Hypomyelinating leukodystrophy-10 presenting with an additional atypical feature of increased body hair and Mongolian spots

Gayatri Nerakh; Vineeth V. S.; Ashwin Dalala; Shagun Aggarwal

doi:10.18203/2349-3291.ijcp20252610

Authors

Gayatri Nerakh Department of Medical Genetics, Nizam’s Institute of Medical Sciences, Hyderabad, Telangana, India
Vineeth V. S. Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India
Ashwin Dalala Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India
Shagun Aggarwal Department of Medical Genetics, Nizam’s Institute of Medical Sciences, Hyderabad, Telangana, India

DOI:

https://doi.org/10.18203/2349-3291.ijcp20252610

Keywords:

Leukodystrophy, Hypomyelination, Demyelination, Whole exome sequencing

Abstract

Hypomyelinating leukodystrophies (HLDs) are genetically heterogeneous disorders. We present the case of a 3.5-year-old male child with global developmental delay, unsteadiness without seizures, episodes of acute encephalopathy, neuroregression, short stature, and microcephaly accompanied by facial dysmorphism and increased hair growth on the forehead, back, and arms. The female sibling of the proband exhibited similar clinical features, excluding the hypertrichosis, but with additional findings of increased Mongolian spots on the back. MRI of the brain revealed bilateral white matter hyperintensities in the frontal and parietal regions of the cerebral hemispheres. Additional findings in the sibling included a diffusely hypoplastic corpus callosum and prominent lateral ventricles. Whole-exome sequencing identified a likely pathogenic homozygous variant in exon 6 of the PYCR2 gene, which is associated with HLD10. This case presents findings of a rare subtype of HLD and highlights the role of exome sequencing in shortening diagnostic odyssey of previously undiagnosed childhood HLDs, including those with atypical clinical presentations.

Metrics

Metrics Loading ...

References

Pouwels PJ, Vanderver A, Bernard G, Wolf NI, Dreha-Kulczewksi SF, Deoni SCL, et al. Hypomyelinating leukodystrophies: translational research progress and prospects. Ann Neurol. 2014;76(1):5-19. DOI: https://doi.org/10.1002/ana.24194

Numata Y, Gotoh L, Iwaki A, Kurosawa K, Takanashi J, Deguchi K, et al. Epidemiological, clinical, and genetic landscapes of hypomyelinating leukodystrophies. J Neurol. 2014;261(4):752-8. DOI: https://doi.org/10.1007/s00415-014-7263-5

Schiffmann R, van der Knaap MS. Invited article: An MRI-based approach to the diagnosis of white matter disorders. Neurology. 2009;72(8):750-9. DOI: https://doi.org/10.1212/01.wnl.0000343049.00540.c8

Kevelam SH, Steenweg ME, Srivastava S, Helman G, Naidu S, Schiffmann R, et al. Update on leukodystrophies: a historical perspective and adapted definition. Neuropediatrics. 2016;47(6):349-54. DOI: https://doi.org/10.1055/s-0036-1588020

Vanderver A, Prust M, Tonduti D, Mochel F, Hussey HM, Helman G, et al. Case Definition and Classification of Leukodystrophies and Leukoencephalopathies. Mol Genet Metab. 2015;114(4):494-500. DOI: https://doi.org/10.1016/j.ymgme.2015.01.006

Van der Knaap MS, Bugiani M. Leukodystrophies: a proposed classification system based on pathological changes and pathogenetic mechanisms. Acta Neuropathol. 2017;134(3):351-82. DOI: https://doi.org/10.1007/s00401-017-1739-1

Barkovich AJ, Deon S. Reprint of Hypomyelinating disorders: An MRI approach. Neurobiol Dis. 2016;92(A):46-54. DOI: https://doi.org/10.1016/j.nbd.2015.10.022

Arai-Ichinoi N, Uematsu M, Sato R, Suzuki T, Kudo H, Kikuchi A, et al. Genetic heterogeneity in 26 infants with a hypomyelinating leukodystrophy. Hum Genet. 2016;135(1):89-98. DOI: https://doi.org/10.1007/s00439-015-1617-7

Perez-Arellano I, Carmona-Alvarez F, Martinez AI, Rodríguez-Díaz J, Cervera J, et al. Pyrroline5-carboxylate synthase and proline biosynthesis: from osmotolerance to rare metabolic disease. Protein Sci. 2010;19(3):372-82. DOI: https://doi.org/10.1002/pro.340

Rakotomamonjy J, Rylaarsdam L, Guemez-Gamboa A. PYRC2-Related Hypomyelinating Leukodystrophy: More to This Than Meets the Eye. Neuron. 2020;107(1):3-5. DOI: https://doi.org/10.1016/j.neuron.2020.06.007

Torii T, Shirai R, Kiminami R, Nishino S, Sato T, Sawaguchi S, et al. Hypomyelinating Leukodystrophy 10 (HLD10)-Associated Mutations of PYCR2 Form Large Size Mitochondria, Inhibiting Oligodendroglial Cell Morphological Differentiation. Neurol Int. 2022;14(4):1062-80. DOI: https://doi.org/10.3390/neurolint14040085

Simons C, Wolf NI, McNeil N, Caldovic L, Devaney JM, Takanohashi A, et al. A de novo mutation in the b-tubulin gene TUBB4A results in the leukoencephalopathy hypomyelination with atrophy of the basal ganglia and cerebellum. Am J Hum Genet. 2013;92(5):767-73. DOI: https://doi.org/10.1016/j.ajhg.2013.03.018

De Koning TJ, Jaeken J, Pineda M, Van Maldergem L, Poll-The BT, van der Knaap MS. Hypomyelination and reversible white matter attenuation in 3-phosphoglycerate dehydrogenase deficiency. Neuropediatrics. 2000;31(6):287-92. DOI: https://doi.org/10.1055/s-2000-12944

Nakayama T, Al-Maawali A, El-Quessny M, Rajab A, Khalil S, Stoler JM, et al. Mutations in PYCR2, Encoding Pyrroline-5-Carboxylate Reductase 2, Cause Microcephaly and Hypomyelination. Am J Hum Genet. 2015;96(5):709-19. DOI: https://doi.org/10.1016/j.ajhg.2015.03.003

Akbari M, Ebrahimi Tapeh Z, Zaersabet M, Rahimi H, Ganji M. Novel pyrroline-5-carboxylate reductase 2 (PYCR2) mutation in an Iranian patient with hypomyelinating leukodystrophy: findings of molecular and in silico investigations. Egypt J Med Hum Genet. 2023;24:12. DOI: https://doi.org/10.1186/s43042-023-00393-2

Hosseini SA, Ghelichi-Ghojogh M. Mutation in PYCR2 gene and hypomyelinating leukodystrophy in children: a case report study. Ann Med Surg (Lond). 2023;85(5):2177-9. DOI: https://doi.org/10.1097/MS9.0000000000000684

Afroze B, Mercimek-Andrews S. Pyrroline-5-Carboxylate Reductase 2 Deficiency: A New Case and Review of the Literature. Can J Neurol Sci. 2020;47(2):280-2. DOI: https://doi.org/10.1017/cjn.2020.5

Zaki MS, Bhat G, Sultan T, Issa M, Jung HJ, Dikoglu E, et al. PYCR2 Mutations cause a lethal syndrome of microcephaly and failure to thrive. Ann Neurol. 2016;80(1):59-70. DOI: https://doi.org/10.1002/ana.24678

Escande-Beillard N, Loh A, Saleem SN, Hiroshi H, Hidetaka S, Bruno R. Loss of PYCR2 Causes Neurodegeneration by Increasing Cerebral Glycine Levels via SHMT2. Neuron. 2020;107(1):82-94.e6. DOI: https://doi.org/10.1016/j.neuron.2020.03.028

Dreha-Kulaczewski SF, Brockmann K, Henneke M, Dechent P, Wilken B, Gärtner J, Helms G. Assessment of myelination in hypomyelinating disorders by quantitative MRI. J Magn Reson Imaging. 2012;36(6):1329-38. DOI: https://doi.org/10.1002/jmri.23774