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Summary Background Given the novelty of gene replacement therapy with onasemnogene abeparvovec in spinal muscular atrophy, efficacy and safety data are limited, especially for children older than 24 months, those weighing more than 8·5 kg, and those who have received nusinersen. We aimed to provide real-world data on motor function and safety after gene replacement therapy in different patient subgroups. Methods We did a protocol-based, multicentre prospective observational study between Sept 21, 2019, and April 20, 2021, in 18 paediatric neuromuscular centres in Germany and Austria. All children with spinal muscular atrophy types 1 and 2 receiving onasemnogene abeparvovec were included in our cohort, and there were no specific exclusion criteria. Motor function was assessed at the time of gene replacement therapy and 6 months afterwards, using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and Hammersmith Functional Motor Scale-Expanded (HFMSE) scores. Additionally, in children pretreated with nusinersen, motor function was assessed before and after treatment switch. Off-target adverse events were analysed with a focus on liver function, thrombocytopaenia, and potential cardiotoxicity. Findings 76 children (58 pretreated with nusinersen and 18 who were nusinersen naive) with spinal muscular atrophy were treated with onasemnogene abeparvovec at a mean age of 16·8 months (range 0·8–59·0, IQR 9–23) and a mean weight of 9·1 kg (range 4·0–15·0, IQR 7·4–10·6). In 60 patients with available data, 49 had a significant improvement on the CHOP-INTEND score (≥4 points) and HFMSE score (≥3 points). Mean CHOP INTEND scores increased significantly in the 6 months after therapy in children younger than 8 months (n=16; mean change 13·8 [SD 8·5]; p Interpretation This study provides class IV evidence that children with spinal muscular atrophy aged 24 months or younger and patients pretreated with nusinersen significantly benefit from gene replacement therapy, but adverse events can be severe and need to be closely monitored. Funding None. Translation For the German translation of the abstract see Supplementary Materials section.

In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later onset can, in the context of biallelic inheritance, cause devastating neurodevelopmental disorders and infantile or childhood-onset neurodegeneration. TOR1A-associated arthrogryposis multiplex congenita 5 (AMC5) is a rare neurodevelopmental disorder arising from biallelic variants in TOR1A, a gene that in the heterozygous state is associated to torsion dystonia-1 (DYT1 or DYT-TOR1A), an early-onset dystonia with reduced penetrance. While 15 individuals with TOR1A-AMC5 have been reported (less than 10 in detail), a systematic investigation of the full disease-associated spectrum has not been conducted. Here, we assess the clinical, radiological and molecular characteristics of 57 individuals from 40 families with biallelic variants in TOR1A. Median age at last follow-up was 3 years (0-24 years). Most individuals presented with severe congenital flexion contractures (95%) and variable developmental delay (79%). Motor symptoms were reported in 79% and included lower limb spasticity and pyramidal signs, as well as gait disturbances. Facial dysmorphism was an integral part of the phenotype, with key features being a broad/full nasal tip, narrowing of the forehead and full cheeks. Analysis of disease-associated manifestations delineated a phenotypic spectrum ranging from normal cognition and mild gait disturbance to congenital arthrogryposis, global developmental delay, intellectual disability, absent speech and inability to walk. In a subset, the presentation was consistent with fetal akinesia deformation sequence with severe intrauterine abnormalities. Survival was 71% with higher mortality in males. Death occurred at a median age of 1.2 months (1 week - 9 years) due to respiratory failure, cardiac arrest, or sepsis. Analysis of brain MRI studies identified non-specific neuroimaging features, including a hypoplastic corpus callosum (72%), foci of signal abnormality in the subcortical and periventricular white matter (55%), diffuse white matter volume loss (45%), mega cisterna magna (36%) and arachnoid cysts (27%). The molecular spectrum included 22 distinct variants, defining a mutational hotspot in the C-terminal domain of the Torsin-1A protein. Genotype-phenotype analysis revealed an association of missense variants in the 3-helix bundle domain to an attenuated phenotype, while missense variants near the Walker A/B motif as well as biallelic truncating variants were linked to early death. In summary, this systematic cross-sectional analysis of a large cohort of individuals with biallelic TOR1A variants across a wide age-range delineates the clinical and genetic spectrum of TOR1A-related autosomal-recessive disease and highlights potential predictors for disease severity and survival. CC BY 4.0Correspondence to: Reza MaroofianDepartment of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, London WC1N 3BG, UKE-mail: R.Maroofian@ucl.ac.ukA.S. is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – SA 4171/1-1. H.H. is funded by The MRC (MR/S01165X/1, MR/S005021/1, G0601943), The National Institute for Health Research University College London Hospitals Biomedical Research Centre, Rosetree Trust, Ataxia UK, MSA Trust, Brain Research UK, Sparks GOSH Charity, Muscular Dystrophy UK (MDUK), Muscular Dystrophy Association (MDA USA). S.E. is supported by an MRC strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) MR/S005021/1’. This work was supported in part by the US National Institutes of Health R35 NS105078 and MDA#512848 to J.R.L., a jointly funded National Human Genome Research Institute (NHGRI) and National Heart, Lung, and Blood Institute (NHLBI) grant to the Baylor-Hopkins Center for Mendelian Genomics (UM1 HG006542) and NHGRI Genomics Research to Elucidate Genetics of Rare (BCM-GREGoR U01 HG011758). D.P. is supported by Clinical Research Training Scholarship in Neuromuscular Disease partnered by the American Brain Foundation (ABF) and Muscle Study Group (MSG). The research conducted at the Murdoch Children’s Research Institute was supported by the Victorian Government’s Operational Infrastructure Support Program. The Chair in Genomic Medicine awarded to J.C. is generously supported by The Royal Children’s Hospital Foundation. H.T. has been supported by the European Union’s Seventh Framework Program for research, technological development and demonstration under grant agreement no. 608473. H.S.D. is supported by the Cologne Clinician Scientist Program/Faculty of Medicine/University of Cologne and funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, Project No. 413543196). H.J. has been supported by a grant from the European Union (H2020- MSCA-ITN-2017). A.M.D. is supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (grant 1R01HD104938-01A1). H.L. receives support from the Canadian Institutes of Health Research (Foundation Grant FDN-167281), the Canadian Institutes of Health Research and Muscular Dystrophy Canada (Network Catalyst Grant for NMD4C), the Canada Foundation for Innovation (CFI-JELF 38412), and the Canada Research Chairs program (Canada Research Chair in Neuromuscular Genomics and Health, 950-232279). This research was funded in part by the Wellcome Trust (WT093205MA, WT104033AIA and the Synaptopathies Strategic Award, 165908) as well as the Medical Research Council (MRC) (MR/S01165X/1, MR/ S005021/1, G0601943). Additonally, we are grateful for funding from The MSA Trust, The National Institute for Health Research University College London Hospitals Biomedical Research Centre, The Michael J Fox Foundation (MJFF), BBSRC, The Fidelity Trust, Rosetrees Trust, Ataxia UK, Brain Research UK, Sparks GOSH Charity, Alzheimer’s Research UK (ARUK) and CureDRPLA.

Little is known about clinical symptomatology and genetics of juvenile onset Pompe disease (JOPD). The aims of this study were to analyze how these children are diagnosed, what clinical problems they have, and how phenotype is related to genotype. To accomplish this, we analyzed retrospectively data of 34 patients diagnosed after their first and before completion of their 18th birthday. Median age at diagnosis was 3.9 (range 1.1–17) years. Eight patients (23.5%) developed initial symptoms in the first year, 12 (35%) between 1 and 7 years, and 6 (18%) thereafter. Eight (23.5%) had no clinical symptoms at the time of diagnosis. Indications for diagnostics were a positive family history in three (9%), hyperCKemia in eight (23.5%), motor developmental delay in three (9%), and muscle weakness and/or pain in 17 (50%). Rare clinical signs were failure to thrive, recurrent diarrhea, and suspected hepatopathy with glycogen storage. Thirty-two different mutations were identified. Twenty-seven patients (79.5%) carried the milder c.32–13T > G mutation, known to be associated with a broad range of phenotypes. Three out of eight patients manifesting within the first year of life showed generalized muscle weakness, hypertrophic cardiomyopathy, and had to be ventilated during the course of disease, thereby demonstrating clinical overlap with infantile onset Pompe disease.These findings demonstrate that the phenotype of JOPD is broad and that the differential is not only restricted to neuromuscular disorders. Genotypic analysis was useful to delineate subjects with early onset JOPD from those with IOPD, but overall genotype–phenotype correlation was poor.

Nusinersen is the first disease-modifying therapy for spinal muscular atrophy (SMA), but there are few data on potential long-term endocrinological and metabolic systemic effects of this novel treatment as well as metabolic alterations in SMA itself. In this retrospective and multicentric study, we analyzed anthropometric, endocrinological, and motor function data of 81 pediatric and adult patients with SMA1 to 3 undergoing treatment with nusinersen. In 39 patients (51%), we observed a slight increase in body mass index (BMI) centiles under treatment with nusinersen, especially in patients with SMA2 and in pediatric patients between 3.1 and 12 years. A correlation to the SMN2 copy number or motor function was not found. Additionally, length centiles decreased significantly under treatment. The results of longitudinal endocrinological assessments were interpreted as not clinically significant in most patients; in three patients, the signs of an altered glucose metabolism were present. Our study indicates a putative effect of treatment with nusinersen on BMI, which might be due to a conjoint effect of weight gain and reduction of height velocity, without evidence of correlation to increased muscle function. Further studies need to address specific effects of targeted therapies such as nusinersen or onasemnogene abeparvovec on body composition including fat and muscle mass.

Acquired polyneuropathies (PN) are rare in childhood and adolescent. We report on a 15-year-old male patient who presented with progressive gait instability, ataxia, neuropathic pain, distal muscle weakness and progressive loss of ambulation. Nerve conduction studies (NCS) revealed a progressive demyelinating sensorimotor polyneuropathy predominantly of the lower limbs. Cerebrospinal fluid (CSF) analyses revealed a cytoalbuminologic dissociation. Extensive diagnostic workup for autoantibodies and inflammatory markers was inconclusive. Corticosteroids and intravenous immunoglobulins did not affect. Cranial MRI revealed leptomeningeal enhancement of the cerebellum and the brainstem. Brain biopsy of the cerebellar lesions revealed an unclassifiable sarcoma. The patient was treated according to the CWS guidance study resulting in a decrease in enhanced lesion size. After two years NCS still revealed a demyelinating sensorimotor PN. This case report describes for the first time the clinical course of a chronic PN, putative paraneoplastic, associated with isolated unclassifiable CNS-sarcoma in an adolescent patient. Paraneoplastic pathogenesis should be considered in an unusual sequence of subacute progressive neurological symptoms even in children and adolescents.

ZusammenfassungIschämische Hirninfarkte sind im Kindesalter selten, können aber bei den betroffenen Individuen zu irreversiblen Schäden und einer schwerwiegenden Beeinträchtigung der Lebensqualität führen. Ein signifikanter Anteil der Infarkte im Kindesalter geht auf primäre ZNS Vaskulitiden (PACNS) zurück. Zur sicheren Diagnose müssen Differenzialdiagnosen, inklusive Systemerkrankungen die mit Vaskulitis einhergehen können ausgeschlossen werden. In Analogie zur Klassifikation der systemischen Vaskulitis, wird die PACNS nach dem Kaliber der betroffenen Gefäße eingeteilt. Die Diagnose und Einteilung erfolgt anhand der klinischen Präsentation, laborchemischer und bildgebender Untersuchungen, sowie Hirnbiospien im Falle von Kleingefäß ZNS Vaskulitiden. In Ermangelung prospektiver und kontrollierter klinischer Studien orientiert sich das therapeutische Vorgehen derzeit an kleinen Fallserien und Expertenempfehlungen. Die zur Verfügung stehende Medikamententherapie umfasst systemische Antikoagulation, hochdosierte Kortikosteroide und, wenn nötig, Cyclophosphamid zur Remissionsinduktion, sowie Basismedikamente zur Remissionserhaltung. Die Pathophysiologie der PACNS wird aktuell nur sehr inkomplett verstanden. Die Untersuchung und Entdeckung genetischer Ursachen wird jedoch zu einer Neuklassifikation und zielgerichteten und individualisierten Therapieoptionen beitragen. Um dies voranzutreiben sind nicht zuletzt aufgrund der Seltenheit der PACNS im Kindesalter internationale Kooperationen notwendig.

Posterior amorphous corneal dystrophy (PACD) (OMIM 612868) is a rare autosomal dominant disorder characterized by partial or complete posterior lamellar corneal opacification, decreased corneal thickness and flattening of the corneal curvature. PACD is associated with heterozygous deletions in chromosome band 12q21.33 harboring DCN, KERA, LUM, and EPYC which encode small leucine-rich proteoglycans.We report on a 7-year-old male patient with PACD who had an interstitial deletion of 1.3 Mb in 12q21.33. His mother carried a balanced insertional translocation involving this 12q21.33 segment which was inserted into the proximal part of the long arm of one chromosome 13.The patient corroborates previous observations that PACD is a contiguous gene syndrome caused by combined haploinsufficiency of DCN, KERA, LUM, and EPYC and provides the first example of a balanced chromosome rearrangement involving 12q21.33 in an unaffected parent.

The natural history of patients with spinal muscular atrophy (SMA) has changed due to advances in standard care and development of targeted treatments. Nusinersen was the first drug approved for the treatment of all SMA patients. The transfer of clinical trial data into a real-life environment is challenging, especially regarding the advice of patients and families to what extent they can expect a benefit from the novel treatment. We report the results of a modified Delphi consensus process among child neurologists from Germany, Austria and Switzerland about the indication or continuation of nusinersen treatment in children with SMA type 1 based on different clinical case scenarios.

Non-arteriosclerotic arteriopathies have emerged as important underlying pathomechanism in pediatric arterial ischemic stroke (AIS). The pathogenesis and classification of cerebral arteriopathies in childhood are heterogeneous. Different classifications base on (i) the anatomic site; (ii) the distribution and size of the affected vessel; (iii) the time course, for example, transient vs. progressive, monophasic vs. recurrent; (iv) the putative pathogenesis; (v) the magnetic resonance imaging morphology of the vasculopathies. Inflammation affecting the cerebral vessels is increasingly recognized as common cause of pediatric AIS. Primary cerebral vasculitis or primary angiitis of the central nervous system (CNS) in childhood (cPACNS) is an important differential diagnosis in pediatric AIS. Primary angiitis of the CNS is a rare disorder, and the pathogenesis is poorly understood so far. The current classification of cPACNS is based on the affected cerebral vessel size, the disease course, and angiographic pattern. Two large subtypes are currently recognized comprising large- and medium-sized vessel CNS vasculitis referred to as angiography-positive cPACNS and angiography-negative small vessel cPACNS. As the clinical manifestations of cPACNS are rather diverse, precise diagnosis can be challenging for the treating pediatrician because of the lack of vital laboratory tests or imaging features. Initial misdiagnosis is common because of overlapping phenotypes and pediatric AIS mimics. As untreated cPACNS is associated with a high morbidity and mortality, timely diagnosis, and induction of immunomodulatory and symptomatic therapy are essential. Survival and neurological outcome depend on early diagnosis and prompt therapy. Primary angiitis of the central nervous system in childhood differs in several aspects from primary cerebral angiitis in adults. The aim of this article is to give a brief comprehensive summary on pediatric primary cerebral vasculitis focusing on the clinical perspective regarding the classification, the putative pathogenesis, the disease course, the diagnostic tools, and emerging treatment options. A modified terminology for clinical practice is discussed.

Hypothalamic obesity (HO) is a devastating complication, that occurs in patients with hypothalamic damage. It is characterized by polyphagia, and adynamia leading to a severe form of obesity, which is intractable to caloric restriction or lifestyle modification. HO is suggested to be a result of hypothalamic damage, leading to declined efferent sympathetic activity and reduced energy expenditure as well as raised vagal activity resulting in increased insulin secretion and adipogenesis. Trials of both single octreotide (OCT) and single dexamphetamin (DEX) were conducted and showed some effect to weight control. However no trial of combined OCT and DEX (OCT/DEX) was reported until now. A monocentric retrospective cohort study was conducted. All patients, who were diagnosed to suffer from HO in between January 1st, 2010 and September 30st, 2018, were included (n =11; mean age: 14.7 years; mean weight 104.6 +/- 11.6 kg; body mass index (BMI), 36.4 +/- 1.3 kg/m2). All subjects were suffering from a brain tumor (craniopharyngioma: 6/11; germinoma 3/11; astrocytoma 1/11) followed by neurosurgery and/or irradiation. Panhypopituitarism and type 2 diabetes, which was verified in all subjects, was replaced in usual hormone dosages and metformin, respectively. A specialized diet and raised physical activity was recommended. Six subjects received a combination of OCT (15-20 µg/kg/d) and DEX (5-15 mg/d) for at least 36 months, when the observation was stopped. Seven patients were not treated with this combination. In the first 12 months patients with OCT/DEX the Δweight (mean ± sem) was -0.7 ± 0.5 kg vs. 9.4 ± 1.6 kg for untreated patients. After 36 months with OCT/DEX the Δweight was +8.2 ± 0.6 kg vs. 27.1 ± 4.7 kg for the untreated group, and ΔBMI was +0.5 ± 0.4 vs. +6.8 ± 3.4 kg/m2, respectively. With oGTT we observed Δinsulin response (peak−basal) of -397± 244 pmol/L and +188±201 pmol/L in the treated and untreated patient groups, respectively. Parents reported marked improvement in physical activity of patients on OCT/DEX, but not in the untreated group. Complications and adverse events were mostly mild and self-limited. One patient with OCT/DEX developed gallstones 32 months after start, when OCT was stopped. Three patients without OCT/DEX leg died probably due to sleep apnea by known obesity-hypoventilation syndrome. Regarding the hypothalamus being extremely sensitive to irradiation and neurosurgical intervention, we consider a brain-saving surgery remains the best treatment. We combined both OCT and DEX in attempt to reduce hyperinsulinemia and increase patients` activity level. We report about a significant lower weight gain in patients treated with OCT/DEX than in the comparative cohort and therefore suggest OCT/DEX as an effective combination to control weight in patients with HO due to hypothalamic damage. Further prospective controlled studies are required to confirm this observation.

Acute necrotizing encephalopathy (ANE) is a rare disease presenting with rapidly progressing encephalopathy. It usually occurs in otherwise healthy children after common viral infections. The hallmarks of ANE are the neuroradiological findings of multiple symmetric lesions in the thalami, midbrain, pons and brainstem. Most cases are sporadic and non recurrent. However, recurrent or familial forms of ANE due to mutations in RANBP2 gene have been reported. It has been suggested to give these cases the term ANE1. We report the clinical course in two male infants (P1, P2) with ANE1 and a variable clinical course and outcome. One patient is heterozygous for the most common RANBP2 missense mutation p.Thr585Met. In the other patient we observed a novel de novo missense mutation p.Trp681Cys in the RANBP2 gene causing recurrent ANE. Clinical and radiological features are presented and differential diagnoses are discussed. This report adds to the current knowledge of the phenotype in ANE, caused by mutations in RANBP2 gene.

Riechstorungen sind haufig, insbesondere im Alter. Atiologisch unterscheidet man daneben sinunasale und nichtsinunasale Ursachen. Als wichtiges Fruhsymptom bei neurodegenerativen Erkrankungen sind Dysov. a. in der Diagnostik von M. Parkinson und M. Alzheimer von Bedeutung. Neben HNO-arztlicher Abklarung und der Testung mittels Riechstiften gewinnen auch qualitativ hochwertige Schnittbildverfahren wie z. B. die MRT weiter an Bedeutung fur die Prognose und die Therapieentscheidung. Im Kindesalter mussen u. a. ein verkurztes Aufmerksamkeitsintervall und eine eingeschrankte Auswahl an bekannten olfaktorischen Reizen Berucksichtigung finden. Riechtraining, antiphlogistische und chirurgische Masnahmen sind – je nach Atiologie – therapeutisch erfolgversprechend. Bei intrakraniellen Ursachen von Riechstorungen ist die Kenntnis und schonende Behandlung der anatomischen Strukturen des olfaktorischen Signalwegs durch den Neurochirurgen wichtig fur die Langzeitprognose.

Objective To evaluate the clinical presentation of patients with GM1 gangliosidosis and to determine whether specific clinical or biochemical signs could lead to a prompt diagnosis. Study design We retrospectively analyzed clinical, biochemical, and genetic data of 22 patients with GM1 gangliosidosis from 5 metabolic centers in Germany and Austria. Results Eight patients were classified as infantile, 11 as late-infantile, and 3 as juvenile form. Delay of diagnosis was 6 ± 2.6 months in the infantile, 2.6 ± 3.79 years in the late-infantile, and 14 ± 3.48 years in the juvenile form. Coarse facial features, cherry red spots, and visceromegaly occurred only in patients with the infantile form. Patients with the late-infantile and juvenile forms presented with variable neurologic symptoms. Seventeen patients presented with dystonia and 14 with dysphagia. Laboratory analysis revealed an increased ASAT concentration (13/20), chitotriosidase activity (12/15), and pathologic urinary oligosaccharides (10/19). Genotype analyses revealed 23 causative or likely causative mutations in 19 patients, 7 of them being novel variants. In the majority, a clear genotype–phenotype correlation was found. Conclusions Diagnosis of GM1 gangliosidosis often is delayed, especially in patients with milder forms of the disease. GM1 gangliosidosis should be considered in patients with progressive neurodegeneration and spastic-dystonic movement disorders, even in the absence of visceral symptoms or cherry red spots. ASAT serum concentrations and chitotriosidase activity may be of value in screening for GM1 gangliosidosis.

Autosomal recessive keratoderma-ichthyosis-deafness (ARKID) syndrome is a rare multisystem disorder caused by biallelic mutations in VPS33B; only three patients have been reported to date. ARKID syndrome is allelic to arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome (MIM #208085), a severe disorder with early lethality whose phenotypic characteristics also include ichthyosis, hearing loss, severe failure to thrive, platelet dysfunction and osteopenia. We report on an 11-year-old male patient with ARKID syndrome and compound heterozygous VPS33B mutations, one of which [c.1440delG; p.(Arg481Glyfs*11)] was novel. Clinical features of this patient included ichthyosis, palmoplantar keratosis, hearing loss, intellectual disability, unilateral hip dislocation, microcephaly and short stature. He also had copper hepatopathy and exocrine pancreatic insufficiency, features that have so far been associated with neither ARKID nor ARC syndrome. The patient broadens the clinical and molecular spectrum of ARKID syndrome and contributes to genotype-phenotype associations of this rare disorder.

We retrospectively evaluated predictors of conversion to multiple sclerosis (MS) in 357 children with isolated optic neuritis (ON) as a first demyelinating event who had a median follow-up of 4.0 years. Multiple Cox proportional-hazards regressions revealed abnormal cranial magnet resonance imaging (cMRI; HR 5.94; 95% CI: 3.39-10.39; p

Objectives Olfactory event-related potentials (OERPs) are widely used to study central odor processing. Only a few studies used this method in children and adolescents. Aim of the current study therefore was to measure OERP and the possible influences of age and sex on central odor processing in this age group. Methods A total of 81 children between 6 and 17 years of age were included in this study. OERP in response to a rose-like odor were measured from three recording positions (Fz, Cz, Pz) according to the 10–20 system. Stimuli were presented by means of a computer-controlled olfactometer. Results Age had a significant influence on the amplitudes of the late positivity with younger children showing larger amplitudes. Although age did not significantly affect the latencies of OERP, interactions of recording positions and latencies between younger and older children and between girls and boys were found. Conclusions OERP can be used to study central odor processing in children older than 6 years of age. Central odor processing changes from childhood to adolescents possibly reflecting maturation of the brain.

Aicardi-Goutieres syndrome (AGS) is a hereditary inflammatory encephalopathy resulting in severe neurological damage in the majority of cases. We report on two siblings with AGS6 due to compound heterozygosity for a known and a novel mutation in the ADAR gene and a strikingly variable phenotype. The first sibling presented at 12 months of age with a subacute encephalopathy following a mild respiratory infection. The child developed a spastic tetraparesis, generalized dystonia and dysarthria. In contrast, the younger sibling presented with an acute episode of neurological impairment in his third year of life, from which he recovered without sequelae within a few weeks. These findings illustrate a striking intrafamilial phenotypic variability in patients with AGS6 and describe the first case of a full recovery from an acute encephalopathy in an AGS patient. Our findings also suggest that AGS should be considered as an important differential diagnosis of an infection-triggered encephalopathy in infancy despite the absence of typical neuroimaging findings.

Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients ( including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype., Radboud University Medical Center; Max Planck Society; European Research Council (ERC); VIDI; Netherlands Organization for Scientific Research (NWO); Netherlands Organization for Scientific Research

Olfactory dysfunction is a common disorder, especially in elderly people. From the etiological point of view a differentiation is made between sinunasal, traumatic and non-sinunasal causes of dysosmia. Olfactory disorders are often observed in neurodegenerative diseases, especially in patients with Parkinson's disease or Alzheimer's disease. Apart from an extensive medical history important diagnostic tools are a complete ear nose and throat (ENT) examination including nasal endoscopy and olfactory testing, for example, with "sniffin' sticks". For diagnostic purposes modern imaging procedures, such as magnetic resonance imaging (MRI) are becoming more and more important. For testing children, olfactory testing needs to be adapted and depending on the etiology, olfactory training, antiphlogistic and surgical procedures are the most promising therapeutic approaches. In cases of intracranial causes of dysosmia neurosurgeons should know and respect the anatomical structures of the olfactory signal pathway, not least for the long-term prognosis.

Knowledge on pediatric herpes simplex virus encephalitis is limited. Here we summarize 6 neonates and 32 children diagnosed by polymerase chain reaction (n = 37) or serological studies (n = 1), respectively. Diagnosis was difficult, as only 15 patients presented neurologic symptoms. Moreover, cerebrospinal fluid glucose, protein, and leukocytes were normal in 6 patients. Subsequently, all but 2 showed neurologic symptoms. Diffusion-weighted neuroimaging was the most sensitive early imaging method. Despite acyclovir treatment, 8 patients experienced early relapses, showing movement abnormalities, impaired vigilance, and seizures. Diffuse white matter changes, found in 3 of 5 relapse patients on neuroimaging, and a negative cerebrospinal fluid herpes simplex virus polymerase chain reaction suggested inflammatory processes. All relapse patients were again treated with acyclovir, and 3 responded to additional corticosteroid treatment. Whereas outcome after relapses was poor, overall outcome was good. No child died; 14 were asymptomatic at discharge, and neuroimaging remained normal in 7 of 30 patients studied.

Subtelomeric deletions of chromosome 6q may result in a syndrome with brain malformations, comprising hydrocephalus and hypoplasia of the corpus callosum. Aplasia of the olfactory bulbs (OB) or anosmia has not been described in this syndrome. We describe a 3-year-old girl and a 25-year-old man with subtelomere 6q deletions. Both patients had aplastic OB and hydrocephalus. Subtelomeric 6q deletions might be underdiagnosed as anosmia can be the only symptom. © 2011 Wiley-Liss, Inc.

Six genes including POMT1, POMT2, POMGNTI, FKRP, Fukutin (FKTN) and LARGE encode proteins involved in the glycosylation of alpha-dystroglycan (alpha-DG). Abnormal glycosylation of alpha-DG is a common finding in Walker-Warburg syndrome (WWS), muscle-eye brain disease (MEB), Fukuyama congenital muscular dystrophy (FCMD), congenital muscular dystrophy types 1C and ID and some forms of autosomal recessive limb-girdle muscular dystrophy (LGMD2I, LGMD2K, LGMD2M), and is associated with mutations in the above genes. FCMD, caused by mutations in Fukutin (FKTN), is most frequent in Japan, but an increasing number of FKTN mutations are being reported outside of Japan. We describe four new patients with FKTN mutations and phenotypes ranging from: severe WWS in a Greek-Croatian patient, to congenital muscular dystrophy and cobblestone lissencephaly resembling MEB-FCMD in two Turkish patients, and limb-girdle muscular dystrophy and no mental retardation in a German patient. Four of the five different FKTN mutations have not been previously described. (C) 2010 Elsevier B.V. All rights reserved.

The olfactory bulb (OB) is considered to be the most important relay station in odor processing. Involving 125 randomly selected subjects (58 men, 67 women; age range: 19 to 79 years), the present study aimed to investigate a possible correlation between OB volume and specific olfactory functions including odor threshold, odor discrimination, and odor identification. The history of all participants was taken in great detail to exclude possible causes of smell dysfunction. All participants received an otolaryngological investigation including a volumetric scan of the brain (MRI), lateralized olfactory tests and a screen for cognitive impairment. Volumetric measurements of the right and left OB were performed by manual segmentation of the coronal slices through the OB. Significant correlations between OB volumes in relation to olfactory function were observed, independent of the subjects' age. Additionally, OB volumes decreased with age. In agreement with previous research the present study confirmed the correlation between OB volume and specific olfactory functions. Furthermore, the correlation between OB volume and olfactory function was not mediated by the subjects' age. In conclusion, the present data obtained from a relatively large group of subjects forms the basis for age-related normative values of OB volumes.

Loop thermosyphon is a simple and reliable device providing several times higher heat transfer than convectional coolers used in cooling electronic. The paper deals with the cooling of power electronic component by means of this device. The main object of the paper is design and construction of the device to provide heat removal from the electronic component. Paper describes function principle of loop thermosyphon, testing of the function and measurement of cooling efficiency in dependence on input electric power of the electronic component. The findings from measurement of loop thermosyphon cooling efficiency are compared with natural convective alumina cooler on the end of paper.

Given the rapid progress in the electronics industry, the thermal management of electronics components becomes an important and serious issue. Natural and forced cooling for heat sink are often deficient. One possibility of heat dissipation for high heat flux is using loop heat pipe. The loop heat pipe (LHP) is a two-phase device with extremely high effective thermal conductivity that utilizes the thermodynamic pressure difference to circulate fluid. It was invented in Russia in the early 1980’s. This work deals with the design of LHP for cooling of Insulated gate bipolar transistor and impact of tilt angle of LHP on temperature of transistor. The maximum temperature of transistor is 100°C. LHP is made of copper pipe. Working fluid is distilled water.

Given the rapid progress in the electronics industry, the thermal management of electronics components becomes an important and serious issue. Natural and forced cooling are often deficient. One possibility for heat dissipation for high heat flux is using loop heat pipe. A loop heat pipe (LHP) is a two-phase device with extremely high effective thermal conductivity that utilizes pressure difference in wick to circulate working fluid. It was invented in Russia in the early 1980’s. LHP is composed by an evaporator, a condenser, a compensation chamber (reservoir) and a vapor and liquid lines. Only the evaporator and part of the compensation chamber are equipped with a wick structure. The use of the wick structure in the evaporator provides a stable physical interface between the liquid and the vapor phases in the LHP. This work deals with the design of LHP for cooling of Insulated gate bipolar transistor and impact of tilt angle of LHP on temperature of transistor. The LHP position is changed from the vertical position (90°) to the horizontal position (0°) during the measurement. The LHP evaporator is made up with copper pipe and alumina saddle. Inside of the evaporator is wick structure and it is made from copper powder. The condenser is made as a tube heat exchanger. The water temperature for cooling is set at 20°C and it is regulated by a thermostat. The temperatures are measured with the thermocouples. As the working fluid was used distilled water. The maximum permissible temperature of transistor is 100°C.

Enzyme replacement therapy (ERT) has been shown to improve outcome in classical infantile Pompe disease. The purpose of this study was to assess mortality, morbidity, and shortcomings of ERT in a larger cohort of patients treated outside clinical trials. To accomplish this, we retrospectively analyzed the data of all 23 subjects with classical infantile Pompe disease having started ERT in Germany between January 2003 and December 2010.Ten patients (43%) deceased and four others (17%) became ventilator dependent. Seven infants (30.5%) made no motor progress at all, while seven (30.5%) achieved free sitting, and nine (39%) gained free walking. Besides all the seven patients (100%) attaining no improvement of motor functions, four out of the seven (57%) achieving to sit without support, and three out of the nine (33%) being able to walk independently, secondarily deteriorated, and died or became ventilator dependent. Sustained reduction of systolic function despite reversal of cardiac hypertrophy (n = 3), gastroesophageal reflux (n = 5), swallowing difficulties or failure to thrive (n = 11), recurrent pneumonias (n = 14), port system complications (n = 4), anesthesia-related incidents (n = 2), severe allergic reactions (n = 6), hearing loss (n = 3), and orthopedic deformities (n = 4) were problems frequently encountered.Although this study has important shortcomings due to its retrospective nature and because important variables potentially influencing outcome were not available for a substantial amount of patients, these data suggest that classical infantile Pompe disease still remains a life-threatening condition associated with high morbidity and often dismal prognosis. Currently, a relevant number of patients do not benefit definitely from ERT.

Fronto-striatal loops are important for many cognitive control processes, like response inhibition, and it has been suggested that the globus pallidus is of particular importance for these processes. In the current study, we investigate the effect of deep brain stimulation in the GP on response inhibition processes by means of neurophysiological (EEG) methods. We perform a case–control study in neuroaxonal dystrophy pantothenate kinase-associated neurodegeneration (PKAN) using single-case statistics. We control the signal-to-noise ratio of the EEG data. The data show that disease-related changes in the globus pallidus lead to dysfunctions in response inhibition processes. Dysfunctions in the GP seem to affect controlled, but not automatized behavior as evidenced by an increased rate of false alarms and attenuation of inhibition-related neurophysiological correlates. With respect to controlled behavior in terms of response inhibition, it seems that pre-motor subprocesses and not evaluation subprocesses are affected. Deep brain stimulation in the globus pallidus seems to be able to compensate the effects of disease-related changes in this structure and normalizes response inhibition performance and their electrophysiological correlates in PKAN.