Htra1 Disorder

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 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 variant or biallelic pathogenic variants in HTRA1 on molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or 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.