Vascular Leukoencephalopathy Associated Chorea Due to A Heterozygous Htra 1 Variant: Novel Presentation of Cadasil Type II

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a rare hereditary cerebral arteriopathy. Autosomal recessive inheritance of HTRA1 causes CARASIL, while autosomal dominant pattern leads to CADASIL type II. Our case describes a rare and novel presentation of CADASIL type‐II, not previously elaborated in literature.

A 73‐year‐old man presented to the movement disorder clinic with a 4‐year history of gradually progressive choreiform movements. He exhibited involuntary facial grimacing, tongue persistence, lip smacking and generalized choreiform movements of the arms, trunk and legs bilaterally (see Video 1). There was no history of intake of antiemetics or neuroleptics. Relevant medical history included peripheral vascular disease for which he was taking Nifedipine. Previous medical records did not indicate any noteworthy risk factors for stroke, chorea or Sydenham's chorea. His parents died from unknown causes. His sister began exhibiting choreiform symptoms and cognitive impairment but has declined investigation. He has five children, three of whom are estranged. None of the children are currently known to display similar symptoms.

Video 1.

Patient showing involuntary facial grimacing, lip smacking and tongue persistence. Video also demonstrates chorea involving the face, trunk and limbs. Speech dysarthria and spastic gait are also evident.

Neurological examination showed intact power, tone, and cranial nerve functions. There were no motor, sensory, reflex abnormalities, cerebellar or parkinsonian signs. No evidence of peripheral neuropathy. Initial investigations including a full blood panel and other chorea‐relevant investigations (see supplemental Tables S1 and S2) was undertaken. MRI neuroradiological assessment exhibited ill‐defined T2 hyperintensities and accompanying moderate small vessel ischemic disease and mild changes of ischemic gliosis (Fig. 1A–E).

Figure 1.

(A–C) are T2 plain imaging (turbo spin echo‐TSE) of axial and coronal sections showing diffuse bilateral cortical atrophy without specific lobar distribution. In addition to moderate small vessel ischemic changes, ischemic gliotic changes are also evident within the brainstem as well. Mild generalized atrophy with commensurate ventricular dilatation seen. T2 hypointensity on imaging can be attributed to small vessel ischemic changes and associated CSVD. (D–E) are T2 flair images indicative of the same findings. (F–G) are T2 flair imaging shows white matter hyperintensities (WMHs) in bilateral frontoparietal, subcortical and periventricular white and subsequent worsening of WMHs following a period of 7 years.

The patient's symptoms were attributed to vascular chorea, and he was commenced on aspirin 75 mg OD. He was offered dopamine antagonists but declined. Over time, his chorea, dysarthria, and memory problems worsened, alongside development of a spastic gait and dysphagia. MMSE score was 22 illustrating moderate cognitive impairment. A differential diagnosis of Huntington's disease, spinocerebellar ataxias, late onset Wilson's disease, brain iron accumulation syndromes and fronto‐subcortical dementia syndromes was considered. MRI was repeated and exhibited worsening of the WMHs (Fig. 1F,G). Genetic analysis report (see supplemental Data S1) revealed no evidence of Huntington's disease, ALS, frontotemporal dementia, or SCA17 associated spinocerebellar ataxia. Analysis of all exons of 27 genes for cognitive impairment and chorea, including NOTCH3 and HTRA1, by next‐generation sequencing was undertaken. The patient exhibited heterozygosity for the c.496C > T, p.(Arg166Cys) likely pathogenic variant in exon 2 of the HTRA1 gene, causing a moderately conservative amino acid substitution supported by in silico analysis confirming its pathogenic potential. This gene's variants relate to autosomal dominant CADASIL type II and CARASIL. Hence, the diagnosis was CADASIL type II, and treatment initiated with Clopidogrel.

Five genotypes can cause hereditary cerebral arteriopathy, with NOTCH3 in CADASIL and HTRA1 in CARASIL being the most prevalent. CADASIL type II includes patients with single heterozygous HTRA1 mutations and an autosomal dominant inheritance. CADASIL presents with recurrent strokes, migraines, and cognitive decline. CARASIL includes early cognitive decline, alopecia, gait issues, and back pain. Neuroimaging for both diseases reveals comparable features: white matter hyperintensities, lacunar infarcts, and cerebral microbleeds. Anterior temporal lobe and external capsule involvement has also been noted. HTRA1‐linked autosomal dominant cases show more vascular risk factors, delayed onset, slower progression, sans extra neurological CARASIL features. ¹ Facial dystonia is an atypical symptom in CADASIL cases. ²

We put forward a novel presentation of CADASIL type II manifesting as progressive choreiform movements, memory loss and disinhibition. His sister has a similar phenotype, but has declined genetic analysis. Choreiform movements as part of the clinical expression in CADASIL in a patient with a typical presentation of NOTCH3 mutations has been described previously. ³ Literature depicts NOTCH‐3 associated chorea linked to gene mutations in exon 11, causing choreiform movements in the right toe, fingers, and orolingual area. ⁴ However, generalized chorea in HTRA1 associated CADASIL has not been described previously. Chorea in this case can be attributed to chronic cerebral hypoperfusion from cerebral small vessel disease (CSVD) and multiple vascular insults, supported by gliosis on MRI. Autosomal dominant heterozygous HTRA1 mutations correlate with CSVD. ¹ Notably, development of chorea post‐ischemic cortical stroke sparing basal ganglia possibly results from decreased direct stimulus from cortex disrupting the direct and indirect pathways. ⁵ Concurrently, hypoxia‐ischaemia may injure the basal ganglia through hypoperfusion of subcortical vascular watershed regions and by altering striatal neurotransmitter systems. ⁶ A prior study proposed that diminished glucose metabolism in cortical and subcortical regions in CADASIL may result from ischemia‐induced neuronal loss. ⁷ Patient's genomic DNA analysis identified a pathogenic exon 2 variant in the HTRA1 gene, documented in both homozygous and heterozygous populations. ⁸ , ⁹ It has not been previously demonstrated in control population on gnomAD.

In a study, homozygotes within the largest family cohort, showed early cognitive and motor decline akin to CARASIL. Heterozygotes, resembling CADASIL type II, exhibited spinal disc degeneration, leukoencephalopathy, and neuroimaging microhaemorrhages despite milder symptoms. ¹⁰ Vascular leukoencephalopathy with chorea due to the HTRA1 variant need to be replicated in order to establish stronger causation.

Author Roles

(1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique; (conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; AND)

A.N.: 3A,3B

A.Z.: 3A, 3B

E.J.: 3B

M.A.: 3B

Disclosures

Ethical Compliance Statement: All the steps involved in this study were in accordance with the ethical standards of the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The approval by the institutional review board was not required for this report however, written consent was obtained from the NOK (next of kin) of the patient, signed and documented. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflicts of Interest: The authors declare that there are no disclosures pertaining to funding or any conflicts of interest relevant to this work. The authors declare that there are no additional disclosures to report.

Financial Disclosures for the previous 12 months: The authors declare that there are no financial Disclosures for the previous 12 months.

Supporting information

TABLE S1. Laboratory investigations.

TABLE S2. Chorea relevant investigations.

Data S1. Genetic analysis report summary (undertaken by next generation sequencing).