Exome sequencing and electro-clinical features in pediatric patients with very early-onset retinal dystrophies: A cohort study.

BACKGROUND AND OBJECTIVE: Inherited retinal dystrophies (IRDs) are a major cause of childhood blindness. Timely diagnosis requires a high level of clinical suspicion from both neurologists and ophthalmologists and is increasingly important given recent advancements in gene therapy. We focused our study on genotype-phenotype associations in very early-onset forms of retinal dystrophy, the least well characterized and most challenging diagnostic subgroup. METHODS: From January 12, 2015 to March 31, 2017, we prospectively performed whole exome sequencing targeted on the phenotype of non-syndromic IRDs and phenotype characterization in a cohort of 68 children affected by very early-onset inherited retinal dystrophies, defined by the onset before five years of age. Phenotype parameters included age at onset, clinical presentation, ophthalmic evaluation, electrophysiological patterns and clinical course. RESULTS: A genetically confirmed diagnosis was achieved in 50 out of 60 (83%) families. The median age at onset was 4 months (<6 m in 70%, < 2 y in 82% of the cases). Clinical presentation was associated with visual loss and nystagmus in the majority of patients. Three (CNGB3, CNGA3 and CACNA1F) out of 22 genes considered pathogenic in the cohort, accounted for 51% of all IRD's, all within the class of stationary IRDs. CONCLUSIONS: This study reports on the largest cohort of very early-onset retinal dystrophies, including a description of electroretinography patterns. The electro-clinical phenotype coupled with genetic diagnosis provided additional clues for child neurologists dealing with low vision and nystagmus in infancy. A high level of clinical suspicion improves the diagnosis with important implications for the future of the affected child.

Biochemistry of primary headaches: role of tyrosine and tryptophan metabolism.

The pathogenesis of migraine as well as cluster headache (CH) is yet a debated question. In this review, we discuss the possible role of the of tyrosine and tryptophan metabolism in the pathogenesis of these primary headaches. These include the abnormalities in the synthesis of neurotransmitters: high level of DA, low level of NE and very elevated levels of octopamine and synephrine (neuromodulators) in plasma of episodic migraine without aura and CH patients. We hypothesize that the imbalance between the levels of neurotransmitters and elusive amines synthesis is due to a metabolic shift directing tyrosine toward an increased decarboxylase and reduced hydroxylase enzyme activities. The metabolic shift of the tyrosine is favored by a state of neuronal hyperexcitability and a reduced mitochondrial activity present in migraine. In addition we present biochemical studies performed in chronic migraine and chronic tension-type headache patients to verify if the same anomalies of the tyrosine and tryptophan metabolism are present in these primary headaches and, if so, their possible role in the chronicity process of CM and CTTH. The results show that important abnormalities of tyrosine metabolism are present only in CM patients (very high plasma levels of DA, NE and tryptamine). Tryptamine plasma levels were found significantly lower in both CM and CTTH patients. In view of this, we propose that migraine and, possibly, CH attacks derive from neurotransmitter and neuromodulator metabolic abnormalities in a hyperexcitable and hypoenergetic brain that spread from the frontal lobe, downstream, resulting in abnormally activated nuclei of the pain matrix. The low tryptamine plasma levels found in CM and CTTH patients suggest that these two primary chronic headaches are characterized by a common insufficient serotoninergic control of the pain threshold.

A saturated N-acylethanolamine other than N-palmitoyl ethanolamine with anti-inflammatory properties: a neglected story...

N-acylethanolamines, which include the endocannabinoid anandamide and the cannabinoid receptor-inactive saturated compounds N-palmitoyl ethanolamine and N-stearoyl ethanolamine, are ethanolamines of long-chain fatty acids degraded by fatty acid amide hydrolase (FAAH) known to accumulate in degenerating tissues and cells. Whilst much evidence supports a protective anti-inflammatory role of both anandamide and N-palmitoyl ethanolamine, very little information is available with regard to the bioactivity of N-stearoyl ethanolamine. Employing a murine model of passive IgE-induced cutaneous anaphylaxis, we have found that N-stearoyl ethanolamine is endowed with marked anti-inflammatory properties in vivo, supporting the hypothesis that endogenous N-stearoyl ethanolamine is, in analogy to N-palmitoyl ethanolamine, a bioactive signalling lipid capable of downregulating allergic inflammation in the skin. This effect, although mimicked by synthetic, non-selective, CB(1)/CB(2) receptor agonists, such as WIN55, 212-2, was not sensitive to CB(1) or CB(2) receptor antagonists, but rather was fully reversed by capsazepine, a competitive antagonist of the TRPV1 receptor. Moreover, CB(1) receptor antagonists, although effective in antagonising the WIN55,212-2-induced hypothermia, did not reduce the anti-inflammatory effect of WIN55,212-2, whilst CB(2) receptor antagonists, per se inactive, potentiated the WIN55,212-2 effect, suggesting an involvement of non-CB(1)/CB(2) receptors in the anti-inflammatory action of WIN55,212-2. All this, together with demonstration of FAAH as a major regulator of the in vivo concentrations of saturated N-stearoyl ethanolamine, in addition to N-palmitoyl ethanolamine, raise the speculation that pharmacological treatments with saturated N-acylethanolamines such as N-stearoyl ethanolamine, or alternatively FAAH inhibitors able to increase their local concentration, rather than selective CB receptor agonists, might be of promising therapeutic benefit in reducing allergic inflammation in the skin.