Incomplete HANAC (Hereditary angiopathy, nephropathy, aneurysms, and muscle cramps) syndrome and the first C0L4A1 gene mutation in Portugal (G236T)

Background: The various phenotypes associated with COL4A1 gene mutations, originally associated with autossomal dominant porencephaly, have recently been expanded, accomodating presentations such as cerebral small vessel disease with intracranial hemorrhages; cerebral small vessel disease and Axenfeld-Rieger anomaly; and the HANAC (Hereditary Angiopathy with nephropathy, aneurysms and muscle cramps) syndrome. Because as few as 65 individuals (17 families) with disease have been reported worldwide so far, there is no information regarding the prevalence of these mutations, however, as far as we know, this seems to be the first report of a COL4A1 mutation in Portugal. Clinical picture: We report the case of a 46 year old male, born in Uganda of indian ascendancy, with previous history of frequent muscle cramps and a post-viral (as a child) convergent strabismus, admitted with sudden left body hemiparesis and dysarthria. His family history disclosed one deceased brother in infancy in Uganda, with a diagnosis of "cerebral palsy"; frequent muscle cramps reported by the father (deceased), one sister and one nephew. His neurological examination showed left hemiparesis and dysarthria. His head CT scan and MRI revealed multiple small hemorrhagic lesions, present on both hemispheres, as well as diffuse leukoencephalopathy; an intracranial digital subtraction angiography showed no vascular malformations or aneurysms. He had slight renal function impairment, microscopic hematuria and bilateral cortical renal cysts; and bilateral retinal tortuosity. A skin biopsy revealed no basal membrane abnormalities. COL4A1 gene sequencing revealed a previously unreported heterozigous mutation at exon 4 (c.236G>T; p.Gly79Val), a replacement of a glicine residue by a valine residue. Conclusions: Regarding the phenotypical variety associated with COL4A1 mutations, this should be kept in mind when faced with young stroke patients with small cerebral vessel disease of unknown origin. If the pathogenicity of this mutation is confirmed it appears to be the first COL4A1 mutation reported in Portugal, with an incomplete HANAC syndrome phenotype.