Francesca Nardecchia

Metabolic epilepsy: an update.

Inborn errors of metabolism comprise a large class of genetic diseases involving disorders of metabolism. Presentation is usually in the neonatal period or infancy but can occur at any time, even in adulthood. Seizures are frequent symptom in inborn errors of metabolism, with no specific seizure types or EEG signatures. The diagnosis of a genetic defect or an inborn error of metabolism often results in requests for a vast array of biochemical and molecular tests leading to an expensive workup. However a specific diagnosis of metabolic disorders in epileptic patients may provide the possibility of specific treatments that can improve seizures. In a few metabolic diseases, epilepsy responds to specific treatments based on diet or supplementation of cofactors (vitamin-responsive epilepsies), but for most of them specific treatment is unfortunately not available, and conventional antiepileptic drugs must be used, often with no satisfactory success. In this review we present an overview of metabolic epilepsies based on various criteria such as treatability, age of onset, seizure type, and pathogenetic background.

Psychiatric disorders in adolescent and young adult patients with phenylketonuria

BACKGROUND AND OBJECTIVES Psychiatric symptoms are a challenging aspect in adolescent and adult early treated phenylketonuric (ETPKU) patients. To assess the occurrence of psychiatric disorders we explored the presence of symptoms requiring intervention and further investigated the link between psychiatric disorders, the quality of biochemical control and cognitive functioning. PATIENTS AND METHODS Forty-six ETPKU patients (aged 12 to 44) and 30 age-matched healthy controls were subjected to cognitive and psychiatric assessment by means of self-report questionnaires and psychiatric interview. Psychiatric diagnoses, if detected, were made according to DSM-5 criteria. Concomitant IQ, historical and concurrent biochemical metabolic controls were included in the statistical analysis. RESULTS Twenty-five out of 46 ETPKUs showed clinical scores on at least one scale of the psychiatric assessment (7/30 in controls); anxiety and withdrawal were the most frequent self-reported symptoms. Seventeen patients (and no controls) met criteria for a psychiatric diagnosis, most of them belonging to the Anxiety Disorders category. The occurrence of psychiatric symptoms was not associated with the life-long and concurrent quality of metabolic control but patients with good metabolic control (≤ 500 μM) in the first 11 years of life showed higher frequency of psychiatric diagnosis (Fishers exact p=.0300). DISCUSSION/CONCLUSION ETPKUs show a higher than normal vulnerability to psychiatric disorders, which cannot be explained by the usual biochemical alterations influencing intellectual outcome. Our data support the hypothesis that the burden of the disease acts as psychological stress for children and their families. Possible involvement of neuromediators in the pathogenesis of these complex symptoms requires further investigation.

The outcome of white matter abnormalities in early treated phenylketonuric patients: A retrospective longitudinal long-term study.

BACKGROUND Pathogenesis and clinical consequences of white matter abnormalities on magnetic resonance imaging (MRI) in phenylketonuric (PKU) patients are incompletely known. OBJECTIVE To study white matter alterations progression and outcome and its relationships with phenylalanine levels and intelligence quotient (IQ) in early treated PKU subjects who underwent serial MRIs during a prolonged follow-up. METHODS 47 early treated PKU patients (mean age 25.1 ± 5.6 years; range 12-37 years) have been enrolled when two or more consecutive brain MRIs, a complete biochemical history, and MRI-concurrent blood phenylalanine levels were available. The severity and extension of white matter abnormalities were expressed in a computed score. Consecutive IQ assessments were available in 24 patients. We analyzed intra- and interindividual white matter alterations variations and their relationship with quality of biochemical control and cognitive outcome. RESULTS Early treated PKU patients showed a high rate of white matter alterations with a relevant increase in frequency/severity from the second decade of life onwards. Age and quality of dietary control before or between subsequent examinations showed an independent cumulative effect on white matter alterations outcome. No significant association was found between white matter alterations and cognitive outcome. A remarkable interindividual variability was found and several patients disclosed incongruity between the trajectory of white matter alterations and biochemical control. About 30% of white matter alterations variability remains unexplained by the disease-associated determinants. CONCLUSIONS The evolution of white matter alterations is not significantly affected by intellectual outcome and is affected by aging, chronic exposure to phenylalanine, and unknown individual factors.

Erythrocyte-mediated delivery of recombinant enzymes.

The possibility to clone, express and purify recombinant enzymes have originated the opportunity to dispose of a virtually infinite array of proteins that could be used in the clinics to treat several inherited and acquired pathological conditions. However, the direct administration of these recombinant proteins faces some intrinsic difficulties, such as degradation by circulating proteases and/or inactivation by the patient immune system. The use of drug delivery systems may overcome these limitations. Concerning recombinant enzyme therapy, the present review will mainly focus on the exploitation of erythrocytes as a carrier system for enzymes removing potentially noxious metabolites from the circulation, either as limiting treatment strategy for auxotrophic tumours or as a detoxing approach for some intoxication type inherited metabolic disorders. Moreover, the possibility of using RBCs as a potential delivering system addressing the enzymes to the monocyte–macrophages of reticular endothelial system for the treatment of diseases associated with this cell lineage, e.g. lysosome storage diseases, will be briefly discussed.

Neurotransmitter trafficking defect in a patient with clathrin (CLTC) variation presenting with intellectual disability and early-onset parkinsonism

INTRODUCTION Clathrins play a key role in endocytosis, recycling, and trafficking as well as the generation of presynaptic vesicles. We report a new clinical condition associated with a de novo variant in the CLTC gene, which encodes the clathrin heavy polypeptide. CASE REPORT This 30-year-old woman presented with a developmental disorder during childhood that progressed to mild cognitive decline in late childhood and relapsing-remitting hypokinetic-rigid syndrome with severe achalasia, weight loss, and mood disorder in adulthood. 123I-Ioflupane SPECT was normal. Blood phenylalanine was slightly increased and PAH sequencing revealed compound heterozygosity for two variants, p.[Asp151Glu]:[Thr380Met]. CSF examination unexpectedly detected a remarkable reduction of homovanillic, 5-hydroxyindolacetic, and 5-methylthetrahydrofolic acids, which could not be ascribed to any alteration of tetrahydrobiopterin and related biogenic amine pathways. METHODS Trio-based exome sequencing was performed. RESULT A de novo missense variant (c.2669C > T/p.Pro890Leu) was detected in CLTC. Treatment with biogenic amine precursors was ineffective, while the inhibitor of MAO-A selegiline resulted in persistent clinical improvement. CONCLUSIONS We suggest CLTC defect as a new disorder of biogenic amine trafficking, resulting in neurodevelopmental derangement and movement disorder. Neurotransmitter depletion in CSF may be a biomarker of this disease, and selegiline a possible treatment option.

Targeting mGlu5 metabotropic glutamate receptors in the treatment of cognitive dysfunction in a mouse model of phenylketonuria

We studied group-I metabotropic glutamate (mGlu) receptors in Pahenu2 (ENU2) mice, which mimic the genetics and neurobiology of human phenylketonuria (PKU), a metabolic disorder characterized, if untreated, by autism, and intellectual disability (ID). Male ENU2 mice showed increased mGlu5 receptor protein levels in the hippocampus and corpus striatum (but not in the prefrontal cortex) whereas the transcript of the mGlu5 receptor was unchanged. No changes in mGlu1 receptor mRNA and protein levels were found in any of the three brain regions of ENU2 mice. We extended the analysis to Homer proteins, which act as scaffolds by linking mGlu1 and mGlu5 receptors to effector proteins. Expression of the long isoforms of Homer was significantly reduced in the hippocampus of ENU2 mice, whereas levels of the short Homer isoform (Homer 1a) were unchanged. mGlu5 receptors were less associated to immunoprecipitated Homer in the hippocampus of ENU2 mice. The lack of mGlu5 receptor-mediated long-term depression (LTD) in wild-type mice (of BTBR strain) precluded the analysis of hippocampal synaptic plasticity in ENU2 mice. We therefore performed a behavioral analysis to examine whether pharmacological blockade of mGlu5 receptors could correct behavioral abnormalities in ENU2 mice. Using the same apparatus we sequentially assessed locomotor activity, object exploration, and spatial object recognition (spatial novelty test) after displacing some of the objects from their original position in the arena. Systemic treatment with the mGlu5 receptor antagonist, MPEP (20 mg/kg, i.p.), had a striking effect in the spatial novelty test by substantially increasing the time spent in exploring the displaced objects in ENU2 mice (but not in wild-type mice). These suggest a role for mGlu5 receptors in the pathophysiology of ID in PKU and suggest that, also in adult untreated animals, cognitive dysfunction may be improved by targeting these receptors with an appropriate therapy.

Paradoxical sleep deprivation in rats causes a selective reduction in the expression of type-2 metabotropic glutamate receptors in the hippocampus

Graphical abstract Figure. No Caption available. Abstract Paradoxical sleep deprivation in rats is considered as an experimental animal model of mania endowed with face, construct, and pharmacological validity. We induced paradoxical sleep deprivation by placing rats onto a small platform surrounded by water. This procedure caused the animal to fall in the water at the onset of REM phase of sleep. Control rats were either placed onto a larger platform (which allowed them to sleep) or maintained in their home cage. Sleep deprived rats showed a substantial reduction in type‐2 metabotropic glutamate (mGlu2) receptors mRNA and protein levels in the hippocampus, but not in the prefrontal cortex or corpus striatum, as compared to both groups of control rats. No changes in the expression of mGlu3 receptor mRNA levels or mGlu1&agr; and mGlu5 receptor protein levels were found with exception of an increase in mGlu1&agr; receptor levels in the striatum of SD rats. Moving from these findings we treated SD and control rats with the selective mGlu2 receptor enhancer, BINA (30 mg/kg, i.p.). SD rats were also treated with sodium valproate (300 mg/kg, i.p.) as an active comparator. Both BINA and sodium valproate were effective in reversing the manic‐like phenotype evaluated in an open field arena in SD rats. BINA treatment had no effect on motor activity in control rats, suggesting that our findings were not biased by a non‐specific motor‐lowering activity of BINA. These findings suggest that changes in the expression of mGlu2 receptors may be associated with the enhanced motor activity observed with mania.