Exploring the Spectrum of RHOBTB2 Variants Associated with Developmental Encephalopathy 64: A Case Series and Literature Review.

Background: Rho-related BTB domain-containing protein 2 (RHOBTB2) is a protein that interacts with cullin-3, a crucial E3 ubiquitin ligase for mitotic cell division. RHOBTB2 has been linked to early infantile epileptic encephalopathy, autosomal dominant type 64 (OMIM618004), in 34 reported patients. Methods: We present a case series of seven patients with RHOBTB2-related disorders (RHOBTB2-RD), including a description of a novel heterozygous variant. We also reviewed previously published cases of RHOBTB2-RD. Results: The seven patients had ages ranging from 2 years and 8 months to 26 years, and all had experienced seizures before the age of one (onset, 4-12 months, median, 4 months), including various types of seizures. All patients in this cohort also had a movement disorder (onset, 0.3-14 years, median, 1.5 years). Six of seven had a baseline movement disorder, and one of seven only had paroxysmal dystonia. Stereotypies were noted in four of six, choreodystonia in three of six, and ataxia in one case with multiple movement phenotypes at baseline. Paroxysmal movement disorders were observed in six of seven patients for whom carbamazepine or oxcarbazepine treatment was effective in controlling acute or paroxysmal movement disorders. Four patients had acute encephalopathic episodes at ages 4 (one patient) and 6 (three patients), which improved following treatment with methylprednisolone. Magnetic resonance imaging scans revealed transient fluid-attenuated inversion recovery abnormalities during these episodes, as well as myelination delay, thin corpus callosum, and brain atrophy. One patient had a novel RHOBTB2 variant (c.359G>A/p.Gly120Glu). Conclusion: RHOBTB2-RD is characterized by developmental delay or intellectual disability, early-onset seizures, baseline movement disorders, acute or paroxysmal motor phenomena, acquired microcephaly, and episodes of acute encephalopathy. Early onsets of focal dystonia, acute encephalopathic episodes, episodes of tongue protrusion, or peripheral vasomotor disturbances are important diagnostic clues. Treatment with carbamazepine or oxcarbazepine was found to be effective in controlling acute or paroxysmal movement disorders. Our study highlights the clinical features and treatment response of RHOBTB2-RD.

Genotype and Phenotype Characterization of Patients with Mucopolysaccharidosis IV-A in Chile.

Introduction: Morquio syndrome or mucopolysaccharidosis type IV-A (MPS IV-A) is an autosomal recessive disease caused by biallelic variants in the GALNS gene, encoding the lysosomal enzyme GalN6S, responsible for glycosaminoglycan keratan sulfate and chondroitin-6-sulfate degradation. Studies have shown that the degree of evolutionary and chemical divergence of missense variants in GalN6S when compared to ancestral amino acids is associated with the severity of the syndrome, suggesting a genotype-phenotype correlation. There is little information on Latin American patients with MPS IV-A that replicate these findings. This study aimed to characterize the phenotype and genotype from patients with MPS IV-A, who are under Enzyme Replacement Therapy at the Children's Neuropsychiatry Service of the Hospital Clínico San Borja Arriarán, Santiago, Chile, and to determine if there is any association between genotype and phenotype with those findings. Methods: Information was collected from medical charts, all patients went through a GalN6S enzymatic activity measurement in leukocytes from peripheral blood, and the GALNS gene was sequenced for all cases. Results: 12 patients with MPS IV-A were recruited, all patients presented multisystem involvement, mostly skeletal, and 75% of cases underwent surgical interventions, and cervical arthrodesis was the most frequent procedure. In regards of the genotype, the two most frequent variants were c.319+2T>C (n = 10, 41.66%) and p.(Arg386Cys) (n = 8, 33.33%), the first one was previously described in 2018 in a patient from Chile [Bochernitsan et al., 2018]. Conclusion: This is the first time that a genotype-phenotype correlation has been studied by analyzing the variants effect on the molecular structure of human GalN6S and the evolutionary conservation degree of affected residues in a cohort of patients in Chile. Albeit our work could not find statistically significant associations, we may infer that the evolutionary conservations of affected amino acids and the effect of variants on enzyme structure may play a main role. Further analyzes should consider a meta-analysis of published cases with genotype data and larger samples and include other variables that could provide more information. Finally, our data strongly suggest that variant c.319+2T>C could have a founder effect in Chilean patients with MPS IV-A.

Hypomyelination and Congenital Cataract: Identification of a Novel likely pathogenic c.414+1G>A in FAM126A gene Variant.

It is key to expand the differential diagnosis and consider possible genetic etiologies on a patient with congenital cataracts associated with clinical features, such as leukodystrophy or polyneuropathy.

Neuronal ceroid lipofuscinosis type CLN2: a new rationale for the construction of phenotypic subgroups based on a survey of 25 cases in South America.

Tripeptidyl-peptidase 1 (TPP1) null or residual activity occurs in neuronal ceroid lipofuscinosis (NCL) with underlying TPP1/CLN2 mutations. A survey of 25 South American CLN2 affected individuals enabled the differentiation of two phenotypes: classical late-infantile and variant juvenile, each in approximately 50% of patients, with residual TPP1 activity occurring in approximately 32%. Each individual was assigned to one of three subgroups: (I) n=11, null TPP1 activity in leukocytes; (II) n=8, residual TPP1 activity of 0.60-15.85 nmol/h/mg (nr 110-476); (III) n=6, activity not measured in leukocytes. Curvilinear bodies (CB) appeared in almost all studied CLN2 subjects; the only exceptions occurred in cases of subgroup II: two individuals had combined CBs/fingerprints (FPs), and one case had pure FPs. There were 15 mutations (4 first published in this paper, 3 previously observed in South America by our group, and 8 previously observed by others). In subgroup I, mutations were either missense or nonsense; in subgroups II and III, mutations prevailed at the non-conserved intronic site, c.887-10A>G (intron 7), and to a lesser extent at c.89+5G>C (intron 2), in heterozygous combinations. Grouping phenotypically and genetically known individuals on the basis of TPP1 activity supported the concept that residual enzyme activity underlies a protracted disease course. The prevalence of intronic mutations at non-conserved sites in subgroup II individuals indicates that some alternative splicing might allow some residual TPP1 activity.

Vitamina D en niños con enfermedades neurológicas en la edad pediátrica / The role of vitamin D in neurological diseases in children

La vitamina D (VD) y sus acciones en el ser humano son objeto de una activa investigación en años recientes, ligada a la descripción de nuevos roles metabólicos, además de su conocida participación en el metabolismo del calcio y del hueso. En niños, algunas enfermedades neurológicas crónicas, como la parálisis cerebral, presentan un riesgo aumentado de deficiencia de VD, explicándose por una ingesta deficiente de ella, una menor exposición solar, requerimiento asociado al proceso de crecimiento, enfermedades intercurrentes y al uso frecuente de drogas antiepilépticas. En esta revisión se analizan los factores asociados a la deficiencia de VD y se plantea la necesidad de evaluar sistemáticamente el estado nutricional de esta vitamina en pacientes con enfermedades neurológicas de riesgo, sus posibles efectos metabólicos, implicancias clínicas y la necesidad de usar alimentos fortificados o suplementación con VD.

Vitamin D (VD) has been object of an active research in the last years, especially in relation with the findings of its new roles, besides its well known participation in calcium and bone metabolism. In children, some chronic neurologic diseases, like cerebral palsy, show an increased risk of VD deficiency, which could be explained by low intake, reduced sun exposure, requirements associated to growth process, intercurrent diseases and frequent use of antiepileptic drugs. In this review, factors associated to VD deficiency are analyzed, pointing to the need of a systematic assessment of the VD nutritional status in patients with neurological diseases associated to this deficiency, its possible metabolic effects, clinical implications and the need of fortified foods or VD supplementation.

Normalización de trastornos de sueño y su efecto en pacientes con epilepsia refractaria / Effects of sleep disorders normalization in patients during the use of antiepileptic drugs

Los trastornos del sueño son un problema frecuente y subdiagnosticado en niños con cuadros neurológicos y en particular con epilepsias refractarias. Evaluamos los efectos de normalización rápida de los patrones de sueño sobre la refractariedad de la epilepsia. Pacientes y Método: Se ingresaron al estudio todos los pacientes pediátricos con alteración severa del ciclo sueño-vigilia y epilepsia refractaria en control en el Servicio de Neuropsiquiatría Infantil del Hospital Clínico San Borja-Arriarán y Liga contra la Epilepsia, Santiago, Chile, entre Marzo 2004 y Marzo 2008. Cada paciente fue su propio control. Durante el primer mes se solicitó a los padres completar un registro diario de frecuencia y tipo de crisis epiléptica y del ciclo sueño-vigilia de su hijo (a). A contar del segundo mes se implementó un tratamiento para normalizar el ciclo sueño-vigilia utilizando luminoterapia, hábitos estrictos de sueño y melatonina, 30 min antes de la hora de dormir. La terapia antiepiléptica no se modificó durante los primeros seis meses de tratamiento. Resultados: Los once pacientes ingresados normalizaron el ciclo sueño-vigilia durante el primer mes de tratamiento. Diez de 11 casos mostraron una reducción dramática de la frecuencia de crisis por día, mayor a un 85 por ciento, durante los primeros tres meses de intervención, independientemente del tipo de crisis, que se mantuvo por más de un año de seguimiento (13-43 meses). En cinco pacientes se discontinuó la melatonina después de un año de tratamiento, sin que hubiese deterioro del patrón de sueño o aumento en la frecuencia de crisis. Conclusión: Es frecuente el subdiagnóstico de trastorno de sueño en niños con epilepsias refractarias. La normalización del patrón de ciclo sueño-vigilia puede disminuir dramáticamente la frecuencia de crisis y por lo tanto mejorar la calidad de vida de los pacientes y sus familias...

Sleep disorders are a frequent and underdiagnosed problem in children with neurological problems, specially in children with refractory epilepsies. We evaluated the effects of fast normalization of sleep pattern on epilepsy refractoriness. Patients and methods: We enrolled all pediatric patients from March 2004 to March 2008, with severe alterations of the sleep-wake pattern and refractory epilepsy, attending to the Neuropsychiatry Service, Hospital Clínico San Borja-Arriarán and League against Epilepsy from Santiago, Chile. Each patient was his own control. Parents were asked to complete a diary during the first month after enrollment with frequency, type of seizures and sleep-wake cycle of each patient. After the month, sleep-wake cycle was normalized using morning luminotherapy, strict sleep habits and melatonin, 30 minutes before bedtime. Antiepileptic therapy was not modified during the first six months. Results: All patients normalized the sleep-wake cycle during the first month treatment. Ten of 11 patients showed a dramatic reduction of seizure frequency (over 85 percent of total day seizures) during the first three months of intervention, independently from the seizure type that has maintained for more than a year (13–43 months) follow-up. Melatonin was discontinued in five patients after a year of treatment, with no deterioration of sleep pattern or seizures frequency. Conclusions: Sleep disorders in children with refractory epilepsies are frequently underestimated. The normalization of the sleep-wake pattern can diminish seizures dramatically, improving patients and family quality of life. This point must be always taken into account before considering a patient refractory to antiepileptic drugs and adding new drugs to polytherapy.