [Fukutake 2011, Nozaki et al 2015]:
  • Symmetrically distributed white matter hyperintensities located in the periventricular and deep white matter
    Note: White matter changes may precede the onset of neurologic symptoms, including gait disturbance, mood change, and cognitive decline.
  • T₂-weighted signal abnormalities in the white matter of the anterior part of the temporal lobe, cerebellum, brain stem, and middle cerebellar peduncle (arc sign), and in the external capsule
  • Relative preservation of U-fibers
  • Lacunar infarcts (linearly arranged groups of rounded and circumscribed lesions with signal intensity identical to that of cerebrospinal fluid) in the basal ganglia and subcortical white matter
  • Microbleeds in the cerebral cortex, basal ganglia, brain stem, and cerebellum
    Note: It is not clear if the white matter changes in the anterior temporal poles and external capsule, which are characteristic signs in CADASIL, are also observed in early stages of CARASIL.

Family history is consistent with:

• Autosomal recessive inheritance in those with classic CARASIL;
• Autosomal dominant inheritance for those with a heterozygous HTRA1 pathogenic variant (HTRA1-CSVD).

Note: Absence of a known family history of HTRA1 disorder does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of HTRA1 disorder is established in a proband by identification of either a heterozygous pathogenic (or likely pathogenic) variant or biallelic pathogenic (or likely pathogenic) variants in HTRA1 on molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include likely pathogenic variants. (2) The identification of variant(s) of uncertain significance cannot be used to confirm or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing or genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of HTRA1 disorder is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of CARASIL has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

HTRA1 disorder is a phenotypic spectrum in which some individuals have few to no symptoms and others manifest with the more severe classic CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy) phenotype. Those who have a heterozygous HTRA1 pathogenic variant may have mild neurologic findings (sometimes identified only on neuroimaging) or mild-to-moderate neurologic signs and symptoms of CARASIL [Verdura et al 2015, Nozaki et al 2016].

Genotype-Phenotype Correlations

No strong genotype-phenotype correlations for HTRA1 have been identified in classic CARASIL [Hara et al 2009, Favaretto et al 2019].

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 [Nozaki et al 2016, Uemura et al 2019].

Nomenclature

Other names for HTRA1 disorder include the following:

• CARASIL, for those who have biallelic HTRA1 pathogenic variants
• Familial young adult-onset arteriosclerotic leukoencephalopathy with alopecia and lumbago without arterial hypertension
• Nemoto disease
• Maeda syndrome
• CADASIL2 (cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2; OMIM 616779)

Prevalence

HTRA1 disorder has been reported in individuals from Asia, Europe, and North America. However, no founder haplotype has been identified; thus, the authors suspect that the disease will be found more widely.

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.

Treatment of Manifestations

Supportive care in the form of practical help, emotional support, and counseling are appropriate for affected individuals and their families.

Surveillance

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.

Agents/Circumstances to Avoid

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

Evaluation of Relatives at Risk

It has been speculated that hypertension or smoking may influence the age of onset and frequency of stroke episodes in individuals with HTRA1 disorder; smoking may result in earlier disease onset [Singhal et al 2004], and smoking or hypertension may increase the frequency of stroke episodes in individuals with the classic CADASIL phenotype [Adib-Samii et al 2010]. Therefore, it is appropriate to test the older and younger sibs of a proband for presence of the HTRA1 pathogenic variant(s) in the family in order to identify early in adulthood (ideally at age ≥18 years) those who would benefit from initiation of treatment and preventive measures such as oral administration of anti-hypertensive drugs and abstinence from smoking.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

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.

Mode of Inheritance

HTRA1 disorder caused by biallelic pathogenic variants (classic CARASIL) is inherited in an autosomal recessive manner.

HTRA1 disorder caused by a heterozygous pathogenic variant (HTRA1-CSVD) is inherited in an autosomal dominant manner.

Autosomal Recessive Inheritance

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• Most individuals diagnosed with autosomal dominant HTRA1 disorder have an affected parent.
• Because simplex cases (i.e., a single occurrence in a family) have not been evaluated sufficiently to determine if a pathogenic variant occurred de novo, the proportion of HTRA1 disorder caused by a de novo pathogenic variant is unknown. (To date, de novo pathogenic variants have not been reported in HTRA1 disorder.)
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Though theoretically possible, no instances of a proband inheriting a pathogenic variant from a parent with germline mosaicism have been reported.
• The family history of some individuals diagnosed with HTRA1 disorder may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
• If the proband has a known HTRA1 pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the HTRA1 pathogenic variant but are clinically unaffected, sibs are still presumed to be at increased risk for HTRA1 disorder because of the possibility of age-related penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with autosomal dominant HTRA1 disorder has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the HTRA1 pathogenic variant, other members of the parent's family may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Predictive testing (i.e., testing of asymptomatic at-risk individuals)

• Predictive testing for at-risk relatives is possible once the HTRA1 pathogenic variant(s) have been identified in an affected family member.
• Potential consequences of such testing including (but not limited to) socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result – as well as the capabilities and limitations of predictive testing – should be discussed in the context of formal genetic counseling prior to testing.

Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals age <18 years)

• For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
• For more information, see the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

In a family with an established diagnosis of HTRA1 disorder, it is appropriate to consider testing symptomatic individuals regardless of age.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being affected or of being heterozygous.

Prenatal Testing and Preimplantation Genetic Testing

Once the HTRA1 pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for HTRA1 disorder are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Introduction. HTRA1 belongs to the HTRA protein family, the members of which have dual roles as chaperones and serine proteases [Clausen et al 2002]. They 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 proteins exist as trimers, thus allowing communication between adjacent subunits to regulate protease activity [Truebestein et al 2011].

In vitro functional expression studies with HTRA1 known pathogenic variants showed a loss of protease activity and consequent inability to repress TGF-β family signaling [Hara et al 2009]. Additionally, the mutated HTRA1 proteins of some pathogenic variants show a dominant-negative effect by interfering with communication between adjacent subunits [Nozaki et al 2016, Uemura et al 2019].

Mechanism of disease causation. Loss of function. Some pathogenic variants have a dominant-negative effect [Hara et al 2009, Nozaki et al 2016, Uemura et al 2019].

Revision History

• 7 November 2019 (ma) Comprehensive update posted live
• 11 September 2014 (me) Comprehensive update posted live
• 17 February 2011 (cd) Revision: prenatal testing available clinically
• 27 April 2010 (me) Review posted live
• 5 January 2010 (oo) Original submission

Published Guidelines / Consensus Statements

• Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 7-11-23.
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available online. 2018. Accessed 7-11-23.

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