Differences between transient neonatal diabetes mellitus subtypes can guide diagnosis and therapy.

OBJECTIVE: Transient neonatal diabetes mellitus (TNDM) is caused by activating mutations in ABCC8 and KCNJ11 genes (KATP/TNDM) or by chromosome 6q24 abnormalities (6q24/TNDM). We wanted to assess whether these different genetic aetiologies result in distinct clinical features. DESIGN: Retrospective analysis of the Italian data set of patients with TNDM. METHODS: Clinical features and treatment of 22 KATP/TNDM patients and 12 6q24/TNDM patients were compared. RESULTS: Fourteen KATP/TNDM probands had a carrier parent with abnormal glucose values, four patients with 6q24 showed macroglossia and/or umbilical hernia. Median age at diabetes onset and birth weight were lower in patients with 6q24 (1 week; -2.27 SD) than those with KATP mutations (4.0 weeks; -1.04 SD) (P = 0.009 and P = 0.007, respectively). Median time to remission was longer in KATP/TNDM than 6q24/TNDM (21.5 weeks vs 12 weeks) (P = 0.002). Two KATP/TNDM patients entered diabetes remission without pharmacological therapy. A proband with the ABCC8/L225P variant previously associated with permanent neonatal diabetes entered 7-year long remission after 1 year of sulfonylurea therapy. Seven diabetic individuals with KATP mutations were successfully treated with sulfonylurea monotherapy; four cases with relapsing 6q24/TNDM were treated with insulin, metformin or combination therapy. CONCLUSIONS: If TNDM is suspected, KATP genes should be analyzed first with the exception of patients with macroglossia and/or umbilical hernia. Remission of diabetes without pharmacological therapy should not preclude genetic analysis. Early treatment with sulfonylurea may induce long-lasting remission of diabetes in patients with KATP mutations associated with PNDM. Adult patients carrying KATP/TNDM mutations respond favourably to sulfonylurea monotherapy.

Identification of a De Novo Xq26.2 Microduplication Encompassing FIRRE Gene in a Child with Intellectual Disability.

Long non-coding RNAs (lncRNAs), defined as transcripts of >200 nucleotides not translated into protein, have been involved in a wide range of regulatory functions. Their dysregulations have been associated with diverse pathological conditions such as cancer, schizophrenia, Parkinson's, Huntington's, Alzheimer's diseases and Neurodevelopmental Disorders (NDDs), including autism spectrum disorders (ASDs). We report on the case of a five-year-old child with global developmental delay carrying a de novo microduplication on chromosome Xq26.2 region characterized by a DNA copy-number gain spanning about 147 Kb (chrX:130,813,232-130,960,617; GRCh37/hg19). This small microduplication encompassed the exons 2-12 of the functional intergenic repeating RNA element (FIRRE) gene (chrX:130,836,678-130,964,671; GRCh37/hg19) that encodes for a lncRNA involved in the maintenance of chromatin repression. The association of such a genetic alteration with a severe neurodevelopmental delay without clear dysmorphic features and congenital abnormalities indicative of syndromic condition further suggests that small Xq26.2 chromosomal region microduplications containing the FIRRE gene may be responsible for clinical phenotypes mainly characterized by structural or functioning neurological impairment.

Pregnancy and human herpesvirus 8 reactivation in human immunodeficiency virus type 1-infected women.

To investigate the impact of pregnancy on human herpesvirus 8 (HHV-8) reactivation in human immunodeficiency virus type 1 (HIV-1)-infected women, the HHV-8 DNA presence and load were analyzed in peripheral blood mononuclear cells (PBMCs) and cervicovaginal secretions (CVSs) from 15 pregnant women coinfected with HIV-1 and HHV-8. HHV-8 detection was analyzed in relation to anti-HHV-8 antibodies and HIV-1-related parameters. Nucleotide sequence analysis of an ORFK1 hypervariable region of the HHV-8 strains was performed. HHV-8 was detected in maternal PBMCs (5/15 women) from the second trimester and in CVSs (5/15 women) mainly from the third trimester. The HHV-8 load significantly increased late in pregnancy in both maternal compartments and was associated with a significant increase in HIV-1 shedding in the genital tract. Antilytic antibodies were significantly more common in HHV-8 DNA-positive women. An elevated HHV-8 load was found in the PBMCs of an infant born to a mother with large amounts of HHV-8 in both compartments at delivery. Different ORFK1 subtypes were found in maternal samples, whereas the same subtype was identified in the mother-child pair. These data suggest that pregnancy may induce HHV-8 replication in HIV-1-infected women. An augmented HHV-8 load may, in turn, influence mother-to-child transmission, since one of the HIV-1-infected mothers with HHV-8 reactivation transmitted her ORFK1 subtype to the infant, who showed a high level of HHV-8 viremia indicative of a primary infection. This finding documents for the first time the perinatal transmission of a specific HHV-8 subtype. Vertical transmission may thus play a role in HHV-8 spread also in areas of subendemicity among HIV-1-infected women.

Newly diagnosed HIV-1 infections in pregnancy: evidences from a cohort study in south-eastern Italy.

The authors report and discuss the characteristics of 22 women who discovered their HIV seropositivity while pregnant. Most of the women had never been tested for HIV and this occurred not only for 'not at risk' women but also for sexual partners of HIV-infected men. Several infections were diagnosed late in pregnancy when most women were already immunodeficient. An implementation of HIV prenatal testing as an early standard clinical practice, should be promoted in all women, regardless of the presence of risk factors.

High seroprevalence of human herpesvirus 8 (HHV-8) in HIV-1-infected pregnant women of Southeastern Italy: association with injection drug use and hepatitis C virus infection.

The seroprevalence of human herpesvirus 8 (HHV-8) in a group of HIV-1-infected pregnant women and in mother-child pairs from Southeastern Italy (Apulia) was determined. Blood was collected from 49 HIV-1-infected women during pregnancy or at delivery as well as from their children. Samples were analysed for the presence of antibodies to the latency-associated nuclear antigen and a structural antigen encoded by open reading frame 65. The presence of antibodies to hepatitis C virus (HCV) was also determined. Nineteen women (38.7%) were found to be positive for HHV-8 antibodies to at least one of the two antigens, and 21 (42.9%) for HCV antibodies. HHV-8 antibodies were more common in injecting drug users (56.3%) than in women infected through heterosexual intercourse (30.3%). HCV antibodies were significantly more prevalent in HHV-8-seropositive (66.7%) than HHV- 8-seronegative (29%) women. Thirteen children born to HIV-1/HHV-8 co-infected women were HHV-8-seroreactive, with a variable pattern of reactivity to the analysed antigens. Follow-up of children showed a prolonged persistence of antibodies, in two cases for more than 12 months. This study has provided serological evidence for a high rate of HHV-8 infection in HIV-1-infected women in the Apulia region, and has identified a possible association between HHV-8 infection, past use of injection drugs and HCV infection. Parenteral transmission may, therefore, be a mode of virus spread.

Correlates of HIV-1 shedding in cervicovaginal secretions and effects of antiretroviral therapies.

OBJECTIVES: To evaluate the determinants of HIV-1 RNA shedding in cervicovaginal secretions and the effects of antiretroviral therapy in a group of infected women. METHODS: A total of 122 women from whom paired peripheral blood and cervicovaginal lavage samples were available were enrolled in the study. HIV-1 RNA was quantified in the plasma and cell-free fraction of cervicovaginal lavages by the nucleic acid sequence-based amplification assay (lower limit of detection 80 copies/ml). RESULTS: Seventy-one per cent of the women had detectable viral load in the cervicovaginal lavage and this appeared to be correlated to plasma viral load and to the degree of immunodeficiency as expressed by the absolute number of CD4 cells. Antiretroviral-treated patients had a lower risk of shedding the virus in the genital tract, but this association was limited to patients treated with highly active antiretroviral therapy (HAART). However, in 25% of women with undetectable plasma viral load, a genital shedding of the virus was demonstrated. CONCLUSION: Plasma viral load may fail as a marker of infectivity of genital secretions. HAART treatment seems to be more efficacious in suppressing viral shedding at the genital level. The female genital tract represents a distinct compartment for HIV-1 replication/evolution.