Co-occurrence of Phelan-McDermid syndrome and metachromatic leukodystrophy

Authors

  • Snehal Mallakmir Apollo Genomics Institutes, Apollo Hospitals, Navi Mumbai, Maharashtra, India
  • Anbukayalvizhi Chandrasekaran Medgenome laboratory Pvt Ltd, Bengaluru, Karnataka, India
  • Kety Phelan Genetics Laboratory Florida Cancer Specialists & Research Institute, 2848 Center Pointe Drive, Fort Myers, USA
  • Rashid Merchant Apollo Genomics Institutes, Apollo Hospitals, Navi Mumbai, Maharashtra, India
  • Shekhar Patil Apollo Hospitals, Navi Mumbai, Maharashtra, India

DOI:

https://doi.org/10.18203/issn.2454-2156.IntJSciRep20250059

Keywords:

Phelan-McDermid syndrome, Metachromatic leukodystrophy, SHANK3, Arylsulfatase A

Abstract

Very few cases have been described so far with co-occurrence of Phelan-McDermid syndrome (PMS) and metachromatic leukodystrophy (MLD). Those patients harbour a chromosome (chr) 22q13deletion encompassing at least the SHANK3 and ARSA genes and a pathogenic variant in the arylsulfatase A (ARSA) gene residing on the other allele. The deletion in chr22q13 results in PMS phenotype and the presence of pathogenic variation on the other intact copy of ARSA gene, leads to MLD phenotype due to biallelic loss of ARSA function. We describe a male infant, born to a third-degree consanguineous couple, who exhibited neuroregression at the age of 8 months, presented with developmental delay, hypotonia which rapidly progressed to feeding difficulties, axial hypotonia, ptosis, sleep disturbance, dystonia, spasticity, and abnormal eye movements. Brain MRI showed T2 hyperintensities consistent with MLD. Biochemical workup showed deficiency of ARSA enzyme activity. Genetic investigations revealed heterozygous deletion of size 2.5 Mb on chr 22q13.3 encompassing the entire ARSA gene and a pathogenic variant in the other copy of ARSA gene. Parents and sibling were tested and informed about the disease management and genetic testing in extended family members to understand the risk and preventive measures. Few case reports have proposed screening for urine sulfatides levels at the time of PMS diagnosis to identify pre-symptomatic or asymptomatic MLD patients to facilitate management and our case supports this proposal.

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References

Phelan K, Boccuto L, Powell CM, Boeckers TM, Ravenswaaij-Arts C, Rogers RC, et al. Phelan-McDermid syndrome: a classification system after 30 years of experience. Orphanet J Rare Dis. 2022;17:27. DOI: https://doi.org/10.1186/s13023-022-02180-5

Cusmano-Ozog K, Manning MA, Hoyme HE. 22q13.3 deletion syndrome: a recognizable malformation syndrome associated with marked speech and language delay. Am J Med Genet C Semin Med Genet. 2007;145(4):393-8. DOI: https://doi.org/10.1002/ajmg.c.30155

Nevado J, García-Miñaúr S, Palomares-Bralo M, Vallespín E, Guillén-Navarro E, Rosell J, et al. Spanish PMS working group. Variability in Phelan-McDermid syndrome in a cohort of 210 individuals. Front Genet. 2022;13:652454. DOI: https://doi.org/10.3389/fgene.2022.652454

Soorya L, Kolevzon A, Zweifach J, Lim T, Dobry Y, Schwartz L, et al. Prospective investigation of autism and genotype-phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency. Mol Autism. 2013;4(1):18. DOI: https://doi.org/10.1186/2040-2392-4-18

Ricciardello A, Tomaiuolo P, Persico AM. Genotype-phenotype correlation in Phelan-McDermid syndrome: A comprehensive review of chromosome 22q13 deleted genes. Am J Med Genet A. 2021;185(7):2211-33. DOI: https://doi.org/10.1002/ajmg.a.62222

Mitz AR, Philyaw TJ, Boccuto L, Shcheglovitov A, Sarasua SM, Kaufmann WE, et al. Identification of 22q13 genes most likely to contribute to Phelan McDermid syndrome. Eur J Hum Genet. 2018;26(3):293-302. DOI: https://doi.org/10.1038/s41431-017-0042-x

Mingbunjerdsuk D, Wong M, Bozarth X, Sun A. Co-occurrence of Metachromatic Leukodystrophy in Phelan-McDermid Syndrome. J Child Neurol. 2021;36(2):148-51. DOI: https://doi.org/10.1177/0883073820960308

Ahn H, Seo GH, Keum C, Heo SH, Kim T, Choi J, et al. Diagnosis of metachromatic leukodystrophy in a patient with regression and Phelan-McDermid syndrome. Brain Dev. 2020;42(5):414-7. DOI: https://doi.org/10.1016/j.braindev.2020.02.003

Coulter-Mackie MB. Rip J, Ludman MD, Beis J, Cole DEC. Metachromatic leukodystrophy (MLD) in a patient with a constitutional ring chromosome 22. J Med Genet. 1995;32:787-91. DOI: https://doi.org/10.1136/jmg.32.10.787

Bisgaard A, Kirchhoff M, Nielsen JE, Kibaek M, Lund A, Schwartz M, Christensen E. Chromosomal deletion umasking a recessive disease: 22q13 deletion syndrome and metachromatic leukodystrophy. Clin Genet. 2009;75(2):175-9. DOI: https://doi.org/10.1111/j.1399-0004.2008.01113.x

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Published

2025-01-24

How to Cite

Mallakmir, S., Chandrasekaran, A., Phelan, K., Merchant, R., & Patil, S. (2025). Co-occurrence of Phelan-McDermid syndrome and metachromatic leukodystrophy. International Journal of Scientific Reports, 11(2), 80–84. https://doi.org/10.18203/issn.2454-2156.IntJSciRep20250059

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Case Series