Cerebral small vessel disease (CSVD) is a chronic, progressive neurologic disease affecting the arterioles, venules, and capillaries of the brain. Consequences of CSVD include stroke, physical debility, and cognitive impairment. Causes include arteriosclerosis, cerebral amyloid angiopathy, immune mediated vasculopathy, and rarely inherited cerebral angiopathy. Pathogenic variants in collagen type IV alpha chain 1 (COL4A1) are associated with a spectrum of autosomal dominantly inherited CSVD including brain small vessel disease with or without ocular anomalies (BSVD1), hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC), and pontine autosomal dominant microangiopathy with leukoencephalopathy (PADMAL). These conditions can have systemic findings including muscle cramps, retinal artery tortuosity, renal cysts, and skin basement membrane abnormalities.

A 56-year-old female with a history of trigeminal neuralgia, Bell’s palsy, renal cysts, and diffuse symmetric subcortical leukoencephalopathy on prior brain MRI presented to neurology clinic for second opinion on diffuse, painful muscle cramping. Onset of muscle cramps was at age 49 predominantly in the lower back and bilateral lower extremities although present throughout. Family history was notable for her father dying from stroke, two sons with muscle cramps, three siblings with headaches, intellectual disability, and hydrocephalus, and paternal grandfather with stroke. Evaluation including serum testing, CSF analysis, MRI of the neuroaxis, and EMG/NCS were performed and unrevealing apart from the previously noted subcortical leukoencephalopathy. Genetic testing was performed identifying a variant of uncertain significance in COL4A1 (c.1391G>A, p.Gly464Glu) in exon 23 that is predicted to disrupt protein function in silico. The variant is rare, not present in population databases and not previously reported with COL4A1 associated conditions.