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BACKGROUND: Information regarding the prevalence of PKU in the Middle East in comparison to other world regions is scarce, which might be explained by difficulties in the implementation of national newborn screening programs. OBJECTIVE: This study seeks for the first time to genotype and biochemically characterize patients diagnosed with hyperphenylalaninemia (HPA) at the Pediatric Metabolic Genetics Clinic at the King Hussein Medical Center, Amman, Jordan. METHODS: A total of 33 patients with HPA and 55 family members were investigated for pterins (neopterin and biopterin) and dihydropteridine reductase (DHPR) activity in dried blood spots. Patients with HPA were genotyped for phenylketonuria (PKU) and the genes involved in tetrahydrobiopterin (BH4) metabolism. RESULTS: In total 20 patients were diagnosed with PKU due to phenylalanine hydroxylase (PAH) deficiency, 2 with GTP cyclohydrolase I (GTPCH) deficiency, 6 with DHPR deficiency, and 3 with the 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency. Diagnosis was not possible in 2 patients. This study documents a high percentage of BH4 deficiencies within HPA patients. With one exception, all patients were homozygous for particular gene variants. CONCLUSIONS: This approach enables differentiation between PKU and BH4 deficiencies and, thus, allows for critical selection of a specific treatment strategies.
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Acid sphingomyelinase (ASM) deficiency (ASMD) is a spectrum that includes Niemann-Pick disease (NPD) types A (NPD A) and B (NPD B). ASMD is characterized by intracellular accumulation of unesterified cholesterol and gangliosides within the endosomal-lysosomal system. It is caused by different mutations in SMPD1 gene that result in reduction or complete absence of acid sphingomyelinase activity in the cells. Herein, four unrelated consanguineous families with two NPD A and three NPD B patients were assessed for their genotypes via sequencing of the SMPD1 gene and their acid sphingomyelinase enzymatic activity. Among the eight identified mutations, three were novel and reported for the first time in Jordanian families (c.120_131delGCTGGCGCTGGC or c.132_143delGCTGGCGCTGGC, c.1758T > G, and c.1344T > A). All the patients displayed ASM activity lower than 1.3 µmol/l/h (P < 0.001). Genotyping and enzymatic assessment might play a significant role in disease identification in people at risk to facilitate genetic counseling in the future.
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Mutación/genética , Enfermedad de Niemann-Pick Tipo A/enzimología , Enfermedad de Niemann-Pick Tipo A/genética , Enfermedad de Niemann-Pick Tipo B/enzimología , Enfermedad de Niemann-Pick Tipo B/genética , Esfingomielina Fosfodiesterasa/genética , Secuencia de Aminoácidos , Secuencia de Bases , Niño , Resultado Fatal , Femenino , Humanos , Lactante , Jordania , Masculino , Linaje , Esfingomielina Fosfodiesterasa/químicaRESUMEN
Biotinidase deficiency is an autosomal recessive metabolic disorder whose diagnosis currently depends on clinical symptoms and a biotinidase enzyme assay. This study aimed to investigate the mutational status and enzymatic activity of biotinidase deficiency in seven unrelated Jordanian families including 10 patients and 17 healthy family members. Amplified DNA was analyzed by the automated Sanger sequencing method, and the enzymatic assay was performed using a colorimetric assessment. Biotinidase level was significantly lower (p < 0.001) in BTD children compare to their non-affected family members. Genetic sequencing revealed six different mutations in Jordanian patients. One mutation was novel and located in exon 4, which could be a prevalent mutation for biotinidase deficiency in the Jordanian population. Identification of these common mutations and combing the enzymatic activity with genotypic data will help clinicians with regard to better genetic counseling and management through implementing prevention programs in the future.
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INTRODUCTION: Glycogen storage diseases (GSD) are genetic metabolic disorders of glycogen metabolism. There are >15 types based on the enzyme deficiency and the affected organ. Glycogen storage disease Type Ib is the only type associated with neutropenia and periodontitis. This type is caused by a deficiency of glucose-6-phosphate (G6P) translocase which prevents the transport of G6P across the endoplasmic reticulum. As a result, glycogen cannot be metabolized into glucose with its subsequent accumulation in tissues. The affected organs involved in Type Ib are the liver, kidney, and intestine. CASE PRESENTATION: A 5-year-old Jordanian boy from a consanguineous family referred to the periodontal clinic in February 2014 with an established diagnosis of GSD-Ib. The systemic manifestations include hepatomegaly, hypoglycemia, hyperprolactenemia, inflammatory bowel disease, osteoporosis, and neutropenia. Oral manifestations include severe gingival inflammation and recurrent oral ulceration disease. CONCLUSIONS: The clinical signs and symptoms of periodontal disease in GSD Type Ib are similar to those found in patients diagnosed with neutropenia. Future studies are needed to clarify whether severe generalized inflammation of the gingiva in children is part of the GSD Type Ib or is a separate entity caused by neutrophil dysfunction.
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Enfermedad del Almacenamiento de Glucógeno Tipo I , Neutropenia , Enfermedades Periodontales , Niño , Preescolar , Enfermedad del Almacenamiento de Glucógeno Tipo I/complicaciones , Enfermedad del Almacenamiento de Glucógeno Tipo I/diagnóstico , Humanos , Riñón , Hígado , Masculino , Neutropenia/diagnóstico , Enfermedades Periodontales/complicaciones , Enfermedades Periodontales/diagnósticoRESUMEN
Recessive mutations in LPIN1, which encodes a phosphatidate phosphatase enzyme, are a frequent cause of severe rhabdomyolysis in childhood. Hence, we sequenced the 19 coding exons of the gene in eight patients with recurrent hereditary myoglobinuria from four unrelated families in Jordan. The long-term goal is to facilitate molecular genetic diagnosis without the need for invasive procedures such as muscle biopsies. Three different mutations were detected, including the novel missense mutation c.2395G>C (Gly799Arg), which was found in two families. The two other mutations, c.2174G>A (Arg725His) and c.1162C>T (Arg388X), have been previously identified, and were found to cosegregate with the disease phenotype in the other two families. Intriguingly, patients homozygous for Arg725His were also homozygous for the c.1828C>T (Pro610Ser) polymorphism, and were exercise-intolerant between myoglobinuria episodes. Notably, patients homozygous for Arg388X were also homozygous for the c.2250G>C silent variant (Gly750Gly). Taken together, the data provide family-based evidence linking hereditary myoglobinuria to pathogenic variations in the C-terminal lipin domain of the enzyme. This finding highlights the functional significance of this domain in the absence of structural information. This is the first analysis of LPIN1 in myoglobinuria patients of Jordanian origin, and the fourth such analysis worldwide.
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Hyperargininaemia is a disorder of the last step of the urea cycle. It is an autosomal recessive disease caused by deficiency of liver arginase-1 and usually presents later in childhood with progressive neurological symptoms including marked spasticity. In contrast with other urea cycle disorders, hyperammonaemia is not usually present but can be a feature. A number of guanidine compounds may accumulate in the blood and cerebrospinal fluid of these patients, which could play an important pathophysiological role. Guanidinoacetate is of particular interest as a well-known potent epileptogenic compound in guanidinoacetate methyltransferase deficiency. We found markedly elevated guanidinoacetate levels in a patient with arginase deficiency, which dropped significantly in response to dietary and medical treatment. Measurement of guanidinoacetate and other guanidino compounds may, therefore, be important for therapeutic monitoring in arginase deficiency.