PMM2-CDG T237M Mutation in a Patient with Cerebral Palsy-Like Phenotypes Reported from South India

Abstract

Congenital disorder of glycosylation (CDG) is an autosomal recessively inherited disorder. Hypotonia, stroke-like episodes, and peripheral neuropathy are also associated with the condition that typically develops during infancy. The patient, a 12-year-old girl born to healthy consanguineous parents, was diagnosed with cerebral palsy as a child. The affected patient has hypotonia, inadequate speech, strabismus, and developmental delay with mild mental retardation, which are key symptoms of CDG. Whole-exome sequencing (WES) identified the known missense pathogenic variant PMM2 c.710 C > T, p.T237M in the patient coding for the phosphomannomutase 2 (PMM2) confirming molecular testing of CDG. The patient's parents carried heterozygous PMM2 c.710 C > T variants. This study highlights the importance of WES in patients with a developmental disability or other neurological conditions, which is also useful in screening risk factors in couples with infertility or miscarriage issues.

Keywords

PMM2-CDG - cerebral palsy - mutation - South India

Ethical Approval

The study was approved by the Ethics Committee of All India Institute of Speech and Hearing, Mysore, India.

Authors' Contributions

N Sreedevi was involved in conceptualization, supervision, and project administration. Swapna N contributed to conceptualization. Santosh Maruthy was involved in supervision and project administration. Meghavathi HS helped in molecular biology and original draft preparation. Charles Sylvester was involved in methodology and database analysis.

Publikationsverlauf

Artikel online veröffentlicht:
01. Juni 2023

• References

• 1 Matthijs G, Schollen E, Bjursell C. et al. Mutations in PMM2 that cause congenital disorders of glycosylation, type Ia (CDG-Ia). Hum Mutat 2000; 16 (05) 386-394
• 2 Barone R, Carrozzi M, Parini R. et al. A nationwide survey of PMM2-CDG in Italy: high frequency of a mild neurological variant associated with the L32R mutation. J Neurol 2015; 262 (01) 154-164
• 3 Ganetzky R, Reynoso FJ, He M. Congenital disorders of glycosylation. In: Uttam Garg, Laurie D. Smith, Eds. Clinical Aspects and Laboratory Determination. 2017. Chapter 15; pp. 343-360
• 4 Monin ML, Mignot C, De Lonlay P. et al. 29 French adult patients with PMM2-congenital disorder of glycosylation: outcome of the classical pediatric phenotype and depiction of a late-onset phenotype. Orphanet J Rare Dis 2014; 9 (01) 207
• 5 Lebredonchel E, Riquet A, Neut D. et al. A PMM2-CDG caused by an A108V mutation associated with a heterozygous 70 kilobases deletion case report. Ital J Pediatr 2022; 48 (01) 178
• 6 Goreta SS, Dabelic S, Dumic J. Insights into complexity of congenital disorders of glycosylation. Biochem Med (Zagreb) 2012; 22 (02) 156-170
• 7 Chang IJ, He M, Lam CT. Congenital disorders of glycosylation. Ann Transl Med 2018; 6 (24) 477
• 8 Sparks SE, Krasnewich DM. Congenital disorders of N-linked glycosylation and multiple pathway overview. GeneReviews®[Internet] 2017
• 9 Altassan R, Péanne R, Jaeken J. et al. International clinical guidelines for the management of phosphomannomutase 2-congenital disorders of glycosylation: diagnosis, treatment and follow up. J Inherit Metab Dis 2019; 42 (01) 5-28
• 10 Park MJ, Yoo YJ, Chung CY, Hwang JM. Ocular findings in patients with spastic type cerebral palsy. BMC Ophthalmol 2016; 16 (01) 195
• 11 Pennefather PM, Tin W. Ocular abnormalities associated with cerebral palsy after preterm birth. Eye (Lond) 2000; 14 (Pt 1): 78-81
• 12 Yurdakul NS, Ugurlu S, Maden A. Strabismus in Down syndrome. J Pediatr Ophthalmol Strabismus 2006; 43 (01) 27-30
• 13 Jeon H, Jung J, Kim H, Yeom JA, Choi H. Strabismus in children with white matter damage of immaturity: MRI correlation. Br J Ophthalmol 2017; 101 (04) 467-471
• 14 Schiff M, Roda C, Monin ML. et al. Clinical, laboratory and molecular findings and long-term follow-up data in 96 French patients with PMM2-CDG (phosphomannomutase 2-congenital disorder of glycosylation) and review of the literature. J Med Genet 2017; 54 (12) 843-851
• 15 Citro V, Cimmaruta C, Monticelli M. et al. The analysis of variants in the general population reveals that PMM2 is extremely tolerant to missense mutations and that diagnosis of PMM2-CDG can benefit from the identification of modifiers. Int J Mol Sci 2018; 19 (08) 2218
• 16 Morgese MG, Trabace L. Maternal malnutrition in the etiopathogenesis of psychiatric diseases: role of polyunsaturated fatty acids. Brain Sci 2016; 6 (03) 24
• 17 Sully EA, Biddlecom A, Darroch JE. et al. Adding It Up: Investing in Sexual and Reproductive Health 2019. 2020. New York: Guttmacher Institute; Accessed May 2, 2023 at: https://www.guttmacher.org/report/adding-it-up-investing-in-sexual-reproductive-health-2019
• 18 Rademaker D, Hukkelhoven CWPM, van Pampus MG. Adverse maternal and perinatal pregnancy outcomes related to very advanced maternal age in primigravida and multigravida in the Netherlands: a population-based cohort. Acta Obstet Gynecol Scand 2021; 100 (05) 941-948
• 19 Weinhold B. Environmental factors in birth defects: what we need to know. Environ Health Perspect 2009; 117 (10) A440-A447
• 20 Heinke D, Nestoridi E, Hernandez-Diaz S. et al; National Birth Defects Prevention Study. Risk of stillbirth for fetuses with specific birth defects. Obstet Gynecol 2020; 135 (01) 133-140
• 21 González-Domínguez CA, Raya-Trigueros A, Manrique-Hernández S. et al. Identification through exome sequencing of the first PMM2-CDG individual of Mexican mestizo origin. Mol Genet Metab Rep 2020; 25: 100637