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Título

Expanding the spectrum of TBK1-related disorders: adult-onset non-5q Spinal Muscular Atrophy

RESUMO

Case Presentation: A 36-yo man presented with a slowly progressive history of weakness and painful cramps in his lower limbs since age 22 years. After 8 years, he noted mild amyotrophy involving the distal portion of the thighs and calves, slow gait speed, and waddling gait. Medical and family history were unremarkable. Parental consanguinity was not present. Examination disclosed crural flaccid paraparesis with proximal predominance, absent tendon reflexes and bilateral pes cavus. Neurophysiological studies disclosed symmetric chronic denervation pattern with reinnervation in the lumbosacral myotomes (L3-S1). Brain and spine MRI and cerebrospinal fluid analysis were unremarkable. Muscle MRI disclosed mild fatty replacement of the vastus medialis, adductor and focal fatty replacement bilaterally in the medial head of the gastrocnemius muscle. As clinical and neurophysiological features were suggestive of non-5q spinal muscular atrophy (SMA), especially SMA with lower extremity predominance (SMALED), a genetic testing with whole-exome sequencing (WES) was performed. WES evidenced the heterozygous pathogenic variant c.1960-1G>T (a splice acceptor variant) in intron 18 of the TBK1 gene, leading to a loss of function effect due to protein truncation and activation of nonsense-mediated decay. Thus, we concluded that our patient presented with a new MND phenotype associated with TBK1 gene. Additional testing for 5q SMA (including MLPA and Sanger sequencing) and a wide NGS-based gene panel test were performed and their results were unremarkable.
Discussion: TBK1 (TANK binding kinase-1) gene (12q14.2) is associated with modulation of autophagy and inflammatory function in neuronal and glial cell types. TBK1 variants are related to Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia, and susceptibility to acute infection-induced herpes simples-specific encephalopathy type 8. Our patient presented with clinical and neurophysiological findings suggestive of long-standing lower MND, mimicking features of SMALED syndrome and atypical ALS variants. SMALED phenotypes have been previously associated with DYNC1H1 and BICD2 heterozygous pathogenic variants, however with distinct muscle imaging findings when compared to our patient.
Final comments: Clinicians must be aware about the possibility of TBK1 variants as new monogenic basis of pure non-5q SMA and SMALED-like phenotypes with specific muscle imaging pattern of involvement.

Palavras Chave

TBK1; non-5q Spinal Muscular Atrophy; neurodegenerative; genetic; motor neuron disease