Sexual, addiction and mental health care needs among men who have sex with men practicing chemsex - a cross-sectional study in the Netherlands.

Drug use during sex ('chemsex') has been associated with sexually transmitted infections (STIs) and mental health harms. Little quantitative evidence exists on the health care needs of MSM practicing chemsex from a patient perspective. This study assessed self-perceived benefits and harms and the needs for professional counselling among MSM practicing chemsex. In 2018, 785 MSM were recruited at nine Dutch STI clinics and 511 (65%) completed the online questionnaire. Chemsex was defined as using cocaine, crystal meth, designer drugs, GHB/GBL, ketamine, speed and/or XTC/MDMA during sex <6 months. Chemsex was reported by 41% (209/511), of whom 23% (48/209) reported a need for professional counselling. The most reported topic to discuss was increasing self-control (52%, 25/48). Most MSM preferred to be counselled by sexual health experts (56%, 27/48). The need for professional counselling was higher among MSM who engaged in chemsex ≥2 times per month (30% vs. 17%, p = 0.03), did not have sex without drugs (sober sex) in the past three months (41% vs. 20%, p = 0.04), experienced disadvantages of chemsex (28% vs. 15%, p = 0.03), had a negative change in their lives due to chemsex (53% vs. 21%, p = 0.002), and/or had an intention to change chemsex behaviours (45% vs. 18%, p < 0.001). Our study shows that almost one in four MSM practicing chemsex expressed a need for professional counselling on chemsex-related issues. STI healthcare providers should assess the need for professional counselling in MSM practicing chemsex, especially in MSM with above mentioned characteristics, such as frequent users.

Novel mutations in two unrelated Italian patients with SSADH deficiency.

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare autosomal recessive disorder of γ-aminobutyric acid (GABA) catabolism caused by mutations in the gene coding for succinic semialdehyde dehydrogenase (ALDH5A1). The abnormal levels of GHB detected in the brain and in all physiological fluids of SSADHD patients represent a diagnostic biochemical hallmark of the disease. Here we report on the clinical and molecular characterization of two unrelated Italian patients and the identification of two novel mutations: a 22 bp DNA duplication in exon 1, c.114_135dup, p.(C46AfsX97), and a non-sense mutation in exon 10, c.1429C > T, p.(Q477X). The two patients showed very different clinical phenotypes, coherent with their age. These findings enrich the characterization of SSADHD families and contribute to the knowledge on the progression of the disease.

Rett syndrome (MECP2) and succinic semialdehyde dehydrogenase (ALDH5A1) deficiency in a developmentally delayed female.

BACKGROUND: We present a patient with Rett syndrome (RTT; MECP2) and autosomal-recessive succinic semialdehyde dehydrogenase deficiency (SSADHD; ALDH5A1 (aldehyde dehydrogenase 5a1 = SSADH), in whom the current phenotype exhibits features of SSADHD (hypotonia, global developmental delay) and RTT (hand stereotypies, gait anomalies). METHODS: γ-Hydroxybutyric acid (GHB) was quantified by UPLC-tandem mass spectrometry, while mutation analysis followed standard methodology of whole-exome sequencing. RESULTS: The biochemical hallmark of SSADHD, GHB was increased in the proband's dried bloodspot (DBS; 673 µM; previous SSADHD DBSs (n = 7), range 124-4851 µM); control range (n = 2,831), 0-78 µM. The proband was compound heterozygous for pathogenic ALDH5A1 mutations (p.(Asn418IlefsTer39); maternal; p.(Gly409Asp); paternal) and a de novo RTT nonsense mutation in MECP2 (p.Arg255*). CONCLUSION: The major inhibitory neurotransmitter, γ-aminobutyric acid (GABA), is increased in SSADHD but normal in RTT, although there are likely regional changes in GABA receptor distribution. GABAergic anomalies occur in both disorders, each featuring an autism spectrum phenotype. What effect the SSADHD biochemical anomalies (elevated GABA, GHB) might play in the neurodevelopmental/epileptic phenotype of our patient is currently unknown.

Succinic semialdehyde dehydrogenase deficiency: The combination of a novel ALDH5A1 gene mutation and a missense SNP strongly affects SSADH enzyme activity and stability.

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare autosomal recessive metabolic disorder of GABA catabolism. SSADH is a mitochondrial homotetrameric enzyme encoded by ALDH5A1 gene. We report the molecular characterization of ALDH5A1 gene in an Italian SSADHD patient, showing heterozygosity for four missense mutations: c.526G>A (p.G176R), c.538C>T (p.H180Y), c.709G>T (p.A237S) and c.1267A>T (p.T423S), the latter never described so far. The patient inherited c.526A in cis with c.538T from the mother and c.709T in cis with c.1267T from the father. To explore the effects of the two allelic arrangements on SSADH activity and protein level, wild type, single or double mutated cDNA constructs were expressed in a cell system. The p.G176R change, alone or in combination with p.H180Y, causes the abolishment of enzyme activity. Western blot analysis showed a strongly reduced amount of the p.176R-p.180Y double mutant protein, suggesting increased degradation. Indeed, in silico analyses confirmed high instability of this mutant homotetramer. Enzyme activity relative to the other p.423S-p.237S double mutant is around 30% of wt. Further in silico analyses on all the possible combinations of mutant monomers suggest the lowest stability for the tetramer constituted by p.176R-p.180Y monomers and the highest stability for that constituted by p.237S-p.423S monomers. The present study shows that when a common SNP, associated with a slight reduction of SSADH activity, is inherited in cis with a mutation showing no consequences on the enzyme function, the activity is strongly affected. In conclusion, the peculiar arrangement of four missense mutations occurring in this patient is responsible for the SSADHD phenotype.

SSADH deficiency in an Italian family: a novel ALDH5A1 gene mutation affecting the succinic semialdehyde substrate binding site.

SSADH deficiency (SSADHD) is a rare autosomal recessively inherited metabolic disorder. It is associated with mutations of ALDH5A1 gene, coding for the homotetrameric enzyme SSADH. This enzyme is involved in γ-aminobutyric acid (GABA) catabolism, since it oxidizes succinic semialdehyde (SSA) to succinate. Mutations in ALDH5A1 gene result in the abnormal accumulation of γ-hydroxybutyrate (GHB), which is pathognomonic of SSADHD. In the present report, diagnosis of SSADHD in a three-month-old female was achieved by detection of high levels of GHB in urine. Sequence analysis of ALDH5A1 gene showed that the patient was a compound heterozygote for c.1226G > A (p.G409D) and the novel missense mutation, c.1498G > C (p.V500 L). By ALDH5A1 gene expression in transiently transfected HEK293 cells and enzyme activity assays, we demonstrate that the p.V500 L mutation, despite being conservative, produces complete loss of enzyme activity. In silico protein modelling analysis and evaluation of tetramer destabilizing energies suggest that structural impairment and partial occlusion of the access channel to the active site affect enzyme activity. These findings add further knowledge on the missense mutations associated with SSADHD and the molecular mechanisms underlying the loss of the enzyme activity.