Neuromyopathy with congenital cataracts and glaucoma: A distinct syndrome caused by POLG variants

We identified three non-related patients manifesting a childhood-onset progressive neuromyopathy with congenital cataracts, delayed walking, distal weakness and wasting, glaucoma and swallowing difficulties. Electrophysiology and nerve biopsies showed a mixed axonal and demyelinating neuropathy, while muscle biopsy disclosed both neurogenic and myopathic changes with ragged red fibers, and muscle MRI showed consistent features across patients, with a peculiar concentric disto-proximal gradient of fatty replacement. We used targeted next generation sequencing and candidate gene approach to study these families. Compound biallelic heterozygous variants, p.[(Pro648Arg)]; [(His932Tyr)] and p.[(Thr251Ile),(Pro587Leu)]; [(Arg943Cys)], were found in the three patients causing this homogeneous phenotype. Our report on a subset of unrelated patients, that showed a distinct autosomal recessive childhood-onset neuromyopathy with congenital cataracts and glaucoma, expands the clinical spectrum of POLG-related disorders. It also confirms the association between cataracts and neuropathy with variants in POLG. Early onset cataract is otherwise rare in POLG-related disorders and so far reported only in a few patients with the clinical pattern of distal myopathy or neuromyopathy

Metabolic and endocrinologic complications in beta-thalassemia major: a multicenter study in Tehran

BACKGROUND: The combination of transfusion and chelation therapy has dramatically extended the life expectancy of thalassemic patients. The main objective of this study is to determine the prevalence of prominent thalassemia complications. METHODS: Two hundred twenty patients entered the study. Physicians collected demographic and anthropometric data and the history of therapies as well as menstrual histories. Patients have been examined to determine their pubertal status. Serum levels of 25(OH) D, calcium, phosphate, iPTH were measured. Thyroid function was assessed by T3, T4 and TSH. Zinc and copper in serum were determined by flame atomic absorption spectrophotometry. Bone mineral density (BMD) measurements at lumbar and femoral regions have been done using dual x-ray absorptiometry. The dietary calcium, zinc and copper intakes were estimated by food-frequency questionnaires. RESULTS: Short stature was seen in 39.3% of our patients. Hypogonadism was seen in 22.9% of boys and 12.2% of girls. Hypoparathyroidism and primary hypothyroidism was present in 7.6% and 7.7% of the patients. About 13 % of patients had more than one endocrine complication with mean serum ferritin of 1678 ± 955 micrograms/lit. Prevalence of lumbar osteoporosis and osteopenia were 50.7% and 39.4%. Femoral osteoporosis and osteopenia were present in 10.8% and 36.9% of the patients. Lumbar BMD abnormalities were associated with duration of chelation therapy. Low serum zinc and copper was observed in 79.6% and 68% of the study population respectively. Serum zinc showed significant association with lumbar but not femoral BMD. In 37.2% of patients serum levels of 25(OH) D below 23 nmol/l were detected. CONCLUSION: High prevalence of complications among our thalassemics signifies the importance of more detailed studies along with therapeutic interventions

The role of molecular genetics in diagnosing familial hematuria(s)

Familial microscopic hematuria (MH) of glomerular origin represents a heterogeneous group of monogenic conditions involving several genes, some of which remain unknown. Recent advances have increased our understanding and our ability to use molecular genetics for diagnosing such patients, enabling us to study their clinical characteristics over time. Three collagen IV genes, COL4A3, COL4A4, and COL4A5 explain the autosomal and X-linked forms of Alport syndrome (AS), and a subset of thin basement membrane nephropathy (TBMN). A number of X-linked AS patients follow a milder course reminiscent of that of patients with heterozygous COL4A3/COL4A4 mutations and TBMN, while at the same time a significant subset of patients with TBMN and familial MH progress to chronic kidney disease (CKD) or end-stage kidney disease (ESKD). A mutation in CFHR5, a member of the complement factor H family of genes that regulate complement activation, was recently shown to cause isolated C3 glomerulopathy, presenting with MH in childhood and demonstrating a significant risk for CKD/ESKD after 40 years old. Through these results molecular genetics emerges as a powerful tool for a definite diagnosis when all the above conditions enter the differential diagnosis, while in many at-risk related family members, a molecular diagnosis may obviate the need for another renal biopsy

Adequate Serum Copper Concentration Could Improve Bone Density, Postpone Bone Loss and Protect Osteoporosis in Women

Background: To determine the protective impact of efficient serum copper concentration on BMD in women and to asses its impression on bone. Methods: six hundred healthy women through a national project in Iran, IMOS, were selected via a cluster random sam¬pling and enrolled the study. They were divided to pre menopausal (404/600, 67.7% of total) and post menopausal (190/600, 32%of total) groups. BMD was measured by biphotonic absorptimetry DEXA for hip and lumbar spine. Morning serum copper concentration was determined by atomic absorption spectrometry. Results: Mean age was 40.92±14.8yr .Mean serum copper concentration= 105.85±40.15µg/dl and mean BMI= 27.13±4.81 kg/m2.Totaly 2.4% was smoking, 5% had regular physical activities three times a week and 17.5% was copper deficient. Prevalence of Osteoporosis in postmenopausal women was 12.9% in copper deficient persons vs.11.3% in normal serum copper ones. No significant difference found according to serum copper concentration associated with BMI, age and vita¬min D. Spine BMD revealed a significant correlation with serum copper content. (P= 0.001). This correlation also existed for Total hip (P< 0.05). Premenopausal women with serum copper level above 105 µg/dl revealed a significant difference in hip BMD compared to whom with less copper concentration.1.02± 0.13kg/m2 vs. 0.97± 0.13kg/m2 (P = 0.001). Copper had an independent role on determining hip BMD in pre menopaused women (P= 0.001). Conclusion: copper has an independent role on bone density in all healthy women. It could have an adjourning factor for bone loss as well as a protective agent for osteoporosis

Genetic variants in ARHGEF6 cause congenital anomalies of the kidneys and urinary tract in humans, mice, and frogs

Background: About 40 disease genes have been described to date for isolated congenital anomalies of the kidneys and urinary tract (CAKUT), the most common cause of childhood chronic kidney disease. However, these genes account for only 20% of cases. ARHGEF6, a guanine nucleotide exchange factor that is implicated in such biologic processes as cell migration and focal adhesion, acts downstream of integrin linked kinase (ILK) and parvin proteins. A genetic variant of ILK that causes murine renal agenesis abrogates the interaction of ILK with a murine focal adhesion protein encoded by Parva, leading to CAKUT in mice with this variant. Methods: To identify novel genes that, when mutated, result in CAKUT, we performed exome sequencing in an international cohort of 1265 families with CAKUT. We also assessed the effects in vitro of wild-type and mutant ARHGEF6 proteins, as well as the effects of Arhgef6 deficiency in mouse and frog models. Results: We detected six different hemizygous variants in the gene ARHGEF6 (which is located on the X chromosome in humans) in eight individuals from six families with CAKUT. In kidney cells, overexpression of wild-type ARHGEF6—but not proband-derived mutant ARHGEF6— increased active levels of CDC42/RAC1, induced lamellipodia formation, and stimulated PARVAdependent cell spreading. ARHGEF6 mutant proteins showed loss of interaction with PARVA. Three-dimensional MDCK cell cultures expressing ARHGEF6 mutant proteins exhibited reduced lumen formation and polarity defects. Arhgef6 deficiency in mouse and frog models recapitulated features of human CAKUT. Conclusions: Deleterious variants in ARHGEF6 may cause dysregulation of integrin-parvinRAC1/CDC42 signaling, thereby leading to X-linked CAKUT