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Barakat-Perenthaler syndrome

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Barakat-Perenthaler syndrome is a rare neurodevelopmental genetic disorder, presenting with a severe epileptic encephalopathy, developmental delay, Intellectual disability, progressive microcephaly and visual disturbance. It is listed by the standard reference, Online Mendelian Inheritance in Man (OMIM) as #618744.[1] and classified as EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 83; EIEE83. It was first described in 2019 by Dr. Stefan Barakat and his team at the Erasmus University Medical Center in Rotterdam in the journal Acta Neuropathologica;[2] the most recent reviews were published in Epilepsy Currents.[3] and Trends in Endocrinology and Metabolism[4]

Presentation

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Barakat-Perenthaler syndrome OMIM 618744 has so far been identified in more than 40 individuals, of which 22 individuals from 15 families were published.,[1] According to OMIM's review of all published cases[1] and the initial study from Perenthaler et al,[2] all children presented in early life with severe and intractable epileptic seizures. Severe developmental delay was found in all individuals, with basically absence of all developmental milestones.[1][2] Children were unable to roll over or sit, did not develop speech, had absent visual tracking and most cases required gastro-intestinal tube feeding due to severe orofacial hypotonia.[1][2] Other neurological features included infantile epileptic spasms, axial hypotonia, peripheral spasticity and/or hyperreflexia, and a few cases showed dystonia.[1][2] Head circumference decreased progressively over time.[1][2] MRI brain imaging did not detect major structural brain abnormalities, but showed progressive brain atrophy over time.[1][2] Mild dysmorphic features were noted amongst several individuals, including a sloping forehead, suture ridging, bitemporal narrowing, high hairline, arched eyebrows, pronounced philtrum, and a relatively small mouth and large ears.[2] Most children died early in life[1][2]

Genetics and disease mechanism

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Barakat-Perenthaler syndrome[1] is an autosomal recessive disorder and is caused by a recurrent homozygous mutation[5] of the UDP-glucose pyrophosphorylase (UGP2) gene.[6][7] UGP2 encodes an essential protein in nucleotide sugar metabolism, which catabolizes the conversion of glucose-1-phosphate to UDP-glucose.[8][9] In humans, two functionally equivalent protein isoforms are encoded by the UGP2 gene, a longer one (isoform 1)[10] and a slightly shorter one (isoform 2),[11] that only differ by 11 amino acids at the N-terminal.[12] The recurrent mutation (chr2:64083454A>G)[13] identified in all patients with the syndrome affects the start codon of the shorter protein isoform.[1][2] Hence, the shorter isoform can no longer be produced in affected individuals.[2] It was shown by Barakat and colleagues that the shorter UGP2 isoform is predominantly expressed in human brain.[2] Therefore, the recurrent mutation leads to a brain-specific depletion of the essential UGP2 protein, resulting in altered glycogen metabolism, upregulated unfolded protein response and premature neuronal differentiation which likely cause the disease symptoms.[2]

A complete loss of UGP2 isoform 1 and isoform 2 in human embryonic stem cells prevented the formation of functional heart and blood cells in in vitro differentiation experiments. Hence it is likely that bi-allelic loss-of-function of all UGP2 isoforms is incompatible with life in humans; in agreement with this, no bi-allelic loss-of-function variants affecting both protein isoforms are reported in the gnomAD database.[14] The syndrome is therefore an example of a disease caused by the loss of expression of a tissue relevant isoform of an essential gene.[2] Recently, bi-allelic loss of UDP-Glucose 6-Dehydrogenase (UGDH), another gene implicated in nucleotide sugar metabolism,[15] was also shown to cause a similar severe epileptic encephalopathy syndrome, referred to by OMIM as Jamuar syndrome (OMIM #618792),[16][17] showing that nucleotide sugar metabolism can be more broadly implicated in epilepsy.

Origin of the founder mutation

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Barakat and colleagues showed that all identified affected individuals harboring the recurrent mutation shared the same haplotype, suggesting a founder effect and a common ancestor.[2] The mutation was estimated to have originated 26 generations (approximately 600 years) ago.[2] Most cases of Barakat-Perenthaler syndrome could be linked to the Balochistan region (consisting of parts of Iran, Pakistan, India). Since Dutch traders were active in that region in the 17th century,[18] this could be an explanation for the introduction of the founder mutation into the Dutch population, from which the first case was described[2]

Treatment

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So far, no treatment is available for Barakat-Perenthaler syndrome.[19]

References

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  1. ^ a b c d e f g h i j k "OMIM Entry - # 618744 - EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 83; EIEE83". omim.org.
  2. ^ a b c d e f g h i j k l m n o p q Perenthaler, E., Nikoncuk, A., Yousefi, S. et al. Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases. Acta Neuropathol 139, 415–442 (2020). https://doi.org/10.1007/s00401-019-02109-6
  3. ^ Happ, H. C., & Carvill, G. L. (2020). A 2020 View on the Genetics of Developmental and Epileptic Encephalopathies. Epilepsy Currents. https://doi.org/10.1177/1535759720906118
  4. ^ Conroy, L.R., Hawkinson, T.R., Lyndsay, Young, E.A., Gentry, M.S., Sun, R.(2021) Emerging roles of N-linked glycosylation in brain physiology and disorders. Trends in Endocrinology and Metabolism. https://doi.org/10.1016/j.tem.2021.09.006
  5. ^ "Unique variants in gene UGP2 - Global Variome shared LOVD". databases.lovd.nl.
  6. ^ "UGP2 UDP-glucose pyrophosphorylase 2 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov.
  7. ^ "OMIM Entry - * 191760 - URIDYL DIPHOSPHATE GLUCOSE PYROPHOSPHORYLASE 2; UGP2". omim.org.
  8. ^ Flores-Diaz M, Alape-Giron A, Persson B, Pollesello P, Moos M, von Eichel-Streiber C et al (1997) Cellular UDP-glucose deficiency caused by a single point mutation in the UDP-glucose pyrophosphorylase gene. J Biol Chem 272:23784–23791; DOI: 10.1074/jbc.272.38.23784. https://www.jbc.org/content/272/38/23784
  9. ^ Turnquist RL, Gillett TA, Hansen RG (1974) Uridine diphosphate glucose pyrophosphorylase. Crystallization and properties of the enzyme from rabbit liver and species comparisons. J Biol Chem 249:7695–7700; https://www.jbc.org/content/249/23/7695.long
  10. ^ "UTP--glucose-1-phosphate uridylyltransferase isoform a [Homo sapiens] - Protein - NCBI". www.ncbi.nlm.nih.gov.
  11. ^ "UTP--glucose-1-phosphate uridylyltransferase isoform b [Homo sapiens] - Protein - NCBI". www.ncbi.nlm.nih.gov.
  12. ^ Fuhring J, Damerow S, Fedorov R, Schneider J, Munster-Kuhnel AK, Gerardy-Schahn R (2013) Octamerization is essential for enzymatic function of human UDP-glucose pyrophosphorylase. Glycobiology 23:426–437; https://doi.org/10.1093/glycob/cws217
  13. ^ "VCV000805980.2 - ClinVar - NCBI". www.ncbi.nlm.nih.gov.
  14. ^ "gnomAD". gnomad.broadinstitute.org.
  15. ^ "UGDH UDP-glucose 6-dehydrogenase [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov.
  16. ^ Hengel, H., Bosso-Lefèvre, C., Grady, G. et al. Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy. Nat Commun 11, 595 (2020). https://doi.org/10.1038/s41467-020-14360-7
  17. ^ "OMIM Entry - # 618792 - EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 84; EIEE84". omim.org.
  18. ^ (2010) Baluchistan i. Geography, history and ethnography. Encyclopædia Iranica City, pp fasc. 6, pp 598–632, available online http://www.iranicaonline.org/articles/baluchistan-i
  19. ^ Durrant, Christelle; Fuehring, Jana I.; Willemetz, Alexandra; Chrétien, Dominique; Sala, Giusy; Ghidoni, Riccardo; Katz, Abram; Rötig, Agnès; Thelestam, Monica; Ermonval, Myriam; Moore, Stuart E. H. (March 16, 2020). "Defects in Galactose Metabolism and Glycoconjugate Biosynthesis in a UDP-Glucose Pyrophosphorylase-Deficient Cell Line Are Reversed by Adding Galactose to the Growth Medium". International Journal of Molecular Sciences. 21 (6): 2028. doi:10.3390/ijms21062028. PMC 7139386. PMID 32188137.
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