Dört Aileden Pelizaeus-Merzbacher Sendromlu Altı Hastanın Klinik ve Moleküler Sitogenetik Analizleri

Yıl 2023, Cilt: 17 Sayı: 6, 445 - 450, 27.11.2023

Nejmiye Akkuş , Pelin Özyavuz Çubuk

https://doi.org/10.12956/tchd.1275274

Öz

Amaç: Pelizaeus-Merzbacher Hastalığı, Xq22 kromozomu üzerindeki proteolipid protein (PLP) genindeki bir mutasyonun neden olduğu X’e bağlı resesif nadir görülen bir lökodistrofidir. PMD, nistagmus, spastik kuadripleji, ataksi ve gelişimsel gecikme ile karakterize erken başlangıçlı bir nörolojik bozukluktur. Genetik analiz, Pelizaeus-Merzbacher Hastalığında PLP genlerinin kodlama bölgesinde Xq22 mikroduplikasyonlarını (%60-70), nokta mutasyonlarını (%10-25) ve delesyonları (%5-10) tanımlamıştır. Bu çalışma, dört Türk ailede PLP1 delesyonu ve duplikasyonu olan altı hastayı değerlendirdi.

Gereç ve Yöntemler: PLP1’in duplikasyonu ve delesyonunu saptamak için kromozomal mikroarray analizi ve multipleks ligasyona bağlı prob amplifikasyon deneyleri yapıldı.

Bulgular: Bu dört ailede, iki erkek kardeşte PLP1 geninde hemizigot delesyonu, taşıyıcı annelerinde PLP1 geninde delesyon ve akraba olmayan diğer iki erkek ve bir kızda PLP1 duplikasyonu vardı. Ayrıca, PLP1 geninde hemizigot delesyona sahip olduğu tespit edilen iki erkek kardeş hastanın nadir vakasını belirledik. Taşıyıcı annelerinde açıklanamayan bunama vardı.

Sonuç: Bu çalışmada, dört farklı aileden altı bireyin genetik etiyolojisi aydınlatılmaya çalışılırken, bu ailelerdeki PLP1 mutasyonunun genotip-fenotip korelasyonları belirlendi.

Anahtar Kelimeler

Pelizaeus-Merzbacher Hastalığı, PLP1 Geni, Dismiyelinizan Hastalıklar

The Clinical and Molecular Cytogenetic Analyses of Six Patients with Pelizaeus-Merzbacher Disease From Four Families

Öz

Objective: Pelizaeus-Merzbacher Disease is a rare X-linked recessive leukodystrophy caused by a mutation in the proteolipid protein (PLP) gene on chromosome Xq22. PMD is an early-onset neurological disorder characterized by nystagmus, spastic quadriplegia, ataxia, and developmental delay. Genetic analysis has identified Xq22 microduplications (60-70%), point mutations (10–25%), and deletions (5-10%) within the coding region of the PLP genes in Pelizaeus-Merzbacher Disease. This study evaluated six patients with PLP1 deletion and duplication in four Turkish families.

Material and Methods: To detect the duplication and deletion of PLP1, chromosomal microarray analysis, and multiplex ligation-related probe amplification assays were performed.

Results: In these four families, two brothers had a hemizygous deletion in the PLP1 gene, their carrier mother had a deletion in the PLP1 gene, and another two unrelated boys and one girl had duplication of the PLP1. Also, we identified the rare case of two brother patients who were found to have a hemizygous deletion in the PLP1 gene. Their carrier mother had unexplained dementia.

Conclusion: Genotype-phenotype correlations of the PLP1 mutation in these families were identified in this study while trying to elucidate the genetic etiology of six individuals from four different families.

Anahtar Kelimeler

Pelizaeus-Merzbacher Disease, PLP1 Gene, Dysmyelinating Disorders

Kaynakça

• Cailloux F, Gauthier – Barichard F, Mimault C, Isabella V, Courtois V, Dastugue B, et al. Genotype-phenotype correlation in inherited brain myelination defects due to proteolipid protein gene mutations. Clinical European Network on Brain Demyelinating Disease. Eur J Hum Genet 2000;8:837–45.
• Merzbacher L. Eine eigenartige familia¨re-heredita¨re Erkrankungsform (Aplasia axialis extracorticalis congenita). Z Ges Neurol Psychiatr 1910;3:1-138.
• Lu Y, Shimojima K , Sakuma T, Nakaoka S,Yamamoto T. A novel PLP1 mutation F240L identified in a patient with connatal type Pelizaeus-Merzbacher disease. Hum Genome Var 2017;4:16044
• Inou K. Pelizaeus-Merzbacher Disease: Molecular and Cellular Pathologies and Associated Phenotypes Adv Exp Med Biol 2019;1190:201-16.
• Mierzewska H, Jamroz E, Mazurczk T, Hoffman-Zacharska D, Szczepanik E. Pelizaeus-Merzbacher disease in patients with molecularly confirmed diagnosis Folia Neuropathol 2016;54:59-65.
• Velasco Parra HM, Maradei Anaya SJ, Acosta Guio JC, Arteaga Diaz CE, Prieto Rivera JC. Clinical and mutational spectrum of Colombian patients with Pelizaeus Merzbacher Disease. Colomb Med 2018;49:182-7.
• Hobson GM, Garbern JY. Pelizaeus–Merzbacher disease, Pelizaeus–Merzbacher-like disease 1, and related hypomyelinating disorders. Semin Neurol 2012;32:062–7.
• Hobson GM, Kamholz J. PLP1-related disorders, in Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, et al (eds): GeneReviews [Internet]. Seattle(WA): University of Washington 2019.
• Kuan CC, Sano M, Kaga K, Kodama M, Kodama K. Hearing profile and MRI myelination of auditory pathway in Pelizaeus– Merzbacher disease. Acta Otolaryngol 2008;128:539–46.
• Koeppen AH, Robitaille Y. Pelizaeus-Merzbacher disease. J Neuropathol Exp Neurol 2002;61:747–59.
• Inoue K, Tanaka H, Scaglia F, Araki A, Shaffer LG, Lupski JR. Compensating for central nervous system dysmyelination: females with a proteolipid protein gene duplication and sustained clinical improvement. Ann Neurol 2001;50:747–54.
• Sarret C, Lemaire JJ, Tonduti D, Sontheimer A, Coste J, Pereira B, et al. Time-course of myelination and atrophy on cerebral imaging in 35 patients with PLP1-related disorders. Dev Med Child Neurol 2016;58:706-13.
• Henneke M, Gegner S, Hahn A, Plecko-Startinig B, Weschke B, Gartner J, et al. Clinical neurophysiology in GJA12-related hypomyelination vs Pelizaeus-Merzbacher disease. Neurology 2010;74:1785–9.
• Shiihara T, Watanabe M, Moriyama K, Uematsu M, Sameshima K. A novel PLP1 frameshift mutation causing a milder form of Pelizaeus-Merzbacher disease. Brain and Development 2015;37:455–8.
• Hubner CA, Orth U, Senning A, Steglich C, Kohlschütter A, Korinthenberg R, et al. Seventeen novel PLP1 mutations in patients with Pelizaeus–Merzbacher disease. Hum Mutat 2005;25:321–2.
• Torii T, Miyamoto Y, Yamauchi J, Tanouel A. Pelizaeus–Merzbacher disease:Cellular pathogenesis and pharmacologic therapy. Pediat Int 2014:56;659–66.
• Martinez-Montero P, Munoz-Calero M, Vallespin E, Campistol J, Martorell L, Ruiz Falco MJ, et al. PLP1 gene analysis in 88 patients with leukodystrophy. Clin Genet 2013;84:566–71.
• Sistermans EA, de Coo RFM, De Wijs IJ, Van Oost BA. Duplication of the proteolipid protein gene is the major cause of Pelizaeus-Merzbacher disease. Neurology 1998;50:1749-54.
• Manning M, Hudgins L. Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities. Genet Med 2020;22:2126.
• Miller DT, Adam MP, Aradhya S, Miller DT, Adam MP, Aradhya S, et al. Consensus statement: Chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet 2010;86:749–64.
• Hochstenbach R, van Binsbergen E, Engelen J, Nieuwint A, Polstra A, Poddighe P, et al. Array analysis and karyotyping: workflow consequences based on a retrospective study of 36,325 patients with idiopathic developmental delay in the Netherlands. Eur J Med Genet 2009;52:161-9.
• Battaglia A, Doccini V, Bernardini L, Novelli A, Loddo S, Capalbo A, et al. Confirmation of chromosomal microarray as a first-tier clinical diagnostic test for individuals with developmental delay, intellectual disability, autism spectrum disorders and dysmorphic features. Eur J Paediatr Neurol 2013;17:589–99.