X-linked agammaglobulinaemia (XLA) is a primary immune deficiency disorder caused by a mutation in the Bruton tyrosine kinase (Btk) gene. A progressive neurodegenerative syndrome of unknown aetiology has been described in patients with XLA on long term immunoglobulin replacement therapy. We present two cousins with XLA caused by the same grandmaternal mutation ((c.1898G>A) in the Btk gene) who developed progressive neurological deterioration in the second decade with prominent extrapyramidal features.
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Patient one is a 28yrs male diagnosed with XLA and treated with immunoglobulin replacement from 20 months. He presented with cognitive and behavioural difficulties at 7yrs, subsequent marked cognitive and motor function decline at 16yrs. MRI brain showed a progressive cerebral and cerebellar atrophy. CSF infection screen was negative. He developed progressive dysarthria, bradykinesia, bilateral upper limb rigidity and loss of fine motor movements.
His 21yrs male cousin was diagnosed with XLA through carrier screening and treated with immunoglobulin replacement from 6 months. He presented with a progressive dystonic tremor, dysarthria, cognitive and balance difficulties at 18yrs. MRI brain showed progressive supra-tentorial atrophy and subtle white matter abnormalities. CSF oligoclonal bands and infection screen were negative. He developed increased muscle tone and apraxia of hand movements.
We highlight the familial presentation and ask whether the neurological phenotype could be a direct consequence of the Btk mutation or of another as yet unidentified gene mutation. We are not aware of other such familial cases. Whole genome sequencing may be beneficial to identify genetic predisposition to these rare neurological sequelae.