Biallelic NUDT2 variants defective in mRNA decapping cause a neurodevelopmental disease.

Dysfunctional RNA processing caused by genetic defects in RNA processing enzymes has a profound impact on the nervous system, resulting in neurodevelopmental conditions. We characterized a recessive neurological disorder in 18 children and young adults from 10 independent families typified by intellectual disability, motor developmental delay and gait disturbance. In some patients peripheral neuropathy, corpus callosum abnormalities and progressive basal ganglia deposits were present. The disorder is associated with rare variants in NUDT2, a mRNA decapping and Ap4A hydrolysing enzyme, including novel missense and in-frame deletion variants. We show that these NUDT2 variants lead to a marked loss of enzymatic activity, strongly implicating loss of NUDT2 function as the cause of the disorder. NUDT2-deficient patient fibroblasts exhibit a markedly altered transcriptome, accompanied by changes in mRNA half-life and stability. Amongst the most up-regulated mRNAs in NUDT2-deficient cells, we identified host response and interferon-responsive genes. Importantly, add-back experiments using an Ap4A hydrolase defective in mRNA decapping highlighted loss of NUDT2 decapping as the activity implicated in altered mRNA homeostasis. Our results confirm that reduction or loss of NUDT2 hydrolase activity is associated with a neurological disease, highlighting the importance of a physiologically balanced mRNA processing machinery for neuronal development and homeostasis.

Cerebral folate deficiency: A report of two affected siblings.

Cerebral folate deficiency (CFD) is a rare progressive neurological condition characterized by normal blood folate level and low 5-methyltetrahydrofolate (5-MTHF) levels in the cerebrospinal fluid. Patients present with different neurological findings including hypotonia and microcephaly. Later, patients develop ataxia, seizures, para or quadri-plagia. Herein, we report two siblings; born to consanguineous parents; who had normal neurological development in early childhood. Subsequently they developed drug-resistant seizures, neurological regression, and spastic quadriplegia. After thorough investigations patients had brain MRI which showed abnormal white matter signals and ventricular dilatation, CSF with low 5-MTHF, and whole exome sequencing (WES) revealed a novel homozygous variant in FOLR1 (c.245A > G; p.Tyr82Cys) consistent with the diagnosis of cerebral folate deficiency. They were treated with folinic acid in addition to standard anti-seizure medications. WES aids in reaching CFD diagnosis due to FOLR1 pathogenic variants. These results can be used for future counselling to prevent recurrence in future pregnancies by preimplantation genetic testing prior to implanting the embryo in the uterus. Treatment with folinic acid was shown to improve the neurological symptoms namely reduced the seizures and spasticity.

Metabolic Seizures.

Metabolic diseases should always be considered when evaluating children presenting with seizures. This is because many metabolic disorders are potentially treatable and seizure control can be achieved when these diseases are appropriately treated. Seizures caused by underlying metabolic diseases (metabolic seizures) should be particularly considered in unexplained neonatal seizures, refractory seizures, seizures related to fasting or food intake, seizures associated with other systemic or neurologic features, parental consanguinity, and family history of epilepsy. Metabolic seizures can be caused by various amino acids metabolic disorders, disorders of energy metabolism, cofactor-related metabolic diseases, purine and pyrimidine metabolic diseases, congenital disorders of glycosylation, and lysosomal and peroxisomal disorders. Diagnosing metabolic seizures without delay is essential because the immediate initiation of appropriate therapy for many metabolic diseases can prevent or minimize complications.

Subacute sclerosing panencephalitis: clinical phenotype, epidemiology, and preventive interventions.

Subacute sclerosing panencephalitis (SSPE) is a preventable condition reported in 6.5 to 11 per 100 000 cases of measles, and highest in children who contracted measles infection when they were less than 5 years of age. Children residing in areas with poor vaccination coverage and high prevalence of human immunodeficiency virus are at increased risk of developing SSPE. SSPE is life-threatening in most affected children. This report documents current data relating to the clinical phenotype, epidemiology, and understanding of SSPE, inclusive of preventive interventions. While improvements in disease progression with immunomodulation may occur, overall there is no cure. Most therapies focus on supportive needs. Seizures and abnormal movements may respond to carbamazepine. Many countries advocate policies to enhance vaccination coverage. Effective preventive health care programmes, assurance of parental perceptions, and crisis support for unprecedented events obstructing effective primary health care are needed. Until measles is eradicated worldwide, children in all regions remain at risk. WHAT THIS PAPER ADDS: Measles contracted under 5 years of age has highest risk of developing subacute sclerosing panencephalitis (SSPE). Children with, or exposed to, human immunodeficiency virus infection, who contract measles may be at increased risk of SSPE.

PANENCEFALITIS ESCLEROSANTE SUBAGUDA: FENOTIPO CLÍNICO, EPIDEMIOLOGÍA E INTERVENCIONES PREVENTIVAS: La panencefalitis esclerosante subaguda (SSPE, por sus siglas en inglés) es una afección prevenible notificada en 6,5 a 11 por cada 100 000 casos de sarampión, y es más alta en los niños que contrajeron una infección de sarampión cuando tenían menos de 5 años de edad. Los niños que residen en áreas con una cobertura de vacunación deficiente y una alta prevalencia del virus de inmunodeficiencia humana tienen un mayor riesgo de desarrollar SSPE. La SSPE es potencialmente mortal en la mayoría de los niños afectados. Este informe documenta los datos actuales relacionados con el fenotipo clínico, la epidemiología y la comprensión del SSPE, incluidas las intervenciones preventivas. Si bien pueden producirse mejoras en la progresión de la enfermedad con la inmunomodulación, en general no hay cura. La mayoría de las terapias se centran en las necesidades de apoyo. Las convulsiones y los movimientos anormales pueden responder a la carbamazepina. Muchos países abogan por políticas para mejorar la cobertura de vacunación. Se necesitan programas de atención médica preventiva eficaces, seguridad de las percepciones de los padres y apoyo a la crisis para eventos sin precedentes que obstruyan la atención primaria de salud efectiva. Hasta que se erradique el sarampión en todo el mundo, los niños en todas las regiones siguen en riesgo.

PANENCEFALITE ESCLEROSANTE SUB-AGUDA: FENÓTIPO CLÍNICO, EPIDEMIOLOGIA, E INTERVENÇÕES PREVENTIVAS: A panencefalite esclerosante sub-aguda (PEES) é uma condição prevenível reportada em 6,5 to 11 por 100.000 casos de sarampo, e é mais alta em crianças que contraíram infecção por sarampo com menos de 5 anos de idade. Crianças que residem em áreas com pobre cobertura vacinal e alta prevalência de vírus da imunodeficiência humana apresentam maior risco de desenvolver PEES. A PEES representa risco de vida para as crianças mais afetadas. Este relato documenta dados atuais relacionados a fenótipo clínico, epidemiologia, e compreensão da PEES, incluindo intervenções preventivas. Enquanto melhoras na progressão da doença com a imunomodulação podem ocorrer, em geral não há cura. A maior parte das terapias foca em necessidades de suporte. Convulsões e movimentos anormais podem responder a carbamazepina. Muitos países defendem políticas para melhorar a cobertura vacinal. Programas efetivos de cuidado preventivo em saúde, reforço das percepções parentais, e suporte de crise para eventos sem precedentes obstruindo o cuidado primário efetivo são necessários. Até que o sarampo esteja erradicado em todo o mundo, crianças de todas as regiões permanecem em risco.