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BACKGROUND: Phenylketonuria (PKU) is the most frequent inborn error in amino acid metabolism caused by a deficiency of the phenylalanine hydroxylase enzyme (PAH). If PKU is left untreated, high concentrations of phenylalanine (Phe) accumulate in the blood, leading to severe brain dysfunction, neurodevelopmental, behavioral and psychological problems. Data concerning the epidemiology of PKU in Jordan are limited. The main objectives of our study were to determine the prevalence of PKU in Jordan, analyze the PKU phenotypes, and identify major challenges in providing dietary management to PKU patients. METHODS: Data were collected utilizing the medical records of PKU patients attending the PKU clinic at the Ministry of Health in Amman, Jordan, between 2008 and 2021. RESULTS: The total number of patients diagnosed with PKU was 294. The prevalence of PKU was estimated to be 1/5263. Most patients were Jordanians (90.8%), and 9.2% were non-Jordanians. More than half of the patients (56%) were diagnosed through the national newborn screening (NBS) program. Regarding the phenotypes of PKU, 46.6% had moderate PKU, whereas 42.9% had the classic type of PKU and only 8 (2.7%) had cofactor Tetrahydrobiopterin (BH4) deficiency (atypical PKU). According to the age of diagnosis, 66% of patients were diagnosed more than 30 days post-birth. Consanguinity was found in 87.4% of patients, and the majority of patients, 218 (74.2%), had first-degree consanguinity. The most common complication was mental retardation (31%). Most patients were committed to dietary management (83%) and developed fewer complications. CONCLUSION: In our study, we demonstrated the importance of the NBS program in the early identification and diagnosis of new PKU cases which allows the initiation of treatment and dietary management to prevent severe complications of PKU in Jordan.
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BACKGROUND: Outcomes from studies employing nitisinone 10 mg and 2 mg in alkaptonuria were compared. PATIENTS AND METHODS: Sixty-nine patients in each of the nitisinone (10 mg daily) and controls of suitability of nitisinone in alkaptonuria 2 (SONIA 2), as well as 37 and 23 in nitisinone (2 mg daily) and control cohorts at the National Alkaptonuria Centre (NAC), respectively, were followed up for 4 years. Severity of alkaptonuria (AKU) was assessed by the AKU Severity Score Index (AKUSSI). 24-h urine homogentisic acid (uHGA24), serum HGA (sHGA), serum tyrosine (sTYR) and serum nitisinone (sNIT) were also analysed at each time point. Dietetic support was used in the NAC, but not in SONIA 2. Safety outcomes were also compared. All statistical analyses were post hoc. RESULTS: The slope of the AKUSSI was 0.55, 0.19, 0.30, and 0.06 per month in the control NAC, nitisinone NAC, control SONIA 2, and nitisinone SONIA 2 cohorts, respectively. The intersection of the slopes on the x-axis was -132, -411, -295, and - 1460 months, respectively. The control and nitisinone slope comparisons were statistically significant both in the NAC (p < 0.001) and the SONIA 2 (p < 0.001). Corneal keratopathy occurred in 3 and 10 patients in the NAC and SONIA 2, respectively. DISCUSSION: The nitisinone 10 mg dose decreased disease progression more than the 2 mg dose although the incidence of corneal keratopathy was 14.5% and 4.9%, respectively. CONCLUSION: Nitisinone 10 mg decreased urine and serum HGA, increased serum tyrosine, and decreased disease progression more than 2 mg. Low-protein dietetic support may be needed to mitigate tyrosinaemia following nitisinone. HIGHLIGHTS: Nitisinone 10 mg apparently slows alkaptonuria disease progression more than 2 mg in adults.Corneal keratopathy during nitisinone therapy was more common in men.Serum nitisinone concentrations increased significantly over time.Nitisinone may inhibit cytochrome P450 self catabolism.
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This study aimed to evaluate the urinary tract for dynamic function and stones and calcifications in patients with alkaptonuria. Thirty-eight patients were prospectively divided into two groups. Study group (A) involved 17 patients; the average age was 42 years. The control group (B) involved 21 patients; the average age was 37 years. All patients from the two groups underwent uroflowmetry assessment and ultrasonography for the kidneys and urinary bladder, and prostate in two phases (full bladder and empty bladder). Group A-Bladder volume ranged between 400 and 520 cc. The peak flow rate was between 7 and 23 mL/s, with an average of 18.6 mL/s. Flow rate curves shape were acceptable to the normal bell-shape curve in 11 patients. Seven patients (41%) had prostate calcification accounting for 5%-35% of prostate size. Group B-Bladder volume ranged between 290 and 510 cc. The peak flow rate was 8-27 ml/s, with an average of 20 mL/sec. Normal bell shape voiding curves were observed in 17 patients (80%). Four patients (19%) had prostate calcification accounting for 2%-12% of prostate size. Renal measurements on ultrasonography were the same in both groups. Patients with alkaptonuria developed prostate calcification at younger age; they have a slight but not statistically significant reduced peak urinary flow rate and post void residual urine.
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Alcaptonúria , Rim/diagnóstico por imagem , Próstata/diagnóstico por imagem , Ultrassonografia/métodos , Bexiga Urinária/diagnóstico por imagem , Micção/fisiologia , Adulto , Estudos de Casos e Controles , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Alkaptonuria (AKU) is an autosomal recessive disorder caused by mutations in homogentisate-1,2-dioxygenase (HGD) gene leading to the deficiency of HGD enzyme activity. The DevelopAKUre project is underway to test nitisinone as a specific treatment to counteract this derangement of the phenylalanine-tyrosine catabolic pathway. We analysed DNA of 40 AKU patients enrolled for SONIA1, the first study in DevelopAKUre, and of 59 other AKU patients sent to our laboratory for molecular diagnostics. We identified 12 novel DNA variants: one was identified in patients from Brazil (c.557T>A), Slovakia (c.500C>T) and France (c.440T>C), three in patients from India (c.469+6T>C, c.650-85A>G, c.158G>A), and six in patients from Italy (c.742A>G, c.614G>A, c.1057A>C, c.752G>A, c.119A>C, c.926G>T). Thus, the total number of potential AKU-causing variants found in 380 patients reported in the HGD mutation database is now 129. Using mCSM and DUET, computational approaches based on the protein 3D structure, the novel missense variants are predicted to affect the activity of the enzyme by three mechanisms: decrease of stability of individual protomers, disruption of protomer-protomer interactions or modification of residues in the region of the active site. We also present an overview of AKU in Italy, where so far about 60 AKU cases are known and DNA analysis has been reported for 34 of them. In this rather small group, 26 different HGD variants affecting function were described, indicating rather high heterogeneity. Twelve of these variants seem to be specific for Italy.
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Alcaptonúria/genética , Doenças Ósseas Metabólicas/genética , Osso e Ossos/enzimologia , Homogentisato 1,2-Dioxigenase/genética , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único , Alcaptonúria/diagnóstico , Alcaptonúria/enzimologia , Alcaptonúria/patologia , Sequência de Bases , Doenças Ósseas Metabólicas/diagnóstico , Doenças Ósseas Metabólicas/enzimologia , Doenças Ósseas Metabólicas/patologia , Osso e Ossos/patologia , Domínio Catalítico , Bases de Dados Genéticas , Éxons , Feminino , Expressão Gênica , Heterogeneidade Genética , Homogentisato 1,2-Dioxigenase/química , Humanos , Íntrons , Itália , Masculino , Modelos Moleculares , Dados de Sequência Molecular , Linhagem , Fenótipo , Estrutura Secundária de Proteína , Análise de Sequência de DNARESUMO
Alkaptonuria (AKU) is a rare inborn metabolic disease characterized by accumulation of homogentisic acid (HGA). Excretion of HGA in urine causes darkening of urine and its deposition in connective tissues causes dark pigmentation (ochronosis), early degeneration of articular cartilage, weakening of the tendons, and subsequent rupture. In this case report, we present a rare case of a patient presented with unilateral spontaneous rupture of Achilles tendon due to AKU. The patient developed most of the orthopedic manifestations of the disease earlier than typical presentations. Alkaptonuria patients should avoid strenuous exercises and foot straining especially in patients developing early orthopedic manifestations.
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Tendão do Calcâneo/lesões , Alcaptonúria/complicações , Ruptura Espontânea/complicações , Adulto , Humanos , Masculino , Ruptura Espontânea/cirurgia , Resultado do TratamentoRESUMO
BACKGROUND: Adverse drug reactions (ADRs) represent a major health care problem. OBJECTIVE: To identify the most common ADRs, drugs implicated in ADRs, and to assess their causality, severity, preventability and risk factors predisposing to reported ADRs in Jordan. SETTING: Al-Karak teaching hospital, southern of Jordan. Method A cross sectional observational study was carried out for 11 months from January to November 2013. Suspected ADRs were recorded in ADRs report forms and analyzed for causality, severity, and preventability. MAIN OUTCOME MEASURE: Most common ADRs, drugs involved in these ADRs, causality, severity, and preventability of suspected ADRs. RESULTS: A total of 64 reports were received. Some patients suffered more than one ADR. The total number of ADRs identified was 108. Forty one drugs were involved in causing these ADRs. About 2/3 of adverse reactions (73.4 %) did not cause admission to the hospital, whereas 26.6 % of the ADRs resulted in admission. Majority of the ADRs were type A (62.5 %). Most of ADRs (92.2 %) were assessed as probable. Nearly, 65.6 % of ADRs were categorized as mild. Majority of ADRs were assessed as "not preventable" (75 %). The most common classes of drugs involved in ADRs were antibiotics, analgesics, vaccines and antiepileptics. The most commonly identified ADRs were abdominal pain, skin rash, shortness of breath, fever, upper gastrointestinal bleeding and vomiting. Risk factors contributed to ADRs were age and polypharmacy. CONCLUSION: Jordanian healthcare providers should be aware of the importance of detecting and reporting ADRs, in order to prevent and reduce the incidence of ADRs. Awareness of risk factors predisposing to ADRs may help in identifying patients with higher risk and therefore reducing the risk of these ADRs and improving patient outcome.
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Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Hospitais de Ensino/estatística & dados numéricos , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Incidência , Lactente , Jordânia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Índice de Gravidade de Doença , Adulto JovemRESUMO
AIMS: Sulfamethoxazole in combination with trimethoprim (cotrimoxazole) is used for prophylaxis and treatment of several opportunistic infections in HIV-infected patients. It is associated with a high incidence of hypersensitivity reactions, which is thought to have an immune basis. Genetic polymorphisms in MHC are known to predispose to hypersensitivity reactions to a structurally diverse group of drugs in HIV-positive patients. The aim of the study was to determine whether functional polymorphisms in TNF, LTA, HSPA1L and HLA-DRB1 genes influence the risk of cotrimoxazole hypersensitivity in HIV-infected patients. METHODS: We genotyped 136 HIV-positive patients with (n = 53) and without (n = 83) cotrimoxazole hypersensitivity using a combination of PCR-based techniques, including PCR-restriction fragment length polymorphisms, PCR-sequence specific oligonucleotides and real-time PCR. Genotypes and the haplotype frequencies were analyzed using the chi(2) test in the Haploview and CLUMP programs. RESULTS: No statistically significant difference in SNP or haplotype frequencies were found in HIV-infected sulfamethoxazole hypersensitive patients compared with controls. CONCLUSION: Our data show that MHC polymorphisms are not major predisposing factors for cotrimoxazole hypersensitivity, although we cannot exclude a minor contribution. An environmental factor (i.e., HIV infection) seems to predominate over any of the genetic factors so far investigated in increasing the risk of cotrimoxazole hypersensitivity.