ABSTRACT
Objective To analyze the clinical characteristics and genetic variation of megalencephalic leu-koencephalopathy with subcortical cysts(MCL),then to explore the genetic characteristics so as to help families by pro-viding genetic counseling. Methods The clinical data of the children and their family members were collected,and the peripheral blood DNA of the children and family members were extracted. Then,the MLC1 gene mutation in the children was detected by using the target sequence capture high-throughput sequencing technology and Sanger sequencing tech-nology. Results (1)MCL often presented abnormal head circumference in infants as the first symptom. The main clini-cal manifestations were hypoevolutism in motor development,retrogression of early school age,then the movement disor-der progressed and finally paralyzed;epilepsy was common in early childhood;head magnetic resonance imaging showed white matter in bilateral cerebral hemisphere diffusing abnormal signal with temporal lobe cystic change in the early stage,and then showed brain atrophy. (2)The gene results showed that the 2 girls with MLC had both c. 368C >T (p. Thr123Ile)and c. 353C > T (p. Thr118Met)complex heterozygous variation,which existed in the MLC1 gene. The girls′ father and a sister carried c. 368C > T (p. Thr123Ile),while the mother carried c. 353C > T (p. Thr118Met) heterozygous variation,all of whom were normal phenotypes. Conclusions MCL is one cause of hypoevolutism in motor development in children and abnormal head circumference of infants is usually the first symptom. The MLC1 gene c. 368C> T(p. Thr123Ile)is a pathogenic mutation for MLC,and may be another new pa-thogenic mutation.
ABSTRACT
Objectives To provide genetic counseling and prenatal molecular diagnosis for two families with megalencephalic leukoencephalopathy with subcortical cysts (MLC).Methods Two MLC patients (probands 1 and 2) were admitted to the Department of Pediatrics of Peking University First Hospital in June 2011 and June 2009,respectively.Peripheral blood was collected and DNA sequencing was performed for genetic analysis for the two MLC patients and their parents.Amniotic fluid and villus of two fetuses (fetus 1 and 2) were collected at 21+4 and 12+3 weeks of gestational age from their mothers when they were pregnant again.The genomic DNA of the two fetuses was extracted and corresponding sites of MLC1 gene were sequenced.Haplotype analysis using a combination of 3 microsatellite markers (AR,DXS6807 and DXS6797) on chromosome X and sex determining region of Y chromosome was performed to detect maternal cell contamination.Verification of the prenatal molecular diagnosis and follow up study after birth were conducted for both fetuses.Results Macrocephaly,motor development delay and typical findings on brain MRI were identified in the two probands,and were clinically diagnosed with MLC.Compound heterozygous mutations were detected in proband 1 [c.353C＞T (p.T118M) and c.803C＞G (p.T268R)] and proband 2 [c.353C＞T (p.T118M) and c.836T＞C(p.L279P)],respectively.MLC was genetically diagnosed.Heterozygous variation in c.353[c.353C＞T (p.T118M)] and wild c.803C were identified in fetus 1,and both wild c.353C and c.836T were found in fetus 2.No maternal cell contamination was detected in both fetuses.Sequencing the corresponding sites after birth confirmed the prenatal diagnosis,and the head circumference and motor development were normal in fetus 1 at 5 months old.No macrocephaly was found and no DNA sequencing was done in fetus 2 at one month old.Conclusions Genetic counseling and prenatal molecular diagnosis for MLC families combined with clinical and genetic diagnosis are important in preventing MLC.Haplotype analysis with a combination of three microsatellite markers on chromosome X and sex determining region of Y chromosome is useful in detecting maternal cell contamination and avoiding its influence on prenatal diagnosis,and confirming the reliability of prenatal diagnosis.
ABSTRACT
BACKGROUND: Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare inherited disorder characterized by infantile-onset macrocephaly, slow neurologic deterioration, and seizures. Mutations in the causative gene, MLC1, are found in approximately 75% of patients and are inherited in an autosomal recessive manner. We analyzed MLC1 mutations in five unrelated Korean patients with MLC. METHODS: Direct Sanger sequencing was used to identify MLC1 mutations. A founder effect of the p.Ala275Asp variant was demonstrated by haplotype analysis using single-nucleotide polymorphic (SNP) markers. Multiple ligation-dependent probe amplification (MLPA) and comparative genomic hybridization plus SNP array were used to detect exonic deletions or uniparental disomy (UPD). RESULTS: The most prevalent pathogenic variant was c.824C>A (p.Ala275Asp) found in 7/10 (70%) alleles. Two pathogenic frameshift variants were found: c.135delC (p.Cys46Alafs*12) and c.337_353delinsG (p.Ile113Glyfs*4). Haplotype analysis suggested that the Korean patients with MLC harbored a founder mutation in p.Ala275Asp. The p.(Ile113Glyfs*4) was identified in a homozygous state, and a family study revealed that only the mother was heterozygous for this variant. Further analysis of MLPA and SNP arrays for this patient demonstrated loss of heterozygosity of chromosome 22 without any deletion, indicating UPD. The maternal origin of both chromosomes 22 was demonstrated by haplotype analysis. CONCLUSIONS: This study is the first to describe the mutational spectrum of Korean patients with MLC, demonstrating a founder effect of the p.Ala275Asp variant. This study also broadens our understanding of the mutational spectrum of MLC1 by demonstrating a homozygous p.(Ile113Glyfs*4) variant resulting from UPD of chromosome 22.
Subject(s)
Humans , Alleles , Chromosomes, Human, Pair 22 , Comparative Genomic Hybridization , Exons , Founder Effect , Haplotypes , Leukoencephalopathies , Loss of Heterozygosity , Megalencephaly , Mothers , Seizures , Uniparental DisomyABSTRACT
La leucoencefalopatía megaencefálica con quistes subcorticales (MLC) o enfermedad de Van der Knaap es un trastorno genético infrecuente. La mutación en el gen MLC1 se ha demostrado como la responsable de esta alteración. La disminución en la expresión de la proteína codificada causa vacuolización en los astrocitos y alteración de la homeostasis del agua y los electrolitos. Los casos presentados permiten ilustrar los hallazgos imaginológicos característicos de esta entidad, debido a que el diagnóstico se fundamenta en las imágenes en resonancia magnética (RM).
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) or Van der Knaap disease is a rare genetic disease. The MLC1 mutation genes participate in the pathogenesis. The decreased expression of the encoded protein in astrocytes causes vacuolation, impaired water, and electrolyte homeostasis. We report two cases and illustrate the typical imaging features. The diagnosis of this disease is based on magnetic resonance imaging findings (MRI).
Subject(s)
Humans , Leukoencephalopathies , Magnetic Resonance Imaging , CerebrumABSTRACT
La leucoencefalopatía megalencefálica con quistes subcorticales es un desorden genético autosómico recesivo, debido a mutaciones en los genes megalencephalic leukoencephalopathy with subcortical cyst 1 (MLC1) o hepatocyte cell adhesion molecule (HEPACAM). Esta enfermedad de la sustancia blanca se caracteriza por macrocefalia de inicio temprano, deterioro motor y mental progresivo, ataxia y crisis epilépticas. La resonancia magnética nuclear muestra edema, compromiso difuso de la sustancia blanca y quistes subcorticales frontotemporales. Se presenta el primer caso reportado en Perú, de una niña con hallazgos clínicos y de la resonancia magnética nuclear típicos, con mutaciones heterocigotas en el gen MLC1.
Megalencephalic leukoencephalopathy with subcortical cysts is a recessive autosomal genetic disorder, due to mutations in the gen megaloencephalic leukoencephalopathy with subcortical cyst 1 (MLC1) or hepatocyst cell adhesion molecule (HEPACAM). This white matter disease is characterized by macroencephaly of early onset, progressive motor or mental deterioration, ataxia and epileptic crises. Magnetic resonance imaging shows edema, diffuse compromise of the white matter and frontotemporal subcortical cysts. Here is the first case reported in Peru; it is a girl with clinical findings and typical findings disclosed in the nuclear magnetic resonance imaging in addition to heterocygotic mutations in the gen MLC1.
ABSTRACT
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare white matter disorder, first described in the early 1990s. The brain in patients with MLC appears swollen on MRI, with diffuse white matter abnormalities; in addition, there is an invariable presence of subcortical cysts, primarily in the anterior temporal region sparing the deep white matter, basal ganglia, thalami, and cerebellum. Patients with MLC present with macrocephaly and neurological abnormalities such as motor deterioration, ataxia, spasticity, and cognitive deficits. We report a twenty-month-old boy who presented with seizures and macrocephaly, delay in development, and abnormal brain MRI findings compatible with the diagnosis of MLC. The brain MRI revealed bilateral hypersignal intense subcortical white matter regions in the frontal, temporal, and parietal lobes on T2-weighted images, which were not yet associated with cystic changes. During follow-up, the frequency of seizures decreased after anticonvulsant medication was started, but the head circumference remained above the 97th percentile, and the patient continued to have developmental delay.