Novel mutation in HTRA1 in a family with diffuse white matter lesions and inflammatory features Amin Ziaei, Xiaohong Xu, Leila Dehghani, Carine Bonnard, Andreas Zellner, Alvin Yu Jin Ng, Sumanty Tohari, Byrappa Venkatesh, Christof Haffner, Bruno Reversade, Vahid Shaygannejad, Mahmoud A. Pouladi Neurol Genet Aug 2019, 5 (4) e345; DOI: 10.1212/NXG.0000000000000345
Objective: To investigate the possible involvement of germline mutations in a neurologic condition involving diffuse white matter lesions.
Methods: The patients were 3 siblings born to healthy parents. We performed homozygosity mapping, whole-exome sequencing, site-directed mutagenesis, and immunoblotting.
Results: All 3 patients showed clinical manifestations of ataxia, behavioral and mood changes, premature hair loss, memory loss, and lower back pain. In addition, they presented with inflammatory-like features and recurrent rhinitis. MRI showed abnormal diffuse demyelination lesions in the brain and myelitis in the spinal cord. We identified an insertion in high-temperature requirement A (HTRA1), which showed complete segregation in the pedigree. Functional analysis showed the mutation to affect stability and secretion of truncated protein.
Conclusions: The patients' clinical manifestations are consistent with cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL; OMIM #600142), which is known to be caused by HTRA1 mutations. Because some aspects of the clinical presentation deviate from those reported for CARASIL, our study expands the spectrum of clinical consequences of loss-of-function mutations in HTRA1.
This study was supported by the Agency for Science Technology and Research (SPF2012/005) to M.A.P. and the
German Research Foundation (DFG, HA2448/6-1) to C.H.