Quality of life in adolescents with narcolepsy type 1- a transversal study in a tertiary hospital.

PURPOSE: - Narcolepsy type 1 (NT1) is a rare chronic sleep disorder, usually arising by adolescence that negatively impacts quality of life. It is characterized by excessive daytime sleepiness (EDS), cataplexy, hypnagogic/hypnopompic hallucinations, sleep paralysis and sleep fragmentation. The goals of this work were to characterize NT1 adolescents regarding sleep characteristics, health-related quality of life (HRQoL) and future life perspectives and later to compare this group with a control group of healthy adolescents (HA). METHODS: - Transversal descriptive/analytical study including NT1 patients followed in a sleep center of a tertiary hospital and 23 HA. Data were collected through an online survey, fulfilled by the participants, including four sections: demographics; questionnaire evaluating sleep and EDS; questionnaire evaluating HRQoL; inquiry regarding future perspectives. An extra section for the NT1 group only, comprising questions about the characterization of narcolepsy, was included. RESULTS: 22 NT1 adolescents were included, with a median age of 15.0 years-old. Beyond EDS, all had presented cataplexy - 19 still reported it. Twenty patients took psychostimulants regularly for EDS, while 13 patients took venlafaxine or fluoxetine for cataplexy. Nineteen adolescents took regular naps and 19 maintained psychological appointments. Self-reported sleep quality was similar between groups (p = 0.112). EDS was identified in seven NT1 patients and none in the control group. HRQOL was significantly lower in NT1 patients only for the physical well-being domain (p = 0.001). Regarding future perspectives, results were similar, except for a lower probability of getting a driver's license in NT1 patients, despite no statistical significance (p = 0.104). DISCUSSION: Daytime sleepiness is difficult to control in NT1, despite specialized treatment. HRQoL was similar between groups in all domains except for the physical well-being. Despite good adherence to pharmacological and non-pharmacological treatments (namely psychological therapy) that account for these good results, the physical well-being domain is difficult to manage.

Diagnostic accuracy and the first genotype-phenotype correlation in glycogen storage disease type V.

BACKGROUND: Glycogen storage disease type V (GSDV) is an autosomal recessive metabolic condition caused by pathogenic PYGM variants. This is an underdiagnosed condition as it presents with exercise intolerance in children. We reviewed the GSDV cases of a tertiary hospital center to assess diagnostic timing/accuracy, as well as potential clinical/analytical predictors of such factors. METHODS: We retrospectively reviewed all GSDV cases with follow-up in both Pediatric and Adult Metabolic Diseases consultations. We included 28 cases and assessed their hospital record for clinical information. RESULTS: Over 90% of our cases had late diagnoses, with more than 50% being diagnosed in adulthood despite symptom onset in preschool (very late diagnosis). Diagnostic age was lower in patients exhibiting myoglobinuria. Interestingly, patients with a positive family history of GSDV had similar rates of very late diagnoses, likely since the index case was already detected very late in life. Finally, we observe that the R50* variant is associated with increased myoglobinuria and CK elevation, in a dosage-dependent manner. CONCLUSION: We concluded that GSDV is severely underdiagnosed, and that some clinical and analytical aspects of the condition can be more indicative of this diagnosis. Furthermore, we propose for the first time a genotype-phenotype correlation in GSDV. IMPACT: GSDV is a pediatric-onset metabolic disorder that is mostly diagnosed late in the adult age and commonly misdiagnosed. We observed the first genotype-phenotype correlation in GSDV, regarding the common R50* variant. Awareness of GSDV for pediatricians and the overall medical community is vital.

Clinical and Laboratory Findings on Glycogen Storage Disease Type V: Results from a Retrospective Observational Study in a Tertiary Hospital.

Introduction - Glycogen storage disease type V (GSDV, MIM #232600) is an autosomal recessive metabolic myopathy caused by pathogenic variants in the PYGM gene. The characteristic symptoms of exercise intolerance, myalgia, and cramps, which improve after a few minutes of rest, are frequently unrecognized in affected children. When there is clinical suspicion, the initial approach with a forearm exercise test has diagnostic value by detecting low post-exercise plasma lactate-to-ammonia ratio values. The diagnostic algorithm is followed by genetic testing if the results suggest myophosphorylase deficiency. Methods - This was a retrospective observational study conducted based on reviewing medical records of patients with GSDV in a tertiary hospital. We assessed demographic variables, including the timing of onset and diagnosis, relevant clinical characteristics, and whether genetic testing was performed, including its results. Results/Case Report - Our goal was to review the GSDV cases in our center to assess our cohort's diagnostic timing and clinical and genetic characteristics. We identified 28 patients from 24 families, three with consanguinity. The mean age at the time of the study was 43 years. While most (26/28; 93%) recalled their first symptoms in childhood/adolescence, only 25% (7/28) were diagnosed then. All patients had exercise intolerance and CK elevation, while about half reported the second wind phenomenon. Genetic testing was performed in 22 patients, revealing biallelic PYGM variants (9 homozygous, 13 compound heterozygous) as the most common (p.R50*). Conclusion - GSDV is rare and presents in the pediatric age, with subtle manifestations often underestimated for decades. A late diagnosis may negatively impact the psychosocial development of affected children. It is essential to recognize some unique features that facilitate diagnosis: history of exercise intolerance, the second wind sign, and high resting serum CK levels. Identifying the disease-causing variants in PYGM is currently the gold standard for diagnosis as it is less invasive than performing a muscle biopsy, and may promptly diagnose the condition and avoid wrongful labelling of patients.

Parental gonadossomatic mosaicism in HIVEP2-related intellectual disability and impact on genetic counseling-case report.

Intellectual development disorder, autosomal dominant 43 (MRD43) is an autosomal dominant disorder caused by heterozygous mutations in the HIVEP2 gene. In this report, we describe a case of a 4-year-old boy with global development delay, hypotonia, and dysmorphic features, in whom the finding of a heterozygous nonsense pathogenic variant in exon 5 of HIVEP2 [c.2827C>T p. (Arg943*)] through WES established a MRD43 diagnosis. Our patient's phenotype overlaps with other MRD43 descriptions in the literature. Unlike previously reported cases, where the condition was almost invariably de novo, the healthy mother in this case presented mosaicism for the pathogenic variant. Thus, the recurrence risk increased significantly from 1% to up to 50%. The description of a variant inherited for MDR43 is singular in the literature and this description highlights the importance of parental studies for accurate genetic counseling, particularly for family planning.

Pediatric Multiple Sclerosis-Experience of a Tertiary Care Center.

BACKGROUND: Pediatric-onset multiple sclerosis (POMS) accounts for 3 to 10% of all MS diagnoses. POMS is usually characterized by prominent disease activity, and patients are at higher risk of developing physical disability and cognitive impairment. OBJECTIVE: This article characterizes a cohort of POMS patients followed at the pediatric neurology unit of a Portuguese tertiary hospital. METHODS: Retrospective observational study. Clinical records of all patients with POMS between 2011 and 2020 were revised. RESULTS: A total of 21 patients, with a female:male ratio of 11:10 and a mean age of onset of 14.8 years were included. Clinical manifestations at presentation included myelitis in eight patients (two with associated brainstem syndrome), optic neuritis in six (one with associated cerebellar syndrome), supratentorial symptoms in four, and isolated brainstem syndrome in two. Twenty patients had oligoclonal immunoglobulin G bands in cerebrospinal fluid. Supra- and infratentorial involvement was identified in the first brain magnetic resonance imaging of nine patients. Initial relapses were treated with intravenous steroids in 19 patients. The mean time for diagnosis was 2.8 months. Eleven patients were on first-line treatment (nine on ß-interferon, two on teriflunomide) and 10 on second-line treatment (six on natalizumab, three on fingolimod, one on ocrelizumab). The mean annual relapse rate was 0.29 (range, 0.01-3), and the median Expanded Disability Status Scale was 1. Four patients reported learning disabilities and/or cognitive deficits. CONCLUSION: About half of patients in this cohort were on second-line disease-modifying treatment, with 19% showing cognitive impairment. Efforts to establish an early diagnosis are crucial to improving these patients' outcomes.

Brain imaging findings in CLCN2-related leukoencephalopathy.

CLCN2-related leukoencephalopathy is a rare autosomal-recessive disease caused by a loss-of-function mutation in the ClC-2 chloride channel, which is fundamental in ion and water brain homeostasis. With only 31 cases published in the literature, its precise pathophysiology is uncertain, clinical manifestations are nonspecific and little is known in terms of prognosis. Neuroimaging plays a fundamental role in the identification of CLCN2-related leukoencephalopathy, which has a typical magnetic resonance imaging pattern that, when recognized, should promote proper genetic study for diagnostic confirmation. We report a paediatric clinical case of CLCN2-related leukoencephalopathy with genetically verified c.1709G > A p(Trp570*) mutation, highlighting typical neuroimaging findings and the importance of imaging in the diagnostic approach.

Pediatric neuromyelitis optica spectrum disorders in Portugal: A multicentre retrospective study.

INTRODUCTION: Neuromyelitis optica spectrum disorders (NMOSD) are more prevalent in adulthood, with few cases reported in pediatric age (<18 years). In this group, anti-aquaporin 4 (AQP4) antibodies are less frequent, while antibodies against myelin oligodendrocyte glycoprotein (MOG) are more commonly detectable than in adults. OBJECTIVE AND METHODS: Description of pediatric NMOSD cases identified in a national multicentric NMOSD Portuguese registry. RESULTS: Twenty (11.1%) NMOSD cases were diagnosed in pediatric age. Twelve (60%) were female, with a median age of onset of 12.5 (6.8-16.5) years. The presenting feature was transverse myelitis in 10 (50%), 4 of which with simultaneous optic neuritis and 2 with concomitant brainstem syndrome. Nine patients (45%) had pleocytosis in the CSF. Six (30.0%) exhibited anti-AQP4 antibodies, 13 (65.0%) anti-MOG antibodies, and one was seronegative for both. Four anti-AQP4 antibodies-positive patients had ≥1 relapse. Most anti-MOG-positive cases were monophasic (53.8%). In the acute phase, all patients received IV methylprednisolone, nine received IVIg and four plasma exchange. One anti-AQP4-positive patient died. Ten patients (5 anti-AQP4-positive/5 anti-MOG-positive) were on maintenance immunosuppressive therapy at the time of data collection. CONCLUSION: NMOSD may present in pediatric age. It is essential to establish the diagnosis and promptly start therapy to improve the prognosis.

Neuromyelitis optica spectrum disorders: A nationwide Portuguese clinical epidemiological study.

INTRODUCTION: Neuromyelitis optica spectrum disorder (NMOSD) is a rare disorder in which astrocyte damage and/or demyelination often cause severe neurological deficits. OBJECTIVE: To identify Portuguese patients with NMOSD and assess their epidemiological/clinical characteristics. METHODS: This was a nationwide multicenter study. Twenty-four Portuguese adult and 3 neuropediatric centers following NMOSD patients were included. RESULTS: A total of 180 patients met the 2015 Wingerchuk NMOSD criteria, 77 were AQP4-antibody positive (Abs+), 67 MOG-Abs+, and 36 seronegative. Point prevalence on December 31, 2018 was 1.71/100,000 for NMOSD, 0.71/100,000 for AQP4-Abs+, 0.65/100,000 for MOG-Abs+, and 0.35/100,000 for seronegative NMOSD. A total of 44 new NMOSD cases were identified during the two-year study period (11 AQP4-Abs+, 27 MOG-Abs+, and 6 seronegative). The annual incidence rate in that period was 0.21/100,000 person-years for NMOSD, 0.05/100,000 for AQP4-Abs+, 0.13/100,000 for MOG-Abs+, and 0.03/100,000 for seronegative NMOSD. AQP4-Abs+ predominated in females and was associated with autoimmune disorders. Frequently presented with myelitis. Area postrema syndrome was exclusive of this subtype, and associated with higher morbidity/mortality than other forms of NMOSD. MOG-Ab+ more often presented with optic neuritis, required less immunosuppression, and had better outcome. CONCLUSION: Epidemiological/clinical NMOSD profiles in the Portuguese population are similar to other European countries.

TyPed study: Natalizumab for the treatment of pediatric-onset multiple sclerosis in Portugal.

BACKGROUND: A significant proportion of pediatric-onset multiple sclerosis (POMS) patients do not respond to first-line disease-modifying therapies. Clinical trials showed that natalizumab is effective and safe in adults, but there are limited clinical trial data for children. Natalizumab is currently prescribed off-label for POMS. We aimed to characterize the effectiveness, safety and tolerability of natalizumab in all POMS cases treated in Portugal (from 2007 to 2018). METHODS: Data from clinical records were retrospectively collected for all POMS cases treated with natalizumab in Portugal. RESULTS: Twenty-one patients were included, 14 (67%) of which were female. The median age at POMS diagnosis was 13 years old. The median duration of treatment with natalizumab was 2 years and 3 months. Median Expanded Disability Status Scale score decreased from 1.5 to 1.0 after 24 months. The Annualized Relapse Rate decreased from 1.31 events/patient/year before treatment with natalizumab to 0 after 12 months of treatment and to 0.04 after 24 months. No gadolinium-enhancing lesions or new or enlarged T2 hyperintense lesions were observed in 8/8 patients (100%) after 12 months, and 4/5 (80%) after 24 months. There was one possible serious adverse event, which did not require dose adjustment. Five patients discontinued treatment due to positive anti-JCV (JC virus) antibody JC serostatus. CONCLUSION: Natalizumab may be an effective and safe disease-modifying therapy for POMS. Our results are in line with data published for the adult population, as well as with similar observational studies in pediatric populations in other regions.

Genomic imbalances defining novel intellectual disability associated loci.

BACKGROUND: High resolution genome-wide copy number analysis, routinely used in clinical diagnosis for several years, retrieves new and extremely rare copy number variations (CNVs) that provide novel candidate genes contributing to disease etiology. The aim of this work was to identify novel genetic causes of neurodevelopmental disease, inferred from CNVs detected by array comparative hybridization (aCGH), in a cohort of 325 Portuguese patients with intellectual disability (ID). RESULTS: We have detected CNVs in 30.1% of the patients, of which 5.2% corresponded to novel likely pathogenic CNVs. For these 11 rare CNVs (which encompass novel ID candidate genes), we identified those most likely to be relevant, and established genotype-phenotype correlations based on detailed clinical assessment. In the case of duplications, we performed expression analysis to assess the impact of the rearrangement. Interestingly, these novel candidate genes belong to known ID-related pathways. Within the 8% of patients with CNVs in known pathogenic loci, the majority had a clinical presentation fitting the phenotype(s) described in the literature, with a few interesting exceptions that are discussed. CONCLUSIONS: Identification of such rare CNVs (some of which reported for the first time in ID patients/families) contributes to our understanding of the etiology of ID and for the ever-improving diagnosis of this group of patients.

HCN1 mutation spectrum: from neonatal epileptic encephalopathy to benign generalized epilepsy and beyond.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels control neuronal excitability and their dysfunction has been linked to epileptogenesis but few individuals with neurological disorders related to variants altering HCN channels have been reported so far. In 2014, we described five individuals with epileptic encephalopathy due to de novo HCN1 variants. To delineate HCN1-related disorders and investigate genotype-phenotype correlations further, we assembled a cohort of 33 unpublished patients with novel pathogenic or likely pathogenic variants: 19 probands carrying 14 different de novo mutations and four families with dominantly inherited variants segregating with epilepsy in 14 individuals, but not penetrant in six additional individuals. Sporadic patients had epilepsy with median onset at age 7 months and in 36% the first seizure occurred during a febrile illness. Overall, considering familial and sporadic patients, the predominant phenotypes were mild, including genetic generalized epilepsies and genetic epilepsy with febrile seizures plus (GEFS+) spectrum. About 20% manifested neonatal/infantile onset otherwise unclassified epileptic encephalopathy. The study also included eight patients with variants of unknown significance: one adopted patient had two HCN1 variants, four probands had intellectual disability without seizures, and three individuals had missense variants inherited from an asymptomatic parent. Of the 18 novel pathogenic missense variants identified, 12 were associated with severe phenotypes and clustered within or close to transmembrane domains, while variants segregating with milder phenotypes were located outside transmembrane domains, in the intracellular N- and C-terminal parts of the channel. Five recurrent variants were associated with similar phenotypes. Using whole-cell patch-clamp, we showed that the impact of 12 selected variants ranged from complete loss-of-function to significant shifts in activation kinetics and/or voltage dependence. Functional analysis of three different substitutions altering Gly391 revealed that these variants had different consequences on channel biophysical properties. The Gly391Asp variant, associated with the most severe, neonatal phenotype, also had the most severe impact on channel function. Molecular dynamics simulation on channel structure showed that homotetramers were not conducting ions because the permeation path was blocked by cation(s) strongly complexed to the Asp residue, whereas heterotetramers showed an instantaneous current component possibly linked to deformation of the channel pore. In conclusion, our results considerably expand the clinical spectrum related to HCN1 variants to include common generalized epilepsy phenotypes and further illustrate how HCN1 has a pivotal function in brain development and control of neuronal excitability.

Resective surgery in the treatment of super-refractory partial status epilepticus secondary to NMDAR antibody encephalitis.

BACKGROUND: Anti-NMDAR encephalitis is an increasingly described clinical entity in children, comprising 40% of all cases. We present a case of super-refractory status epilepticus secondary to anti-NMDAR encephalitis treated with emergent resective surgery. CASE STUDY: A 7 years-old boy presented with progressive abnormal irritability. On the day after admission he had multiple seizures, characterized by head and eye version to the right. EEG revealed left parietal-occipital continuous paroxysmal activity. Anti-NMDAR antibodies were positive in CSF and serum. After almost 3 months in the Intensive Care Unit, in barbituric coma, and given the failure of all treatment regimens, a preoperative evaluation was conducted. Ictal SPECT showed significant hiperperfusion and brain FDG-PET a cortical hypometabolism in the left occipital lobe; a left occipital lobectomy was performed. In the next days it was possible to progressively suspend Thiopental. Currently, patient presents right homonymous hemianopsia, eats by his own hand but needs help in almost all other activities. DISCUSSION: Status epilepticus (SE) in the setting of anti-NMDAR encephalitis is unusual but described. Whilst the role of surgery in the management of refractory focal epilepsy is established, it is seldom used in the treatment of SE. In the patient with refractory SE (RSE), awareness of surgery as a potentially life saving treatment is an important issue. To our knowledge, this is the first report of a partial RSE secondary to anti-NMDAR encephalitis treated with resective surgery and illustrates the need to consider anti-NMDAR encephalitis as a cause of super-refractory SE.