Craniofacial features of POLR3-related leukodystrophy caused by biallelic variants in POLR3A, POLR3B and POLR1C.

BACKGROUND: RNA polymerase III-related or 4H leukodystrophy (POLR3-HLD) is an autosomal recessive hypomyelinating leukodystrophy characterized by neurological dysfunction, hypodontia and hypogonadotropic hypogonadism. The disease is caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C or POLR3K. Craniofacial abnormalities reminiscent of Treacher Collins syndrome have been originally described in patients with POLR3-HLD caused by biallelic pathogenic variants in POLR1C. To date, no published studies have appraised in detail the craniofacial features of patients with POLR3-HLD. In this work, the specific craniofacial characteristics of patients with POLR3-HLD associated with biallelic pathogenic variants in POLR3A, POLR3B and POLR1C are described. METHODS: The craniofacial features of 31 patients with POLR3-HLD were evaluated, and potential genotype-phenotype associations were evaluated. RESULTS: Various craniofacial abnormalities were recognized in this patient cohort, with each individual presenting at least one craniofacial abnormality. The most frequently identified features included a flat midface (61.3%), a smooth philtrum (58.0%) and a pointed chin (51.6%). In patients with POLR3B biallelic variants, a thin upper lip was frequent. Craniofacial anomalies involving the forehead were most commonly associated with biallelic variants in POLR3A and POLR3B while a higher proportion of patients with POLR1C biallelic variants demonstrated bitemporal narrowing. CONCLUSION: Through this study, we demonstrated that craniofacial abnormalities are common in patients with POLR3-HLD. This report describes in detail the dysmorphic features of POLR3-HLD associated with biallelic variants in POLR3A, POLR3B and POLR1C.

The clinical and biochemical hallmarks generally associated with GLUT1DS may be caused by defects in genes other than SLC2A1.

Glucose transporter 1 deficiency syndrome (GLUT1DS) is a neurometabolic disorder caused by haploinsufficiency of the GLUT1 glucose transporter (encoded by SLC2A1) leading to defective glucose transport across the blood-brain barrier. This work describes the genetic analysis of 56 patients with clinical or biochemical GLUT1DS hallmarks. 55.4% of these patients had a pathogenic variant of SLC2A1, and 23.2% had a variant in one of 13 different genes. No pathogenic variant was identified for the remaining patients. Expression analysis of SLC2A1 indicated a reduction in SLC2A1 mRNA in patients with pathogenic variants of this gene, as well as in one patient with a pathogenic variant in SLC9A6, and in three for whom no candidate variant was identified. Thus, the clinical and biochemical hallmarks generally associated with GLUT1DS may be caused by defects in genes other than SLC2A1.

Value of Thyroid Peroxidase Antibodies in Neuroimmune Diseases: Analysis of Interference During Treatment with Intravenous Immunoglobulins.

OBJECTIVE: The absence of specific markers can make the diagnosis of neuroimmune disorders difficult, making other biomarkers such as thyroid peroxidase antibodies (TPO-Abs) more relevant. Laboratory tests are susceptible to interference, especially those tests performed using immunoassay techniques. The effect of treatment with human intravenous immunoglobulin (IVIG) on the results of TPO-Abs assays has not been previously characterized. MATERIALS AND METHODS: We analyzed TPO-Abs levels in 170 children monitored in the neuroimmune disease department of a tertiary hospital. We analyzed the characteristics of patients with increased TPO-Abs values and compared their progress with and without treatment. RESULTS: We found that 97% of patients with elevated TPO-Abs had received IVIG. After withdrawal from IVIG, a mean TPO-Abs decrease of 62.5% at 1 month was observed. The IVIG drug preparation was found to contain 1176 U/mL of TPO-Abs. An interferogram confirmed interference. CONCLUSION: It is advisable to measure levels of TPO-Abs before starting immunotherapy and remain vigilant regarding possible interference in the event of unsubstantiated elevations of this analyte.

Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.

Phosphoinositides are lipids that play a critical role in processes such as cellular signalling, ion channel activity and membrane trafficking. When mutated, several genes that encode proteins that participate in the metabolism of these lipids give rise to neurological or developmental phenotypes. PI4KA is a phosphoinositide kinase that is highly expressed in the brain and is essential for life. Here we used whole exome or genome sequencing to identify 10 unrelated patients harbouring biallelic variants in PI4KA that caused a spectrum of conditions ranging from severe global neurodevelopmental delay with hypomyelination and developmental brain abnormalities to pure spastic paraplegia. Some patients presented immunological deficits or genito-urinary abnormalities. Functional analyses by western blotting and immunofluorescence showed decreased PI4KA levels in the patients' fibroblasts. Immunofluorescence and targeted lipidomics indicated that PI4KA activity was diminished in fibroblasts and peripheral blood mononuclear cells. In conclusion, we report a novel severe metabolic disorder caused by PI4KA malfunction, highlighting the importance of phosphoinositide signalling in human brain development and the myelin sheath.

Classic Ketogenic Diet and Modified Atkins Diet in SLC2A1 Positive and Negative Patients with Suspected GLUT1 Deficiency Syndrome: A Single Center Analysis of 18 Cases.

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 >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.

Delineating the neurological phenotype in children with defects in the ECHS1 or HIBCH gene.

The neurological phenotype of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) and short-chain enoyl-CoA hydratase (SCEH) defects is expanding and natural history studies are necessary to improve clinical management. From 42 patients with Leigh syndrome studied by massive parallel sequencing, we identified five patients with SCEH and HIBCH deficiency. Fourteen additional patients were recruited through collaborations with other centres. In total, we analysed the neurological features and mutation spectrum in 19 new SCEH/HIBCH patients. For natural history studies and phenotype to genotype associations we also included 70 previously reported patients. The 19 newly identified cases presented with Leigh syndrome (SCEH, n = 11; HIBCH, n = 6) and paroxysmal dystonia (SCEH, n = 2). Basal ganglia lesions (18 patients) were associated with small cysts in the putamen/pallidum in half of the cases, a characteristic hallmark for diagnosis. Eighteen pathogenic variants were identified, 11 were novel. Among all 89 cases, we observed a longer survival in HIBCH compared to SCEH patients, and in HIBCH patients carrying homozygous mutations on the protein surface compared to those with variants inside/near the catalytic region. The SCEH p.(Ala173Val) change was associated with a milder form of paroxysmal dystonia triggered by increased energy demands. In a child harbouring SCEH p.(Ala173Val) and the novel p.(Leu123Phe) change, an 83.6% reduction of the protein was observed in fibroblasts. The SCEH and HIBCH defects in the catabolic valine pathway were a frequent cause of Leigh syndrome in our cohort. We identified phenotype and genotype associations that may help predict outcome and improve clinical management.

Síndrome opsoclonus mioclonus. Experiencia en los últimos 12 años en un hospital terciario / Opsoclonus-myoclonus syndrome: Experience in a tertiary hospital in the last 12 years

No disponible

Tocilizumab in pediatric refractory status epilepticus and acute epilepsy: Experience in two patients.

There is growing evidence for inflammation as a cause and/or consequence of seizures in epilepsy as certain inflammatory biomarkers are elevated. Interleukin (IL)-6, with pro-inflammatory and epileptogenic effects, can perpetuate seizures. Clinical and experimental data support its involvement in acute refractory situations, with some cases responding to treatment with tocilizumab, a humanized monoclonal antibody against the IL-6 receptor. We describe 2 pediatric cases of refractory epilepsy with an abrupt debut responding to tocilizumab. Advances in the knowledge of inflammatory biomarkers involved in epilepsy and the targeted treatment could have important benefits, especially in cases that are refractory to usual treatments.

Encefalitis por anticuerpos contra el receptor de NMDA con afectación hemisférica unilateral / Anti-NMDA receptor encephalitis with unilateral hemispheric affectation

No disponible

Dos nuevos casos de síndrome de Leigh por mutación m.13513G>A en el gen MTND5 / Two new cases of Leigh syndrome caused by mutation m.13513G> A in the MTND5 gene

No disponible

Clinical and molecular diagnosis of non-phosphomannomutase 2 N-linked congenital disorders of glycosylation in Spain.

The congenital disorders of glycosylation (CDG) are defects in glycoprotein and glycolipid glycan synthesis and attachment. They affect multiple organ/systems, but non-specific symptoms render the diagnosis of the different CDG very challenging. Phosphomannomutase 2 (PMM2)-CDG is the most common CDG, but advances in genetic analysis have shown others to occur more commonly than previously thought. The present work reports the clinical and mutational spectrum of 25 non-PMM2 CDG patients. The most common clinical symptoms were hypotonia (80%), motor or psychomotor disability (80%) and craniofacial dysmorphism (76%). Based on their serum transferrin isoform profile, 18 were classified as CDG-I and 7 as CDG-II. Pathogenic variations were found in 16 genes (ALG1, ALG6, ATP6V0A2, B4GALT1, CCDC115, COG7, DOLK, DPAGT1, DPM1, GFPT1, MPI, PGM1, RFT1, SLC35A2, SRD5A3, and SSR4). Overall, 27 variants were identified, 12 of which are novel. The results highlight the importance of combining genetic and biochemical analyses for the early diagnosis of this heterogeneous group of disorders.

Diagnosis and follow-up of patients with Hunter syndrome in Spain: A Delphi consensus.

Hunter syndrome or mucopolysaccharidosis type II (MPSII) is a progressive multisystem X-linked lysosomal storage disease caused by mutations in the IDS gene that shows a wide spectrum of clinical symptoms and severity. Idursulfase, a specific enzyme replacement therapy (ERT) for MPSII, has been available since 2007. ERT, along with symptomatic management of patients, is fundamental for improving patient prognosis and quality of life. The aims of this study were to investigate whether Spanish pediatricians who are experts in managing the disease agreed with current international guidelines regarding MPSII patient diagnosis and follow-up; and to reach a consensus regarding which items are essential for the diagnosis, follow-up, and treatment of these patients in Spain.An advisory panel of 5 experts from the Hunter Spanish Working Group reviewed key studies, developed a questionnaire based on a modified Delphi method, sent the questionnaire to selected experts, and reviewed the responses. The final questionnaire had 83 items in the following categories: diagnosis, ERT considerations after diagnosis, Periodic assessments, and ERT considerations during follow-up. A total of 85 experts were invited to participate; 28 (35%) responded and showed a strong consensus for most items. The advisory panel decided not to perform a second Delphi round. There was strong agreement (>3.1 median value; range, 1 to 4) for 43/56 items in Diagnosis, for 4/6 items in "ERT considerations after diagnosis," for 6/16 items in "Periodic assessments," and for 3/5 items in "ERT considerations during follow-up." Most responses were in agreement with international guidelines, and controversial items were discussed by the advisory panel. Based on the results, on the key studies, and on clinical experience and opinions, the panel developed and scheduled recommendations for the diagnosis and follow-up of patients with MPSII.An expert 5-person panel oversaw a Delphi survey of 28 pediatricians and reached a consensus on recommendations for the diagnosis and follow-up of MPSII patients. This document will help guide clinicians involved in the diagnosis, management, and treatment of MPSII.

Early Diagnosis of CAPOS Syndrome Before Acute-Onset Ataxia-Review of the Literature and a New Family.

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.

Proceso de transición de la asistencia pediátrica a la adulta en pacientes con errores congénitos del metabolismo. Documento de consenso / Transition process from paediatric to adult care in patients with inborn errors of metabolism. Consensus statement

Antecedentes y objetivo: El proceso de transición de la asistencia pediátrica a la adulta es un tema de gran interés en los últimos años, especialmente en enfermedades crónicas de inicio en la infancia, como los errores congénitos del metabolismo (ECM). Los avances en el diagnóstico y el tratamiento de estas enfermedades han mejorado su pronóstico, encontrando en la actualidad un elevado número de pacientes con ECM que alcanzan la edad adulta y necesitan ser atendidos por profesionales no pediátricos. El objetivo de este trabajo es establecer unas pautas de actuación para que los especialistas involucrados garanticen una transición exitosa de la atención sanitaria de estos pacientes. Metodología: Tras realizar una revisión bibliográfica del tema, los autores, partiendo de su propia experiencia, elaboraron un documento inicial que fue sometido a sucesivos debates hasta obtener el documento definitivo. En caso de discrepancia de criterio, la recomendación de consenso se decidió por mayoría. Resultados: Se presentan una serie de recomendaciones para el mejor abordaje clínico de la transición asistencial de los pacientes con ECM desde el entorno pediátrico a la asistencia de adultos, con el objetivo de conseguir los mejores resultados en este proceso, dadas las características especiales de este subgrupo de pacientes, así como las principales dificultades que conlleva el proceso de transición Conclusiones: Se resalta el papel del médico internista en este proceso de transición y su correcta articulación con el entorno pediátrico y social. Asimismo, se recomiendan acciones y actitudes para mejorar la calidad de dicha transición (AU)

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 (AU)

[Transition process from paediatric to adult care in patients with inborn errors of metabolism. Consensus statement]. / Proceso de transición de la asistencia pediátrica a la adulta en pacientes con errores congénitos del metabolismo. Documento de consenso.

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.

Autoimmune post-herpes simplex encephalitis of adults and teenagers.

OBJECTIVE: To report 14 patients with immune-mediated relapsing symptoms post-herpes simplex encephalitis (HSE) and to compare the clinical and immunologic features of the teenage and adult group with those of young children. METHODS: Prospective observational study of patients diagnosed between June 2013 and February 2015. Immunologic techniques have been reported previously. RESULTS: Among the teenage and adult group (8 patients, median age 40 years, range 13-69; 5 male), 3 had an acute symptom presentation suggesting a viral relapse, and 5 a presentation contiguous with HSE suggesting a recrudescence of previous deficits. Seven patients developed severe psychiatric/behavioral symptoms disrupting all social interactions, and one refractory status epilepticus. Blepharospasm occurred in one patient. Five patients had CSF antibodies against NMDA receptor (NMDAR) and 3 against unknown neuronal cell surface proteins. In 5/6 patients, the brain MRI showed new areas of contrast enhancement that decreased after immunotherapy and clinical improvement. Immunotherapy was useful in 7/7 patients, sometimes with impressive recoveries, returning to their baseline HSE residual deficits. Compared with the 6 younger children (median age 13 months, range 6-20, all with NMDAR antibodies), the teenagers and adults were less likely to develop choreoathetosis (0/8 vs 6/6, p < 0.01) and decreased level of consciousness (2/8 vs 6/6, p < 0.01) and had longer delays in diagnosis and treatment (interval relapse/antibody testing 85 days, range 17-296, vs 4 days, range 0-33, p = 0.037). CONCLUSION: In teenagers and adults, the immune-mediated relapsing syndrome post-HSE is different from that known in young children as choreoathetosis post-HSE and is underrecognized. Prompt diagnosis is important because immunotherapy can be highly effective.

Neurofibromatosis type 1 associated with moyamoya syndrome in children.

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.

Clinical case of anti-N-methyl-D-aspartate receptor encephalitis in an 8-month-old patient with hyperkinetic movement disorder.

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.

Immune-mediated mechanisms in the pathogenesis of Hopkins syndrome.

Hopkins syndrome occurs after an acute asthma attack. An immune-mediated mechanism has been suggested. Immunoglobulin or methylprednisone pulse therapies comprise the most useful treatment. We describe a 3-year-old girl who developed severe weakness in her left arm, 7 days after an acute asthma attack. A complete blood count with autoimmune biomarkers, immunoglobulin profile, and virology study and magnetic resonance of the brain, spine, and brachial plexus produced normal results. In the cerebrospinal fluid, T lymphocytes comprised the predominant leukocyte population, and oligoclonal bands were positive. An electromyogram revealed a partial axonal lesion (normal motor nerve conduction velocity with low amplitude) of the axillary, musculocutaneus, and interosseous nerves of the left arm, with normal sensory nerve conduction and partial denervation. We began therapy with intravenous immunoglobulin for 5 consecutive days, repeated every 4 weeks for 2 months. Afterward, our patient recovered. This report contributes to understanding the role of immune-mediated mechanisms in the pathogenesis of this disease, and the importance of immunotherapy in its treatment.