TBCK Syndrome



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The information below is intended for families and caregivers of patients with mutations in the TBC1 DOMAIN-CONTAINING KINASE (TBCK) gene, including clinical data, molecular data, management and research options.

Dr. Xilma Ortiz-Gonzalez and Dr. Elizabeth Bhoj are amongst the co-discoverers of the syndrome and have been collaborating with the common goal of advancing the understanding and ultimately treatment for TBCK syndrome.

Research at CHOP

Currently we are enrolling patients to learn more about natural history and phenotypic variability. If fibroblasts samples are available, we would be very interested in receiving those as we have on-going human studies using human fibroblasts and iPSC cells. We are also developing various animal models with goal of therapeutic screen. We still do not have enough data to recommend a leucine treatment dose but are actively working in testing it in cell and animal models. Goals are to learn more about why mutations in TBCK lead to these phenotypes, and to perform targeted drug discovery for this progressive disease. Contact us at [email protected] if you have a patient that you would like to refer to our studies.

For Clinicians

TBCK-related encephalopathy (also called Hypotonia, infantile, with psychomotor retardation and characteristic facies 3 in OMIM), is a rare neurogenetic disorder. It is an autosomal recessive disease characterized by hypotonia, developmental delay and intellectual disability. Many patients also have evidence of  neurodegeneration, progressive neuromuscular weakness, seizures and progressive coarse facial features reminiscent of lysosomal storage disorders.

There are about 30 reported cases worldwide. There is a founder variant in the Caribbean region (“Boricua mutation” p.R126X) that is associated with severe disease, also known as TBCK-encephaloneuronopathy due to its significant neuromuscular involvement.

The severity of the neurologic symptoms varies and there are some patients reported with chronic static encephalopathy without evidence of progression to date.


Most patients have been diagnosed by Whole Exome Sequencing. Nevertheless, as more patients have been reported, a distinguishable clinical syndrome has emerged.

All reported patients have biallelic variants in TBCK, some patients do have small exon-level deletions that may be missed by Sanger sequencing and exome sequencing. Therefore if there is a high level of suspicion, both sequencing and deletion/duplication analysis should be performed.

Neurophysiological studies show axonal motor neuropaty/neuronopathy in severely affected patients. On a research level we have found urine oligosaccharide abnormalities (Ortiz-Gonzalez, et al 2018).

Common Clinical Symptoms

  • Coarse facies
  • Congenital Hypotonia
  • Global developmental delay, ranging from moderate to profound
  • Dysphagia
  • Respiratory insufficiency
  • Epilepsy
  • MRI features include white matter changes, cerebellar atrophy, thin corpus callosum
  • Absent/severely delayed expressive language
  • Hyporeflexia/areflexia

Less common but especially in severely affected/older patients

  • Hypothyroidism
  • Osteopenia
  • Hypercholesterolemia
  • Frequent UTIs/nephrolithiasis


All patients with TBCK-related encephalopathy should be evaluated for developmental delays and started on appropriate therapies.  There should also be a careful evaluation for feeding difficulties, seizures, and respiratory insufficiency. Seizures should be treated symptomatically, with no specific antiepileptic currently recommended currently, although many patients respond well initially to levetiracetam. Many patients present initially with provoked seizures (in setting of fever or illness) and then progress to symptomatic epilepsy.

Teenage patients with the Boricua mutation have been found to have mtDNA depletion, therefore caution is advised with valproate. Also anecdotally, some patients with the Boricua mutation had reported complications with ketogenic diet and bisphosphonate infusion. Therefore, until more data is available, caution is advised