Dados do Trabalho

Título

TBCK SYNDROME: A RARE BUT DEVASTATING GENETIC DISEASE

Apresentação do caso único

The patient is a two years old male, son of a healthy consanguineous couple. Pregnancy and prenatal period were unremarkable. Parents noticed, early in his childhood, hypotonia, delayed global milestones, including walking and talking, and 2 focal seizures. Levetiracetam was introduced and no more seizures occurred. On examination, he presented with extraocular muscles and facial nerve palsy, left eye exotropia, floppiness, diminished deep tendon reflexes and bilateral Babinski sign. MRI showed hypomyelination. SNP-array demonstrated the homozygous deletion on the long arm of chromosome 4q24. This deleted part comprehends an intragenic sequence of TBCK and its loss of function is related to infantile hypotonia with psychomotor retardation and characteristic facies 3 (IHPRF3).

Discussão

TBCK syndrome, also known as infantile hypotonia with psychomotor retardation and characteristic facies 3 (IHPRF3 – OMIN: 616900), is a rare genetic disorder caused by homozygous or compound heterozygous mutations in the encoding gene TBC1 domain-containing kinase (TBCK), located at chromosome 4q24. It is a severe autosomal recessive neurodevelopmental disorder, with onset at birth or in early infancy, and It can also affect other organs and systems. The most common symptoms include hypotonia, profound developmental delay, intellectual disability, seizures, skeletal abnormalities and abnormal craniofacial features. Brain imaging usually shows ventriculomegaly and cerebral atrophy, thinning of the corpus callosum, cerebellar hypoplasia and white matter abnormalities. The usual dysmorphic facial features are: bitemporal narrowing, arched eyebrows, high nasal bridge, deep set eyes and macroglossia. Other common findings include vision and hearing impairment, cardiac diseases, early-onset osteoporosis, sleep apnea and respiratory complications. TBCK deficiency seems to cause suppression of the mTOR axis, which helps in the differentiation of Schwann cells, contributing to myelination, and in cellular proliferation. This mTOR pathway down-regulation seems to lead to decreased brain development and hypomyelination. Treatment for TBCK syndrome is currently limited to palliative care for specific symptoms.

Comentários finais

TBCK syndrome is a rare but devastating disorder and TBCK seems to participate in many still unknown functions. More research is necessary to fully comprehend the mechanism leading to this disease.

Referências

Durham EL, Angireddy R , Black A, Melendez-Perez A, Smith S, Gonzalez EM, Navarro KG, Díaz A, Bhoj EJK, Katsura KA. TBCK syndrome: a rare multi-organ neurodegenerative disease. Trends in Molecular Medicine, October 2023, Vol. 29, No. 10.
Chand P, Sulaiman A, Kirmani S. Mutation of TBC1 Domain containing kinase (TBCK) with associated intellectual disability and hypotonia. Journal of the Pakistan Medical Association, 73(10), 2083–2085.
Guerreiro RJ, Brown R, Dian D, de Goede C, Bras J, Mole SE. Mutation of TBCK causes a rare recessive
developmental disorder. Neurol Genet 2016;2:e76; doi: 10.1212/NXG.0000000000000076.
Wu J, Lu G. Multiple functions of TBCK protein in neurodevelopment disorders and tumors (Review). Oncology Letters, 21: 17, 2021. DOI: 10.3892/ol.2020.12278

Palavras Chave

Neurodevelopmental Delay; Hypotonia; Hypomyelination