Clinical, neuroimaging, and genetic characteristics of megalencephalic leukoencephalopathy with subcortical cysts in Egyptian patients

Iman G. Mahmoud, Marwa Mahmoud, Miral Refaat, Marian Girgis, Nevin Waked, Ameera El Badawy, Laila Selim, Sawsan Hassan, Alice Kamal Abd El Aleem

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Background Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare and genetically heterogeneous cerebral white matter disease. Clinically, it is characterized by macrocephaly, developmental delay, and seizures. We explore the clinical spectrum, neuroimaging characteristics, and gene involvement in the first patients with megalencephalic leukoencephalopathy with subcortical cysts described from Egypt. Patients Six patients were enrolled from three unrelated families. Patient inclusion criteria were macrocephaly, developmental delay, normal urinary organic acids, and brain imaging of diffuse cerebral white matter involvement. Direct sequencing of the MLC1 gene in patients' families and GliaCAM in one questionable case was performed using BigDye Terminator cycle sequencing. Results Clinical heterogeneity, both intra- and interfamilial, was clearly evident. Developmental delays ranged from globally severe or moderate to mild delay in achieving walking or speech. Head circumference above the ninety-seventh percentile was a constant feature. Neuroimaging featured variability in white matter involvement and subcortical cysts. However, findings of posterior fossa changes and brain stem atrophy were frequently (66.6%) identified in these Egyptian patients. Discrepancy between severe brain involvement and normal mental functions was evident, particularly in patients from the third family. MLC1 mutations were confirmed in all patients. Deletion/insertion mutation in exon 11 (c.908-918delinsGCA, p.Val303 Gly fsX96) was recurrent in two families, whereas a missense mutation in exon 10 (c.880 C > T, p.Pro294Ser) was identified in the third family. Conclusions This report extends our knowledge of the clinical and neuroimaging features of megalencephalic leukoencephalopathy with subcortical cysts. It confirms the apparent lack of selective disadvantage of MLC1 mutations on gamete conception and transmission as supported by the presence of multiple affected siblings in Egyptian families.

Original languageEnglish
Pages (from-to)140-148
Number of pages9
JournalPediatric Neurology
Volume50
Issue number2
DOIs
Publication statusPublished - Feb 2014

Fingerprint

Neuroimaging
Megalencephaly
Exons
INDEL Mutation
Leukoencephalopathies
Mutation
Megalencephalic leukoencephalopathy with subcortical cysts
Egypt
Missense Mutation
Germ Cells
Genes
Brain Stem
Walking
Atrophy
Cysts
Siblings
Seizures
Head
Acids
Brain

Keywords

  • developmental delay
  • GliaCAM gene
  • macrocephaly
  • megalencephalic leukodystrophy
  • MLC1 gene
  • subcortical cysts
  • Van der Knaap disease

ASJC Scopus subject areas

  • Clinical Neurology
  • Pediatrics, Perinatology, and Child Health
  • Developmental Neuroscience
  • Neurology

Cite this

Clinical, neuroimaging, and genetic characteristics of megalencephalic leukoencephalopathy with subcortical cysts in Egyptian patients. / Mahmoud, Iman G.; Mahmoud, Marwa; Refaat, Miral; Girgis, Marian; Waked, Nevin; El Badawy, Ameera; Selim, Laila; Hassan, Sawsan; Kamal Abd El Aleem, Alice.

In: Pediatric Neurology, Vol. 50, No. 2, 02.2014, p. 140-148.

Research output: Contribution to journalArticle

Mahmoud, Iman G. ; Mahmoud, Marwa ; Refaat, Miral ; Girgis, Marian ; Waked, Nevin ; El Badawy, Ameera ; Selim, Laila ; Hassan, Sawsan ; Kamal Abd El Aleem, Alice. / Clinical, neuroimaging, and genetic characteristics of megalencephalic leukoencephalopathy with subcortical cysts in Egyptian patients. In: Pediatric Neurology. 2014 ; Vol. 50, No. 2. pp. 140-148.
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AU - Girgis, Marian

AU - Waked, Nevin

AU - El Badawy, Ameera

AU - Selim, Laila

AU - Hassan, Sawsan

AU - Kamal Abd El Aleem, Alice

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N2 - Background Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare and genetically heterogeneous cerebral white matter disease. Clinically, it is characterized by macrocephaly, developmental delay, and seizures. We explore the clinical spectrum, neuroimaging characteristics, and gene involvement in the first patients with megalencephalic leukoencephalopathy with subcortical cysts described from Egypt. Patients Six patients were enrolled from three unrelated families. Patient inclusion criteria were macrocephaly, developmental delay, normal urinary organic acids, and brain imaging of diffuse cerebral white matter involvement. Direct sequencing of the MLC1 gene in patients' families and GliaCAM in one questionable case was performed using BigDye Terminator cycle sequencing. Results Clinical heterogeneity, both intra- and interfamilial, was clearly evident. Developmental delays ranged from globally severe or moderate to mild delay in achieving walking or speech. Head circumference above the ninety-seventh percentile was a constant feature. Neuroimaging featured variability in white matter involvement and subcortical cysts. However, findings of posterior fossa changes and brain stem atrophy were frequently (66.6%) identified in these Egyptian patients. Discrepancy between severe brain involvement and normal mental functions was evident, particularly in patients from the third family. MLC1 mutations were confirmed in all patients. Deletion/insertion mutation in exon 11 (c.908-918delinsGCA, p.Val303 Gly fsX96) was recurrent in two families, whereas a missense mutation in exon 10 (c.880 C > T, p.Pro294Ser) was identified in the third family. Conclusions This report extends our knowledge of the clinical and neuroimaging features of megalencephalic leukoencephalopathy with subcortical cysts. It confirms the apparent lack of selective disadvantage of MLC1 mutations on gamete conception and transmission as supported by the presence of multiple affected siblings in Egyptian families.

AB - Background Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare and genetically heterogeneous cerebral white matter disease. Clinically, it is characterized by macrocephaly, developmental delay, and seizures. We explore the clinical spectrum, neuroimaging characteristics, and gene involvement in the first patients with megalencephalic leukoencephalopathy with subcortical cysts described from Egypt. Patients Six patients were enrolled from three unrelated families. Patient inclusion criteria were macrocephaly, developmental delay, normal urinary organic acids, and brain imaging of diffuse cerebral white matter involvement. Direct sequencing of the MLC1 gene in patients' families and GliaCAM in one questionable case was performed using BigDye Terminator cycle sequencing. Results Clinical heterogeneity, both intra- and interfamilial, was clearly evident. Developmental delays ranged from globally severe or moderate to mild delay in achieving walking or speech. Head circumference above the ninety-seventh percentile was a constant feature. Neuroimaging featured variability in white matter involvement and subcortical cysts. However, findings of posterior fossa changes and brain stem atrophy were frequently (66.6%) identified in these Egyptian patients. Discrepancy between severe brain involvement and normal mental functions was evident, particularly in patients from the third family. MLC1 mutations were confirmed in all patients. Deletion/insertion mutation in exon 11 (c.908-918delinsGCA, p.Val303 Gly fsX96) was recurrent in two families, whereas a missense mutation in exon 10 (c.880 C > T, p.Pro294Ser) was identified in the third family. Conclusions This report extends our knowledge of the clinical and neuroimaging features of megalencephalic leukoencephalopathy with subcortical cysts. It confirms the apparent lack of selective disadvantage of MLC1 mutations on gamete conception and transmission as supported by the presence of multiple affected siblings in Egyptian families.

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