Recognized and Emerging Features of Erythropoietic and X-Linked Protoporphyria

Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are inherited disorders resulting from defects in two different enzymes of the heme biosynthetic pathway, i.e., ferrochelatase (FECH) and delta-aminolevulinic acid synthase-2 (ALAS2), respectively. The ubiquitous FECH catalyzes the insertion of iron into the protoporphyrin ring to generate the final product, heme. After hemoglobinization, FECH can utilize other metals like zinc to bind the remainder of the protoporphyrin molecules, leading to the formation of zinc protoporphyrin. Therefore, FECH deficiency in EPP limits the formation of both heme and zinc protoporphyrin molecules. The erythroid-specific ALAS2 catalyses the synthesis of delta-aminolevulinic acid (ALA), from the union of glycine and succinyl-coenzyme A, in the first step of the pathway in the erythron. In XLP, ALAS2 activity increases, resulting in the amplified formation of ALA, and iron becomes the rate-limiting factor for heme synthesis in the erythroid tissue. Both EPP and XLP lead to the systemic accumulation of protoporphyrin IX (PPIX) in blood, erythrocytes, and tissues causing the major symptom of cutaneous photosensitivity and several other less recognized signs that need to be considered. Although significant advances have been made in our understanding of EPP and XLP in recent years, a complete understanding of the factors governing the variability in clinical expression and the severity (progression) of the disease remains elusive. The present review provides an overview of both well-established facts and the latest findings regarding these rare diseases.

Heterogeneity in biomarkers, mitogenome and genetic disorders of Arab population with special emphasis on large-scale whole-exome sequencing

More than 25 million DNA variations were discovered as novel including major alleles from Arab population. Exome studies on Arabs discovered >3000 novel nucleotide variants associated with >1200 rare genetic disorders. Reclassification of many pathogenic variant into benign through the Arab database enhance building a detailed and comprehensive map of Arab morbid genome. Intellectual disability stands first with the combined and observed carrier frequency. Genome studies and advanced computational biology discovered interesting novel candidate disease marker variations in many genes from consanguineous families with intellectual disability, neurogenetic disorders, blood and bleeding disorder and rare genetic diseases. Pathogenic variants in C12orf57 gene are prominently associated with the etiology of developmental delay/intellectual impairment. Arab mitogenome exposed hundreds of variations in mtDNA genome and its association with obesity. Further study is needed in genomics to fully comprehend the molecular abnormalities and associated pathogenesis that cause inherited disorders in Arab ancestries.

Neuroradiological Mimics of Periventricular Leukomalacia

Aim: Periventricular leukomalacia (PVL) is a term reserved to describe white matter injury in the premature brain. In this review article, the authors highlight the common and rare pathologies mimicking the chronic stage of PVL and propose practical clinico-radiological criteria that would aid in diagnosis and management. Methods and Results: The authors first describe the typical brain MRI (magnetic resonance imaging) features of PVL. Based on their clinical presentation, pathologic entities and their neuroimaging findings were clustered into distinct categories. Three clinical subgroups were identified: healthy children, children with stable/nonprogressive neurological disorder, and those with progressive neurological disorder. The neuroradiological discriminators are described in each subgroup with relevant differential diagnoses. The mimics were broadly classified into normal variants, acquired, and inherited disorders. Conclusions: The term “PVL” should be used appropriately as it reflects its pathomechanism. The phrase “white matter injury of prematurity” or “brain injury of prematurity” is more specific. Discrepancies in imaging and clinical presentation must be tread with caution and warrant further investigations to exclude other possibilities.

Ineffective erythropoiesis and its treatment

The erythroid marrow and circulating red blood cells (RBCs) are the key components of the human erythron. Abnormalities of the erythron that are responsible for anemia can be distinguished into 3 major categories, that is, erythroid hypoproliferation, ineffective erythropoiesis, and peripheral hemolysis. Ineffective erythropoiesis is characterized by erythropoietin-driven expansion of early-stage erythroid precursors, associated with apoptosis of late-stage precursors. This mechanism is primarily responsible for anemia in inherited disorders like β-thalassemia, inherited sideroblastic anemias, and congenital dyserythropoietic anemias, as well as in acquired conditions like some subtypes of myelodysplastic syndromes (MDS). The inherited anemias due to ineffective erythropoiesis are also defined as iron loading anemias because of the associated parenchymal iron loading caused by the release of erythroid factors that suppress hepcidin production. Novel treatments specifically targeting ineffective erythropoiesis are being developed. Iron restriction through enhancement of hepcidin activity or inhibition of ferroportin function has been shown to reduce ineffective erythropoiesis in murine models of β-thalassemia. Luspatercept is a TGF-β ligand trap that inhibits SMAD2/3 signaling. Based on pre-clinical and clinical studies, this compound is now approved for the treatment of anemia in adult patients with β-thalassemia who require regular RBC transfusions. Luspatercept is also approved for the treatment of transfusion-dependent anemia in patients with MDS with ring sideroblasts, most of whom carry a somatic SF3B1mutation. While long-term efficacy and safety of luspatercept need to be evaluated both in β-thalassemia and MDS, defining the molecular mechanisms of ineffective erythropoiesis in different disorders might allow the discovery of new effective compounds.

Combining Protein Expression and Molecular Data Improves Mutation Characterization of Dystrophinopathies

Duchenne and Becker muscular dystrophy are X-linked recessive inherited disorders characterized by progressive weakness due to skeletal muscle degeneration. Different mutations in the DMD gene, which encodes for dystrophin protein, are responsible for these disorders. The aim of our study was to investigate the relationship between type, size, and location of the mutation that occurs in the DMD gene and their effect on dystrophin protein expression in a cohort of 40 male dystrophinopathy patients and nine females, possible carriers. We evaluated the expression of dystrophin by immunofluorescence and immunoblotting. The mutational spectrum of the DMD gene was established by MLPA for large copy number variants, followed by HRM analysis for point mutations and sequencing of samples with an abnormal melting profile. MLPA revealed 30 deletions (75%) and three duplications (7.5%). HRM analysis accounted for seven-point mutations (17.5%). We also report four novel small mutations (c. 8507G>T, c.3021delG, c.9563_9563+1insAGCATGTTTATGATACAGCA, c.7661-60T>A) in DMD gene. Our work shows that the DNA translational open reading frame and the location of the mutation both influence the expression of dystrophin and disease severity phenotype. The proposed algorithm used in this study demonstrates its accuracy for the characterization of dystrophinopathy patients.

Safety, clinical and laboratory characteristics of donors with thalassemia minor in living donor kidney transplant: a case series

Background Due to the increasing demand for kidney transplants, sometimes donors with underlying medical conditions can be considered for living kidney donor transplant. Thalassemia is amongst the most common inherited disorders of hemoglobin globally, which is not restricted as an exclusion criterion. However, there is currently no study examine the safety and characteristics of kidney donors with thalassemia minor. Methods All eligible live kidney donors between 2016 and 2019 with thalassemia minor at a tertiary hospital were recruited. Baseline characteristics, clinical and laboratory outcomes were investigated. Results Fifteen donors (11 women, 55.5 ± 15.0 year-old) were included with a follow-up duration of 2 (1-4) years since operation. The most prevalent gene mutation among participants was DEL-SEA. No clinical manifestations of anemia were seen but 10 participants had mild anemia diagnosed from blood tests. Cardiovascular, liver and renal function were normal before nephrectomy. Until now, all donors are alive and maintain overall good health. Anemia condition is not affected, and the post-donation eGFR = 71.04 ± 11.54 mL/min/1.73m2 is comparable to outcomes of healthy donors reported in previous studies. Two donors are at risk of proteinuria at 1-year post-transplant with A/C ratio > 30 mg/g. Conclusions Thalassemia minor individuals who are non-transfusion-dependent, without anemia clinical manifestations and have no contraindications to kidney donation are safe to be donors in short-term. An eGFR of at least 80 mL/min/1.73m2 should be considered to avoid low post-donation eGFR, and awareness should be raised on thalassemia donors with even mild albuminuria. Nephrectomy does not worsen thalassemia.

Insights into energy balance dysregulation from a mouse model of methylmalonic aciduria

Inherited disorders of mitochondrial metabolism, including isolated methylmalonic aciduria (MMAuria), present unique challenges to energetic homeostasis by disrupting energy producing pathways. To better understand global responses to energy shortage, we investigated a hemizygous mouse model of methylmalonyl-CoA mutase (Mmut) type MMAuria. We found Mmut mutant mice to have reduced appetite, energy expenditure and body mass compared to littermate controls, along with a relative reduction in lean mass but increase in fat mass. Brown adipose tissue showed a process of whitening, in line with lower body surface temperature and lesser ability to cope with cold challenge. Mutant mice had dysregulated plasma glucose, delayed glucose clearance and a lesser ability to regulate energy sources when switching from the fed to fasted state, while liver investigations indicated metabolite accumulation and altered expression of peroxisome proliferator-activated receptor and Fgf21-controlled pathways. Together, these indicate hypometabolism, energetic inflexibility and increased stores at the expense of active tissue as energy shortage consequences.

The Possible Hepatoprotecive Effects of ''Krill Oil and Silymarin against Carbon Tetrachloride (CCl4)-Induced Rats Model of Liver Fibrosis: In Vivo Study''

Liver fibrosis is considered now as one of the most spread disease worldwide. It is attributed to different underlying causative agents such as viral infections, ethanol-induced liver steatosis, and non-ethanol-induced hepatic steatosis, autoimmune and inherited disorders. Hepatic fibrosis was known to behave as tissue repair mechanism in which the initiation occurred through complicated series of interrelated and regulated signaling. These signals involved interactions between different types of cells. Among these cells are hepatocytes, non-parenchymal cells such as hepatic stellate cells (HSCs), liver sinusoidal endothelial cells, Kupffer cells, biliary epithelial cells, liver associated lymphocytes, and the non-resident infiltrating immune cells. current work was aimed to investigate the possible potential hepatopretective effects of krill oil alone and in combination with silymarin against Carbone tetrachloride-induced liver fibrosis/injury in white albino rats. Moreover, fifty white albino rats of both genders were utilized in this study. During such study liver fibrosis/damage was induced by intraperitoneal (I.P) injection of Carbone tetrachloride (CCl4) 50% in olive oil 1ml/kg twice weekly for 6 consecutive weeks in the induction group. Krill oil alone and in combination with silymarin was administered orally concurrently with I.P CCl4 for 6 consecutive weeks in the treatment groups. At the end of treatment period all animals were killed ,serum and tissue samples were collected for subsequent analyses. Serum levels of aminotransferases (ALT,AST), albumin , total serum bilirubin (T.S.B), and total anti-oxidant capacity were measured spectrophotometrically. In addition tissue level (content) of liver hudroxyproline content (Hyp) was determined by ELISA and relative liver weight percentage (R.L.W%) was also estimated.Results were significantly revealed that krill oil potentiate the hepatoprotective effects of silymarin against Carbone tetrachloride-induced liver fibrosis/injury.

Overview of the Updated Evidence of Multiple Endocrinal Neoplasia (MEN) in Children and Adolescents

MEN syndromes are a collection of autosomal dominant disease including MEN 1 and MEN 2. Multiple endocrine neoplasia (MEN) syndromes are infrequent inherited disorders in which more than one endocrine glands develop noncancerous (benign) or cancerous (malignant) tumors or grow excessively without forming tumors. There are 3 famous and well-known forms of MEN syndromes (MEN 1, MEN 2A, and MEN 2B) and a newly documented one (MEN4). These syndromes are infrequent and occurred in all ages and both men and women. MEN1 is the most often happening form of MENs. The information of MEN’s genetic alterations and the connection among genotype and phenotype could be beneficial for MEN disease management. (MEN1) implicated IN primarily by tumors of the parathyroid glands, endocrine gastroenteropancreatic (GEP) tract and anterior pituitary. Before MEN-1 can be diagnosed it must be suspected, genetic screening for MEN-1 is recommended when an individual has 2 or more MEN-1 related tumors, MEN2 associates with medullary thyroid carcinoma, pheochromocytoma, and primaryhype- rparathyroidism. MEN2A and MEN2B should be suspected in any patient diagnosed with MTC or pheochromocytoma, particularly when the age of presentation is very young (younger than 35), the genetic testing for RET proto-oncogene is employed to diagnose and identify a specific type of mutation present. Treatment is mainly surgical in most cases of multiple endocrine neoplasia syndrome.