Raising awareness of TBC1 domain‐containing kinase (TBCK) epileptic encephalopathy among Puerto Rican children

Abstract

Background

TBC1 domain‐containing kinase (TBCK) syndrome is a rare autosomal recessive genetic disorder that presents with infantile hypotonia, intellectual disability, motor impairment, and drug‐resistant epilepsy. The abnormal TBCK protein alters the mammalian target of rapamycin complex 1 (mTORC1), leading to accumulation of autophagic vesicles within fibroblasts. Thirty‐five previously reported individuals with TBCK were identified.

Methods

We present four children with TBCK due to the p.R126X (p.ARG126*) mutation, a variant predominating among children of Puerto Rican descent. This mutation has been associated with TBCK‐encephaloneuropathy or Boricua syndrome.

Discussion

These four of our patients were diagnosed within a span of 6 months, suggesting that the prevalence of the syndrome could be higher than expected among individuals from Puerto Rico. We believe this finding was largely due to the increasing availability and affordability of modern genetic testing in Puerto Rico, illustrating the importance of equitable access to genetic testing to all pediatric patients with similar symptomatology. Prompt diagnosis facilitates appropriate medical management and prognosis counseling.

Introduction

TBC1 domain‐containing kinase (TBCK) syndrome is a rare genetic disorder caused by a mutation in the TBCK gene that leads to an atypical production of the TBCK protein. The TBCK protein contains three domains: TBC, rhodanese‐like, and a kinase domain. A dysfunction within the kinase domain has been shown to cause dysregulated autophagic processes. ¹ Autophagy is the process by which proteins, lipids, and other organelles are trafficked to the lysosomes for degradation. ² In order for the contents to be degraded, vesicles must first fuse with the lysosomal membrane. The TBCK protein plays an active role in this process through the mammalian target of rapamycin complex 1 (mTORC1) pathway. mTORC1 is a complex that regulates cellular autophagy. It is made up of five components, including the mTOR protein, which serves as its catalytic domain. ¹ Individual subunit function is still mostly unknown and currently under investigation. Aside from its role in autophagy, the mTORC1 complex promotes cell growth via stimulation of anabolic processes and biosynthesis of proteins, organelles, and lipids. ³ A mutation within the TBCK gene inhibits mTORC1 activation, thereby reducing lysosomal content and increasing autophagic activity. ² Defects in the TBCK gene lead to increased production of vesicles and decreased vesicle fusion with the lysosomal membrane (Figure). ¹ This results in accumulation of vesicles within fibroblasts, leading to the characteristic symptoms of TBCK patients. ²

Figure. Pathophysiology of TBC1 domain‐containing kinase (TBCK)/Boricua syndrome.

TBCK is characterized by profound intellectual disability, infantile muscular hypotonia, marked psychomotor retardation, and early‐onset epilepsy. ¹ , ² The onset of epilepsy is between 6 and 24 months of age. ⁴

Patients begin to show developmental regression prior to the age of 10, along with cerebral atrophy and white matter degeneration (encephalopathy). ¹ , ⁴ The early onset of seizures strongly contributes to the encephalopathic picture caused by this mutation. The combination of the leukoencephalopathy, epilepsy, and progressive neuromuscular weakness leads to a shortened lifespan, with most patients dying during their teenage years. ²

There have been 35 TBCK patients reported to date, ⁵ with the highest prevalence among children of Puerto Rican descent. ¹ Increased access to more genetic testing in the island led to the discovery of the “Boricua” variant mutation p.R126X, which is related to severe manifestations of TBCK disease. ² The Boricua TBCK mutation is distinctively characterized by the degeneration of cerebellar and motor neurons, referred to as TBCK‐encephaloneuropathy (TBCK‐E). ⁶ Additionally, Boricua TBCK also presents with prominent muscle fasciculations. ²

Patient 1

This 8‐month‐old Puerto Rican girl presented with a history of global developmental delay, hypotonia, and tongue fasciculations. She was diagnosed with epilepsy at 1 month of age after arriving at the emergency department with focal right body seizures.

Patient 2

This 3‐year‐old Puerto Rican boy presented with global developmental delay and generalized tonic–clonic seizures (GTCS) starting at 2 years and 8 months of age. His examination revealed hypotonia, generalized weakness, and absent tendon reflexes. Head computerized tomography (CT) showed a mega cisterna magna and asymmetric lateral ventricles. The electroencephalogram (EEG) revealed left central–parietal epileptiform discharges.

Patient 3

This 3‐year‐old Puerto Rican girl experienced recurrent GTCS. Her examination showed generalized hypotonia, decreased tendon reflexes, and bilateral weakness that was more prominent in the left extremities. Her EEG showed generalized slowing of the background rhythm and focal epileptiform discharges (Table). Imaging studies are pending.

Table. Genetic, EEG, and imaging findings.

Patient #	c376C > T (Arg126*)	EEG	Imaging
1	+HOM	Focal slowing of the background over the left frontal and temporal areas	Prominent lateral ventricles bilaterally
2	+HOM	Left central–parietal spike and wave	Asymmetric lateral ventricles with mega cisterna magna
3	+HOM	Generalized slowing right frontoparietal spike and wave
4	+HOM	Generalized slowing	Prominent subarachnoid spaces and ventriculomegaly

Abbreviations: EEG, electroencephalogram; +HOM, homozygous.

Patient 4

This 2‐year‐old Puerto Rican girl presented at 6 months old with complaints of hypotonia and developmental delay. A physical examination revealed an asymmetric skull, a large anterior fontanelle, facial diplegia, and bilateral exotropia. The patient was admitted to the pediatric intensive care unit (PICU) 10 months later while in status epilepticus. Her EEG was abnormal due to generalized slowing of the background. Head CT (without contrast) showed no intracranial calcifications or mass effect but did show prominent subarachnoid spaces and borderline ventriculomegaly due to cerebral atrophy (Table).

Discussion

The TBCK p.R126X mutation is classified as a variant only seen in patients of Puerto Rican descent, adopting the name “Boricua” syndrome. ² We report four additional Puerto Rican children under the age of 4 years with a TBCK p.R126X mutation.

TBCK syndrome is an autosomal recessive disorder that is associated with infantile hypotonia, intellectual disability, and characteristic facies such as deeply set eyes and tenting of the upper lip vermilion. ¹ Systemic features include hypothyroidism, dyslipidemia, and osteoporosis. ² Our four patients have similar manifestations to previously reported individuals except for their characteristic facies or systemic features.

The mTORC1 complex must be activated for lysosomal autophagy to function adequately. The TBCK symptoms result from mTORC1 inhibition with accumulation of vesicles and an overstimulation of lysosomal autophagy. Recent studies suggest that the alteration of mTORC1 could be a common link among various neurodegenerative disorders that feature intellectual disability and epilepsy. ² One example of such disease is tuberous sclerosis complex (TSC), which results from a loss of function mutation within the genes that code for the TSC1/TSC2 proteins, disrupting the mTOR complex. In contrast to TBCK, TSC leads to an increased activity of the mTOR pathway. This is an important contrast to note as both conditions present with similar symptoms, regardless of differences in pathophysiology. In general, the activation of mTORC1 in TSC induces brain overgrowth, either global or focal, while TBCK syndrome patients show decreased brain volumes. ⁷

Because our four patients were diagnosed within a span of 6 months, we believe that the prevalence of the syndrome could be higher among the Puerto Rican population than previously expected. The increased frequency may be explained by the increasing availability and affordability of modern genetic testing in Puerto Rico, highlighting the importance of equitable access to genetic testing to all pediatric patients with hypotonia, global developmental delay, and new‐onset epilepsy, regardless of Puerto Rican descent, to appropriately screen for TBCK mutations. Prompt recognition facilitates appropriate medical management and prognosis counseling. Additionally, aside from contributing toward bridging the gap between the lack of available biodemographic data, it can also aid in our understanding and in the development of treatment for complex neurologic disorders. ⁷

Due to the need for further research on the pathophysiology of TBCK‐E and the wide variety of symptoms, there is currently no curative treatment available. Previous literature suggests that mTORC1 activators could ameliorate autophagic‐lysosomal system dysfunction symptoms in all patients that do not have TBCK‐E. ² However, this finding has not been tested. Treatment for all TBCK patients has instead been focused on symptom management, such as antiepileptic medications and disability accommodations.

Author Contributions

Johanna De Luca‐Ramirez: Conceptualization; data curation; formal analysis; investigation; methodology; project administration; resources; validation; visualization; writing—original draft; writing—review and editing. Sofia Rosado Fernández: Conceptualization; data curation; formal analysis; investigation; methodology; project administration; resources; validation; visualization; writing—original draft; writing—review and editing. Orlando A. Torres: Project administration; supervision; writing—review and editing. All authors have read and approved the final manuscript.

Conflict of Interest

The authors declare no conflicts of interest.