Does Early Treatment Prevent Deafness in Thiamine-Responsive Megaloblastic Anaemia Syndrome?

Thiamine-responsive megaloblastic anaemia (TRMA; OMIM 249270) syndrome is an autosomal recessive disorder characterized by diabetes mellitus, megaloblastic anaemia, and sensorineural deafness. Progressive hearing loss is one of the cardinal findings of the syndrome and is known to be irreversible. Whether the deafness in TRMA syndrome can be prevented is not yet known. Here, we report a four-month-old female infant diagnosed with TRMA syndrome at an early age. There was no hearing loss at the time of diagnosis. The patient’s initial auditory evoked brainstem response measurements were normal. Although she was given thiamine supplementation regularly following the diagnosis, the patient developed moderate sensorineural hearing loss at 20 months of age, indicating that early diagnosis and treatment with oral thiamine (100 mg/day) could not prevent deafness in TRMA syndrome. It would be premature to draw general conclusions from one case, but we believe that further patient-based observations can shed light on the pathophysiology of this rare syndrome as well as prediction of its prognosis

Does Dietary Treatment Cause Obesity In Phenylketonuria? Comparison Of Obesity Ratios Of Patients Receiving Dietary Treatment And Tetrahydrobiopterin Treatment

Phenylketonuria is treated by either with tetrahydrobiopterin (BH4) or with phenylalanine-restricted diet. Patients on diet group may have a tendency of consume carbohydrate-rich foods and henceforth a risk of developing obesity. In this study, the prevalence of obesity+overweight among phenylketonuria patients either treated with phenylalanine-restricted diet or with BH4 are compared. Patients with phenylketonuria were divided into two groups as on dietary treatment and on BH4 treatment. Body mass index (BMI), BMI-percentile and z-score values of patients were calculated and classified as malnutrition, normal-weight, overweight and obese according to their nutritional status. The annual mean phenylalanine level of each patient is also evaluated. The study was done retrospectively.Total of 130 patients were included. 77 were receiving diet (female (n,%):37, 48.1%; male (n,%):40, 51.9%) and 53 were receiving BH4 (female(n,%):33, 62.3%; male(n,%):20, 37.7%) respectively. According to BMI-z-score, 35.1% were obese+overweight in the diet group vs. 16.9% in the BH4 group. The percentage was significantly higher in the diet group (p = 0.02). Obesity+overweight percentages in female/male patient groups showed no significant difference. Considering the correlation between obesity+overweight and age in the BH4 group, the median age of the patients with normal weight+malnutrition were found as 46-months, and that of obese+overweight patients were 137-months (p=0,001). For the same correlation, there was no significant difference in the dietary treatment group (p = 0.92). Mean annual phenylalanine levels were significantly higher in obese+overweight patients (p=0.047) in the BH4 treatment group but this difference was not significant in the diet group (p=0.051). Patients on phenylalanine-restricted diet have a risk of obesity or overweight. Therefore, attention should be paid not only to the phenylalanine levels of these patients, but also to their weight control and dietary content

Male Oxidative Stress Infertility (MOSI): Proposed Terminology and Clinical Practice Guidelines for Management of Idiopathic Male Infertility

Despite advances in the field of male reproductive health, idiopathic male infertility, in which a man has altered semen characteristics without an identifiable cause and there is no female factor infertility, remains a challenging condition to diagnose and manage. Increasing evidence suggests that oxidative stress (OS) plays an independent role in the etiology of male infertility, with 30% to 80% of infertile men having elevated seminal reactive oxygen species levels. OS can negatively affect fertility via a number of pathways, including interference with capacitation and possible damage to sperm membrane and DNA, which may impair the sperm’s potential to fertilize an egg and develop into a healthy embryo. Adequate evaluation of male reproductive potential should therefore include an assessment of sperm OS. We propose the term Male Oxidative Stress Infertility, or MOSI, as a novel descriptor for infertile men with abnormal semen characteristics and OS, including many patients who were previously classified as having idiopathic male infertility. Oxidation-reduction potential (ORP) can be a useful clinical biomarker for the classification of MOSI, as it takes into account the levels of both oxidants and reductants (antioxidants). Current treatment protocols for OS, including the use of antioxidants, are not evidence-based and have the potential for complications and increased healthcare-related expenditures. Utilizing an easy, reproducible, and cost-effective test to measure ORP may provide a more targeted, reliable approach for administering antioxidant therapy while minimizing the risk of antioxidant overdose. With the increasing awareness and understanding of MOSI as a distinct male infertility diagnosis, future research endeavors can facilitate the development of evidence-based treatments that target its underlying cause

Pathogenic variants in RNPC3 are associated with hypopituitarism and primary ovarian insufficiency

Purpose We aimed to investigate the molecular basis underlying a novel phenotype including hypopituitarism associated with primary ovarian insufficiency. Methods We used next-generation sequencing to identify variants in all pedigrees. Expression of Rnpc3/RNPC3 was analyzed by in situ hybridization on murine/human embryonic sections. CRISPR/Cas9 was used to generate mice carrying the p.Leu483Phe pathogenic variant in the conserved murine Rnpc3 RRM2 domain. Results We described 15 patients from 9 pedigrees with biallelic pathogenic variants in RNPC3, encoding a specific protein component of the minor spliceosome, which is associated with a hypopituitary phenotype, including severe growth hormone (GH) deficiency, hypoprolactinemia, variable thyrotropin (also known as thyroid-stimulating hormone) deficiency, and anterior pituitary hypoplasia. Primary ovarian insufficiency was diagnosed in 8 of 9 affected females, whereas males had normal gonadal function. In addition, 2 affected males displayed normal growth when off GH treatment despite severe biochemical GH deficiency. In both mouse and human embryos, Rnpc3/RNPC3 was expressed in the developing forebrain, including the hypothalamus and Rathke’s pouch. Female Rnpc3 mutant mice displayed a reduction in pituitary GH content but with no reproductive impairment in young mice. Male mice exhibited no obvious phenotype. Conclusion Our findings suggest novel insights into the role of RNPC3 in female-specific gonadal function and emphasize a critical role for the minor spliceosome in pituitary and ovarian development and function