Severe Cerebral Small Vessel Disease Caused by the Uniallelic p.A252T Variant of HTRA1

Case Presentation

Patient 1 (II-2, Figure 1A, Table) developed knee pain at 34 years and had a stroke episode at 37 years. Neurologic examination at 40 years showed cognitive decline, emotional instability, pseudobulbar palsy, urinary incontinence, and bilateral pyramidal signs. She became bedridden and died at 51 years. Based on both clinical and postmortem pathologic findings, we diagnosed patient 1 as likely CARASIL.^1,3

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Figure 1 Pedigree and Sanger Sequencing of HTRA1

(A) The numbers below the symbols indicate the age in years (y) at death (d) of deceased individuals indicated by a strikethrough. The proband and the younger brother are indicated by arrows. II-8 had been genetically tested and confirmed to have an HTRA1 homozygous variant in a previous report.¹ Filled symbols indicate that the patient had leukoencephalopathy, lumbago, or spondylosis. A symbol with a secant line indicates an asymptomatic patient. (B) Sanger sequencing of HTRA1.

Patient 2 (II-4) first noticed dysarthria, followed by recurrent episodes of transient hemiparesis at 28 years. Neurologic examination at 29 years revealed cognitive decline, rigidity, bradykinesia, and pyramidal tract signs. At 30 years, she developed emotional instability and pseudobulbar palsy. She died at 38 years.

Patient 3 (II-8) had genetically confirmed CARASIL and carried homozygous HTRA1 p.A252T.^1,3 She developed lumbago and knee pain as a teenager. At 38 years, she had recurrent episodes of stroke and showed dysarthria, hemiparesis, and gait disturbance. She became a wheelchair user because of spastic paresis and cerebellar ataxia at 48 years.

Patient 4 (II-5) was a 70-year-old man who carried heterozygous p.A252T with multiple atherosclerotic risks (Figure 1B). He developed lacunar infarction at 62 years. He was diagnosed with hypertension and diabetes mellitus and treated with cilostazol, pitavastatin, amlodipine, and sitagliptin. At 70 years, he showed neither cognitive dysfunction nor gait disturbance, although MRI showed cerebral atrophy, white matter hyperintensities (WMHs), and microbleeds (eFigure A–D, links.lww.com/NXG/A568).

Patient 5 (III-4) was a 49-year-old man with heterozygous p.A252T. At 37 years, he developed gait disturbance, and MRI showed acute lacunar infarction in the left radiate crown with multiple previous infarctions. He was a smoker but had no other atherosclerosis risks. He repeatedly developed cerebrovascular events, and his gait and cognitive functions deteriorated progressively, despite dual antiplatelet therapy. At 43 years, he was diagnosed with hyperlipidemia and started statin therapy that reduced the frequency of stroke attacks. In serial MRI analyses, WMHs had expanded from the center of the semicircle to the periventricular area of lateral ventricles, and progressive diffuse brain atrophy and microbleeds were evident (Figure 2, A and B; eFigure E, F, links.lww.com/NXG/A568). Intensive screening tests showed no typical causes or risk factors known to be associated with ischemic stroke in young adults, such as vasculitis, antiphospholipid antibody syndrome, protein C/S deficiency, and Fabry disease.

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Figure 2 MRI of Symptomatic HTRA1 Variant Carriers

(A and B) Patient 5 (III-4) at 49 years of age. (C and D) Patient 6 (III-6) at 47 years of age. Fluid-attenuated inversion recovery images (A and C) showed periventricular to subcortical white matter hyperintensities, lacunar infarctions, and cerebral atrophy. Susceptibility-weighted imaging (B) and T2*(D) showed microbleeds in both the cerebral cortex and the brainstem surface.

Patient 6 (III-6) was a 47-year-old man with heterozygous p.A252T. He developed lumbago in his twenties. At 39 years, he developed headaches, and MRI showed multiple cerebral infarctions. Neurologic findings were normal. He had no risk of atherosclerosis. He was treated with antiplatelet therapy but had repeated cerebrovascular events. At 43 years, he was diagnosed with hyperlipidemia and hypertension and treated with pitavastatin and amlodipine. At 48 years, he developed cognitive decline and parkinsonism. On the basis of the Wechsler Adult Intelligence Scale 4th edition, he had a full-scale IQ of 78, verbal comprehension index of 96, perceptual reasoning index of 76, working memory index of 91, and processing speed index of 66. Serial MRI analyses showed WMHs around the lateral ventricles that gradually fused and extended subcortically (Figure 2C). Abnormal intensity was also observed in the external capsule and brainstem (eFigure G, H, links.lww.com/NXG/A568). Microbleeds were prominent on the brainstem surface and increased over time (Figure 2D). We also ruled out disease-causative variants of NOTCH3, CTSA, GLA, COL4A1, and TREX1.

Patient 7 (III-2) was a 52-year-old woman with heterozygous p.A252T. She developed lumbago at 38 years. She had no medical history of stroke but had hypertension and hyperlipidemia. MRI showed asymptomatic WMHs.

Patient 8 (III-8) was a 39-year-old woman with heterozygous p.A252T. She developed lumbago in her twenties but had no other clinical symptoms or brain imaging abnormalities.

Patient 9 (III-10) was a 39-year-old unaffected woman with heterozygous p.A252T.