Analysis of a child with megalencephalic leukoencephalopathy with subcortical cyst type 2B caused by HEPACAM variant / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical features and genetic variant in a child featuring megalencephalic leukoencephalopathy with subcortical cyst (MLC) type 2B.@*METHODS@#Clinical and imaging data of the child was collected. Potential variant of hepatocyte adhesion molecule (HEPACAM) gene was detected by Sanger sequencing. The growth and development of her mother and uncle was also reviewed.@*RESULTS@#The patient, a 1-year-and-7-month female, presented with convulsion, mental retardation and abnormally increased head circumference. Cranial MRI revealed extensive long T1 long T2 signals in the white matter of bilateral cerebral hemisphere, right anterior sac cyst, cerebral gyrus widening, and shallow sulcus. Sanger sequencing identified a c.437C>T missense variant in exon 3 of the HEPACAM gene. The same variant was detected in her mother but not father. Her mother and maternal uncle both had a history of increased head circumference when they were young. In their adulthood, the head circumference was in the normal range but still greater than the average.@*CONCLUSION@#The heterozygous variant of the HEPACAM gene probably underlies the MLC2B in this child. The variant has derived from her asymptomatic mother, which suggested incomplete penetrance of the MLC2B.

Identification of a novel MLC1 mutation in a Chinese patient affected with megalencephalic leukoencephalopathy with subcortical cysts / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To detect potential mutation of MLC1 gene in a child affected with megalencephalic leukoencephalopathy with subcortical cysts (MLC).</p><p><b>METHODS</b>Clinical symptoms of the patient were retrieved. Peripheral blood DNA samples from the patient, her parents and healthy controls were collected. Potential mutation of the MLC1 gene was detected by polymerase chain reaction and Sanger sequencing.</p><p><b>RESULTS</b>The patient presented with severe motor developmental delay and a giant skull. Magnetic resonance scan showed diffuse white matter swelling in bilateral hemispheres. DNA sequencing identified a novel homozygous c.177-c.180delC mutation of the MLC1 gene. The parents of the patient both carried a heterozygous mutation c.177-c.180delC but had a normal phenotype.</p><p><b>CONCLUSION</b>A novel MLC1 mutation c.177-c.180delC has been identified in a patient with MLC. The mutation is presumably disease-causing and has derived from parents who are both carriers.</p>

Analysis of MLC1 gene mutation in a Chinese family with megalencephalic leukoencephalopathy with subcortical cysts / 中国当代儿科杂志

The clinical data of a patient with megalencephalic leukoencephalopathy (MLC) with subcortical cysts and her parents were collected. MLC1 gene mutation was detected by polymerase chain reaction and direct DNA sequencing. The patient presented with motor developmental delay and giant skull, and brain magnetic resonance imaging showed diffuse white matter swelling accompanied by subcortical cysts in bilateral frontal and parietal lobes. Gene sequencing identified two heterozygous mutations of MLC1, including missense mutation in exon 3 (c.217G>A, p.Gly73Arg) and splice site mutation in intron 9 (c.772-1G>C in IVS9-1). The patient's parents both had heterozygous mutation c.772-1G>C in IVS9-1 with normal phenotype. It can be presumed that c.772-1G>C in IVS9-1 comes from the parents, and c.217G>A (p.Gly73Arg) is a de novo mutation.

Imaging of adult leukodystrophies / Imagem nas leucodistrofias do adulto

Leukodystrophies are genetically determined white matter disorders. Even though leukodystrophies essentially affect children in early infancy and childhood, these disorders may affect adults. In adults, leukodystrophies may present a distinct clinical and imaging presentation other than those found in childhood. Clinical awareness of late-onset leukodystrophies should be increased as new therapies emerge. MRI is a useful tool to evaluate white matter disorders and some characteristics findings can help the diagnosis of leukodystrophies. This review article briefly describes the imaging characteristics of the most common adult leukodystrophies.

Leucodistrofias são doenças geneticamente determinadas. Apesar das leucodistrofias afetarem principalmente crianças lactentes e infantes, estas doenças podem acometer a faixa etária adulta. Nos adultos, as leucodistrofias podem ter uma apresentação clínica e de imagem distinta daquela da infância. Um aumento na suspeita clínica de leucodistrofias com início tardio deve ocorrer associado ao aparecimento de novas alternativas terapêuticas. Este artigo de revisão descreve sumariamente as características de imagem nas leucodistrofias no adulto.

Neuromielitis óptica tratada inicialmente como esclerosis múltiple: a propósito de un caso / Neuromyelitis optica initially treated as multiple sclerosis: a propos a case

Introducción: El síndrome de Devic o neuromielitis óptica (NMO) es una entidad clínica infrecuente autoinmune, desmielinizante e inflamatoria que se caracteriza por la presencia de hallazgos clínicos, imagenológicos y de laboratorio que evidencian neuritis óptica, mielitis aguda con lesión longitudinal de más de tres segmentos medulares y seropositividad para anticuerpos IgG específicos para el canal de acuaporina 4. Caso: Presentamos el caso de una mujer de 28 años con diagnóstico inicial de Esclerosis múltiple de hace 14 meses, quien consulta al servicio de urgencias del Hospital Universitario San Jorge de Pereira por disminución progresiva de la fuerza en miembros inferiores y retención urinaria con cinco días de evolución. Como antecedentes refiere neuritis óptica bilateral en tratamiento con Interferón Beta, con pobre mejoría clínica y corticoide parenteral para los cuadros agudos. Se realiza resonancia magnética de columna vertebral que reporta columna lumbar sin alteraciones y columna dorsal con mielopatía en los segmentos T5-T8, posible desmielinización. Cuadro hemático, química sanguínea, Proteína C Reactiva, complemento C3 y C4 dentro de los rangos normales. Discusión: La presentación aislada de neuritis óptica como debut en un cuadro clínico nos lleva a sospechar inicialmente en una enfermedad desmielinizante tipo esclerosis múltiple, lo que puede alterar el manejo inicial de los pacientes con neuromielitis óptica de base.

Background: Devic’s syndrome or neuromyelitis optica (NMO) is an autoimmune, inflammatory and demyelinating uncommon clinical entity characterized by the presence of clinical, imagining and laboratory evidence of optic neuritis, acute myelitis with longitudinal injury in more than three spinal segments and finally, NMO IgG seropositive for antibodies specific for the aquaporin channel 4. Case: We report a 28 years old woman diagnosed with multiple sclerosis 14 months ago, who consulted to emergency of Hospital Universitario San Jorge from Pereira by progressive reduction of strength in lower extremities and unrinary retention with duration of five days. She had a history of bilateral optic neuritis in treatment with interferon Beta 1-B, with poor clinical improvement, and parenteral corticosteroid for acute symptoms. Is performed a spinal Magnetic Resonance Imaging (MRI) reported a lumbar spine without changes and a dorsal spine with myelopathy in segments T5-T8, possible demyelinitation. Blood count, blood chemistry, C Reactive Protein, complement C3 and C4 within normal ranges. Discussion: The presentation of isolated optic neuritis as a clinical debut leads us to suspect initially in a demyelinating disease, multiple sclerosis type which can alter the initial management of patients with NMO.

Analysis of HEPACAM mutations in a Chinese family with megalencephalic leukoencephalopathy with subcortical cysts / 中华儿科杂志

<p><b>OBJECTIVE</b>To explore HEPACAM mutations in a Chinese family with megalencephalic leukoencephaloptathy with subcortical cysts (MLC).</p><p><b>METHOD</b>Genomic DNA samples were extracted from peripheral blood of the proband and her parents. All exons and exon-intron boundaries of HEPACAM and MLC1 were amplified in the MLC family by polymerase chain reaction (PCR) followed by direct DNA sequencing.</p><p><b>RESULT</b>Two heterozygous mutations of HEPACAM located in exon 2, c.203A > T(p.K68M) and c.395C > A(p.T132N), were identified in the proband. The proband's mother had the heterozygous mutations c.203A > T(p.K68M), and her father had the heterozygous mutation-c.395C > A(p.T132N). There was no variation found in MLC1 gene.</p><p><b>CONCLUSION</b>The proband was heterozygous compound MLC patient carrying on one allele with the c.203A > T(p.K68M) mutation inherited from her mother, and the other allele with the c.395C > A(p.T132N) mutation inherited from her father. The parents both are heterozygous carriers with normal phenotype. The disease-causing gene for this family was resulted in HEPACAM mutation other than MLC1 mutation.</p>

Leucodystrophy induced by late onset 3-hydroxy-3-methylglutaric aciduria / 中国当代儿科杂志

3-Hydroxy-3-methylglutaric aciduria is a rare disorder of organic acid metabolism caused by 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency. The disorder was common in neonatal or infant period. Here a case of late onset 3-hydroxy-3-methylglutaric aciduria complicated by leucodystrophy was reported. The patient was a 7-year-old boy. He presented with progressive headache, drowsiness and vomiting. Hepatic lesions, ketosis and leucopenia were found. Symmetrical diffused leucodystrophy was shown by MRI. Blood levels of isovalerylcarnitine and acetylcarnitine increased significantly. Urinary levels of 3-hydroxy-3-methylglutaric, 3-methylglutaconic, 3-hydroxyglutaric acids and 3-methyl-crotonylglycine increased significantly. Symptoms were released by intravenous infusion of L-carnitine and glucose. After treatment for 6 months, urinary levels of 3-hydroxy-3-methylglutaric aciduria decreased in the boy and his health improved.

Genetic analysis and prenatal diagnosis for a family with megalencephalic leukoencephalopathy and subcortical cysts / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To identify potential mutation in the MLC1 gene in a Chinese family affected with megalencephalic leukoencephalopathy and subcortical cysts (MLC), and to provide prenatal diagnosis.</p><p><b>METHODS</b>Genomic DNA of the patients, their parents and younger sister were extracted from peripheral blood. That of the fetus was extracted from an amniotic fluid sample. A total of 12 exons and at least 100 bp flanking the intronic sequence of the MLC1 gene were amplified with PCR. MLC1 mutations were screened by sequencing. Linkage analysis was performed for the family to assure accuracy of prenatal diagnosis.</p><p><b>RESULTS</b>The two patients were both heterozygote for c.177_178delG (p.Ser60AlafsX5) mutation in exon 2 and c.598-2A>C change in intron 7. The c.177_178delG mutation was inherited from the father, and the c.598-2A>C mutation was inherited from the mother. The younger sister and the fetus have both inherited c.177_178delG from the father but did not inherit c.598-2A>C from the mother. Prenatal diagnosis suggested the fetus to be a carrier for a MLC1 mutation. Linkage analysis was consistent with the result of mutation detection. The fetus was born normal as predicted.</p><p><b>CONCLUSION</b>The c.598-2A>C is a novel splicing mutation. Prenatal diagnosis through DNA sequencing and linkage analysis were performed for the first time on Chinese patients with MLC.</p>

A case of megalencephalic leukoencephalopathy with subcortical cysts / 소아과

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.

Leukodystrophies: Indian scenario.

The leukodystrophies are familial disorders with onset usually in infancy or childhood. The clinical features consist of motor dysfunction with varying degree of cognitive decline. Magnetic Resonance Imaging (MRI) has helped to identify and characterize these disorders. In some leukodystrophies, biochemical enzymatic and genetic defects have been identified. The commonest leukodystrophy seen in India is Megalencephalic Leukodystrophy with subcortical cysts. The essential features consist of large head, mild pyramidal and cerebellar dysfunction, and occasional seizures. MRI studies show extensive white matter changes with temporal cysts. It is common in the Agarwal community in India. An identical mutation in exon 2 of the MLC 1 gene has been identified in this community suggesting a founder effect.

Megalencephalic leukoencephalopathy with subcortical cysts.

Megalencephalic leukoencephalopathy with subcortical cysts is a rare disease first described in 1995. It is characterized by macrocephaly and early onset white matter degeneration. We report two siblings who were diagnosed to have this disease. This disease must be included in differential diagnosis of macrocephaly with early onset leukoencephalopathy.

Megalencephalic leukoencephalopathy with subcortical cysts.

Megalencephalic leukocncephalopathy is rare disorder seen in India in patient belonging to Agarwal community. Many of the patients may have a mild clinical course with gradual worsening of neurological disability. A case is being reported who was followed for 17 years and paradoxically showed radiological and clinical improvement.