Neurodegenerative changes detected by neuroimaging in a patient with contiguous X-chromosome deletion syndrome encompassing BTK and TIMM8A genes

Abstract

Introduction: In this study we describe a patient with gross deletion containing the BTK and TIMM8A genes. Mutations in these genes are responsible for X-linked agammaglobulinemia and Mohr-Tranebjaerg syndrome, respectively. X linked agammaglobulinemia is a rare primary immunodeficiency characterized by low levels of B lymphocytes and recurrent microbial infections, whereas, Mohr-Tranebjaerg syndrome is a progressive neurodegenerative disorder with early onset of sensorineural deafness.

Material and methods: For neuroimaging, the magnetic resonance imaging and magnetic resonance spectroscopy of the brain were performed. Microarray analysis was performed to establish the extent of deletion.

Results: The first clinical symptoms observed in our patient at the age of 6 months were connected with primary humoral immunodeficiency, whereas clinical signs of MTS emerged in the third year of live. Interestingly, the loss of speech ability was not accompanied by hearing failure. Neuroimaging of the brain suggested leukodystrophy. Molecular tests revealed contiguous X-chromosome deletion syndrome encompassing BTK (from exons 6 through 19) and TIMM8A genes. The loss of the patient's DNA fragment was accurately localized from 100 601 727 to 100 617 576 bp on chromosome's loci Xq22.1.

Conclusions: We diagnosed XLA-MTS in the first Polish patient on the basis of particular molecular methods. We detected neurodegenerative changes in MRI and MR spectroscopy in this patient. Our results provide further insight into this rare syndrome.

Keywords: BTK; Mohr-Tranebjaerg syndrome; TIMM8A; Vanishing white matter leukodystrophy; X-linked agammaglobulinemia; neuroimaging.

Fig. 1

A) Multiplex ligation-dependant probe amplification analysis of BTK gene in patient (ii) and patient’s mother (i). B) Array comparative genomic hybridisation analysis of the X-chromosome of our patient (gene view – TIMM8A and BTK genes deletions; cytoband – affected chromosome’s loci Xq22.1; chromosome view – affected chromosome X). C) Complete deletion of both exons of TIMM8A confirmed with PCR reaction and electrophoresis. D) Scheme of detected TIMM8A and BTK gene deletions

Fig. 2

Magnetic resonance imaging pictures of our patient with XLA-MTS. The images show that the lateral ventricles, and to a lesser degree the subarachnoid spaces, are dilated. The third ventricle, aqueduct, and fourth ventricle are enlarged. Extensive but not diffused signal abnormalities are seen in the cerebral white matter. The corpus callosum is involved in the white matter abnormality. There is cerebellar atrophy. No enhancement after contrast is observed