Alexander disease (AD) is a rare leukodystrophy of the central nervous system of unknown etiology. AD is characterized by progressive failure of central myelination and the accumulation of Rosenthal fibers in astrocytes, and is inevitably lethal in nature. Symptomatically, AD is associated with leukoencephalopathy with macrocephaly, seizures, and psychomotor retardation in infants, and usually leads to death within the first decade. Its characteristic magnetic resonance imaging (MRI) findings have been described as demyelination predominantly in the frontal lobe. Moreover, dominant mutations in the GFAP gene, coding for glial fibrillary acidic protein (GFAP), a principal astrocytic intermediate filament protein, have been shown to lead to AD. The disease can now be detected by genetic diagnosis. We report the Korean case of an 8-month-old male patient with AD. He was clinically characterized due to the presence of psychomotor retardation, megalencephaly, spasticity, and recurrent seizures including infantile spasms which is a remarkable presentation. Demyelination in the frontal lobe and in a portion of the temporal lobe was demonstrated by brain MRI. Moreover, DNA analysis of peripheral blood showed the presence of a R239L mutation in the GFAP gene, involving the replacement of guanine with thymine.
Spasms, Infantile/*etiology ; *Mutation ; Male ; Magnetic Resonance Imaging ; Infant ; Humans ; Glial Fibrillary Acidic Protein/*genetics ; Electroencephalography ; Alexander Disease/complications/*diagnosis

OBJECTIVETo study the clinical features of early-onset epileptic encephalopathies (EEEs) of unknown cause, and to identify pathogenic microdeletion/microduplication of EEEs by genome-wide analysis of copy number variations (CNVs).

METHODSThe clinical data of 60 children diagnosed with unexplained EEEs between July 2012 and April 2013 were obtained and analyzed. Specimens were collected from the selected children and their parents. Single nucleotide polymorphism array was used to detect genome-wide CNVs, and fluorescence in situ hybridization was performed to verify the results and analyze the source of the parents, further to identify suspected pathogenic CNVs of EEEs.

RESULTSAmong the 60 children with unexplained EEEs, 34 were diagnosed with West syndrome, 3 with Ohtahara syndrome, 3 with Dravet syndrome, and 20 with unclassified EEEs. In total, 77% of the patients were associated with moderate to severe mental retardation. Head imaging test implied that 35% of the patients had brain dysplasia or astrophy. Among 54 patients, 17% showed microcephalus. After treatment, 28 patients had clinical seizures under control, 16 out of control, 5 dead, and 1 lost to follow-up. Genome-wide analysis of CNVs showed that 7 pathogenic or suspected pathogenic CNVs were present in 5 patients.

CONCLUSIONSEEEs of unknown cause are associated with high phenotypic heterogeneity and poor prognosis. Genome-wide CNVs analysis can demonstrate pathogenic or suspected pathogenic CNVs. This research expands the gene bank of EEEs and improves the understanding about possible etiology of unexplained EEEs. The results provide a reference for genetic counseling regarding reproduction in the patient's family.

Child ; DNA Copy Number Variations ; Female ; Genome-Wide Association Study ; Humans ; Infant ; Infant, Newborn ; Spasms, Infantile ; etiology ; genetics

Child, Preschool ; Diagnosis, Differential ; Electroencephalography ; Electroretinography ; Eye Movements ; Head Movements ; Humans ; Infant ; Infant, Newborn ; Nystagmus, Pathologic ; diagnosis ; etiology ; physiopathology ; Retinal Diseases ; diagnosis ; physiopathology ; Risk Factors ; Spasms, Infantile ; diagnosis ; etiology ; physiopathology ; Torticollis ; etiology ; physiopathology

1-Alkyl-2-acetylglycerophosphocholine Esterase ; genetics ; Chromosome Aberrations ; Humans ; Infant ; Infant, Newborn ; Ion Channels ; physiology ; Melanocyte-Stimulating Hormones ; genetics ; Microtubule-Associated Proteins ; genetics ; Mutation ; Neurons ; physiology ; Neuropeptides ; genetics ; Spasms, Infantile ; etiology ; genetics ; Tumor Suppressor Proteins ; genetics

OBJECTIVETo investigate the clinical and electroencephalographic (EEG) characteristics, therapeutic response and long-term prognosis of early myoclonic encephalopathy.

METHODThe clinical and EEG data of three patients with early myoclonic encephalopathy were analyzed. These patients were admitted to our hospital between September 2008 and January 2012. The patients were followed up for therapeutic response and long-term prognosis.

RESULTThe age of onset was from 2 to 23 days after birth. All patients had the onset of erratic or fragmentary myoclonus. Two patients had frequent simple focal seizures. One patient had tonic spasms when he was 3 months old. The EEG characteristic of all patients was repetitive suppression-burst pattern. The suppression-burst pattern was characterized by paroxysmal short bursts and long periods of suppression. The EEG paroxysms of one patient was asynchronous over both hemispheres. There is no effective therapy for early myoclonic encephalopathy. A patient died before two years of age. Two patients had severe partial epilepsy and showed very severe retardation.

CONCLUSIONEarly myoclonic encephalopathy usually starts in the first month of life. Erratic myoclonus appears first. Myoclonus is the principal features of early myoclonic encephalopathy. Frequent focal seizures occur shortly after erratic myoclonus. Tonic epileptic spasms may develop within 3 - 5 months. The suppression-burst pattern is EEG characteristic. There is no effective therapy for early myoclonic encephalopathy and the prognosis is poor.

Anticonvulsants ; therapeutic use ; Electroencephalography ; Epilepsies, Myoclonic ; diagnosis ; drug therapy ; physiopathology ; Female ; Humans ; Infant ; Infant, Newborn ; Male ; Prognosis ; Psychomotor Disorders ; diagnosis ; etiology ; physiopathology ; Spasms, Infantile ; diagnosis ; drug therapy ; physiopathology ; Survival Rate ; Valproic Acid ; therapeutic use