Prosaposin (PSAP) deficiency is an ultra‐rare, fatal infantile lysosomal storage disorder (LSD) caused by variants in the PSAP gene, with seven subjects reported so far. Here, we provide the ...clinical, biochemical and molecular characterization of two additional PSAP deficiency cases. Lysoplex, a targeted resequencing approach was utilized to identify the variant in the first patient, while quantification of plasma lysosphingolipids (lysoSLs), assessed by liquid chromatography mass spectrometry (LC‐MS/MS) and brain magnetic resonance imaging (MRI), followed by Sanger sequencing allowed to attain diagnosis in the second case. Functional studies were carried out on patients' fibroblast lines to explore the functional impact of variants. The two patients were homozygous for two different truncating PSAP mutations (c.895G>T, p.Glu299*; c.834_835delGA, p.Glu278Aspfs*27). Both variants led to a complete lack of processed transcript. LC‐MS/MS and brain MRI analyses consistently provided a distinctive profile in the two children. Quantification of specific plasma lysoSLs revealed elevated levels of globotriaosylsphingosine (LysoGb3) and glucosylsphingosine (GlSph), and accumulation of autophagosomes, due to a decreased autophagic flux, was observed. This report documents the successful use of plasma lysoSLs profiling in the PSAP deficiency diagnosis, as a reliable and informative tool to obtain a preliminary information in infantile cases with complex traits displaying severe neurological signs and visceral involvement.
Biogenic amine defects constitute a complex and expanding group of neurotransmitter disorders affecting cognitive, motor and autonomic system development, mostly in the pediatric age. In recent years ...different enzymatic defects have been identified impairing the tetrahydrobiopterin cofactor pathway and/or biogenic amine synthesis, catabolism and transport, with subsequent new disease entities described. The lumbar puncture, with subsequent withdrawal of cerebrospinal fluid (CSF), remains a key step in the diagnostic procedure. Due to the specific nature of CSF, timing of analysis, sample collection and storage, technical issues of the analytic process are still crucial for the diagnosis and follow-up of patients. A progressive approach to the diagnosis of biogenic amine defects is presented, pointing out criticalities and difficulties concerning sample collection and results interpretation, especially due to the increasing reports of secondary neurotransmitter alterations that, at present, constitute a challenge.
Hereditary spastic paraparesis (HSP) comprises a clinically and genetically heterogeneous group of disorders characterized by progressive spasticity and hyperreflexia of the lower limbs. The past few ...years have witnessed an exponential increase in knowledge of this disease and we can now list 19 loci mapped on the human genome and eight genes cloned. However, this wider knowledge of the molecular basis of HSP has had limited impact on clinical practice: the use of antispastic drugs and regular physiotherapy still remain crucial in the therapeutic management of patients. Nonetheless, the identification of new genes mutated in HSP furthers comprehension of the pathomechanisms involved and helps in genetic counseling, especially of asymptomatic individuals who request molecular analyses.
Newborn screening for phenylketonuria (PKU) and early introduction of dietary therapy has been remarkably successful in preventing the severe neurological features of PKU, including mental ...retardation and epilepsy. However, concerns remain that long‐term outcome is still suboptimal, particularly in adult patients who are no longer on strict phenylalanine‐restricted diets. With our systematic literature review we aimed to describe the neurological phenotype of adults with early‐treated phenylketonuria (ETPKU). The literature search covered the period from 1 January 1990 up to 16 April 2018, using the NLM MEDLINE controlled vocabulary. Of the 643 records initially identified, 83 were included in the analysis. The most commonly reported neurological signs were tremor and hyperreflexia. The overall quality of life (QoL) of ETPKU adults was good or comparable to control populations, and there was no evidence for a significant incidence of psychiatric disease or social difficulties. Neuroimaging revealed that brain abnormalities are present in ETPKU adults, but their clinical significance remains unclear. Generally, intelligence quotient (IQ) appears normal but specific deficits in neuropsychological and social functioning were reported in early‐treated adults compared with healthy individuals. However, accurately defining the prevalence of these deficits is complicated by the lack of standardized neuropsychological tests. Future research should employ standardized neurological, neuropsychological, and neuroimaging protocols, and consider other techniques such as advanced imaging analyses and the recently validated PKU‐specific QoL questionnaire, to precisely define the nature of the impairments within the adult ETPKU population and how these relate to metabolic control throughout life.
Background
Status epilepticus (SE) is a life-threatening neurologic disorder comprising prolonged and unremitting crisis, and two or more series of seizures without complete intercritical recovery.
...Data sources
We reviewed the literature through a Pubmed/Medline research using key words including status epilepticus, antiepileptic drugs and children, in order to revise and compare international/national protocols and to examine pediatric guidelines in SE management.
Results
Neurologic impairment and SE etiology seem to be the most independent risks for mortality. A deep semiologic evaluation is essential to addressing diagnostic work-up. Ematochemical parameters, plasma levels of antiepileptic drugs and clinically oriented toxic/metabolic screening should be mandatory for investigating both causes and effects of SE. Electroencephalography is clearly helpful to characterize focal from generalized SE and to distinguish epileptic events from pseudoseizures, and it is deal to find nonconvulsive SE. Neuroimaging techniques could detect epileptogenic lesions (such as cortical malformations, tumors, demyelinating disorders or strokes) but are common in practice to find negative or controversial results. Pharmacologic management can be essentially arranged in three stages: benzodiazepines for early SE (lasting less than 30 minutes), phenytoin/fosphenytoin, phenobarbital, valproate, levetiracetam or lacosamide for established SE (30–90 minutes), and anesthetics for refractory SE (more than 90 minutes).
Conclusions
Status epilepticus is the most common neurologic emergency in childhood. A systematic diagnostic work-up and a three steps based therapeutic approach is required at this age.
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