Cardiomyopathies.

The most common cardiomyopathies often present to primary care physicians with similar symptoms, despite the fact that they involve a variety of phenotypes and etiologies (1). Many have signs and symptoms common in heart failure, such as reduced ejection fraction, peripheral edema, fatigue, orthopnea, exertion dyspnea, paroxysmal nocturnal dyspnea, presyncope, syncope and cardiac ischemia (1). In all cardiomyopathies, the cardiac muscle (myocardium) may be structurally and/or functionally impaired. They can be classified as hypertrophic, dilated, left-ventricular non compaction, restrictive and arrhythmogenic right ventricular cardiomyopathies.

Non-syndromic monogenic female infertility.

Infertility is a significant clinical problem. It affects 8-12% of couples worldwide, about 30% of whom are diagnosed with idiopathic infertility (infertility lacking any obvious cause). In 2010, the World Health Organization calculated that 1.9% of child-seeking women aged 20-44 years were unable to have a first live birth (primary infertility), and 10.5% of child-seeking women with a prior live birth were unable to have an additional live birth (secondary infertility). About 50% of all infertility cases are due to female reproductive defects. Several chromosome aberrations, diagnosed by karyotype analysis, have long been known to be associated with female infertility and monogenic mutations have also recently been found. Female infertility primarily involves oogenesis. The following phenotypes are associated with monogenic female infertility: premature ovarian failure, ovarian dysgenesis, oocyte maturation defects, early embryo arrest, polycystic ovary syndrome and recurrent pregnancy loss. Here we summarize the genetic causes of non-syndromic monogenic female infertility and the genes analyzed by our genetic test.

Non-syndromic monogenic male infertility.

Infertility is a widespread clinical problem affecting 8-12% of couples worldwide. Of these, about 30% are diagnosed with idiopathic infertility since no causative factor is found. Overall 40-50% of cases are due to male reproductive defects. Numerical or structural chromosome abnormalities have long been associated with male infertility. Monogenic mutations have only recently been addressed in the pathogenesis of this condition. Mutations of specific genes involved in meiosis, mitosis or spermiohistogenesis result in spermatogenic failure, leading to the following anomalies: insufficient (oligozoospermia) or no (azoospermia) sperm production, limited progressive and/or total sperm motility (asthenozoospermia), altered sperm morphology (teratozoospermia), or combinations thereof. Androgen insensitivity, causing hormonal and sexual impairment in males with normal karyotype, also affects male fertility. The genetic causes of non-syndromic monogenic of male infertility are summarized in this article and a gene panel is proposed.

Syndromic infertility.

Infertility due to genetic mutations that cause other defects, besides infertility, is defined as syndromic. Here we describe three of these disorders for which we perform genetic tests. 1) Hypopituitarism is an endocrine syndrome characterized by reduced or absent secretion of one or more anterior pituitary hormones with consequent dysfunction of the corresponding peripheral glands. Deficiencies in all the hormones is defined as pan-hypopituitarism, lack of two or more hormones is called partial hypopituitarism, whereas absence of a single hormone is defined as selective hypopituitarism. Pan-hypopituitarism is the rarest condition, whereas the other two are more frequent. Several forms exist: congenital, acquired, organic and functional. 2) The correct functioning of the hypothalamic-pituitary-gonadal axis is fundamental for sexual differentiation and development during fetal life and puberty and for normal gonad function. Alteration of the hypothalamic-pituitary system can determine a condition called hypogonadotropic hypogonadism, characterized by normal/low serum levels of the hormones FSH and LH. 3) Primary ciliary dyskinesia is frequently associated with infertility in males because it impairs sperm motility (asthenozoospermia). Primary ciliary dyskinesia is a group of genetically and phenotypically heterogeneous disorders that show morpho-structural alterations of the cilia. Adult women with primary ciliary dyskinesia can be subfertile and have an increased probability of extra-uterine pregnancies. This is due to delayed transport of the oocyte through the uterine tubes.

Familial 1q22 microduplication associated with psychiatric disorders, intellectual disability and late-onset autoimmune inflammatory response.

BACKGROUND: Despite the extensive use of chromosomal microarray technologies in patients with neurodevelopmental disorders has permitted the identification of an increasing number of causative submicroscopic rearrangements throughout the genome, constitutional duplications involving chromosome 1q22 have seldom been described in those patients. RESULTS: We report on a pedigree with seven affected members showing varying degrees of behavioural and emotional disturbances including general anxiety disorder, mood disorders, and intellectual disability. Two adult female patients also showed late onset autoimmune inflammatory responses characterized by alopecia, skin ulcers secondary to inflammatory vasculitis, interstitial lung disease, and Raynaud's phenomenon. Array-CGH analysis identified in the affected individuals a 290 Kb microduplication in the chromosome 1q22. The rearrangement involves eleven known genes and is not present in the databases of polymorphic copy number variants. CONCLUSIONS: The rearrangement segregates with the neurological clinical features observed in our patients, suggesting that dosage imbalance of one or more genes in this genomic region may lead to the observed phenotype. The association between the microduplication and the inflammatory disease is much less evident. Additional reported patients carrying similar microduplications are needed to clarify this aspect.

Effects of losartan and delapril on the fibrinolytic system in patients with mild to moderate hypertension.

BACKGROUND AND OBJECTIVES: Angiotensin-converting enzyme (ACE) probably influences the fibrinolytic system at a central point by converting angiotensin I to angiotensin II, which increases plasminogen activator inhibitor-1 (PAI-1) activity. This effect appears to be mediated in humans via the angiotensin II type 1 (AT(1)) receptor. The objective of this study was to evaluate, in patients with mild to moderate hypertension, the change in tissue plasminogen activator (t-PA) and PAI-1 plasma levels after treatment with an AT(1)-receptor blocker (losartan 50 mg/day) or an ACE inhibitor (delapril 60 mg/day). PATIENTS AND METHODS: 30 hypertensive patients and 15 controls were enrolled. Essential hypertension was established by a medical history, physical examination and the absence of clinical findings suggestive of a secondary form of hypertension. Preliminary investigations, routine biochemical tests (including clearance of creatinine and oral glucose tolerance test), chest x-ray, standard and 24-hour ECG monitoring, M- and B-mode echocardiography and fundus oculi examinations were performed. No patients had previously received ACE inhibitors or AT(1)-receptor blockers. After a 14-day run-in period with placebo, patients were randomised in a double-blind fashion into two groups: 15 patients were randomised to losartan 50 mg/day (group 1), 15 patients were randomised to delapril 60 mg/day (group 2), and 15 healthy subjects were used as controls (group 3). Plasma PAI-1 and t-PA antigen were determined by enzyme-linked immunosorbent assay and a photometric method at the end of the run-in period and after 6 months of treatment. RESULTS: There were no significant differences among the three groups regarding age, sex, body mass index and smoking. After 6 months, both groups of patients showed a reduction in blood pressure values. The losartan group did not demonstrate significant changes in PAI-1 levels (96.52 +/- 23.73 and 99.89 +/- 22.18 mug/L, pre- and post-treatment, respectively) or in t-PA antigen levels (26.17 +/- 6.18 and 27.32 +/- 5.91 mug/L, pre- and post-treatment, respectively). The delapril group showed no significant changes in PAI-1 levels (97.73 +/- 25.75 and 86.12 +/- 13.12 mug/L, pre- and post-treatment, respectively), but did show a statistically significant difference (p < 0.005) in t-PA antigen levels (25.71 +/- 6.40 and 32.24 +/- 5.31 mug/L, pre- and post-treatment, respectively). The losartan group demonstrated significantly higher post-treatment PAI-1 values than the delapril group (p = 0.048). CONCLUSION: The study showed that losartan does not affect fibrinolytic parameters, while delapril resulted in an insignificant reduction in PAI-1 and a significant increase in t-PA levels. Further studies are clearly required in order to establish whether these different effects on the fibrinolytic system between ACE inhibitors and AT(1)-receptor blockers may have clinical relevance.