Here, we describe the case of two brothers with symptomatic HTRA1 heterozygous mutations who presented with multi-territory infarcts, confluent white matter disease and hydrocephalus. To our knowledge, the literature to date contains only one case of a heterozygous HTRA1 mutation with hydrocephalus.

HTRA1 is the mutation associated with cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), a rare cause of inherited cerebral small vessel disease (CSVD). HTRA1 in CARASIL requires a bi-allelic mutation to cause disease. There are fewer than 100 patients in the literature with a heterozygous HTRA1 mutation who manifest clinical disease. These patients present later in life than CARASIL, with a milder phenotype. The extra-neurological features seen in CARASIL are less common in HTRA1 heterozygotes.

The first brother presented with progressive cognitive decline, gait disturbance and urinary incontinence. He was bradyphrenic and perseverative, with pyramidal weakness in both legs and his left arm. He had globally brisk reflexes with upgoing plantars. Bloods were unremarkable. CSF protein, glucose, cell count and opening pressure were all normal. His MRI showed disproportionately enlarged subarachnoid space hydrocephalus (DESH) with confluent white matter hyperintensities (WMH) on T2/FLAIR. Diffusion weighted imaging (DWI) identified multiple areas of restricted diffusion.

The second brother presented with an acute pontine stroke, followed by bilateral supratentorial MCA territory infarcts. He had a mixed dysphasia, dysarthria, bilateral pyramidal weakness and spasticity. His MRI showed similar findings to his brother, with WMH and established ischaemic events on T2/FLAIR, DESH and a single acute infarct on DWI.

Both brothers tested positive for one likely pathogenic variant in HTRA1 c.883G>A (p.Gly295Arg).

These cases add to a growing cohort of heterozygous HTRA1 mutations that result in clinical disease. In these cases, there were radiological features of normal pressure hydrocephalus in addition to the classical features of inherited CSVD.