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Niemann–Pick type C (NP-C) disease is a neurovisceral atypical lysosomal lipid storage disorder with a poor prognosis. We present the 5-year neuropsychological follow-up of a patient with juvenile onset NP-C, spanning the pre-diagnostic stage to the period after treatment with miglustat (Actelion Pharmaceuticals Inc., CA, US). In the initial stages of the disease, the patient presented behavioral dysexecutive symptoms resembling those frequently observed in adult-onset forms and frontotemporal dementia, which frequently makes early diagnosis difficult in children. After 4 years of treatment, the impaired cognitive function and behavioral dysexecutive syndrome had been completely reversed. The variability of NP-C disease makes early diagnosis challenging. Evaluations of long-term neuropsychological development can help diagnose this neurodegenerative disease and document its progression.

Mucopolysaccharidosis are multisystem diseases that require large multidisciplinary teams for their care. Specific recommendations are therefore needed for the transition from childhood to adulthood in this patient group. To overcome the barriers that might arise during the transition, the authors consider it essential to implement a flexible plan with a coordinator for the entire process, systematizing the information through a standardized pediatric discharge report and educating the patient and their family about the disease, showing the characteristics of the healthcare system in this new stage. The final objective is that, once the transition to adulthood has been completed, the patient's autonomy and potential development are maximized and that the patient receives appropriate healthcare during this transition.

Background CAPOS syndrome (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) is a rare disease that has been reported in 22 patients so far. In all cases, the mutation c.2452G>A (p.Glu818Lys) in the ATP1A3 gene was identified. Patients typically present at an early age with an acute-onset fever-induced episode of ataxia frequently associated with encephalopathy and weakness. They usually present one to three episodes. The acute symptoms improve within days, but most patients show slow progression afterward. Methods We describe three new patients, a woman and her two sons diagnosed with CAPOS syndrome. A systematic review of literature on previously reported patients was performed. Results The first son presented with acute-onset ataxia, encephalopathy, and sensorineural hearing loss, induced by febrile illness. The second one developed generalized areflexia and mild instability without an acute episode. The mother had been previously diagnosed with sensorineural hearing loss and optic nerve atrophy. The c.2452G>A mutation in ATP1A3 was found in all three patients. Conclusion Only 25 Individuals with CAPOS syndrome have been reported, including our family. This is the first time a Spanish family has been described. The fact that both siblings were assessed before the first acute-onset episode contributes to the description of early symptoms and signs of the disease, which could aid early diagnosis and management before the onset of acute episodes.

BACKGROUND: Investigations of myelin oligodendrocyte glycoprotein (MOG) antibodies are usually focused on demyelinating syndromes, but the entire spectrum of MOG antibody-associated syndromes in children is unknown. In this study, we aimed to determine the frequency and distribution of paediatric demyelinating and encephalitic syndromes with MOG antibodies, their response to treatment, and the phenotypes associated with poor prognosis. METHODS: In this prospective observational study, children with demyelinating syndromes and with encephalitis other than acute disseminated encephalomyelitis (ADEM) recruited from 40 secondary and tertiary centres in Spain were investigated for MOG antibodies. All MOG antibody-positive cases were included in our study, which assessed syndromes, treatment and response to treatment (ie, number of relapses), outcomes (measured with the modified Rankin scale [mRS]), and phenotypes associated with poor prognosis. We used Fisher's exact and Wilcoxon rank sum tests to analyse clinical features, and survival Cox regression to analyse time to antibody negativity. FINDINGS: Between June 1, 2013, and Dec 31, 2018, 239 children with demyelinating syndromes (cohort A) and 296 with encephalitis other than ADEM (cohort B) were recruited. 116 patients had MOG antibodies, including 94 (39%) from cohort A and 22 (7%) from cohort B; 57 (49%) were female, with a median age of 6·2 years (IQR 3·7-10·0). Presenting syndromes in these 116 patients included ADEM (46 [68%]), encephalitis other than ADEM (22 [19%]), optic neuritis (20 [17%]), myelitis (13 [11%]), neuromyelitis optica spectrum disorders (six [5%]), and other disorders (nine [8%]). Among the patients with autoimmune encephalitis in cohort B (n=64), MOG antibodies were more common than all neuronal antibodies combined (22 [34%] vs 21 [33%]). After a median follow-up of 42 months (IQR 22-67), 33 (28%) of the 116 patients had relapses, including 17 (17%) of 100 diagnosed at first episode. Steroids, intravenous immunoglobulin, or plasma exchange were used in 100 (86%) patients at diagnosis, and 32 (97%) of 33 at relapses. Rituximab was mainly used at relapses (11 [33%]). 99 (85%) of 116 patients had substantial recovery (mRS 2; one died). Phenotypes of poor prognosis included ADEM-like relapses progressing to leukodystrophy-like features, and extensive cortical encephalitis evolving to atrophy. Time to antibody negativity was longer in patients with relapses (HR 0·18, 95% CI 0·05-0·59). INTERPRETATION: The spectrum of paediatric MOG antibody-associated syndromes is wider than previously reported and includes demyelinating syndromes and encephalitis. Recognition of these disorders has important clinical and prognostic implications. FUNDING: Mutua Madrileña Foundation; ISCIII-Subdirección General de Evaluación y Fomento de la Investigación Sanitaria; Fondo Europeo de Desarrollo Regional; Pediatrics Spanish Society; Departament de Salut, Generalitat de Catalunya; Marato TV3 Foundation; Red Española de Esclerosis Múltiple; La Caixa Foundation; and Fundació CELLEX.

Background: Glucose transporter type 1 deficiency syndrome (GLUT1DS) is caused by mutations in the SLC2A1 gene and produces seizures, neurodevelopmental impairment, and movement disorders. Ketogenic dietary therapies (KDT) are the gold standard treatment. Similar symptoms may appear in SLC2A1 negative patients. The purpose is to evaluate the effectiveness of KDT in children with GLUT1DS suspected SLC2A1 (+) and (-), side effects (SE), and the impact on patients nutritional status. Methods: An observational descriptive study was conducted to describe 18 children (January 2009–August 2020). SLC2A1 analysis, seizures, movement disorder, anti-epileptic drugs (AEDS), anthropometry, SE, and laboratory assessment were monitored baseline and at 3, 6, 12, and 24 months after the onset of KDT. Results: 6/18 were SLC2A1(+) and 13/18 had seizures. In these groups, the age for debut of symptoms was higher. The mean time from debut to KDT onset was higher in SLC2A1(+). The modified Atkins diet (MAD) was used in 12 (5 SLC2A1(+)). Movement disorder improved (4/5), and a reduction in seizures &gt, 50% compared to baseline was achieved in more than half of the epileptic children throughout the follow-up. No differences in effectiveness were found according to the type of KDT. Early SE occurred in 33%. Long-term SE occurred in 10, 5, 7, and 5 children throughout the follow-up. The most frequent SE were constipation, hypercalciuria, and hyperlipidaemia. No differences in growth were found according to the SLC2A1 mutation or type of KDT. Conclusions: CKD and MAD were effective for SLC2A1 positive and negative patients in our cohort. SE were frequent, but mild. Permanent monitoring should be made to identify SE and nutritional deficits.

Supported in part by Instituto Carlos III (FIS PI12/00611, F.G.; FIS 14/00203, J.D.; and CM14/00081, T.A.), NIH RO1NS077851 (J.D.), Fundacio Cellex (J.D.), Mutual Medica, and a grant from the Spanish Society of Pediatric Neurology (T.A.)., Armangue, T., Moris, G., Cantarín-Extremera, V., Conde, C.E., Rostasy, K., Erro, M.E., Portilla-Cuenca, J.C., Turón-Viñas, E., Málaga, I., Muñoz-Cabello, B., Torres-Torres, C., Llufriu, S., González-Gutiérrez-Solana, L., González, G., Casado-Naranjo, I., Rosenfeld, M., Graus, F., Dalmau, J.

Vanishing white matter (VWM) leukoencephalopathy is one of the most prevalent hereditary white matter diseases. It has been associated with mutations in genes encoding eukaryotic translation initiation factor ( eIF2B). We have compiled a list of all the patients diagnosed with VWM in Spain; we found 21 children. The first clinical manifestation in all of them was spasticity, with severe ataxia in six patients, hemiparesis in one child, and dystonic movements in another. They suffered from progressive cognitive deterioration and nine of them had epilepsy too. In four children, we observed optic atrophy and three also had progressive macrocephaly, which is not common in VWM disease. The first two cases were diagnosed before the 1980s. Therefore, they were diagnosed by necropsy studies. The last 16 patients were diagnosed according to genetics: we found mutations in the genes eIF2B5 (13 cases), eIF2B3 (2 cases), and eIF2B4 (1 case). In our report, the second mutation in frequency was c.318A>T; patients with this mutation all followed a slow chronic course, both in homozygous and heterozygous states. Previously, there were no other reports to confirm this fact. We also found some mutations not described in previous reports: c.1090C>T in eIF2B4, c.314A>G in eIF2B5, and c.877C>T in eIF2B5.

Two-thirds of patients with mucopolysaccharidosis type II (MPS II Hunter syndrome), a rare lysosomal disease characterized by iduronate-2-sulfatase deficiency, have cognitive impairment. This observational, prospective, longitudinal study (NCT01822184) assessed cognitive status and adaptive behavior in patients aged 2− 70 (n=26) were −2.4 (p=0.5657) at month 12 and −7.4 (p=0.1461) at month 24. Similarly, for VABS-II ABC scores, differences in LSM changes from baseline between the GCA subgroups (≤70/>70) were −1.9 (p=0.5545) at month 12 and 0.3 (p=0.9484) at month 24. Overall, cognitive ability and adaptive behavior in the pediatric MPS II population who completed this study remained relatively stable over 24 months. However, some patients experienced a rapid decline in cognitive ability, while others retained stable, but impaired, cognitive function. Shire funded this study and medical writing support.

Background We aim to delineate the progression of cerebellar syndrome in children with phosphomannomutase-deficiency (PMM2-CDG) using the International Cooperative Ataxia Rating Scale (ICARS). We sought correlation between cerebellar volumetry and clinical situation. We prospectively evaluated PMM2-CDG patients aged from 5 to 18 years through ICARS at two different time points set apart by at least 20 months. We reviewed available MRIs and performed volumetric analysis when it was possible. Results From the eligible 24, four patients were excluded due to severe mental disability (n = 2) and supratentorial lesions (n = 2). Two different ICARS evaluations separated by more than 20 months were available for 14 patients showing an improvement in the cerebellar syndrome: ICARS1: 35.71 versus ICARS2: 30.07 (p

The transition process from paediatric to adult care is a subject of great interest in recent years, especially in chronic diseases with childhood onset, such as inborn errors of metabolism (IEM). Advances in diagnosis and treatment of these diseases have improved their prognosis, with a high number of patients with IEM who currently reach adult age and need to be attended to by non-paediatric professionals. The objective of this work is to establish action guidelines so that the specialists involved can guarantee a successful transition of these patients' healthcare.After carrying out a bibliographic review of the subject, the authors, beginning with their own experience, produced an initial document which was subjected to successive debates until the final document was obtained. The consensus recommendation was decided by the majority in case of criterion discrepancy.A series of recommendations are presented for the best clinical management of the transitions of care of patients with IEM from the paediatric to adult care setting in order to achieve the best results in this process given the special characteristics of this patient subgroup and the main difficulties entailed in the transition process.The role of the internal medicine doctor in this transition process and correct interrelation with the paediatric and social setting is stressed. Furthermore, actions and attitudes are suggested to improve the quality of said transition.

Objective: Sepiapterin reductase deficiency (SRD) is an under-recognized levodopa-responsive disorder. We describe clinical, biochemical, and molecular findings in a cohort of patients with this treatable condition. We aim to improve awareness of the phenotype and available diagnostic and therapeutic strategies to reduce delayed diagnosis or misdiagnosis, optimize management, and improve understanding of pathophysiologic mechanisms.Methods: Forty-three individuals with SRD were identified from 23 international medical centers. The phenotype and treatment response were assessed by chart review using a detailed standardized instrument and by literature review for cases for which records were unavailable.Results: In most cases, motor and language delays, axial hypotonia, dystonia, weakness, oculogyric crises, and diurnal fluctuation of symptoms with sleep benefit become evident in infancy or childhood. Average age of onset is 7 months, with delay to diagnosis of 9.1 years. Misdiagnoses of cerebral palsy (CP) are common. Most patients benefit dramatically from levodopa/carbidopa, often with further improvement with the addition of 5-hydroxytryptophan. Cerebrospinal fluid findings are distinctive. Diagnosis is confirmed by mutation analysis and/or enzyme activity measurement in cultured fibroblasts.Interpretation: Common, clinical findings of SRD, aside from oculogyric crises and diurnal fluctuation, are nonspecific and mimic CP with hypotonia or dystonia. Patients usually improve dramatically with treatment. Consequently, we recommend consideration of SRD not only in patients with levodopa-responsive motor disorders, but also in patients with developmental delays with axial hypotonia, and patients with unexplained or atypical presumed CP. Biochemical investigation of cerebrospinal fluid is the preferred method of initial investigation. Early diagnosis and treatment are recommended to prevent ongoing brain dysfunction. ANN NEUROL 2012; 71: 520-530

Background Vascular abnormalities in neurofibromatosis type 1 may arise anywhere in the cardiovascular system, and cerebrovascular involvement is the predominant feature of moyamoya syndrome. Because neurofibromatosis type 1 is a neurocutaneous disorder and routine follow-up with cranial MRI is not standard practice in asymptomatic children, accurate epidemiologic data are lacking. On follow-up, clinical and radiologic progression is often found in patients with moyamoya syndrome. Methods We performed a retrospective analysis on children with neurofibromatosis type 1 who had been diagnosed with moyamoya syndrome on cranial MRI. Results Of the 197 children diagnosed with neurofibromatosis type 1, 168 had undergone a cranial MRI, and four (2.3%) of them had moyamoya syndrome. At diagnosis, one child had headache and vomiting related to a right frontal hematoma and the other three children were asymptomatic, including one child with a previous history of renal arteriopathy. In two children moyamoya syndrome was unilateral. Conclusions The association between moyamoya syndrome and neurofibromatosis type 1 is rare, but it poses a potential risk of clinicoradiologic progression. Targeted monitoring of children with neurofibromatosis type 1 ensures an early diagnosis of moyamoya syndrome.

This article describes an 8-month-old boy with the full clinical spectrum anti-N-methyl-d-aspartate receptor encephalitis. He was admitted to the hospital with involuntary orofacial head movements, behavioral changes, and fluctuation in consciousness. His examination showed tongue thrusting, decreased responsiveness, and hypotonia without fever. Analysis of the cerebrospinal fluid revealed increased protein levels (62 mg/dL). The next day he developed oral dyskinesia and choreoathetosis. Video-electroencephalogram polygraphy showed coreo-dystonic movements without electrographic correlation. A putative diagnosis of autoimmune encephalopathy was made, and treatment with intravenous immunoglobulin and methylprednisolone was started, with improvement in the abnormal movements. Antibodies to the N-methyl-d-aspartate receptor were identified in the cerebrospinal fluid and blood. He began receiving immunoglobulin once a month for a year. Two months after the treatment had started, the involuntary movement disappeared and his development has been normal. N-methyl-d-aspartate receptor encephalitis is a recently identified disorder. This is the youngest case reported. Prompt diagnosis and treatment are important to obtain full recovery.

En la literatura médica son cada vez más frecuentes los trabajos que relacionan la hipertensión intracraneal benigna (HIB) y los estados protrombóticos. Recientemente se ha relacionado la resistencia a la proteína C activada y la mutación para el factor V de Leiden (FVL), con patología tromboembólica. La alta prevalencia del FVL ha originado que se relacione este factor procoagulante en patología trombótica del territorio cerebrovascular. La alteración de la reabsorción del líquido cefalorraquídeo por los microtrombos que se formarían en las vellosidades aracnoideas explicaría la fisiopatología de la HIB y el FVL. En este sentido aportamos 2 pacientes con diagnóstico de HIB que presentaron como único factor de riesgo heterocigosis para el FVL. : Benign idiopathic intracranial hypertension (BIH) in association with prothrombotic conditions has been reported with increasing frequency in the medical literature. Recently, activated protein C resistance (APCR) has been identified as a factor in some cases. Because of its high prevalence, factor V Leiden mutation (FVL) is the most frequent coagulation abnormality associated with cerebral venous thrombosis. Reduced craniospinal fluid reabsorption due to damaged arachnoid villi secondary to microthrombus formation has been proposed as an explanation for the physiopathology of BIH and FVL. We describe two patients with a diagnosis of BIH, in whom the only risk factor was heterozygosity for FVL mutation.

Background and objective The transition process from paediatric to adult care is a subject of great interest in recent years, especially in chronic diseases with childhood onset, such as inborn errors of metabolism (IEM). Advances in diagnosis and treatment of these diseases have improved their prognosis, with a high number of patients with IEM who currently reach adult age and need to be attended to by non-paediatric professionals. The objective of this work is to establish action guidelines so that the specialists involved can guarantee a successful transition of these patients’ healthcare. Methodology After carrying out a bibliographic review of the subject, the authors, beginning with their own experience, produced an initial document which was subjected to successive debates until the final document was obtained. The consensus recommendation was decided by the majority in case of criterion discrepancy. Results A series of recommendations are presented for the best clinical management of the transitions of care of patients with IEM from the paediatric to adult care setting in order to achieve the best results in this process given the special characteristics of this patient subgroup and the main difficulties entailed in the transition process. Conclusions The role of the internal medicine doctor in this transition process and correct interrelation with the paediatric and social setting is stressed. Furthermore, actions and attitudes are suggested to improve the quality of said transition.

Hunter syndrome (Mucopolysaccharidosis type II) is an inherited lysosomal storage disorder with potentially severe degenerative consequences. Clinical diagnosis is not easy, although biochemical confirmation is straightforward, and sometimes patients are diagnosed at a late age. It is widely believed, for inborn errors of metabolism in general, that early diagnosis and management is of paramount importance for improving the prognosis of the disease. The objective of this study was to identify specific populations at risk of suffering from Hunter syndrome. Urine samples were obtained from children between the ages of 0 to 18, belonging to known risk groups of mucopolysaccharidosis (MPS) type II, for the semi-quantitative (GAG test) and quantitative determination of glycosaminoglycans (GAG). One case of Hunter syndrome was found among the 130 samples that were collected and analysed. This study supports the feasibility of early diagnosis and the usefulness of screening tests for MPS II in specific paediatric populations.

Hunter syndrome (mucopolysaccharidosis type II [MPS II], OMIM309900) is a rare X-linked lysosomal storage disorder caused by deficiency of the enzyme iduronate-2-sulphatase, resulting in accumulation of glycosaminoglycans (GAGs), multisystem organ failure and early death. Enzyme replacement therapy (ERT) with idursulfase is commercially available since 2007. Early access programs were established since 2005. However, limited information on the effects of ERT in young children is available to date. The aim of this analysis was therefore to determine the effects of ERT on patients younger than 5 years of age. We report data from six Spanish patients with confirmed Hunter syndrome who were younger than 5 years at the start of ERT, and had been treated with weekly intravenous infusions of idursulfase between 6 and 14 months. Baseline and treatment data were obtained from the Hunter Outcome Survey (HOS). HOS is an international database of MPS II patients on ERT or candidates to be treated, that collects data in a registry manner. HOS is supported by Shire Human Genetic Therapies, Inc. (Cambridge, MA, USA). At baseline, all patients showed neurological abnormalities, including ventriculomegaly, hydrocephaly, cerebral atrophy, perivascular changes and white matter lesions. Other signs and symptoms included thoracic deformity, otitis media, joint stiffness and hepatosplenomegaly, demonstrating that children under 5 years old can also be severely affected. ERT reduced urinary GAG levels, and reduced spleen (n = 2) and liver size (n = 1) after only 8 months. Height growth was maintained within the normal range during ERT. Joint mobility either stabilized or improved during ERT. In conclusion, this case series confirms the early onset of signs and symptoms of Hunter syndrome and provides the first evidence of ERT beneficial effects in patients less than 5 years of age. Similar efficacy and safety profiles to those seen in older children can be suggested, although further studies including a direct comparison with older patients would still be required.

Objective To report our findings from a sample of narcoleptic children and adolescents evaluated in our unit from 1988 to 2005. Patients and methods The sample was composed of nine children (5 boys) with a mean age of 14.5 years at diagnosis. The protocol included the following: Epworth, Ullanlinna narcolepsy scale, and Stanford cataplexy questionnaires; physical, psychological and neurological examinations; neuroimaging; PSG + MSLT recordings; HLA and in two cases Hcrt-1 level in CSF. Results Narcolepsy was sporadic in all cases. The first symptom was EDS with a mean age at onset of 9.4 ± 2.5 years (range 6–13 years). All patients complained of cataplexy. Other symptoms were hypnagogic hallucinations (4 children) and sleep paralysis (3 children). All the children performed poorly at school, 4 had emotional disorders with depression, 4 displayed nocturnal eating and weight gain. Mean BMI was 25.0 kg/m2. One girl was diagnosed as having precocious puberty, polycystic ovary syndrome (PCOS), hyperandrogenism and insulin resistance. The MRI showed a partial empty sella. Hcrt-1 was undetectable in her CSF. The mean Ullanlinna score was 24.6; PSG showed disturbed nocturnal sleep and the MSLT showed a mean sleep latency of 2.1 min and 3 SOREMPs. Eight children were DR2-DQ1-positive, whereas one boy was DR2-negative but DQ1-positive. In two patients, Hcrt-1 was undetectable. All children, in addition to scheduled naps during the day, were treated with modafinil or methylphenidate combined with an antidepressant and in two cases with sodium oxybate. Conclusion NC was sporadic in all children and associated with precocious puberty and PCOS, hyperandrogenism and insulin resistance in one case. EDS, cataplexy, disturbed nocturnal sleep, nocturnal eating, poor school performance, and emotional disorders were the principal complaints. All patients had DQB1∗0602 and Hcrt-1 was evaluated in two cases (undetectable in both).

INTRODUCTION Malaria is one of the main health problems in the Third World. Plasmodium falciparum infects as many as 300 million people, causing up to three million deaths each year, most of which occur in African children. Cerebral malaria is the most common lethal complication of P. falciparum infection in children and is defined by three criteria: disturbances of consciousness, presence of P. falciparum parasitaemia and absence of other causes of acute encephalopathy. Cerebral malaria is a medical emergency and parenteral quinine is the most recommended treatment because of the frequency of chloroquine-resistant strains. Mortality is as high as 50 per cent and residual disability is present in about 20 per cent of survivors. OBJECTIVE We want to warm Spaniard neuropaediatricians about the existence of cases of cerebral malaria in our country in order to get a better diagnose and treatment for those children. PATIENTS AND METHODS A retrospective medical scores review of 20 hospitalised children diagnosed of malaria from 1990 to 1998. We selected three cases with neurological signs and we analysed clinical onset, EEG, neuroimaging, and permanent sequels. RESULTS All patients had acute encephalopathy with fever, obtundation and seizures. They all presented residual disability (mainly hemiparesis). CONCLUSION We must know better about cerebral malaria because of an increasing incidence of imported malaria due to emigration from African countries and Spaniard tourism to areas of endemic paludism.