Biallelic Mutations in P4HTM Cause Syndromic Obesity.

We previously demonstrated that 50% of children with obesity from consanguineous families from Pakistan carry pathogenic variants in known monogenic obesity genes. Here, we have discovered a novel monogenetic recessive form of severe childhood obesity using an in-house computational staged approach. The analysis included whole-exome sequencing data of 366 children with severe obesity, 1,000 individuals of the Pakistan Risk of Myocardial Infarction Study (PROMIS) study, and 200,000 participants of the UK Biobank to prioritize genes harboring rare homozygous variants with putative effect on human obesity. We identified five rare or novel homozygous missense mutations predicted deleterious in five consanguineous families in P4HTM encoding prolyl 4-hydroxylase transmembrane (P4H-TM). We further found two additional homozygous missense mutations in children with severe obesity of Indian and Moroccan origin. Molecular dynamics simulation suggested that these mutations destabilized the active conformation of the substrate binding domain. Most carriers also presented with hypotonia, cognitive impairment, and/or developmental delay. Three of the five probands died of pneumonia during the first 2 years of the follow-up. P4HTM deficiency is a novel form of syndromic obesity, affecting 1.5% of our children with obesity associated with high mortality. P4H-TM is a hypoxia-inducible factor that is necessary for survival and adaptation under oxygen deprivation, but the role of this pathway in energy homeostasis and obesity pathophysiology remains to be elucidated.

Investigation of wound healing activity Cynara humilis of root extracts.

BACKGROUND: Wound healing is among the frequent illnesses that affects the skin, and therefore, the screening of natural preparation to treat skin burn is important. In Morocco, Cynara humilis is a Moroccan medicinal plant widely used for the treatment of skin burn. OBJECTIVES: The aim of this study was to investigate the safety of C. humilis and its wound healing potential against skin burn. METHODS: In this work, C. humilis was selected based on an ethnopharmacological survey. As revealed by traditional medicine, C. humilis powder extract (CHPE) was used to test wound healing effects. Furthermore, to assure the safety of this powder, acute and subchronic dermal toxicities were investigated on animal models. RESULTS: The oral acute toxicity test of CHPE did not show mortality in treated rats (LD50 >2000 mg/kg). Moreover, in the acute dermal toxicity, CHPE at 5 g/kg did not induce clinical signs observed during the observation period of 48 h. In the subchronic toxicity test, CHPE did not cause significant abnormalities in the physiological parameters and pathological changes in the major organs of the rats. Body weight evolution and macroscopic analysis of skin burn showed CHPE exhibited important wound healing effects in a time-dependent manner. CHPE reduced significantly wound surface (6.93 ± 0.25 cm2 ) compared with the SDA group (8.30 ± 0.37 cm2 ) and the no-treated group (10.05 ± 0.28 cm2 ). Moreover, the retention rate was increased importantly after the treatment with CHPE (61.66 ± 1.42%) compared with the SDA-treated group (53.57% ± 2.83%) and the no-treated group control animals (43.34% ± 1.27%). CONCLUSION: These results were confirmed by a histological evaluation, which showed that CHPE increased the neovascularization, the collagen deposition, and the re-epithelialization. The findings of this work suggest that CHPE could be a promising source for developing drugs against skin burn.

Undiagnosed Phenylketonuria Can Exist Everywhere: Results From an International Survey.

Many countries do not have a newborn screening (NBS) program, and immigrants from such countries are at risk for late diagnosis of phenylketonuria (PKU). In this international survey, 52 of 259 patients (20%) with late diagnosed PKU were immigrants, and 145 of the 259 (55%) were born before NBS or in a location without NBS.

[Difficult immunofixation electrophoresis interpretation of serum proteins]. / Interprétation délicate de l'immunofixation des protéines sériques.

Immunofixation is currently very used in medical laboratories. The interpretation of the results is usually easy, but some cases raise interpretative problems. We here report two cases difficult to interpret. In the first case, we report a case of nonspecific precipitation of the protein on each track, in the second case we report a case of double monoclonal band on immunofixation electrophoresis. Reducing agent such as ß2-mercaptoethanol used in these two cases allowed to solve the problem and to make a diagnosis. A comparison between clinical radiological and laboratory test data is necessary before making a diagnosis of monoclonal immunoglobulin.

In Vitro and In Vivo Antioxidant and Anti-Hyperglycemic Activities of Moroccan Oat Cultivars.

Improvement of oat lines via introgression is an important process for food biochemical functionality. This work aims to evaluate the protective effect of phenolic compounds from hybrid Oat line (F11-5) and its parent (Amlal) on hyperglycemia-induced oxidative stress and to establish the possible mechanisms of antidiabetic activity by digestive enzyme inhibition. Eight phenolic acids were quantified in our samples including ferulic, p-hydroxybenzoic, caffeic, salicylic, syringic, sinapic, p-coumaric and chlorogenic acids. The Oat extract (2000 mg/kg) ameliorated the glucose tolerance, decreased Fasting Blood Glucose (FBG) and oxidative stress markers, including Superoxide dismutase (SOD), Catalase (CAT), Glutathione peroxidase (GPx), Glutathione (GSH) and Malondialdehyde (MDA) in rat liver and kidney. Furthermore, Metformin and Oat intake prevented anxiety, hypercholesterolemia and atherosclerosis in diabetic rats. In vivo anti-hyperglycemic effect of Oat extracts has been confirmed by their inhibitory activities on α-amylase (723.91 µg/mL and 1027.14 µg/mL) and α-glucosidase (1548.12 µg/mL & 1803.52 µg/mL) enzymes by mean of a mixed inhibition.

[Overview of X-linked adrenoleukodystrophy in Morocco: results of the implementation of the program of clinical and biological diagnosis]. / Développement d'un programme multidisciplinaire de diagnostic de l'adrénoleucodystrophie liée à l'X au Maroc: résultats de la mise en œuvre du programme de diagnostic clinique et biologique.

INTRODUCTION: X-linked adrenoleukodystrophy (X-ALD) is a severe neurodegenerative disease, due to mutations in the ABCD1 gene. It manifests as a damage to the central and peripheral nervous system, adrenal insufficiency and testicular damage in children. Diagnosis is based on the determination of long-chain saturated fatty acids. Early diagnosis is essential because it defines treatment accessibility according to disease stage. METHODS: We implemented a X-ALD diagnostic test program in Morocco at the Children's Hospital and at the Central Laboratory for inherited and metabolic diseases in Rabat. The program was based around three priorities, namely: the recruitment of patients, diagnosis and awareness. Diagnosis is based on three protocols: a protocol for symptomatic cases, a protocol for asymptomatic cases and a protocol for heterozygous women. RESULTS: During the first three years after implementation of our X-ALD diagnostic test program, we diagnosed the disease in seven families, with nine boys and three heterozygous women. All children were diagnosed with demyelinating brain. All heterozygous women were asymptomatic. Different symptom-based therapies were established. CONCLUSION: X-ALD is a rare disease. Our diagnostic program has helped to diagnose a significant number of cases, hence its importance. Campaigns focused on raising awareness among health care professionals will enable a better understanding of the disease and a more accurate diagnosis as well as to improve access to health care for a higher number of patients.

[Biological disturbances during the lupus-associated pancreatitis: case report]. / Les perturbations biologiques au cours de la pancréatite lupique : à propos d'un cas.

We report in this paper the case of female patient, hypertriglyceridemia associated with milky serum and hyperglycemia have been the alarm signal of a lupus-associated pancreatitis, the confirmation of this entity was done with elevated rate of serum lipase activity. It is about a 33 years age female. She has as unique antecedent a lupus diagnosed on January of the same. The patient was admitted on august 2013 for another episode of lupus associated to the lower lamb edema with a rate of C3 at 0.4 g/L (0.82-1,93) and C4 at 0.05 g/L (0.15-0.57). One day after the beginning of the corticotherapy, the patient presented hyperthermia, ataxis and behavior troubles, epigastric and articular pains and vomiting. Biochemical tests found hyperglycemia at 38.9 mmol/L (3.9-6.1), dyslipidemia with hypertriglyceridemia at 15.7 mmol/L (0.3-1.7) and total cholesterol rate at 5.2 mmol/L (<5.2) associated with milky serum. Haematological tests objective normocytic normochromic anemia with 81 g/L of hemoglobin, lymphopenia at 0.88 G/L and normal platelet rate. Lupus associated pancreatitis was suggested and confirmed biologically with an hyperlipasemia at 180 UI/L (8-78) and radiologicaly with the image of focal hepatic steatosis. We conclude that on the presence of lupus, gastrointestinal and/or biological signs must motivate the measurement of the serum lipase activity as quickly as possible to assess the diagnosis of lupus-associated pancreatitis.

[Difficulties in interpreting the monoclonal gammopathy of chance discovery: transitional gammopathy case in a significant inflammatory syndrome]. / Difficultés d'interprétation des gammapathies monoclonales de découverte fortuite : cas d'une gammapathie transitoire au cours d'un syndrome inflammatoire important.

The discovery of a monoclonal immunoglobulin is usually witnessed a malignant lymphoproliferative disease, but sometimes it is a transient event during viral, bacterial or fungal infections and during an inflammatory syndrome. Achieving electrophoresis performed in an elderly patient aged 55 with anemia to 63 g/L hemoglobin showed a consistent profile with intense inflammatory syndrome and chronic atypical with elevated C-reactive protein (CRP) greater than 300 mg/L (normal values: 0-8 mg/L) associated with the presence of two thin appearance monoclonal migrating bands in gamma position. Achieving immunofixation showed IgM kappa monoclonal confirmed by using betamercaptoethanol (BME). Radiological findings, hematological, revealed nothing. The recovery of blood away from the inflammation on another sample report presented a CRP at 5 mg/L and a subnormal profile electrophoresis and immunofixation revealed nothing. The comparison of the results of biochemical investigations, haematological and clinical and radiological control of the electrophoretic profile of a remote inflammatory syndrome to exclude cases of transient gammopathies.

[Familial hypertriglyceridemia: biochemical, clinical and molecular study in a Moroccan family]. / Hypertriglycéridémie familiale : étude biochimique, clinique et moléculaire dans une famille marocaine.

Familial hypertriglyceridemia is a rare autosomal recessive inborn error of metabolism. Mutation within the LPL gene constitutes the first cause of monogenic etiology. Lipoprotein lipase (LPL) is the key enzyme in triglyceride-rich lipoproteins catabolism. Familial LPL deficiency is expressed by eruptive xanthomatosis and acute pancreatitis. We report a Moroccan case with a monstrous hypertriglyceridemia caused by LPL gene mutation. We discuss pathophysiology aspects according to available investigations data and the relevance of familial screening. The proband is a 19-year-old woman originating from the village of Taourirt (South of Morocco). She was admitted in emergency for diabetic ketoacidosis. Clinical investigations and routine laboratory tests were performed upon admission. Then lipoprotein electrophoresis and sequencing of the LPL gene were practiced. A monstrous hypertriglyceridemia up to 199 mmol/L was found. Lipoprotein electrophoresis has objectified profound disturbances on chylomicrons, VLDL and IDL. The sequencing detected a missense mutation p.S286R at homozygous state in a consanguinity context. Discovery of this LPL gene mutation is the first indigenous and documented case, never related in any other ethnic group. It constitutes a novel proof of a founder effect in the south Moroccan population. Prevalence studies with familial screening should be done for preventative action which is the only acceptable way to limit the cardiovascular and pancreatitis risks in this population where inbreeding is a general rule.

Relationships between vertebral fractures, sex hormones and vitamin D in Moroccan postmenopausal women: a cross sectional study.

BACKGROUND: Vertebral Fractures (VFs) are associated with bone loss that occurs before menopause but is accelerated at menopause as a result of sex hormone deficiency. To determine the association of sex hormones, bone remodeling markers and vitamin D levels with bone mineral density (BMD) and asymptomatic VFs prevalence using vertebral fracture assessment (VFA) in a cohort of Moroccan menopausal women. METHODS: This was a cross-sectional study conducted from October 2012 to April 2013 with menopausal women aged 50 years old and over. A total of 207 women who had no previous diagnosis of osteoporosis were enrolled in this cross-sectional study. Women were recruited prospectively from our laboratory department. VFA images and scans of the lumbar spine and proximal femur were obtained using a GE Healthcare Lunar Prodigy densitometer. VFs were defined using a combination of Genant semiquantitative approach and morphometry. Serum levels of estradiol, dehydroepiandrosterone sulfate, Sex hormone binding globulin, vitamin D, Osteocalcin, Crosslaps, intact parathormone were measured by Electrochemiluminescent immunoassay technique. RESULTS: Among the 207 women, 18.3 % (n = 38) had densitometric osteoporosis. On VFA, VFs were detected in 134 (62.3 %), including 96 (44.6 %) grade 1 and 38 (17.6 %) grade 2/3. There was no difference in the plasma levels of sex steroids, bone remodeling markers and vitamin D in the group of women with VFs (grade 1 and grade 2/3) and without VFs. The combination of variables that best predicted grade 2/3 VFs included the number of years since menopause and the lumbar spine T-score. CONCLUSION: These data confirm the importance of postmenopausal estrogen and SHBG concentrations in the bone loss and the pathogenesis of osteoporosis in elderly women, but not in the occurrence of the VFs.

Relationship between sex hormone levels, bone mineral density and bone turnover markers in healthy moroccan men: a cross-sectional study.

INTRODUCTION: Gonadal steroid hormones play a crucial role during skeletal growth and maturation in both men and women. The aim of this study is to evaluate the relationship of sex hormone levels, bone mineral density and biochemical markers of bone turnover in healthy Moroccan men. METHODS: 142 Moroccan men who had no previous diagnosis of osteoporosis were enrolled prospectively in this cross-sectional study between December 2009 and August 2010. Also, subjects were excluded from the study if they had conditions affecting bone metabolism. Different biochemical parameters were assayed: Testosterone, Estradiol, sex hormone binding globulin, Osteocalcin, vitamin D, crosslaps, intact parathyroid hormone and alkaline phosphatase. Dual-energy X-ray absorptiometry was used to measure the Bone mineral density (BMD) (g/cm2). RESULTS: In this study, among the 142 Moroccan men, 29 (20.1%) had densitometry osteoporosis and the prevalence of vitamin D insufficiency was 94%. No correlation was found between Estradiol, Testosterone and bone mineral density but we found significant differences in the levels of Estradiol between patients with osteoporosis, osteopenia and normal patients. Bone mineral density at the lumbar spine was negatively correlated to hormone-binding globulin and positively correlated to free androgen index, free estrogen index and the Body mass index. BMD at the total hip was positively correlated to free androgen index, Body mass index and negatively correlated to sex hormone binding globulin, alkaline phosphatase, intact parathyroid hormone, osteocalcin, Crosslaps and age. CONCLUSION: Our study showed that increasing age, intact parathyroid hormone and alkaline phosphatase levels and decreasing body mass index were the most important independent factors associated to the presence of a low BMD at the total hip. Increasing body mass index and free androgen index level were the most important independent factors associated to the presence of a low BMD at the lumbar spine. The combination of variable that best predicted the male osteoporosis is age, body mass index, alkaline phosphatase and cigarette smoking.

Relationship between Sex Hormone Levels; Bone Mineral Density and Bone Turnover Markers in Healthy Moroccan Men: a Cross-Sectional Study

Introduction: gonadal steroid hormones play a crucial role during skeletal growth and maturation in both men and women. The aim of this study is to evaluate the relationship of sex hormone levels; bone mineral density and biochemical markers of bone turnover in healthy Moroccan men. Methods: 142 Moroccan men who had no previous diagnosis of osteoporosis were enrolled prospectively in this cross-sectional study between December 2009 and August 2010. Also; subjects were excluded from the study if they had conditions affecting bone metabolism. Different biochemical parameters were assayed: Testosterone; Estradiol; sex hormone binding globulin; Osteocalcin; vitamin D; crosslaps; intact parathyroid hormone and alkaline phosphatase. Dual-energy X-ray absorptiometry was used to measure the Bone mineral density (BMD) (g/cm2). Results: in this study; among the 142 Moroccan men; 29 (20.1%) had densitometry osteoporosis and the prevalence of vitamin D insufficiency was 94%. No correlation was found between Estradiol; Testosterone and bone mineral density but we found significant differences in the levels of Estradiol between patients with osteoporosis; osteopenia and normal patients. Bone mineral density at the lumbar spine was negatively correlated to hormone-binding globulin and positively correlated to free androgen index; free estrogen index and the Body mass index. BMD at the total hip was positively correlated to free androgen index; Body mass index and negatively correlated to sex hormone binding globulin; alkaline phosphatase; intact parathyroid hormone; osteocalcin; Crosslaps and age. Conclusion: our study showed that increasing age; intact parathyroid hormone and alkaline phosphatase levels and decreasing body mass index were the most important independent factors associated to the presence of a low BMD at the total hip. Increasing body mass index and free androgen index level were the most important independent factors associated to the presence of a low BMD at the lumbar spine. The combination of variable that best predicted the male osteoporosis is age; body mass index; alkaline phosphatase and cigarette smoking

[Association of Kaposi's disease-immunoglobulin monoclonal: a new case]. / Association maladie de Kaposi et immunoglobuline monoclonale: un nouveau cas.

Kaposi disease, a tumor virus-induced, is a cutaneomucosis disease, generated by the virus infection HHV 8 of the gamma-Herpesviridae family. This virus is involved in several lymphoid pathologies. Its role in the plasma cell proliferation genesis during monoclonal gammopathy is discussed, and results are contradictory. The occurrence of Kaposi disease during multiple myeloma was described in the literature. Through this observation, we report the first case associated with monoclonal gammopathy, evolved for 3 years by HIV negative patient, and we discuss the involvement of HHV8 virus in the development of monoclonal immunoglobulin.

[Congenital nephrogenic diabetes insipidus: about a case report]. / Diabète insipide néphrogénique congénital : à propos d'une observation.

Congenital nephrogenic diabetes insipidus is a rare, hereditary in nature, characterized by an inability of the kidney to concentrate urine, secondary to the manifold resistance to the action of vasopressin. X-linked forms of transmission (90%) are expressed in boys, from the neonatal period in general, by polyuria and polydipsia. Symptomatology in transmissive girls is variable but can sometimes be quite marked. These forms are secondary to mutations in the gene encoding the vasopressin V2 receptor, located at position Xq28, responsible for a loss of function of this receptor. Some of these mutations may cause a partial phenotype, less severe. Forms of autosomal, recessive or dominant are more rare (10%). Treatment is symptomatic, sometimes difficult in infants. It aims to avoid episodes of dehydration. It is based on a conventional diet hypo-osmotic and administration of hydrochlorothiazide and indomethacin. We report here the case of a child with congenital nephrogenic diabetes insipidus hospitalized at Children's Hospital of Rabat and throughout this case we review the pathophysiology and clinical and biological characteristics of the disease and including importance of contribution of clinical biochemistry laboratory in the diagnosis and monitoring of this disease.

[Homozygous familial hypercholesterolemia: development and a case illustration]. / Hypercholestérolémie familiale homozygote : mise au point et illustration par un cas.

Familial hypercholesterolemia (FH) is a genetic disease caused by a mutation of the gene encoding for the low density lipoproteins (LDL) membrane receptor. The mutation is transmitted in an autosomal dominant mode and is manifested by permanent elevation of the plasma LDL-cholesterol concentration; such elevation is responsible for the early onset of cardiovascular complications. The other clinical manifestation is the existence of extravascular cholesterol deposits: xanthomas and corneal arcus. There are two forms of familial hypercholesterolemia: homozygous FH and heterozygous FH which is generally less severe biologically and clinically. We report in this work, a case of FH diagnosed at the laboratory of clinical chemistry of Rabat children's hospital. The lipid profile revealed a dramatic LDL-cholesterol elevation (24 mmol/L) with normal triglycerides concentration (0.84 mmol/L). The physical examination revealed cutaneous xanthomas. The diagnosis of homozygous FH was strongly suggested by family study.

[Mantle cell lymphoma diagnosis]. / Diagnostic du lymphome du manteau.

Recent classifications of non-Hodgkin's lymphomas based on combination of morphologic, immunophenotypic, and cytogenetic criteria have individualized mantle cell lymphoma (MCL). This clinico-biological entity which accounts for 3 to 10% of all non-Hodgkin's lymphomas, now appears to be a biological and therapeutic model for the understanding and treatment of hematologic malignancies. The present study consisting of two cases of MCL collated at laboratory of hematology of Rabat Ibn Sina hospital. The morphological appearance of MCL is characterized by diffuse or nodular lymph infiltration in the mantle zone, the osteo-medullary biopsy shows an interstitial infringement characterized by the presence of lymphocytes resembling centrocytes with cleaved and angular nuclei, dispersed chromatin, inconspicuous nucleoli and scanty cytoplasm. The flow cytometry showed immunophenotype positive for surface Ig, CD19, CD20, CD22, CD79b, CD5 and cyclin D1, and negative for CD10, CD23 and CD25. In conclusion, the methods of diagnosis and prognosis evaluation of mantle cell lymphoma are based on the nodular, medullary and blood morphology, the immunophenotypic, cytogenetic and molecular study of neoplastic cells.

An autosomal recessive leucoencephalopathy with ischemic stroke, dysmorphic syndrome and retinitis pigmentosa maps to chromosome 17q24.2-25.3.

BACKGROUND: Single-gene disorders related to ischemic stroke seem to be an important cause of stroke in young patients without known risk factors. To identify new genes responsible of such diseases, we studied a consanguineous Moroccan family with three affected individuals displaying hereditary leucoencephalopathy with ischemic stroke, dysmorphic syndrome and retinitis pigmentosa that appears to segregate in autosomal recessive pattern. METHODS: All family members underwent neurological and radiological examinations. A genome wide search was conducted in this family using the ABI PRISM linkage mapping set version 2.5 from Applied Biosystems. Six candidate genes within the region linked to the disease were screened for mutations by direct sequencing. RESULTS: Evidence of linkage was obtained on chromosome 17q24.2-25.3. Analysis of recombination events and LOD score calculation suggests linkage of the responsible gene in a genetic interval of 11 Mb located between D17S789 and D17S1806 with a maximal multipoint LOD score of 2.90. Sequencing of seven candidate genes in this locus, ATP5H, FDXR, SLC25A19, MCT8, CYGB, KCNJ16 and GRIN2C, identified three missense mutations in the FDXR gene which were also found in a homozygous state in three healthy controls, suggesting that these variants are not disease-causing mutations in the family. CONCLUSION: A novel locus for leucoencephalopathy with ischemic stroke, dysmorphic syndrome and retinitis pigmentosa has been mapped to chromosome 17q24.2-25.3 in a consanguineous Moroccan family.

[Multiple myeloma with D immunoglobulin]. / Myélome multiple à immunoglobuline D.

The immunoglobulin D multiple myeloma is a rare form of multiple myeloma and affects a young population. It is characterized by its clinical severity and poor prognosis. We report four cases of multiple myeloma immunoglobulin D diagnosed and supported in the university hospital Center of Sale and Rabat-Morocco. We propose to study the epidemiological, clinical and biological characteristics of this rare type of monoclonal gammopathy. Through the observations reported, the clinical aspect of myeloma is characterized by the high frequency of extra-bone manifestations including impaired kidney function. The immunoglobulin D multiple myeloma is mainly type λ, the IgD κ is rare, the predominance of λ light chains could be explained by rearrangements at the immunoglobulin genes. Bence-Jones proteinuria is almost constant in the multiple myeloma immunoglobulin D, it is mainly type λ, reflecting excess production of light chains by plasma cells. The marrow is invaded by plasma cells in very different proportions of up to 95%. It's a clinical entity, difficult to diagnose, particularly when low homogeneous band on electrophoresis goes unnoticed for an eye inexperienced or when immune serum anti-IgD was not used during the immunotyping.