Outbreak of Enterovirus Infection with Neurological Presentations in a Pediatric Population in Northern Spain: A Clinical Observational Study.

OBJECTIVE: The study aimed to describe the cases of neurological disease related to the outbreak of enterovirus (EV) in three regions in Northern Spain during 2016. MATERIALS AND METHODS: Multicenter retrospective observational study. Clinical, radiological, and microbiological data were analyzed from patients younger than 15 years with confirmed EV-associated neurological disease admitted to 10 hospitals of Asturias, Cantabria, and Castile and Leon between January 1 and December 31, 2016. RESULTS: Fifty-five patients were included. Median age was 24 months (interquartile range = 18.5 months). Fifteen patients were classified as aseptic meningitis (27.3%). In total, 37 cases presented brainstem encephalitis (67.3%), 25 of them due to EV-A71 with excellent prognosis (84.6% asymptomatic 2 months following the onset). Three cases of acute flaccid myelitis (5.5%) by EV-D68 were reported and presented persistent paresis 2 months following the onset. Microbiological diagnosis by reverse transcriptase polymerase chain reaction was performed in all cases, finding EV in cerebrospinal fluid in meningitis, but not in brainstem encephalitis and acute flaccid myelitis, where EV was found in respiratory or rectal samples. Step therapy was administrated with intravenous immunoglobulin (IVIG; 32.7%), methylprednisolone (10%), and plasmapheresis (3.6%). Four patients received fluoxetine (7.3%). Twenty patients needed to be admitted to pediatric intensive care unit (36.4%). CONCLUSION: Clinical, microbiological, and radiological diagnosis is essential in outbreaks of EV neurological disease, taking into account that it can be difficult to identify EV-A71 and EV-D68 in CSF, requiring throat or rectal samples. There is not specific treatment to these conditions and the efficacy and understanding of the mechanism of action of immune-modulatory treatment (IVIG, corticosteroids, and plasmapheresis) is limited.

Juvenile neuronal ceroid lipofuscinosis: clinical course and genetic studies in Spanish patients.

BACKGROUND: Juvenile neuronal ceroid lipofuscinosis (JNCL, NCL3, Batten disease) is usually caused by a 1.02-kb deletion in the CLN3 gene. Mutations in the CLN1 gene may be associated with a variant form of JNCL (vJNCL). We report the clinical course and molecular studies in 24 patients with JNCL collected from 1975 to 2010 with the aim of assessing the natural history of the disorder and phenotype/genotype correlations. PATIENTS AND METHODS: Patients were classified into the groups of vJNCL with mutations in the CLN1 gene and/or granular osmiophilic deposit (GROD) inclusion bodies (n = 11) and classic JNCL (cJNCL) with mutations in the CLN3 gene and/or fingerprint (FP) profiles (n = 13). Psychomotor impairment included regression of acquired skills, cognitive decline, and clinical manifestations of the disease. We used Kaplan-Meier analyses to estimate the age of onset of psychomotor impairment. RESULTS: Patients with vJNCL showed learning delay at an earlier age (median 4 years, 95% confidence interval [CI] 3.1-4.8) than those in the cJNCL group (median 8 years, 95% CI 6.2-9.7) (P = 0.001) and regression of acquired skills at a younger age. Patients with vJNCL showed a more severe and progressive clinical course than those with cJNCL. There may be a Gypsy ancestry for V181L missense mutation in the CLN1 gene. CONCLUSIONS: The rate of disease progression may be useful to diagnose vJNCL or cJNCL, which should be confirmed by molecular studies in CLN1/CLN3 genes. Further studies of genotype/phenotype correlation will be helpful for understanding the pathogenesis of this disease.

Assessment of a targeted resequencing assay as a support tool in the diagnosis of lysosomal storage disorders.

BACKGROUND: With over 50 different disorders and a combined incidence of up to 1/3000 births, lysosomal storage diseases (LSDs) constitute a major public health problem and place an enormous burden on affected individuals and their families. Many factors make LSD diagnosis difficult, including phenotype and penetrance variability, shared signs and symptoms, and problems inherent to biochemical diagnosis. Developing a powerful diagnostic tool could mitigate the protracted diagnostic process for these families, lead to better outcomes for current and proposed therapies, and provide the basis for more appropriate genetic counseling. METHODS: We have designed a targeted resequencing assay for the simultaneous testing of 57 lysosomal genes, using in-solution capture as the enrichment method and two different sequencing platforms. A total of 84 patients with high to moderate-or low suspicion index for LSD were enrolled in different centers in Spain and Portugal, including 18 positive controls. RESULTS: We correctly diagnosed 18 positive blinded controls, provided genetic diagnosis to 25 potential LSD patients, and ended with 18 diagnostic odysseys. CONCLUSION: We report the assessment of a next-generation-sequencing-based approach as an accessory tool in the diagnosis of LSDs, a group of disorders which have overlapping clinical profiles and genetic heterogeneity. We have also identified and quantified the strengths and limitations of next generation sequencing (NGS) technology applied to diagnosis.

Initiation and discontinuation of substrate inhibitor treatment in patients with Niemann-Pick type C disease.

Niemann-Pick type C disease (NP-C) is a lysosomal storage disorder characterized by a progressive neurological deterioration. Different clinical forms have been defined based on patient age at neurological symptoms onset: perinatal, early infantile (EI), late infantile (LI), juvenile and adult. There is no curative treatment for NP-C. Miglustat is the first effective therapy for the neurological manifestations of NP-C patients, as it can slow down the progression of the disease. Our aim is to establish recommendations on the initiation and discontinuations with miglustat therapy based on the modified disability scale scores and describe therapeutic options to prevent treatment-related adverse effects. Four patients with different clinical forms of NP-C are reported. The modified disability scale was applied at baseline and treatment on follow up. Treatment with miglustat was initiated in patient 1 (EI form) at onset of delayed speech. Patient 2 (LI form) who started miglustat therapy in the advanced stage of the disease, died 2 years thereafter. Patient 3 (juvenile form) started treatment with miglustat at diagnosis and remains stable at four years on follow up. Patient 4, asymptomatic, is not currently treated. Miglustat has demonstrated efficacy to slow down the neurological impairment in NP-C patients assessed by the modified disability scale. Miglustat should be initiated at the onset of the first neurological symptoms. Disability scores above 20 reflect an advanced neurological impairment of the disease and miglustat therapy should be discontinued or not initiated. The gastrointestinal adverse effects can be prevented by dose titration and dietary modifications.

Infantile neuronal ceroid lipofuscinosis: follow-up on a Spanish series.

Infantile neuronal ceroid lipofuscinosis (INCL; NCL1, Haltia-Santavuori disease) is caused by mutations in the CLN1/PPT gene which are associated with an early onset INCL phenotype. The most detailed descriptions of INCL have come from Finland and a few series have been reported from southern European countries. Clinical course and follow-up of six Spanish patients with INCL are reported with the aim of assessing the chronological evolution and severity of this disease. The age at disease onset ranged from 8 to 15 months. Delayed motor skills were the initial symptom when the disease began before 12 months of age, and ataxia was the first sign when the disease began later. Cognitive decline, which is described between 12 and 18 months of age, occurred from 16 to 20 months of age. In our series early stage is characterized by motor impairment, cognitive decline and autistic features. Visual failure may appear simultaneously with the neurological symptoms, leading quickly to blindness. As reported, psychomotor regression appeared between 2 and 3 years of age. Myoclonic jerks occurred after 24 months of age and epilepsy was the last symptom of the disease. We report two novel mutations in a patient without epilepsy to date and describe the features of two siblings homozygous for the V181M (c.541G>A) mutation, associated with the most severe INCL phenotype. The clinical evolution might be helpful to identify patients affected by this rare disease. Early diagnosis is essential in order to provide genetic counselling to affected families. Our series may contribute to the study of the genotype-phenotype INCL correlation in the Mediterranean countries.