Identification of Novel Mutations in the MMAA and MUT Genes among Methylmalonic Aciduria Families.

Background: Methylmalonic aciduria is a rare inherited metabolic disorder with autosomal recessive inheritance pattern. There are still MMA patients without known mutations in the responsible genes. This study aimed to identify mutations in Iranian MMA families using autozygosity mapping and NGS. Methods: Multiplex PCR was performed on DNAs isolated from 12 unrelated MMA patients and their family members using 19 STR markers flanking MUT, MMAA, and MMAB genes, followed by Sanger sequencing. WES was carried out in the patients with no mutation. Results: Haplotype analysis and Sanger sequencing revealed two novel, mutations, A252Vf*5 and G87R, within the MMAA and MUT genes, respectively. Three patients showed no mutations in either autozygosity mapping or NGS analysis. Conclusion: High-frequency mutations within exons 2 and 3 of MUT gene and exon 7 of MMAB gene are consistent with the global expected frequency of genetic variations among MMA patients.

Complications in patients with transfusion dependent thalassemia: A descriptive cross-sectional study.

Background and Aims: One of the most common hemoglobinopathies globally related to blood transfusion and iron overload in the body is thalassemia syndrome. Increasing ferritin levels can cause severe damage to the patient's body organs. This study aims to evaluate the complications of iron overload on vital body organs in patients with transfusion-dependent beta-thalassemia. Methods: This descriptive cross-sectional study was performed in Iran University of Medical Sciences Hospitals on patients with a beta-thalassemia major with frequent blood transfusions. To evaluate the effect of iron overload on vital body organs, hematologic and blood analysis, echocardiography with measurement of pulmonary artery pressure (PAP) and ejection fraction (EF) tests, bone densitometry, and audiometric tests were performed for all patients. Results: Of the 1010 patients participating in this study, 497 (49%) were males, 513 were (51%) females aged 5-74 years, and the majority of participants (85%) were over 20 years old. This study demonstrated that increasing ferritin levels had no notable correlation with sex, cholesterol, low-density lipoprotein, parathyroid hormone, T4, and aspartate aminotransferase. However, elevating ferritin levels had significant correlations with increasing triglyceride, phosphorus, thyroid stimulating hormone, alkaline phosphatase, alanine transaminase, and PAP levels, age, hearing disorders, splenectomy, osteoporosis, and decreasing high-density lipoprotein, body mass index, calcium, and EF levels. Conclusion: Improvement in beta-thalassemia patients' survival and quality of life can be due to multidisciplinary care in a comprehensive unit through regular follow-up and early complication detection.

Estrogen replacement therapy: effects of starting age on final height of girls with chronic kidney disease and short stature.

INTRODUCTION: We investigated the age of starting Estrogen replacement therapy as a key parameter for reaching near normal Final Height (FH) in Chronic Kidney Disease (CKD) girls with growth retardation. METHOD: This open label, quasi-experimental designed and matched controlled clinical trial was performed on CKD girls with short stature and later onset of puberty or delayed puberty according to clinical and laboratory investigations. Participants of group 1 and 2 had been treated with Growth Hormone (GH), and Ethinyl Estradiol (EE). EE was administered from 11 and 13 yrs. old in groups 1 and 2 respectively. Group 3 was selected from patients that did not accept to start GH or EE till 15 years old. The effect of the age of starting EE on FH, GH therapy outcomes, bone density, and calcium profile were evaluated. RESULT: Overall, 16, 22, and 21 patients were analyzed in groups 1, 2, and 3 respectively. Mean Mid-Parental Height (MPH) had no significant difference between the 3 groups. GH therapy significantly enhanced mean FH in groups 1 and 2 in comparison with group 3 (ß = - 4.29, p < 0.001). Also, multivariable backward linear regression illustrated significant negative association between FH and age of starting EE (ß = 0.26, p < 0.001). Mean Para Thyroid Hormone (PTH), mean femoral and lumbar bone density were significantly enhanced after GH and EE therapy (p value: < 0.001). CONCLUSION: We recommend starting EE from 11 yrs. old in CKD short stature girls who have no clinical and laboratory sign of sexual maturity at 11 yrs. to enhance the cost effectiveness of GH therapy.

The treatment and clinical follow-up outcome in Iranian patients with tetrahydrobiopterin deficiency.

OBJECTIVES: This study aimed to evaluate the biochemical factors, genetic mutations, outcome of treatment, and clinical follow-up data of Iranian patients with tetrahydrobiopterin (BH4) deficiency from April/2016 to March/2020. METHODS: Forty-seven BH4 deficiency patients were included in the study and underwent biochemical and genetic analyses. The clinical outcomes of the patients were evaluated after long-term treatment. RESULTS: Out of the 47 (25 females and 22 males) BH4 deficiency patients enrolled in the study, 23 were Dihydropteridine reductase (DHPR) deficient patients, 23 were 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficient patients, and one was GTP-Cyclohydrolase 1 deficiency (GTPCH-1) patient. No clinical symptoms were observed in 10 of the DHPR deficient patients (before and after the treatment). Also, most patients diagnosed at an early age had a proper response to the treatment. However, drug therapy did not improve clinical symptoms in three of the patients diagnosed at the age of over 10 years. Also, 16 PTPS deficiency patients who were detected within 6 months and received treatment no clinical symptoms were presented. One of the patients was detected with GTPCH deficiency. Despite being treated with BH4, this patient suffered from a seizure, movement disorder, mental retardation, speech difficulty, and hypotonia. CONCLUSIONS: The study results showed that neonatal screening should be carried out in all patients with hyperphenylalaninemia because early diagnosis and treatment can reduce symptoms and prevent neurological impairments. Although the BH4 deficiency outcomes are highly variable, early diagnosis and treatment in the first months of life are crucial for good outcomes.

The Nomogram of Clitoral Length and Width in Iranian Term and Preterm Neonates.

Background and Objectives: Clitoromegaly is an important parameter in the evaluation of ambiguous genitalia in neonates, but the normative data for clitoral size in newborns have racial/ethnic differences. The present study aimed to determine clitoral length (CL) and clitoral width (CW) values and establish cutoff measurement to define clitoromegaly in both term and preterm Iranian neonates for the first time. Methods: A total number of 580 female newborn infants delivered at 28-42 weeks of gestation were enrolled in the study, and their CL and CW were measured on the first 72 h of birth. Data about birth weight (BW), body length (BL), and head circumference (HC) of newborns; mothers' age; and gestational age (GA) were recorded, too. Results were presented as mean ± standard deviation (SD) for quantitative variables and were summarized by frequency (percentage) for categorical variables. Backward stepwise regression analysis was used for prediction of CL and CW. Results: Among 580 Iranian female newborns studied, 187 were term neonates and the other 393 newborns were preterm. Mean ± SD values of CL were 6.11 ± 0.39 mm in term infants and 5.45 ± 0.64 mm in preterm infants (P < 0.001). Mean ± SD values of CW were 4.22 ± 0.43 in term infants and 3.68 ± 0.53 in preterm infants (P < 0.001). Regression analysis showed that CL was correlated with GA considered by last menstrual period, BL, BW, and HC; and CW was associated with GA, BL, and BW. Conclusion: This study suggests normative values (mean + 1, 2, and 3 SD) of CL and CW according to GA, which can be used as a reference for Middle East's newborns, especially Iranian newborn babies.

Psychological factors of vulnerability to suicide ideation: Attachment styles, coping strategies, and dysfunctional attitudes.

BACKGROUND: Suicide ideation is one of the common mental health problems among university students. This study aimed to explain suicide ideation susceptibility by examining the relationships between psychological factors. METHODOLOGY: The population of the study included all female undergraduate students at the University of Isfahan in autumn 2018. A sample of 180 individuals were selected through multistage sampling from different faculties and majors. The scales used in this study included adults attachments inventory, Coping Inventory for Stressful Situation, Dysfunctional Attitudes Scale, and Suicide Ideation Scale. The statistical analyses included t-test, Pearson correlation, and path analysis. RESULTS: Suicide ideation was reported in 25% of the participants. The t-test analysis indicated that the mean scores for dysfunctional attitudes (P < 0.01) and problem-focused coping (P < 0.01) were significantly different in with and without suicide ideation groups. Suicide ideation significantly correlated with problem-focused coping (r = -0.42, P < 0.01), emotion-focused coping (r = 0.25, P < 0.05), and dysfunctional attitudes (r = 0.23, P < 0.05). Path analysis showed that dysfunctional attitudes and emotion-focused coping significantly influenced suicide ideation. Moreover, the indirect effect of insecure (ambivalent and avoidant) attachment styles by mediating role of dysfunctional attitudes and emotion-focused coping was statistically significant (P < 0.01) and the indirect effect of dysfunctional attitudes by mediating role of emotion-focused coping as well (P < 0.05). CONCLUSION: Insecure attachment styles and dysfunctional attitudes work as stress-diathesis model in predicting suicide ideation and increase suicide ideation susceptibility by affecting emotion-focused coping strategy. The hypothesized model in this study can help formulate, evaluate, and prevent suicide risk.

Association between body mass index and insulin resistance in survivors of pediatric acute lymphoblastic leukemia.

In this retrospective cohort study, oral glucose tolerance testing (OGTT) was performed for all enrolled survivors of patients who suffered from acute lymphoblastic leukemia (ALL) at least 9 months after ending chemotherapy, as well as for control group. All demographic, treatment and anthropomorphic data were obtained from medical records. Furthermore, insulin resistance was evaluated according to insulin level, Matsuda and HOMA-IR index. Of 53 subjects, 28 exhibited B-cell ALL, and 25 were healthy children (F/M = 1.12/1). Mean age (±SD) was determined to be 10.77 ± 2.83 years, and meantime off for therapy was also recorded as 3.0 ± 1.6 years. ALL patients were diagnosed at age 1-15 years; none of them received the cranial radiotherapy, and demographic characteristics (age, sex, and sexual maturity) were found to be the same in both groups. Seven patients showed transient hyperglycemia during ALL treatment, however, no significant differences were found in terms of body mass index (BMI) means between ALL patients with and without transient hyperglycemia. Based on the data presented herein, insulin resistance could not be predicted by glucose levels during therapy, cumulative asparaginase, and steroid. Our findings demonstrated that elevated BMI could be a valuable predictor of insulin resistance probability in ALL patients. The presence of transient hyperglycemia does not appear to be associated with the increased risk of glucose intolerance or insulin resistance in the first few years after completion of therapy.

Letrozole Effect on Final Height of Patients with Constitutional Delay of Growth and Puberty.

INTRODUCTION: The inhibitory effect of aromatase on predicted adult height and near final height has been studied in patients with constitutional delay of growth and puberty (CDGP). AIM: This is the first study aimed at verifying the letrozole (Lz) effect on final height of patients with CDGP. MATERIAL AND METHODS: In this study 8 patients with CDGP underwent treatment with Lz (2.5 mg/day) for a year, and 8 patients with CDGP, who did not receive Lz were followed -up to reaching final height. Height discrepancy was calculated by subtracting PAH from final height measurement. RESULTS: the final height for Lz and Control Groups were 171± 4.5 cm and 168.8±4.1Cm respectively. The final heights for Lz group were significantly (p=0.04) higher than the control group. Final height in comparison with PAH at the beginning of the study showed significant difference (p=0.022) in Lz group whereas the difference was not significant (p=0.8) in control group. For height discrepancy the measurements were +1.9 cm and +0.1 cm for Lz and control group respectively with significant difference (p=0.04). CONCLUSION: Our study, which is the first one in evaluating the impact of Lz on FH, illustrated that Lz treatment will ultimately lead to augmentation of FH in boys with CDGP.

Investigation of association between maternal 25-OH vitamin D serum levels and neonatal early onset sepsis in newborns by evaluating key factors.

BACKGROUND: The goal of this study was to evaluate the relationship between maternal 25-OH Vitamin D serum levels and neonatal early-onset sepsis in newborns by the effective factors. METHODS: A case-control study was done and 64 neonates hospitalized in Akbar Abadi Hospital (Tehran- Iran; 2016) and their mothers were enrolled. The case group consisted of 32 NICU term hospitalized neonates due to neonatal early-onset sepsis. Thirty-two term newborns that referred to hospital for rule out hyperbilirubinemia during the first 72 h of life were also considered as the control. RESULTS: Sixty- four mothers with mean age 28.76 ± 6.60 years and mean gestational age 39.64 ± 1.62 weeks entered the study. There was a significant correlation between sepsis and older age of mothers and low Apgar score (P-value = 0.02, 0.01 respectively). The maternal vitamin D serum level was reversely correlated with neonatal sepsis occurrence (P-value = 0.03). There was a significant correlation between maternal vitamin D supplement intake during pregnancy and lower risk for neonatal sepsis (P-value = 0.003). CONCLUSION: The level of maternal serum Vitamin D was inversely correlated with neonatal sepsis occurrence and intake of vitamin D supplement during pregnancy could decrease the risk of early neonatal sepsis.

Mutation analysis of Phenylalanine hydroxylase gene in Iranian patients with Phenylketonuria.

Background: Phenylketonuria as the most common genetic metabolic disorder is the result of disruption of the phenylalanine hydroxylase gene. This study was carried out to explore the phenylalanine hydroxylase gene mutation status of Iranian phenylketonuria patients. Methods: Blood samples were collected from 30 patients, and hot spot areas of the phenylalanine hydroxylase gene, including exons 6, 7, 8, 11, and 12 were studied through polymerase chain reaction and sequencing techniques. Results: Eight different mutations, including 5 missense mutations, 1 splice mutation, 1 nonsense mutation, and 1 Silent/Splice mutation were detected. These mutations were R243X, R261Q, R261X, P281L, R241C, V399V, E280K, and IVS11+1G>C. V399V and R241C were reported for the first time in Iranian population. Three polymorphisms including Q232Q, V245V and L385L and 3 novel intronic variants including IVS10-15A>C, IVS6+44T>G, and IVS6+36 T>G were also detected in this study. Conclusion: The results of this study prove the heterogeneous status of phenylalanine hydroxylase gene mutations in the Iranian population, which can be useful in carrier testing and genetic counseling.

The Nomogram of Penile Length and Circumference in Iranian Term and Preterm Neonates.

BACKGROUND AND OBJECTIVES: The normal length of penis in preterm and term neonates is different among different nations, and is affected by various factors. The present study aimed to determine stretched penile length (SPL) values and cutoff level of micropenis in term and preterm Iranian neonates, for the first time. MATERIALS AND METHODS: All male neonates born in two general hospitals of Tehran (Akbarabadi, and Rasoul hospitals), center of Iran, with gestational age of 28-42 weeks were included and their SPL and penile circumference (PC) were examined on the first 3 days after birth by the same physician. Birth weight (BW), and height, gestational age, type of delivery, mother's age, twin/multiple pregnancy, drug, and medical history of mother during pregnancy were recorded and cutoff levels of two variables were calculated based on the collected variables for different gestational ages. RESULTS: Among a total of 587 neonates, 203 neonates were born term and 384 preterm. Mean ± SD of neonates' BW were 2,682.51 ± 739.30 (850-4800) gr. Mean ± SD of their SPL was 22.48 ± 3.34 mm; 25.92 ± 1.54 mm in term and 20.66 ± 2.50 mm in preterm infants (P = 0.001). Mean ± SD of PC was 6.71 ± 1.31 mm; 8.14 ± 0.48 in term and 5.96 ± 0.92 in preterm infants (P = 0.001). SPL and PC were significantly correlated with type of delivery, number of parity, gestational age, BW, and crown-heel length, head circumference (P < 0.001). CONCLUSION: This study suggested that SPL in male neonates was 22.48 mm and PC was 6.71 mm, both correlated with gestational age and BW. Due to the ethnical variety of this cutoff points and lack of an appropriate study in Iran, these cutoff points can be used by all physicians as a reference for Iranian newborns (term and preterm), in order to prevent misdiagnosis of micropenis and genital disorders.

Are There Neurological Symptoms in Type 1 of Gaucher Disease?

OBJECTIVE: Gaucher disease (GD) is a rare inborn error of metabolism, classified as a lipid storage disorders. This disease is caused by a deficiency in glucocerebrosidase enzyme. It has been classified according to the presence or absence of neurological symptoms into the following types: type 1 non-neuropathic, type 2 acute infantile neuropathic and type 3 or chronic neuropathic. We evaluated neurological symptoms in patients with GD1 and GD3 and compared both of these groups. MATERIALS & METHODS: Eleven patients were identified according to their clinical presentation and the presence of disease confirmed by genetic testing, from 2006-2016, at the Mofid Children Hospital Clinic, Tehran, Iran. We included eight patients with GD 1 and three patients with GD3. Careful neurological examination was performed on these patients during treatment by pediatric neurologist. RESULTS: Patients with GD1 had some neurological symptoms including cognitive impairment, developmental disability, behavioral disorder, microcephaly and increased deep tendon reflexes (DTR). Of course, neurological signs in patients with type 3 of GD were different and were included seizures, supranuclear gaze palsy, cerebellar signs, and ataxia. CONCLUSION: The current nomenclature for 3 types of Gaucher disease does not meet all clinical symptoms. Patients with GD1 display many neurological deficits in young ages not reported adequately earlier.

A New Case of Chanarin-Dorfman Syndrome with a Novel Deletion in ABHD5 Gene

Chanarin-Dorfman syndrome (CDS) is a rare autosomal recessive metabolic disorder caused by mutations in gene encoding the domain-5 of α/ß-hydrolase enzyme (ABHD5). It is known as a natural lipid storage disorder arising from impaired lipid metabolism often characterized by hepatomegaly, myopathy, ataxia, non-bullous ichthyosiform erythroderma, hearing loss, and mental retardation. In the present study, we report two affected 28-month-old monozygotic twin boys as new cases of CDS. Genetic analysis was performed in patients, and the results showed a homozygote deletion in exon 4 of ABHD5. According to the the American College of Medical Genetics and Genomics, this variant is categorized as a pathogenic variant.

Evaluation of near final height in boys with constitutional delay in growth and puberty.

BACKGROUND: This study was conducted to find out whether boys with constitutional delay in growth and puberty (CDGP) could attain their target height and predicted adult height (PAH) in adulthood or not. METHODS: After measuring the height, weight, pubertal stage, parental height and bone age data of the patients at their first presentation were extracted from the files and their height and weight were measured at the end of the study, wrist X-Ray was performed in order to determine the bone age. PAH was calculated using Bayley-Pinneau method and target height was estimated by mid parental height. Final or near final heights of the patients were measured and compared with the target height and PAH. RESULTS: The mean age at presentation and the end of study was 15.2 ± 0.95, 20 ± 0.75 years respectively. Mean of bone age at the beginning of study was 12.97 ± 1 years and at the end of study were 17.6 ± 0.58 years. Mean of delayed bone age was 2.2 ± 0.82 years. Mean of the primary measured heights was 150.16 ± 7 cm (138-160 cm). Mean of final or near final heights was 165.7 ± 2.89 cm (161-170.5 cm). Final or near final heights in our subjects were smaller than either their PAH (165.7 ± 2.89 vs 170.7 ± 5.17) (P value <0.005) or target height (165.7 ± 2.89 vs 171.8 ± 4.65) (P value <0.0001). CONCLUSION: Most patients with CDGP do not reach their target height or predicted adult height; they are usually shorter than their parents and general population. Such patients need to be followed up until they reach their final height and, in some cases, adjunctive medical treatment might be indicated.

The association between the number of office visits and the control of cardiovascular risk factors in Iranian patients with type2 diabetes.

INTRODUCTION: Patients with diabetes type2 should receive regular medical care. We aimed at investigating the association between the number of office visits and improvement of their cardiovascular-risk factors. METHODS: Four hundred and ninety patients with type 2 diabetes mellitus who were followed in a tertiary center were enrolled in this longitudinal study. The minimum follow up period was 3 years. Patient data were extracted from manual or electronic records. RESULTS: Sixty- four percent of cases were females, the mean age was 61 ± 12.45 years, and the mean disease duration was 6.5 ±7.9 years. The mean number of office visits was 2.69 ± 0.91 per year. Comparing the means of each of the cardio-vascular risk factors showed a significant decrease in all cardiovascular risk factors, while there was a significant weight gain over the same period. The association between changes in these parameters and the number of patients' office visits per year were not statistically significant. In patients with disease duration less than 5 years, each additional office visits by one visit per year was associated with a decrease in serum total cholesterol by 6.94 mg/dl. The mean number of office visits per year in patients older than 60 years old was more than younger patient (p = 0.001). CONCLUSION: The decrease in the mean values of the investigated parameters was statistically significant between the first year of follow up and the following years. Yet, these changes were not related to the mean number of patients' office visits per year, which may reflect the poor compliance of patients to treatment regardless of the number of their office visits.

Thyroid function test in diabetic ketoacidosis.

BACKGROUND: Metabolism of thyroid hormones is influenced by acute systemic illnesses including diabetic ketoacidosis. In these cases T3 level is usually decreased and this condition is called "low T3 syndrome" which is usually reversed by treating the under lying Disease. OBJECTIVES: thyroid function test analysis before and after diabetic ketoacidosis treatment. METHOD: In this cross sectional study thyroid function tests were analyzed in 16 diabetic ketoacidosis patients according to American diabetic association before and after insulin therapy. RESULT: mean triiodothyronine (T3) level before and after ketoacidosis treatment were 63.2±28.2ng/dl/and 78.5±26.2ng/dl (P. value 0.00) respectively and the mean thyroxin level (T4) before and after ketoacidosis were 3.18±1.4ng/dl and 5.17±2.4ng/dl (P. value=0.00) .Mean thyrotropin (TSH) level and triiodothyronine uptake (T3RU) before and after treatment showed no significant difference. CONCLUSION: Diabetic ketoacidosis is a sever systemic disease which along with reduction in T3 level, T4 level is also decreased and TSH level is normal. The changes in Thyroid hormones are reversed to normal after treatment of ketoacidosis so it is recommended in interpreting results of TFT in these patients we should consider these facts and thyroid function test should be repeated after treatment.

Relationship Between Obesity and Liver Enzymes Levels in Turner's Syndrome.

BACKGROUND: Liver enzyme abnormalities have been reported in Turner's syndrome (TS). There are some studies about possible causes of abnormal levels of liver enzymes. One of the main suggestions is obesity. The study aimed to determine the relationship between obesity and liver enzymes levels in patients with TS. METHODS: Forty-one karyotype-proven TS patients referred to Endocrinology and Metabolism Research Center were included in this cross-sectional study. Height and weight of patients were measured and their body mass index (BMI) was calculated. The patients were divided into two groups as the control group including 27 cases (65.8%) with normal BMI (defined as < 85th percentile for age and gender), and the overweight group including 14 cases (34.2%) (defined as BMI > 85th percentile for age and gender). Serum levels of aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (AlkPh) were measured. RESULTS: There were no statistically significant differences regarding AST (27 ± 2.7 vs. 29.6 ± 5.85 U/L; P = 0.3), ALT (20.1 ± 2.45 vs. 22.2 ± 5.85 U/L; P = 0.5), and AlkPh (583.4 ± 2.45 vs. 472.8 ± 161.5 U/L; P = 0.28) between overweight TS patients and those with normal BMI. CONCLUSION: There was no significant difference in liver enzyme levels between TS patients with normal BMI and those who were overweight.

Bone Mineral Density in Survivors of Childhood Acute Lymphoblastic Leukemia

Background: The objective of this study was to evaluate bone mineral density (BMD) after completion of treatment for childhood acute lymphoblastic leukemia (ALL). Methods: In this cross-sectional study, 103 survivors of ALL aged 13.5 ± 0.45 who completed their treatment at least one year earlier were enrolled. Among these, 49.5% and 51.5% received chemotherapy alone and chemotherapy plus cranial radiotherapy, respectively. Bone mineral content, BMD, and bone mineral apparent density in the lumbar spine (LS), femoral neck (FN) and forearm were assessed using dual-energy X-ray absorptiometry (DEXA). BMD Z-scores were classified according to International Society for Clinical Densitometry (ISCD) criteria. Results: The mean BMD Z-scores ± SD forLS, FN and forearm were -1.60 ± 0.12, -1.21 ± 0.9 and -2.43 ± 0.14 respectively with significant differences (P<0.001). Considering the lowest BMD Z-score in LS and FN areas (at any site) and according to the ISCD classification, 62.1%, 33% and 4.9% of the patients had normal BMD, low BMD and osteoporosis, respectively. Also, 8.7% of patients had developed fractures after completion of the treatment period, 4.9% having BMD Z-Scores <-2 SD at any site. A direct relationship was apparent between BMD Z-scores at LS and FN at any sites and risk of fracture (P<0.001). Conclusions: ALL patients are at risk for low BMD and fracture. Therefore, applying DEXA scanning is recommended after completion of therapy for prevention of BMD reduction and osteoporosis.

Four Years of Diagnostic Challenges with Tetrahydrobiopterin Deficiencies in Iranian Patients.

Hyperphenylalaninemia (HPA) is a condition caused by tetrahydrobiopterin (BH4) and phenylalanine hydroxylase (PAH) deficiencies. It is essential that differential diagnosis be conducted to distinguish these two causes of HPA, because BH4 deficiency is a more severe disease involving progressive neurologic deterioration. Based on the biological findings, HPA is defined as a plasma phenylalanine level of >2.0 mg/dl (>120 µmol/l). The National Biochemistry Reference Laboratory at the Pasteur Institute of Iran initiated BH4 deficiency screening tests for the first time during the implementation of a nationwide phenylketonuria (PKU) screening program. Measurement of blood phenylalanine and urinary neopterin and biopterin was conducted by high-performance liquid chromatography in 617 patients with HPA. Dihydropteridine reductase (DHPR) activity was measured in all patients by kinetic spectrophotometry. Differential diagnosis was conducted for PKU, transient HPA, and BH4 deficiencies.Our results indicated that out of 76 cases involving BH4 deficiencies, 37 had 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency, 35 had DHPR deficiency, 1 case had pterin-4a-carbinolamine dehydratase (PCD) deficiency, and 3 cases had GTP cyclohydrolase I (GTPCH) deficiency. In this study, 1 novel deletion mutation and 18 novel missense mutations were reported in addition to mutations that had previously been identified and registered in BIOMDB. At present, the screening program for PKU in Iran includes tests that detect different forms of BH4 deficiency presenting with HPA. Newborns that are BH4-deficient benefit from the availability of the tests because they can receive necessary care before being clinically affected.

Factors Influencing Verbal Intelligence and Spoken Language in Children with Phenylketonuria.

OBJECTIVE: To determine verbal intelligence and spoken language of children with phenylketonuria and to study the effect of age at diagnosis and phenylalanine plasma level on these abilities. DESIGN: Cross-sectional. SETTING: Children with phenylketonuria were recruited from pediatric hospitals in 2012. Normal control subjects were recruited from kindergartens in Tehran. PARTICIPANTS: 30 phenylketonuria and 42 control subjects aged 4-6.5 years. Skills were compared between 3 phenylketonuria groups categorized by age at diagnosis/treatment, and between the phenylketonuria and control groups. MAIN OUTCOME MEASURES: Scores on Wechsler Preschool and Primary Scale of Intelligence for verbal and total intelligence, and Test of Language Development-Primary, third edition for spoken language, listening, speaking, semantics, syntax, and organization. RESULTS: The performance of control subjects was significantly better than that of early-treated subjects for all composite quotients from Test of Language Development and verbal intelligence (P<0.001). Early-treated subjects scored significantly higher than the two groups of late-treated subjects for spoken language (P=0.01), speaking (P=0.04), syntax (P=0.02), and verbal intelligence (P=0.019). There was a negative correlation between phenylalanine level and verbal intelligence (r=-0.79) in early-treated subjects and between phenylalanine level and spoken language (r=-0.71), organization (r=-0.82) and semantics (r=-0.82) for late-treated subjects diagnosed before the age one year. CONCLUSION: The study confirmed that diagnosis of newborns and control of blood phenylalanine concentration improves verbal intelligence and spoken language scores in phenylketonuria subjects.