Early prognostic factors for acute encephalopathy with reduced subcortical diffusion.

OBJECTIVE: The aim of this study was to determine the prognostic factors for acute encephalopathy with reduced diffusion (AED) during the acute phase through retrospective case evaluation. METHODS: The participants included 23 patients with AED. The diagnosis of AED was based on their clinical course and radiological findings. We divided the patients into severe and non-severe groups based on the neurodevelopmental outcome. The severe group included seven patients (median age, 21 months; range, 6-87 months) and the non-severe group included 16 patients (19 months, 9-58 months). Clinical symptoms, laboratory data and electroencephalogram (EEG) findings within 48 h from the initial seizure onset were compared between the two groups to identify neurological outcome predictors. RESULTS: The incidence of coma 12-24 h after onset, serum creatinine (Cr) levels within 2 h after onset, maximum aspartate aminotransferase (AST) levels within 24 h after onset, and the rate of electrographic seizures in EEG were significantly higher in the severe group (Coma, 80%; Cr, 0.40 mg/dl, 0.37-0.73; AST, 363 IU/L, 104-662; electrographic seizures, 80%) than the non-severe group (Coma, 0%; Cr, 0.29 mg/dL, 0.19-0.45; AST, 58.5 IU/L, 30-386; electrographic seizures, 0%). CONCLUSIONS: Coma 12-24 h after onset, elevation of Cr levels within 2 h after onset, elevation of AST levels within 24 h after onset, and non-convulsive status epileptics (NCSE) in comatose patients were early predictors of severe AED. Patients in a coma after a febrile seizure should be checked for NCSE signs in EEG to terminate NCSE without delay.

Comparison of the phenotypes of patients harboring in-frame deletions starting at exon 45 in the Duchenne muscular dystrophy gene indicates potential for the development of exon skipping therapy.

Exon skipping therapy has recently received attention for its ability to convert the phenotype of lethal Duchenne muscular dystrophy (DMD) to a more benign form, Becker muscular dystrophy (BMD), by correcting the open reading frame. This therapy has mainly focused on a hot-spot (exons 45-55) mutation in the DMD gene. Exon skipping of an entire stretch of exons 45-55 is an approach applicable to 46.9% of DMD patients. However, the resulting phenotype is not yet fully understood. Here we examined the clinical profiles of 24 patients with BMD resulting from deletions starting at exon 45. The Δ45-55 group ranged in age from 2 to 87 years; no mortality was observed, and one patient was ambulatory at 79 years of age. The age at which patients became wheelchair-bound in the Δ45-48 group (18-88 years old) was approximately 50 years. Cardiomyopathy was well controlled by pharmaceuticals in both deletion groups. In contrast, the Δ45-47 and Δ45-49 groups exhibited more severe phenotypes than those with other mutations: the age at which patients in the Δ45-49 group became wheelchair-bound was around 30-40 years. Our study shows that clinical severity differs between each hot-spot deletion.

Biallelic TBCD Mutations Cause Early-Onset Neurodegenerative Encephalopathy.

We describe four families with affected siblings showing unique clinical features: early-onset (before 1 year of age) progressive diffuse brain atrophy with regression, postnatal microcephaly, postnatal growth retardation, muscle weakness/atrophy, and respiratory failure. By whole-exome sequencing, we identified biallelic TBCD mutations in eight affected individuals from the four families. TBCD encodes TBCD (tubulin folding co-factor D), which is one of five tubulin-specific chaperones playing a pivotal role in microtubule assembly in all cells. A total of seven mutations were found: five missense mutations, one nonsense, and one splice site mutation resulting in a frameshift. In vitro cell experiments revealed the impaired binding between most mutant TBCD proteins and ARL2, TBCE, and ß-tubulin. The in vivo experiments using olfactory projection neurons in Drosophila melanogaster indicated that the TBCD mutations caused loss of function. The wide range of clinical severity seen in this neurodegenerative encephalopathy may result from the residual function of mutant TBCD proteins. Furthermore, the autopsied brain from one deceased individual showed characteristic neurodegenerative findings: cactus and somatic sprout formations in the residual Purkinje cells in the cerebellum, which are also seen in some diseases associated with mitochondrial impairment. Defects of microtubule formation caused by TBCD mutations may underlie the pathomechanism of this neurodegenerative encephalopathy.

Deletion of exons 3-9 encompassing a mutational hot spot in the DMD gene presents an asymptomatic phenotype, indicating a target region for multiexon skipping therapy.

Few cases of dystrophinopathy show an asymptomatic phenotype with mutations in the 5' (exons 3-7) hot spot in the Duchenne muscular dystrophy (DMD) gene. Our patient showed increased serum creatine kinase levels at 12 years of age. A muscle biopsy at 15 years of age led to a diagnosis of Becker muscular dystrophy. The patient showed a slight decrease in cardiac function at the age of 21 years and was administered a ß-blocker, but there was no muscle involvement even at the age of 27 years. A deletion of exons 3-9 encompassing a mutational hot spot in the DMD gene was detected, and dystrophin protein expression was ∼15% that of control level. We propose that in-frame deletion of exons 3-9 may produce a functional protein, and that multiexon skipping therapy targeting these exons may be feasible for severe dystrophic patients with a mutation in the 5' hot spot of the DMD gene.

[A case of acute necrotizing encephalopathy and acute encephalopathy with biphasic seizures and late reduced diffusion].

Acute necrotizing encephalopathy (ANE) has a characteristic imagimg finding of bilateral symmetrical thalamic lesions. Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is characterized by biphasic clinical course and high intensity of subcortical white matter in MRI diffusion images appearing around the late seizure. We herein report a case of an 8-month-old girl who presented with fever and status epilepticus associated with human herpes 6 infection. Although MRI first demonstrated images of ANE, typical AESD images were observed several days after the onset. We therefore concluded that this case had a combination of ANE and AESD. A proper therapeutic strategy should be established, and acute encephalopathy needs to be better clarified by identifying diagnostic markers and improving the genetical analysis.

Protracted juvenile neuronal ceroid lipofuscinosis--an autopsy report and immunohistochemical analysis.

The juvenile form of neuronal ceroid lipofuscinosis (JNCL) is caused by mutations in the CLN3 gene, and is characterized by progressive loss of vision and development of motor deficits. A few patients exhibit a more protracted clinical course and are diagnosed with protracted JNCL (PJNCL). Here, we report the autopsy in a case of PJNCL in a 55-year-old male and immunohistochemical examination of the involvement of oxidative stress and glutamate excitotoxicity in neurodegeneration. The patient was born to consanguineous parents (I assume this means that the parents were related. If not, then the sentence will need to be changed again.) and had brothers with similar neurological disease. He showed mental retardation and visual impairment in the first decade which gradually developed along with motor dysfunction for over 40 years. At autopsy, the cerebral pyramidal neurons revealed deposition of lipopigments, which demonstrated 'finger print' and curvilinear profiles on electron microscopy. He also exhibited cerebellar cortical atrophy, fibrillary gliosis in the white matter, and rarefication in the globus pallidus. Immunohistochemically, the number of neurons immunoreactive for advanced glycation end product was elevated in the cerebellar cortex and midbrain. Immunoreactivity for excitatory amino acid transporter 1 was reduced in the cerebellar dentate and inferior olivary nuclei. These findings suggest that oxidative damage to proteins and disturbed glutamate transport can be involved in PJNCL.

Periventricular low intensities on fluid attenuated inversion recovery imaging in the newborn infant: Relationships to chronic white matter lesions.

BACKGROUND: Neurological disadvantages due to hypoxic ischemic encephalopathy (HIE) are still very serious problems. In order to support the infant with HIE, it is important to evaluate the severity of the brain injury early. The authors performed a magnetic resonance imaging (MRI) study of the neonatal brain in order to assess the clinical value of periventricular low intensities (PVLI) detected on fluid attenuated inversion recovery (FLAIR) imaging. METHODS: A total of 451 MRI from 167 preterm and 113 term infants were sorted into groups according to the corrected age at the time of scanning. Intensities in the white matter were then divided into five grades according to the severity of the finding on FLAIR imaging. Chronic abnormalities such as periventricular hyperintensities (PVHI) were also analyzed. RESULTS: In early MRI, which was obtained before 2 months corrected age, the incidence of PVLI was 63%, while it was only 3% and 0% in the middle (2-8 months) and the late (8-18 months) scans, respectively. Instead of PVLI, PVHI were commonly observed both on late FLAIR imaging (89%) and late T2-weighted imaging (72%). The severity of the white matter damage diagnosed on early FLAIR imaging had a significant correlation with that of late FLAIR imaging. CONCLUSIONS: F-PVLI on early FLAIR imaging would be a good predictor of chronic white matter damage. FLAIR imaging would be also useful in follow-up of infants because of its high sensitivity to the chronic white matter lesion.

Periventricular low intensities on fluid attenuated inversion recovery imaging in the newborn infant: relationships to the clinical data and long-term outcome.

BACKGROUND: The author's previous study showed that it is possible to predict the severity of white matter injury in early infancy by using fluid attenuated inversion recovery (FLAIR) imaging. A follow-up study was performed in order to assess the correlation between the incidence of periventricular low intensities on FLAIR imaging (F-PVLI) and the clinical data including the physiological variables at birth and the long-term outcome of the infant. METHODS: The authors reviewed MRI of 328 newborn infants, which were obtained before 2 months corrected age. Abnormal findings in the periventricular white matter and other part of the brain were recorded. Periventricular abnormal intensities were sorted into four groups according to the FLAIR grade, which comprised normal, F-PVLI 1 (focal), F-PVLI 2 (extensive), cystic periventricular leukomalacia (C-PVL), and diffused leukomalacia. RESULTS: Significantly more periventricular abnormal intensities were detected by FLAIR imaging than by conventional T1 and T2 weighted imaging. In the groups of F-PVLI 2 and C-PVL, the birth weight (BW), gestational age (GA), blood pH and base excess at birth were significantly lower than in the normal group. However, when the study population was defined into very low birth weight infants, F-PVLI 2 had significantly larger BW and GA than normal. The FLAIR grade had a strong correlation with the developmental outcome at 12 and 36 months corrected age. CONCLUSIONS: F-PVLI is a silent but very important white matter injury, which has many features in common with C-PVL. FLAIR imaging could be a strong tool in screening newborn infants at high risk of neurological impairment.

Further delineation of the behavioral and neurologic features in Costello syndrome.

To describe clinical and neurodevelopmental phenotypes of Costello syndrome, we performed a retrospective review of the clinical records and findings in 10 children with Costello syndrome. All patients showed significant postnatal growth retardation and severe feeding difficulties leading to failure to thrive from early infancy. All required tube feeding and some needed high-calorie formulas for variable periods. Developmental quotients/IQs in seven children were 50 or less, and three were in the mildly retarded range. Five had seizures. Remarkable manifestations not previously reported were the characteristic behavior in infancy. Although happy and sociable personality was always emphasized in the genetic literature, all children showed significant irritability, including hypersensitivity to sound and tactile stimuli, sleep disturbance, and excess shyness with strangers in infancy. Those symptoms usually disappeared around age 2-4 years. Other clinical signs included cardiac abnormalities (8), musculoskeletal abnormalities (10), ophthalmological manifestations (5), increased urinary vanillymandelic acid (VMA) and homovanillic acid (HVA) (3), rhabdomyosarcoma (1), laryngomalacia (1), and cryptorchidism (1). Only three girls had papillomata. Family histories were negative for Costello syndrome. In conclusion, we confirm the wide spectrum of mental function in patients with Costello syndrome, which ranges from severe to mild. During infancy Costello syndrome showed remarkable irritability with severe feeding problems, which attributes significant difficulties to the parents of affected children.