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• Evidence for a mitochondrial disease phenotype due to APOO deletion.
  Kumarie Latchman, Antonio Barrientos
  Published on: 31 May 2021

• Published on: 31 May 2021

  Evidence for a mitochondrial disease phenotype due to APOO deletion.

  • Kumarie Latchman, Assistant Clinical Professor, Clinical Geneticist University of Miami Miller School of Medicine
  • Other Contributors:
    • Antonio Barrientos, Professor, Department of Neurology and Biochemistry

  Evidence for a mitochondrial disease phenotype due to APOO deletion.
  Kumarie Latchman1*, Antoni Barrientos 2*

  1. Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, United States
  2. Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, United States.
  *Corresponding authors

  The APOO (Apolipoprotein O) gene codes for MIC26, a subunit of the MICOS complex (mitochondrial contact site and cristae organizing system). APOO was recently reported as a novel mitochondrial disease locus upon identification of a loss-of-function missense variant, c. 350T>C , (p.I117T in MIC26 ) in a hemizygous male proband with mitochondrial myopathy, lactic acidosis, cognitive impairment, and autistic features. 1
  Here, we present a six-year-old African American male with a history of epilepsy, developmental delay, hypotonia, coordination and balance difficulties, cognitive impairment, autism disorder, and microcytic anemia. Birth history was unremarkable, and he walked at 24 months despite coordination and balance deficits. His vocabulary is less than ten words at six years old, and he does not recognize body parts, letters, or numbers. Laboratory findings include normal lactic acid, 1.8 (0.4-1.8 mmol/L), and creatine kinase 126 U/L (<160 U/L). Brain magnetic resonance image was unremarkable. Family history is positive for schizophrenia and intellectual disability in his mother and psychi...

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  Evidence for a mitochondrial disease phenotype due to APOO deletion.
  Kumarie Latchman1*, Antoni Barrientos 2*

  1. Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, United States
  2. Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, United States.
  *Corresponding authors

  The APOO (Apolipoprotein O) gene codes for MIC26, a subunit of the MICOS complex (mitochondrial contact site and cristae organizing system). APOO was recently reported as a novel mitochondrial disease locus upon identification of a loss-of-function missense variant, c. 350T>C , (p.I117T in MIC26 ) in a hemizygous male proband with mitochondrial myopathy, lactic acidosis, cognitive impairment, and autistic features. 1
  Here, we present a six-year-old African American male with a history of epilepsy, developmental delay, hypotonia, coordination and balance difficulties, cognitive impairment, autism disorder, and microcytic anemia. Birth history was unremarkable, and he walked at 24 months despite coordination and balance deficits. His vocabulary is less than ten words at six years old, and he does not recognize body parts, letters, or numbers. Laboratory findings include normal lactic acid, 1.8 (0.4-1.8 mmol/L), and creatine kinase 126 U/L (<160 U/L). Brain magnetic resonance image was unremarkable. Family history is positive for schizophrenia and intellectual disability in his mother and psychiatric and seizure disorders in two previous maternal generations.
  Whole-exome sequencing with copy number variant analysis revealed a ~275kb-deletion on Xp22.11, arr [GRCh37] Xp22.11(23731277_24006696)x0, which includes five annotated genes: exon 4 of KLHL15, ACOT9 (no associated conditions), and, in agreement with DNA microarray analysis, the entire genes APOO, SAT1 (associated with keratosis follicularis spinulosa decalvans), and CXorf58 (no associated conditions).
  The phenotype of this patient is consistent with a mitochondrial disease due to a complete APOO gene deletion. Like the previously reported APOO case 1, our patient presented with muscle weakness -hypotonia and poor coordination-, cognitive impairment, and an autism spectrum disorder. Differently, our patient presents with epilepsy, which could result from the KLHL15 exon 4 deletion. 2-3 Functional studies are needed to determine how the absence of MIC26 impacts the MICOS complex integrity and function and overall mitochondrial physiology.

  Acknowlegements
  We thank the family for allowing us to report this case.
  Research in the Barrientos laboratory is supported by National Institutes of Health grant R35-GM118141
  Correspondence: Kumarie Latchman, kxl604@med.miami.edu, and Antoni Barrientos, ABarrientos@med.miami.edu

  Conflict of interest: None declared.

  REFERENCES
  1. Benincá C, Zanette V, Brischigliaro M, Johnson M, Reyes A, Valle DAD, J Robinson A, Degiorgi A, Yeates A, Telles BA, Prudent J, Baruffini E, S F Santos ML, R de Souza RL, Fernandez-Vizarra E, J Whitworth A, Zeviani M. Mutation in the MICOS subunit gene APOO (MIC26) associated with an X-linked recessive mitochondrial myopathy, lactic acidosis, cognitive impairment and autistic features. J Med Genet 2021; 58:155-167.

  2. Hu H, Haas SA, Chelly J, Van Esch H, Raynaud M, de Brouwer AP, Weinert S, Froyen G, Frints SG, Laumonnier F, Zemojtel T, Love MI, Richard H, Emde AK, Bienek M, Jensen C, Hambrock M, Fischer U, Langnick C, Feldkamp M, Wissink-Lindhout W, Lebrun N, Castelnau L, Rucci J, Montjean R, Dorseuil O, Billuart P, Stuhlmann T, Shaw M, Corbett MA, Gardner A, Willis-Owen S, Tan C, Friend KL, Belet S, van Roozendaal KE, Jimenez-Pocquet M, Moizard MP, Ronce N, Sun R, O'Keeffe S, Chenna R, van Bömmel A, Göke J, Hackett A, Field M, Christie L, Boyle J, Haan E, Nelson J, Turner G, Baynam G, Gillessen-Kaesbach G, Müller U, Steinberger D, Budny B, Badura-Stronka M, Latos-Bieleńska A, Ousager LB, Wieacker P, Rodríguez Criado G, Bondeson ML, Annerén G, Dufke A, Cohen M, Van Maldergem L, Vincent-Delorme C, Echenne B, Simon-Bouy B, Kleefstra T, Willemsen M, Fryns JP, Devriendt K, Ullmann R, Vingron M, Wrogemann K, Wienker TF, Tzschach A, van Bokhoven H, Gecz J, Jentsch TJ, Chen W, Ropers HH, Kalscheuer VM. X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes. Mol Psychiatry 2016; 21:133-48.

  3. Mignon-Ravix C, Cacciagli P, Choucair N, Popovici C, Missirian C, Milh M, Mégarbané A, Busa T, Julia S, Girard N, Badens C, Sigaudy S, Philip N, Villard L. Intragenic rearrangements in X-linked intellectual deficiency: results of a-CGH in a series of 54 patients and identification of TRPC5 and KLHL15 as potential XLID genes. Am J Med Genet A 2014; 164A:1991-7.

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  Conflict of Interest:
  None declared.

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