XLA-MTS: a distinct clinical genetic entity characterized by immunodeficiency and neurodevelopmental delay

BACKGROUND: Mohr-Tranebjærg syndrome (MTS) is a rare X-linked recessive neurodegenerative disorder, typically presenting with progressive sensorineural hearing loss in early childhood, followed by neurological deterioration, dystonia, ataxia, and visual impairment. OBJECTIVE: This study aimed to conduct a comprehensive clinical, genetic, and phenotypic review of MTS, with particular emphasis on mutations in the TIMM8A gene and contiguous deletions involving Bruton tyrosine kinase (BTK), which give rise to an extended phenotype known as XLA-MTS. METHODS: A systematic literature review was performed between February 1995 and May 2025 using PubMed, Embase, and Scopus databases. Clinical and genetic data from 75 individual patients with molecularly confirmed MTS or XLA-MTS were extracted and stratified into two groups: classical MTS (TIMM8A mutations only, n = 51) and XLA-MTS (contiguous deletions of TIMM8A and BTK, n = 24). Key clinical features were compared using Fisher's exact test and Student's t-test. RESULTS: Immunodeficiency with agammaglobulinemia (XLA) was present in 100% of XLA-MTS cases (24/24) versus 0% of classical MTS cases (0/51). Delayed language development (DLD) was significantly more frequent in XLA-MTS (52,4%, 13/24) than in classical MTS (19.6%, 10/51) (p = 0.004). In contrast, progressive cortical blindness (PCB) was markedly more common in classical MTS (58,8%, 30/51) than in XLA-MTS (12,3%, 3/24) (p < 0.001). CONCLUSIONS: Contiguous deletions encompassing TIMM8A and BTK define a distinct clinical-genetic entity-XLA-MTS-characterized by the triad of early-onset deafness, neurodevelopmental delay, and immunodeficiency. These findings underscore the critical need for expanded genetic testing beyond TIMM8A alone to ensure accurate diagnosis, prognostic stratification, and appropriate clinical management, particularly in patients with syndromic deafness and developmental delay.