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Abstract
We report the case of a Puerto Rican girl who presented with multiple seizure types, epileptic spasms and severe global developmental delay. Her examination was significant for myopathic face, profound hypotonia, and areflexia. Her genetic workup revealed a homozygous pathogenic c.376C>T (p.R126X) mutation in the TBCK gene. A second homozygous likely pathogenic c.908G>T (p.G303V) mutation in the HADH gene, responsible for medium/short chain 3 hydroxyacyl-CoA dehydrogenase deficiency (M/SCHAD), was also found. Her seizures responded dramatically to IV methylprednisolone infusions, and she has remained stable without metabolic crisis.
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Copyright (c) 2026 Jorge Vidaurre, Tamara Reynolds, Shubhangi Chitnis
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References
- Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424. https://doi.org/10.1038/gim.2015.30
- Bhoj EJ, Li D, Harr M, Edvardson S, Elpeleg O, Chisholm E, et al. Mutations in TBCK, encoding TBC1-domain-containing kinase, lead to a recognizable syndrome of intellectual disability and hypotonia. Am J Hum Genet. 2016;98(4):782-788. https://doi.org/10.1016/j.ajhg.2016.03.016
- Chong JX, Caputo V, Phelps IG, Stella L, Worgan L, Dempsey JC, et al. Recessive inactivating mutations in TBCK, encoding a Rab GTPase-activating protein, cause severe infantile syndromic encephalopathy. Am J Hum Genet. 2016;98(4):772-781. https://doi.org/10.1016/j.ajhg.2016.01.016
- Ortiz-González XR, Tintos-Hernández JA, Keller K, Li X, Foley AR, Bharucha-Goebel DX, et al. Homozygous boricua TBCK mutation causes neurodegeneration and aberrant autophagy. Ann Neurol. 2018;83(1):153-165. https://doi.org/10.1002/ana.25130
- 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(3):e76. https://doi.org/10.1212/NXG.0000000000000076
- Mandel H, Khayat M, Chervinsky E, Elpeleg O, Shalev S. TBCK-related intellectual disability syndrome: case study of two patients. Am J Med Genet A. 2017;173(2):491-494. https://doi.org/10.1002/ajmg.a.38019
- Tein I, De Vivo DC, Hale DE, Clarke JTR, Zinman H, Laxer R, et al. Short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency in muscle: a new cause for recurrent myoglobinuria and encephalopathy. Ann Neurol. 1991;30(3):415-419. https://doi.org/10.1002/ana.410300315
- Bennett MJ, Spotswood SD, Ross KF, Comfort S, Koonce R, Boriack RL, et al. Fatal hepatic short-chain L-3-hydroxyacyl-coenzyme A dehydrogenase deficiency: clinical, biochemical, and pathological studies on three subjects with this recently identified disorder of mitochondrial beta-oxidation. Pediatr Dev Pathol. 1999;2(4):337-345. https://doi.org/10.1007/s100249900132
- Yang SY, He XY, Schulz H. 3-Hydroxyacyl-CoA dehydrogenase and short chain 3-hydroxyacyl-CoA dehydrogenase in human health and disease. FEBS J. 2005;272(19):4874-4883. https://doi.org/10.1111/j.1742-4658.2005.04911.x
- Lux AL, Edwards SW, Hancock E, Johnson AL, Kennedy CR, Newton RW, et al. The United Kingdom Infantile Spasms Study comparing vigabatrin with prednisolone or tetracosactide at 14 days: a multicentre, randomised controlled trial. Lancet. 2004;364(9447):1773-1778. https://doi.org/10.1016/S0140-6736(04)17400-X
- Lindner M, Gramer G, Haege G, Fang-Hoffmann J, Schwab KO, Tacke U, et al. Efficacy and outcome of expanded newborn screening for metabolic diseases: report of 10 years from South-West Germany. Orphanet J Rare Dis. 2011;6:44. https://doi.org/10.1186/1750-1172-6-44
- Wilcken B, Haas M, Joy P, Wiley V, Chaplin M, Black C, et al. Outcome of neonatal screening for medium-chain acyl-CoA dehydrogenase deficiency in Australia: a cohort study. Lancet. 2007;369(9555):37-42. https://doi.org/10.1016/S0140-6736(07)60029-4
References
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424. https://doi.org/10.1038/gim.2015.30
Bhoj EJ, Li D, Harr M, Edvardson S, Elpeleg O, Chisholm E, et al. Mutations in TBCK, encoding TBC1-domain-containing kinase, lead to a recognizable syndrome of intellectual disability and hypotonia. Am J Hum Genet. 2016;98(4):782-788. https://doi.org/10.1016/j.ajhg.2016.03.016
Chong JX, Caputo V, Phelps IG, Stella L, Worgan L, Dempsey JC, et al. Recessive inactivating mutations in TBCK, encoding a Rab GTPase-activating protein, cause severe infantile syndromic encephalopathy. Am J Hum Genet. 2016;98(4):772-781. https://doi.org/10.1016/j.ajhg.2016.01.016
Ortiz-González XR, Tintos-Hernández JA, Keller K, Li X, Foley AR, Bharucha-Goebel DX, et al. Homozygous boricua TBCK mutation causes neurodegeneration and aberrant autophagy. Ann Neurol. 2018;83(1):153-165. https://doi.org/10.1002/ana.25130
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(3):e76. https://doi.org/10.1212/NXG.0000000000000076
Mandel H, Khayat M, Chervinsky E, Elpeleg O, Shalev S. TBCK-related intellectual disability syndrome: case study of two patients. Am J Med Genet A. 2017;173(2):491-494. https://doi.org/10.1002/ajmg.a.38019
Tein I, De Vivo DC, Hale DE, Clarke JTR, Zinman H, Laxer R, et al. Short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency in muscle: a new cause for recurrent myoglobinuria and encephalopathy. Ann Neurol. 1991;30(3):415-419. https://doi.org/10.1002/ana.410300315
Bennett MJ, Spotswood SD, Ross KF, Comfort S, Koonce R, Boriack RL, et al. Fatal hepatic short-chain L-3-hydroxyacyl-coenzyme A dehydrogenase deficiency: clinical, biochemical, and pathological studies on three subjects with this recently identified disorder of mitochondrial beta-oxidation. Pediatr Dev Pathol. 1999;2(4):337-345. https://doi.org/10.1007/s100249900132
Yang SY, He XY, Schulz H. 3-Hydroxyacyl-CoA dehydrogenase and short chain 3-hydroxyacyl-CoA dehydrogenase in human health and disease. FEBS J. 2005;272(19):4874-4883. https://doi.org/10.1111/j.1742-4658.2005.04911.x
Lux AL, Edwards SW, Hancock E, Johnson AL, Kennedy CR, Newton RW, et al. The United Kingdom Infantile Spasms Study comparing vigabatrin with prednisolone or tetracosactide at 14 days: a multicentre, randomised controlled trial. Lancet. 2004;364(9447):1773-1778. https://doi.org/10.1016/S0140-6736(04)17400-X
Lindner M, Gramer G, Haege G, Fang-Hoffmann J, Schwab KO, Tacke U, et al. Efficacy and outcome of expanded newborn screening for metabolic diseases: report of 10 years from South-West Germany. Orphanet J Rare Dis. 2011;6:44. https://doi.org/10.1186/1750-1172-6-44
Wilcken B, Haas M, Joy P, Wiley V, Chaplin M, Black C, et al. Outcome of neonatal screening for medium-chain acyl-CoA dehydrogenase deficiency in Australia: a cohort study. Lancet. 2007;369(9555):37-42. https://doi.org/10.1016/S0140-6736(07)60029-4