How to Detect Isolated PEX10-Related Cerebellar Ataxia?

A 4-year-old boy presented with subacute onset of cerebellar ataxia. Neuroimaging revealed cerebellar atrophy. Metabolic screening tests aiming to detect potentially treatable ataxias showed an increased value (fourfold upper limit of normal) for phytanic acid and elevated very-long-chain fatty acid (VLCFA) ratios (C24:0/C22:0 and C26:0/C22:0), while absolute concentrations of VLCFA were normal. Genetic analysis identified biallelic variants in PEX10. Immunohistochemistry confirmed pathogenicity in the patients' cultured fibroblasts demonstrating peroxisomal mosaicism with a general catalase import deficiency as well as conspicuous peroxisome morphology as an expression of impaired peroxisomal function. We describe for the first time an elongated peroxisome morphology in a patient with PEX10-related cerebellar ataxia.A literature search yielded 14 similar patients from nine families with PEX10-related cerebellar ataxia, most of them presenting their first symptoms between 3 and 8 years of age. In 11/14 patients, the first and main symptom was cerebellar ataxia; in three patients, it was sensorineural hearing impairment. Finally, all 14 patients developed ataxia. Polyneuropathy (9/14) and cognitive impairment (9/14) were common associated findings. In 12/13 patients brain MRI showed cerebellar atrophy. Phytanic acid was elevated in 8/12 patients, while absolute concentrations of VLCFA levels were in normal limits in several patients. VLCFA ratios (C24:0/C22:0 and/or C26:0/C22:0), though, were elevated in 11/11 cases. We suggest including measurement of phytanic acid and VLCFA ratios in metabolic screening tests in unexplained autosomal recessive ataxias with cerebellar atrophy, especially when there is an early onset and symptoms are mild.

Neurofibromatosis type 1 (NF1) with an unusually severe phenotype due to digeny for NF1 and ryanodine receptor 1 associated myopathy.

UNLABELLED: We describe a 5-year-old girl with marked hypotonia, poor feeding and reduced facial expression since birth. Congenital myopathy was suspected; muscle biopsy showed unspecific type 1 fibre predominance. The possibility of a ryanodine receptor 1 gene (RYR1)-associated myopathy was considered, but not further investigated. At the age of 2 years, she presented with exophthalmos. Brain MRI revealed optic pathway glioma. On clinical examination, she had six café-au-lait spots, thus fulfilling the diagnostic criteria for neurofibromatosis type 1 (NF1). The hypotonia was then attributed to NF1. At the age of 3 years, she developed scoliosis and had an unusually severe motor delay for NF1, as she was not able to walk independently. Dual pathology was suspected, and muscle MRI showed the typical pattern for RYR1-related myopathy. This was genetically confirmed with the discovery of two heterozygous mutations. CONCLUSION: NF1 is one of the most frequent genetic diseases in children. RYR1-related myopathy is one of the most frequent causes of congenital myopathy. The combination of these two pathologies has not yet been described. In cases of unusual presentations or clinical course, the possibility of genetic "double trouble" should be considered.

Martial Arts and Cognitive Control in Children with Attention-Deficit Hyperactivity Disorder and Children Born Very Preterm: A Combined Analysis of Two Randomized Controlled Trials.

INTRODUCTION: Very preterm birth and attention-deficit hyperactivity disorder (ADHD) are associated with impairments in response inhibition that often persist beyond childhood. Athletes skilled in martial arts show a neurocognitive profile that is associated with an improved inhibition processing stream, suggesting that engagement in this kind of sport has the potential to reduce impairments in this cognitive function. We investigated the behavioral and neurocognitive effects of judo training on response inhibition in children born very preterm and children with ADHD by a combined analysis of two randomized controlled trials. METHODS: In both the CHIPMANC ( n = 65) and JETPAC ( n = 63) studies, participants were randomly allocated to a waitlist or a 12-wk judo training program in a 1:1 ratio. At pretest and posttest, participants completed a Go/NoGo task, the Movement Assessment Battery for Children-2 and a physical work capacity test on a bicycle ergometer. During the cognitive task, event-related potentials (N2, P3a, P3b) were recorded via electroencephalography. RESULTS: The effects of the judo training were moderated by the study group. In contrast to children with ADHD (JETPAC), judo training reduced the commission error rate on the Go/NoGo task and increased the P3a amplitude in children born very preterm (CHIPMANC). No treatment effects were found for N2, P3b and physical fitness outcomes. CONCLUSIONS: The neurodevelopmental condition influences the cognitive benefits of judo training. Whereas judo may be ineffective in children with ADHD, children born very preterm can expect improved response inhibition due to a more effective engagement of focal attention to resolve the task-related response conflict.

Behavioral and neurocognitive effects of judo training on working memory capacity in children with ADHD: A randomized controlled trial.

BACKGROUND: Children with Attention Deficit Hyperactivity Disorder (ADHD) face deficits in working memory capacity that often persist into adulthood. In healthy peers, exercise targeting motor skill acquisition benefits visuospatial working memory, but its potential to reduce ADHD-related deficits remains unclear. We investigated the effect of a judo training program targeting motor skills on behavioral and neurocognitive indices of working memory capacity in children with ADHD. METHODS: Children with ADHD aged 8 to 12 years (N = 57) were randomly allocated to a judo training group and a wait-list control group. The training program encompassed 120 min of judo per week over three months. Before and after the intervention period, participants completed a bilateral Change Detection task with low and high memory load conditions and the Movement Assessment Battery for Children-2 (MABC-2). The contralateral delay activity (CDA) elicited by the cognitive task was recorded using electroencephalography. RESULTS: Compared to the control group, the judo training group showed a higher K-score on the Change Detection task and an increased negativity of the CDA on the high load condition following the intervention, when pretest scores (and confounders) were accounted for. In contrast, no group differences were found for MABC-2 score. CONCLUSION: In children with ADHD, judo training may complement the pharmacological treatment by increasing the effectiveness of working memory maintenance processes. On a behavioral level, this improvement is accompanied with an increased capacity to store visuospatial information.

Atypical presentation of sunflower epilepsy featuring an EEG pattern of continuous spike waves during slow-wave sleep.

Sunflower epilepsy is a rare photosensitive and commonly pharmacoresistant reflex epilepsy characterized by stereotyped seizures involving turning of the head towards light, similar to a sunflower turning towards the sun, and waving of the hands in front of the eyes, sometimes followed by absence seizures, myoclonic jerks, and tonic-clonic seizures. In the original description, seizures in sunflower epilepsy have been perceived as self-induced, but contemporary case series suggest that hand waving corresponds to an ictal phenomenon and not to a precipitating factor. We describe a nine-year-old girl featuring absence seizures with eye rolling or fluttering associated with hand waving movements. The chronological sequence of events based on a video-EEG-documented episode of our patient adds to the controversy surrounding the hypothesis of "self-induced" epileptic seizures in sunflower epilepsy. Shortly after epilepsy diagnosis, our patient presented with an EEG pattern of continuous spike waves in slow-wave sleep, an EEG feature that has not been described before and may relate to the cognitive deficit observed in some patients with sunflower epilepsy. Continuous spike waves in slow-wave sleep resolved, and lasting seizure freedom was achieved by a combination of ethosuximide and lamotrigine, which may be a possible alternative to valproic acid, particularly in girls and women of childbearing age. However, an attempt to taper anti-seizure drugs two years later led to seizure recurrence. We suggest performing sleep EEG recordings for sunflower epilepsy, particularly in patients with developmental stagnation or regression, to timely diagnose and treat continuous spike waves in slow-wave sleep syndrome.

Very preterm birth and cognitive control: The mediating roles of motor skills and physical fitness.

The neurophysiological mechanisms underlying executive function deficits in very preterm born children still remain unclear. Moreover, evidence on factors that can be modified by behavior and exert an influence on these deficits is lacking. The present case-control study examined the association between very preterm birth and neurophysiological indices of response inhibition (i.e. the N200-P300 complex) as well as the potential mediation of this association by aspects of physical fitness. 54 children born very preterm completed a submaximal cycling ergometer test and a motor skill test battery. Event-related potentials elicited by a Go/NoGo task were recorded using electroencephalography. Cases were then matched to full-term children (age: 11 ± 0.7 y). A higher error rate on NoGo trials was found in children born very preterm compared to those born full-term. Path-analyses further revealed that very preterm birth was associated with decreased NoGo P300 amplitude. Motor skills, but not aerobic fitness, fully mediated this association. In early adolescence, very preterm birth is associated with less effective recruitment of attentional resources for stimulus evaluation processes. The improvement of motor skills rather than cardiorespiratory fitness appears promising for reducing this specific impairment in cognitive control.

Deletion of 7q11.21-q11.23 and infantile spasms without deletion of MAGI2.

We report on the clinical and cytogenetic findings and on the array-based characterization of an interstitial 7q11.21-q11.23 deletion initially recognized by standard karyotyping in a 15-month-old female patient. Beginning at the age of 3 months and 2 weeks the patient had severe infantile spasms. Recently, it was reported that infantile spasms are associated with deletion of the MAGI2 gene on chromosome 7q11.23. Nevertheless, not all patients reported with deletions of MAGI2 developed infantile spasms and at least one reported patient with a deletion 7q11.23 without missing the MAGI2 gene was diagnosed with infantile spasms. Molecular karyotyping of our patient confirmed a large 13 Mb deletion encompassing the 7q11.21-q11.23 region without involvement of MAGI2. Critical review of published data and the results of our patient underline the importance to map precisely the deletion boundaries of further patients to reevaluate the significance of MAGI2 hemizygosity in the pathogenesis of infantile spasms.

Analysis of severely affected patients with dihydropyrimidine dehydrogenase deficiency reveals large intragenic rearrangements of DPYD and a de novo interstitial deletion del(1)(p13.3p21.3).

Dihydropyrimidine dehydrogenase (DPD) deficiency is an infrequently described autosomal recessive disorder of the pyrimidine degradation pathway and can lead to mental and motor retardation and convulsions. DPD deficiency is also known to cause a potentially lethal toxicity following administration of the antineoplastic agent 5-fluorouracil. In an ongoing study of 72 DPD deficient patients, we analysed the molecular background of 5 patients in more detail in whom initial sequence analysis did not reveal pathogenic mutations. In three patients, a 13.8 kb deletion of exon 12 was found and in one patient a 122 kb deletion of exon 14-16 of DPYD. In the fifth patient, a c.299_302delTCAT mutation in exon 4 was found and also loss of heterozygosity of the entire DPD gene. Further analysis demonstrated a de novo deletion of approximately 14 Mb of chromosome 1p13.3-1p21.3, which includes DPYD. Haploinsufficiency of NTNG1, LPPR4, GPSM2, COL11A1 and VAV3 might have contributed to the severe psychomotor retardation and unusual craniofacial features in this patient. Our study showed for the first time the presence of genomic deletions affecting DPYD in 7% (5/72) of all DPD deficient patients. Therefore, screening of DPD deficient patients for genomic deletions should be considered.

Circumferential abdominoplasty.

BACKGROUND: In Italy, 34.2% of the population has a BMI higher than 25, and another 9.8% of the population has a BMI higher than 30. In Italy, there are 4 million and 700,000 obese people. Bariatric surgery has evolved as a very effective therapy for morbid obesity. After such dramatic weight loss, patients are usually left with redundant skin and unwieldy subcutaneous tissue. The circumferential truncal excess cannot be corrected by a regular abdominoplasty alone. In this group of patients, lateral excess can actually be over accentuated by a traditional abdominoplasty. In our institution, we are used performing abdominoplasty according to Pascal-Le Louarn's surgical technique. In our cases, the adoption of this technique has been successful with a high rate of very satisfied patients, no major complications and few minor complications primarily in the smoker patients. METHODS: The charts of 41 consecutive circumferential abdominoplasty were reviewed. The preoperative markings, the surgical technique, the post-operative course, and the complications are described. RESULTS: The average operative time was 220 min. The average lipoaspirate was 1,600 cc. The mean weight loss during the surgery was 3.4 kg. There were 18 immediate complications, including 11 seromas, and 7 partial wound dehiscences. There were 26 late complications, including 8 hypertrophic scars and 18 local hypoestesia. All seromas were resolved within 3 weeks. All patients were satisfied. CONCLUSION: Circumferential abdominoplasty performed with Pascal-Le Louarn's surgical technique is an effective, appropriate, and safe method to treat patients with lipodistrophy of the trunk following massive weight loss.

Incidence and outcomes of symptomatic neonatal arterial ischemic stroke.

BACKGROUND AND OBJECTIVES: Neonatal arterial ischemic stroke (NAIS) is associated with considerable lifetime burdens such as cerebral palsy, epilepsy, and cognitive impairment. Prospective epidemiologic studies that include outcome assessments are scarce. This study aimed to provide information on the epidemiology, clinical manifestations, infarct characteristics, associated clinical variables, treatment strategies, and outcomes of NAIS in a prospective, population-based cohort of Swiss children. METHODS: This prospective study evaluated the epidemiology, clinical manifestations, vascular territories, associated clinical variables, and treatment of all full-term neonates diagnosed with NAIS and born in Switzerland between 2000 and 2010. Follow-up was performed 2 years (mean 23.3 months, SD 4.3 months) after birth. RESULTS: One hundred neonates (67 boys) had a diagnosis of NAIS. The NAIS incidence in Switzerland during this time was 13 (95% confidence interval [CI], 11-17) per 100,000 live births. Seizures were the most common symptom (95%). Eighty-one percent had unilateral (80% left-sided) and 19% had bilateral lesions. Risk factors included maternal risk conditions (32%), birth complications (68%), and neonatal comorbidities (54%). Antithrombotic and antiplatelet therapy use was low (17%). No serious side effects were reported. Two years after birth, 39% were diagnosed with cerebral palsy and 31% had delayed mental performance. CONCLUSIONS: NAIS in Switzerland shows a similar incidence as other population-based studies. About one-third of patients developed cerebral palsy or showed delayed mental performance 2 years after birth, and children with normal mental performance may still develop deficits later in life.

Factors affecting cognitive outcome in early pediatric stroke.

OBJECTIVE: We examined cognitive performance in children after stroke to study the influence of age at stroke, seizures, lesion characteristics, neurologic impairment (NI), and functional outcome on cognitive outcome. METHODS: This was a prospectively designed study conducted in 99 children who sustained an arterial ischemic stroke (AIS) between the age of 1 month and 16 years. All children underwent cognitive and neurologic follow-up examination sessions 2 years after the insult. Cognitive development was assessed with age-appropriate instruments. RESULTS: Although mean cognitive performance was in the lower normative range, we found poorer results in subtests measuring visuoconstructive skills, short-term memory, and processing speed. Risk factors for negative cognitive outcome were young age at stroke, seizures, combined lesion location (cortical and subcortical), as well as marked NI. CONCLUSIONS: We recommend that all children with a history of AIS undergo regularly scheduled neuropsychological assessment to ensure implementation of appropriate interventions and environmental adjustments as early as possible.

A novel combined surgical approach to head and neck dermatofibrosarcoma protuberans.

INTRODUCTION: The surgical management of dermatofibrosarcoma protuberans has historically been a challenge, particularly in the head and neck and other aesthetic areas. The current priority is to achieve local oncologic control and a good reconstructive outcome. Here, we present our experience using a novel combined approach with a dermal regenerative template, sub-atmospheric pressure and skin graft. MATERIALS AND METHODS: Five patients presenting at the Department of Plastic and Reconstructive Surgery of the University of Florence between January 2010 and October 2011 were included in the study following Institutional Review Board approval. All patients underwent a wide local excision of dermatofibrosarcoma protuberans affecting the head and neck. RESULTS: The combined approach using the negative-pressure device, a dermal regenerative template and skin grafting proved effective in the management of this type of sarcoma with a good aesthetic and functional outcome, particularly on the neck or the supraclavicular region. CONCLUSION: Although the present multi-step technique requires patient compliance, it results in good local oncologic control of the resection margins. It is possible to perform a wider excision in the event of positive margins without interfering with the last reconstructive outcome.

Vacuum-assisted closure, dermal regeneration template and degloved cryopreserved skin as useful tools in subtotal degloving of the lower limb.

The standard management of degloving injuries involves either immediate grafting with the avulsed skin or full- or split-thickness grafts at a later date. Alternative methods include pedicle and free flaps and revascularisation. The authors present an innovative technique of treating degloving injuries with cryopreserved split-thickness skin grafts harvested from degloved flap, artificial dermal replacement and vacuum-assisted closure (VAC therapy). To the authors' knowledge, this is the first reported case of such bilaminar reconstruction of a degloving injury.

High resolution array in the clinical approach to chromosomal phenotypes.

Array genomic hybridization (AGH) has recently been implemented as a diagnostic tool for the detection of submicroscopic copy number variants (CNVs) in patients with developmental disorders. However, there is no consensus regarding the choice of the platform, the minimal resolution needed and systematic interpretation of CNVs. We report our experience in the clinical diagnostic use of high resolution AGH up to 100 kb on 131 patients with chromosomal phenotypes but previously normal karyotype. We evaluated the usefulness in our clinics and laboratories by the detection rate of causal CNVs and CNVs of unknown clinical significance and to what extent their interpretation would challenge the systematic use of high-resolution arrays in clinical application. Prioritizing phenotype-genotype correlation in our interpretation strategy to criteria previously described, we identified 33 (25.2%) potentially pathogenic aberrations. 16 aberrations were confirmed pathogenic (16.4% syndromic, 8.5% non-syndromic patients); 9 were new and individual aberrations, 3 of them were pathogenic although inherited and one is as small as approx 200 kb. 13 of 16 further CNVs of unknown significance were classified likely benign, for 3 the significance remained unclear. High resolution array allows the detection of up to 12.2% of pathogenic aberrations in a diagnostic clinical setting. Although the majority of aberrations are larger, the detection of small causal aberrations may be relevant for family counseling. The number of remaining unclear CNVs is limited. Careful phenotype-genotype correlations of the individual CNVs and clinical features are challenging but remain a hallmark for CNV interpretation.