Diagnostic challenge for the rare lysosomal storage disease: Late infantile GM1 gangliosidosis

Publication date: May 2018
Source:Brain and Development, Volume 40, Issue 5
Author(s): Jin Sook Lee, Jong-Moon Choi, Moses Lee, Soo Yeon Kim, Sangmoon Lee, Byung Chan Lim, Jung-Eun Cheon, In-One Kim, Ki Joong Kim, Murim Choi, Moon-Woo Seong, Jong-Hee Chae
BackgroundGM1 gangliosidosis is a rare lysosomal storage disorder caused by GLB1 mutations. Because of its extreme rarity and symptoms that overlap with other neurodegenerative diseases, its diagnosis is sometimes challenging, especially in the late infantile form with less severe phenotype. We aim to expand the clinical and genetic spectrum of late infantile GM1 gangliosidosis.MethodsWe confirmed a diagnosis of GM1 gangliosidosis based on GLB1 mutations and/or the deficiency of β-galactosidase activity. We identified the first two cases by whole-exome sequencing, and then the other six cases by direct sequencing of GLB1 with enzyme analysis.ResultsAll eight patients presented with developmental delay or regression during late infancy and later developed epilepsy, mostly intractable generalized tonic seizures. No clinical signs of storage disorders were noted except for skeletal abnormalities. Interestingly, we found aspartate transaminase (AST) elevations alone with normal alanine transaminase (ALT) levels in all patients. The recurrent mutation, p.D448V in GLB1, accounted for 50.0% of total alleles in our cohort.ConclusionsWith a high index of clinical suspicion, skeletal survey and AST level would be important for early diagnosis of GM1 gangliosidosis. In addition, we would highlight the clinical usefulness of whole-exome sequencing in the diagnosis of non-classical presentation of ultra-rare neurodegenerative disease in children.



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The assessment of sniff nasal inspiratory pressure in patients with Duchenne muscular dystrophy in China

Publication date: May 2018
Source:Brain and Development, Volume 40, Issue 5
Author(s): Shu Zhang, Qian-qian Mei, Jing Xin, Hong-ying Zhang, Shi-wen Wu, Chun-feng Liu
ObjectiveProgressive weakness of respiratory muscles remains one of the leading causes of death among patients with Duchenne muscular dystrophy (DMD). Currently, there are few pulmonary function data among Chinese DMD patients. This study was carried out to evaluate the sniff nasal inspiratory pressure (SNIP) change among a group of Chinese DMD patients, and compare it with the SNIP value of patients with neuromuscular disorders in other countries.MethodsSNIP data were collected in three research groups that consists of 581 subjects: 125 DMD boys who have taken steroid (Age 5.0–13.3, DMD-steroid group), 145 DMD steroid-naive boys (Age 5.0–13.9, DMD-nonsteroid group), and 311 healthy controls (Age 5.0–14.0, Control group).ResultsThe SNIP for DMD-nonsteroid group, DMD-steroid group and Control group were: 56.5 (±14.3) cm H2O,66.4 (±15.5) cm H2O and 78.9 (±21.5) respectively. The SNIP in the DMD-nonsteroid group became significantly different from that of the healthy controls since age 7.0–8.9. The significant difference of SNIP between DMD-steroid group and DMD-nonsteroid group at age 7.0–10.9. The peak value of SNIP in the DMD-nonsteroid group appeared at age 8.7, and decreased dramatically thereafter, while in DMD-steroid group and the Control group peaked at 10.2 years and 12.2 years respectively. There was a bit difference between SNIP in this group and that in previous researches which may be due to geographical distribution and ethnic backgrounds.ConclusionThis study strengthens the previous findings that SNIP can be used to evaluate respiratory dysfunction during the early stage of young patients with neuromuscular disorders, and demonstrates that steroid is effective in slowing the decrease of SNIP in this group of Chinese DMD boys.



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Detection of fast (40–150 Hz) oscillations from the ictal scalp EEG data of myoclonic seizures in pediatric patients

Publication date: May 2018
Source:Brain and Development, Volume 40, Issue 5
Author(s): Katsuhiro Kobayashi, Yuji Ohuchi, Takashi Shibata, Yoshiyuki Hanaoka, Mari Akiyama, Makio Oka, Fumika Endoh, Tomoyuki Akiyama
ObjectiveWe explored fast (40–150 Hz) oscillations (FOs) from the ictal scalp electroencephalogram (EEG) data of myoclonic seizures in pediatric patients to obtain insight into the pathophysiological mechanisms involved in the generation of myoclonic seizures.Subjects and methodsThe participants were 21 children (11 boys, 10 girls; age ranging from 5 months to 17 years 2 months) with myoclonic seizures associated with generalized (poly)spike-wave bursts in the ictal EEG data. The patients had heterogeneous etiologies and epilepsy diagnoses. In the ictal data, we detected FOs that clearly showed oscillatory morphology in filtered EEG traces and an outstanding spectral blob in time-frequency analysis.ResultsWe identified FOs in 61 (88.4%) of all 69 myoclonic seizures. Every patient had at least one myoclonic seizure-associated FO. The observed FOs were embedded in the spike component of (poly)spike-wave discharges, and they had a focal distribution with frontal predominance. They ranged in frequency from 41.0 to 123.0 Hz and involved both the gamma and ripple bands, and their spectral peak frequencies were higher in the group of patients with a genetic background free of apparent fundamental brain pathology than in the group of other patients (p = 0.019).ConclusionFOs were found to represent at least part of the cortical pathophysiological process in the generation of myoclonic seizures that should involve the thalamocortical network system.



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Editorial Board

Publication date: May 2018
Source:Brain and Development, Volume 40, Issue 5





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Efficacy and safety of everolimus in patients younger than 12 months with congenital subependymal giant cell astrocytoma

Publication date: May 2018
Source:Brain and Development, Volume 40, Issue 5
Author(s): Ichiro Kuki, Hisashi Kawawaki, Shin Okazaki, Eiji Ehara, Yoko Yoshida, Noritsugu Kunihiro, Yasuhiro Matsusaka
Tuberous sclerosis complex (TSC) is a multisystem genetic disorder that activates mammalian target of rapamycin and produces tumor growth in several organs. We present five patients younger than 12 months who were diagnosed with TSC and treated with everolimus (EVL), after which congenital subependymal giant astrocytoma (cSEGA) promptly regressed in all patients. All patients achieved at least 50% reduction in the volume of cSEGA within 6 months. The most rapid reduction of cSEGA volume (79.1%) was found during the initial 3 months of EVL treatment. Patients underwent EVL treatment for an average of 27 months (range: 4–55 months). Mean EVL maintenance dose was 1.35 mg per day. EVL blood trough concentrations ranged from 2.0 to 11.7 ng/ml. The cSEGA became larger after discontinuing EVL in two patients. In all four patients who had multiple cardiac rhabdomyomas (CRMs), the CRMs showed accelerated regression after receiving EVL. Adverse events were noted in four patients: infection, stomatitis, and increased triglycerides. Four patients had febrile status epilepticus, which occurred during acute encephalopathy in a patient, and after discontinuing EVL in another. Three patients were still receiving EVL at their latest evaluations. Maintenance therapy with EVL is an effective therapeutic option for patients with cSEGA, and moreover may have additional favorable effects on other complications, even in early infancy; however, adverse effects should be carefully monitored.



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Successful use of non-invasive positive pressure ventilation in a patient with the severe form of X-linked myotubular myopathy

Publication date: May 2018
Source:Brain and Development, Volume 40, Issue 5
Author(s): Kenji Inoue, Tomohiro Kumada, Ikuko Hiejima, Tatsuya Fujii
The severity of X-linked myotubular myopathy (XLMTM) ranges from mild to severe, depending on the level of ventilatory support required. Patients with the severe form of XLMTM usually die within the first year of life due to respiratory failure. Most survivors need tracheostomies, and there has only been one report about the use of non-invasive positive pressure ventilation (NPPV) in patients with the severe form of XLMTM because of the severity of the associated respiratory failure. We successfully applied NPPV with high-span positive inspiratory pressure (PIP) in a patient with the severe form of XLMTM, who also had secondary pectus excavatum. About a year after the initiation of NPPV with high-span PIP, the patient's pectus excavatum had improved. As the patient's pectus excavatum improved, his respiratory disturbance was ameliorated, and the frequency of respiratory infections gradually decreased. NPPV might be the first-choice respiratory management strategy for patients with XLMTM.



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Anti-N-methyl-d-aspartate receptor encephalitis in children: Incidence and experience in Hong Kong

Publication date: Available online 26 March 2018
Source:Brain and Development
Author(s): Alvin Chi-chung Ho, Sophelia Hoi-shan Chan, Eric Chan, Sheila Suet-na Wong, Sharon Tsui-hang Fung, Sharon Wan-wah Cherk, Eva Lai-wah Fung, Kam-hung Ma, Kwing-wan Tsui, Eric Kin-cheong Yau, Virginia Chun-nei Wong
AimThe study aims to analyze the incidence, clinical features, investigation findings and treatment outcomes of anti-N-methyl-d-aspartate receptor encephalitis in children from Hong Kong.MethodA retrospective study was carried out on paediatric patients diagnosed with anti-NMDAR encephalitis in Hong Kong from January 2009 to December 2015.ResultsFifteen patients (67% female, 93% Chinese) were identified over seven years and the estimated incidence in Hong Kong was 2.2/million children per year (95% CI 1.2–3.6). The median age of presentation was 12 years (range 1–17 years). The most common symptom groups observed were abnormal psychiatric behavior or cognitive dysfunction (14/15, 93%) and seizures (14/15, 93%), followed by speech dysfunction (13/15, 87%), movement disorders (12/15, 80%), decreased level of consciousness (10/15, 67%) and autonomic dysfunction or central hypoventilation (5/15, 33%). The median number of symptom groups developed in each patient was 5 (range 3–6). All patients were treated with intravenous immunoglobulin and/or steroids. Three patients (20%) with more severe presentation required additional plasmapheresis and rituximab. Outcome was assessable in 14 patients. Among those eleven patients who had only received intravenous immunoglobulin and/or steroids, nine patients (82%) achieved full recovery. One patient (9%) had residual behavioral problem, while another one (9%) who developed anti-NMDAR encephalitis after herpes simplex virus encephalitis was complicated with dyskinetic cerebral palsy and epilepsy. Among those three patients who required plasmapheresis and rituximab, one (33%) had full recovery and two (66%) had substantial recovery. The median duration of follow up was 20.5 months (range 3–84 months).ConclusionAnti-NMDAR encephalitis is an acquired, severe, but potentially treatable disorder. Ethnicity may play a role in the incidence of anti-NMDAR encephalitis and we have provided a local incidence with the majority of patients being Chinese. The diagnosis of anti-NMDAR encephalitis should be considered in children presenting with a constellation of symptoms including psychiatric and neurological manifestations. Patients may respond to first line immunotherapy. For those who do not, second line therapy is indicated in order to achieve a better outcome.



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Hemiconvulsion-hemiplegia-epilepsy evolving to contralateral hemi-Lennox-Gastaut-like phenotype

Publication date: May 2018
Source:Brain and Development, Volume 40, Issue 5
Author(s): Kenneth A. Myers, Ingrid E. Scheffer, John S. Archer
BackgroundHemiconvulsion-hemiplegia-epilepsy (HHE) involves infantile-onset acute hemiconvulsive febrile status epilepticus with subsequent unilateral cerebral atrophy and hemiparesis. Chronic epilepsy later develops, typically involving refractory focal seizures; however, the underlying pathophysiology of this epilepsy is not well understood.PatientWe present a boy who had a typical acute presentation of HHE at 23 months, but an unusual evolution to chronic epilepsy in which the initially unaffected hemisphere was significantly abnormal. His initial acute presentation was right-sided hemiconvulsive febrile status epilepticus, with subsequent left cerebral hemiatrophy and hemiparesis affecting the right face, arm and leg. Focal seizures began at 5 years and were refractory to medical treatment. At 9 years, video EEG monitoring showed a striking pattern of interictal slow spike-wave and paroxysmal fast activity, maximal over the right, initially unaffected, hemisphere. He had primarily focal tonic seizures involving left-sided stiffening, also appearing to originate from the right hemisphere. Following left functional hemispherotomy he became seizure-free and parents reported improved cognitive function, attention and quality of life.DiscussionThis boy had classic features of Lennox-Gastaut syndrome, but expressed almost exclusively over the right hemisphere, which was initially unaffected in his acute presentation of HHE. His evolution to "hemi-Lennox-Gastaut-like phenotype" illustrates the importance of monitoring chronic epilepsy in patients with HHE; early surgical intervention might prevent pathologic recruitment of bilateral secondary networks leading to the refractory seizures and cognitive impairment associated with Lennox-Gastaut syndrome.



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Familial cases of progressive myoclonic epilepsy caused by maternal somatic mosaicism of a recurrent KCNC1 p.Arg320His mutation

Publication date: May 2018
Source:Brain and Development, Volume 40, Issue 5
Author(s): Hyuna Kim, Sangmoon Lee, Murim Choi, Hunmin Kim, Hee Hwang, JiEun Choi, Jong Hee Chae, Ki Joong Kim, Byung Chan Lim
PurposeA recurrent de novo mutation in KCNC1 (c.959G > A, p.Arg320His) has been identified recently as one of the important genetic causes of progress myoclonic epilepsy (PME). The clinical phenotype resulting from this mutation has been named as myoclonus epilepsy and ataxia due to potassium channel mutation (MEAK). This finding carries important clinical implications in that autosomal dominant inheritance and de novo occurrence need to be considered when conducting genetic tests in patients with PME. We present two familial cases of MEAK in siblings with a recurrent p.Arg320His mutation in KCNC1.MethodWhole exome sequencing and subsequent Sanger sequencing were performed for the cases and their parents.ResultsA recurrent p.Arg320His mutation in KCNC1 was identified in the two brothers who showed characteristic features of MEAK: near normal early development, onset of myoclonus around 10 years of age, infrequent generalized tonic-clonic seizures, relatively mild cognitive impairment, and generalized epileptiform discharges. Interestingly, the asymptomatic mother was suspected as being mosaic for this mutation. This finding could lead to misleading inheritance patterns and make genetic diagnosis of PME more complicated.ConclusionsOur familial MEAK cases show that consideration of parental mosaicism in addition to meticulous phenotyping is needed when conducting KCNC1 genetic testing.



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ATP1A3-related epileptic encephalopathy responding to ketogenic diet

Publication date: May 2018
Source:Brain and Development, Volume 40, Issue 5
Author(s): Tommaso Schirinzi, Federica Graziola, Raffaella Cusmai, Lucia Fusco, Francesco Nicita, Mirella Elia, Lorena Travaglini, Enrico Bertini, Paolo Curatolo, Federico Vigevano, Alessandro Capuano
BackgroundAlternating Hemiplegia of Childhood (AHC) is a rare neurological disease caused by mutations in ATP1A3 gene codifying for alpha3 subunit of Na⁺-K⁺ ATPase pump. Repeated and transient attacks of hemiplegia, usually affecting one side of the body or the other, or both sides of the body at once, are the core features of AHC. Monocular nystagmus, other abnormalities in ocular movements, dystonic posturing and epilepsy are commonly associated to AHC. However, the spectrum of ATP1A3 related diseases is still expanding and new phenotypes have been reported.Case reportHere, we described a patient who developed a severe early onset drug-resistant epileptic encephalopathy and months later, he presented episodes of hemiplegic attacks and monocular nystagmus. Thus, AHC was hypothesized and a novel mutation in ATP1A3 gene was found. Interestingly, ketogenic diet (KD) was started and both epileptic seizures and classical AHC paroxysmal episodes stopped. Long-term follow-up shows a global improvement of neurological development.ConclusionsOur case reinforces the role of KD as a novel therapeutic option for ATP1A3-related conditions. However, proper dedicated confirmatory trials on KD are necessary.



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Guillain-Barré syndrome and optic neuritis after Mycoplasma pneumoniae infection

Publication date: May 2018
Source:Brain and Development, Volume 40, Issue 5
Author(s): Manaka Matsunaga, Yuichi Kodama, Shinsuke Maruyama, Akinori Miyazono, Shunji Seki, Takayuki Tanabe, Michiyoshi Yoshimura, Junichiro Nishi, Yoshifumi Kawano
We report the case of a 12-year-old girl who developed Guillain-Barré syndrome (GBS) and optic neuritis (ON) following Mycoplasma pneumoniae infection.Her symptoms, including bilateral vision impairment and tingling in her hands and right foot, were resolved after methylprednisolone pulse therapy. Serum anti-galactocerebroside (Gal-C) IgM antibodies were detected in our patient.This is the first report of a child with GBS and ON associated with M. pneumoniae infection.



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Announcements and reports

Publication date: May 2018
Source:Brain and Development, Volume 40, Issue 5





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Cover

Publication date: May 2018
Source:Brain and Development, Volume 40, Issue 5





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Contents

Publication date: May 2018
Source:Brain and Development, Volume 40, Issue 5





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Life cycle of PCBs and contamination of the environment and of food products from animal origin

Abstract

This report gives a summary of the historic use, former management and current release of polychlorinated biphenyls (PCBs) in Germany and assesses the impact of the life cycle of PCBs on the contamination of the environment and of food products of animal origin. In Germany 60,000 t of PCBs were used in transformers, capacitors or as hydraulic oils. The use of PCB oils in these "closed applications", has been banned in Germany in 2000. Thirty to 50% of these PCBs were not appropriately managed. In West Germany, 24,000 t of PCBs were used in open applications, mainly as additive (plasticiser, flame retardant) in sealants and paints in buildings and other construction. The continued use in open applications has not been banned, and in 2013, an estimated more than 12,000 t of PCBs were still present in buildings and other constructions. These open PCB applications continuously emit PCBs into the environment with an estimated release of 7–12 t per year. This amount is in agreement with deposition measurements (estimated to 18 t) and emission estimates for Switzerland. The atmospheric PCB releases still have an relevant impact on vegetation and livestock feed. In addition, PCBs in open applications on farms are still a sources of contamination for farmed animals. Furthermore, the historic production, use, recycling and disposal of PCBs have contaminated soils along the lifecycle. This legacy of contaminated soils and contaminated feed, individually or collectively, can lead to exceedance of maximum levels in food products from animals. In beef and chicken, soil levels of 5 ng PCB-TEQ/kg and for chicken with high soil exposure even 2 ng PCB-TEQ/kg can lead to exceedance of EU limits in meat and eggs. Areas at and around industries having produced or used or managed PCBs, or facilities and areas where PCBs were disposed need to be assessed in respect to potential contamination of food-producing animals. For a large share of impacted land, management measures applicable on farm level might be sufficient to continue with food production. Open PCB applications need to be inventoried and better managed. Other persistent and toxic chemicals used as alternatives to PCBs, e.g. short chain chlorinated paraffins (SCCPs), should be assessed in the life cycle for exposure of food-producing animals and humans.

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Corrigendum to “Immune-enhancing effects of polysaccharides extracted from Lilium lancifolium Thunb” [Int. Immunopharmacol. 52 (2017) 119–126]

Publication date: Available online 26 March 2018
Source:International Immunopharmacology
Author(s): Guifang Pan, Zhongwen Xie, Shixia Huang, Yuling Tai, Qingshuang Cai, Wei Jiang, Jiameng Sun, Yi Yuan




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Comparative Study in Oral, Breast Approach and Open Thyroidectomy

Condition:   Thyroid Neoplasms
Intervention:   Procedure: Thyroid Surgical Methods
Sponsor:   Second Affiliated Hospital, School of Medicine, Zhejiang University
Recruiting

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Can Early Initiation of Rehabilitation With Wearable Sensor Technology Improve Outcomes in mTBI?

Conditions:   Mild Traumatic Brain Injury;   Balance; Distorted;   Gait, Unsteady;   Quality of Life;   Veterans
Intervention:   Behavioral: Rehabilitation
Sponsors:   Oregon Health and Science University;   United States Department of Defense
Not yet recruiting

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Deconstructing skill learning and its physiological mechanisms

Publication date: Available online 27 March 2018
Source:Cortex
Author(s): D. Spampinato, P. Celnik
Acquiring complex motor skills involves learning a number of distinct motor components. Two fundamental elements that constitute a skill are the internal representation (i.e. the calibration of a sensorimotor map) and the sequence of movements needed to execute the task. Learning each of these likely rely on different neural substrates such as the cerebellum and primary motor cortex (M1), and physiological mechanisms. However, the specific neurophysiological processes underlying the acquisition of these components remains poorly understood. Here we used non-invasive brain stimulation to identify distinct physiological contributions arising from the cerebellum and M1 associated with learning the internal representation and the sequence of movements to execute a skill. Experiment one evaluated neurophysiological markers of the cerebellum and M1 while participants learned a sensorimotor map. Participants learned to calibrate the appropriate motor outputs to interact with a new device, prior to learning a new motor skill. We found that plastic changes in the cerebellum, but not in M1, are linked to learning the internal representation. Experiment two assessed the same neurophysiological markers while participants learned a sequence of movements, independent of acquiring a novel sensorimotor map. Here, both M1 LTP-like plasticity and cerebellar plasticity mediated movement sequence learning. Our findings indicate that learning the different components that will constitute a motor skill engages multiple nodes of a brain network in a concerted manner. In addition, it calls into question the expectation that targeting specific brain regions, such as M1, with brain stimulation to augment complex skill learning will have positive results.



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Simple dissociations for a higher-powered neuropsychology

Publication date: Available online 27 March 2018
Source:Cortex
Author(s): Robert D. McIntosh
Dissociations in cognitive neuropsychology are often investigated at the level of the single-case, and formal criteria exist for the detection of dissociations, and their sub-classification into 'classical' and 'strong' types. These criteria require a patient to show a frank deficit on one task (for a classical dissociation) or both tasks (for a strong dissociation), and a significantly extreme difference between tasks. I propose that only the significant between-task difference is logically necessary, and that if this simple criterion is met, the patient should be said to show a dissociation. Using Monte Carlo simulations, I show that this simplification increases the power to detect dissociations across a range of practically-relevant conditions, whilst retaining excellent control over Type I error. Additional testing for frank deficits on each task provides further qualifying information, but using these test outcomes to categorise dissociations as classical or strong may be too uncertain to guide theoretical inferences reliably. I suggest that we might instead characterise the strength of the dissociation using a continuous index, such as the effect size of the between-task difference.



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