Growth and Nutritional Status of Phenylketonuric Children and Adolescents.

BACKGROUND: The goal of this study was to assess the anthropometric and biochemical parameters of children and adolescents with phenylketonuria (PKU). METHODS: The participants in this cross-sectional study ranged in age from four to 18 years old. Biochemical markers such as vitamin B12, folic acid, iron, ferritin, calcium, 25-hydroxy vitamin D3, zinc, plasma phenylalanine (Phe) and tyrosine (Tyr) levels in blood were evaluated, as well as demographics and anthropometric measurements. A three-day dietary recall questionnaire was completed by all individuals. RESULTS: 80% (64) of the 80 patients (42 females, 52.5%) had typical PKU. Consanguineous marriages were found in 57.5% (46) of the patients' parents. According to the height for age index, 17.5% of the study group (n = 14) were short or very short. According to age-related weight and body mass index (BMI), 37.5% (n = 30) and 43.8% (n = 35) of people are obese or overweight, respectively. Biochemical tests revealed increased vitamin B12 levels and 25-hydroxy vitamin D3 deficiency in 35% (n = 28) of the patients, insufficient folic acid in 12.5% (n = 10), and elevated phenylalanine levels in 70.3% (n = 45) of children under 12 years old, and adolescents 62.5% (n = 10). A high Phe intake (OR = 4.44, CI %95 = 1.27-15.57) is a risk factor for obesity and overweight. CONCLUSION: Patients with PKU had a high rate of overweight and obesity. PKU patients who are overweight or obese do not differ from normal-weight patients in terms of dietary intake or laboratory findings (except for serum iron levels). One-third of patients with phenylketonuria were vitamin D deficient and had a BMI/A index of overweight/obese. It is recommended to use special medical food to help solve energy and nutrient deficiencies.

Indicators of Obesity and Cardio-metabolic Risks: Important Consideration in Adults and Children.

The prevalence of obesity has dramatically increased all over the world. Body mass index (BMI) has been used as the most common available measure to determining obesity status. While the site of excessive fat mass accumulation is a stronger determinant of cardio-metabolic complication, with respect to systemic and generalized obesity, which is only determined through BMI. So, it is concluded that using traditional anthropometric indices such as BMI for interpreting the obesity status and cardio-metabolic risk has considerable limitations. Thus, the main aims of the present study are to discuss possible drawbacks of anthropometric indices especially BMI, which in epidemiological studies are usually neglected, as well as lend important consideration to using other anthropometric indices such as measurement of obesity and related cardio-metabolic complications with a special emphasis on the use of waist circumference, waist-to-hip ratio and waist-to-height ratio.

Benefits of metformin add-on insulin therapy (MAIT) for HbA1c and lipid profile in adolescents with type 1 diabetes mellitus: preliminary report from a double-blinded, placebo-controlled, randomized clinical trial.

OBJECTIVES: Metabolic control during puberty is impaired in Type 1 Diabetes Mellitus (T1DM) patients due to increased insulin resistance. Metformin is one of the oral medications typically used in type 2 diabetes mellitus to reduce insulin resistance. We aimed to examine the effect of metformin on glycemic indices and insulin daily dosage in adolescents with T1DM. METHODS: The present clinical trial was carried out on 50 adolescents aged 10-20 years with T1DM referred to the Endocrinology Clinic of Mofid Children's Hospital in Tehran for nine months. The patients were randomly divided into two groups. In the first group, metformin was added to insulin therapy, while the second group continued routine insulin therapy combined with placebo. Hemoglobin A1c (HbA1c), weight, BMI, insulin dosage, and blood pressure were measured at the beginning of the study and repeated every three months. Serum lipid profile, creatinine, blood urea nitrogen, and liver enzymes were also measured twice: At the beginning and end of the study (after nine months). RESULTS: The HbA1c level (p<0.001) and insulin dosage (p=0.04) were lower in the metformin group than in the placebo group after nine months. Daily insulin dosage variability was significantly lower in the metformin recipient group (p=0.041). Serum triglyceride, cholesterol, and creatinine were significantly lower in the metformin arm than in the placebo arm (p<0.05). However, metformin did not affect LDL, HDL, liver enzymes, and BUN. CONCLUSIONS: Adjunctive metformin therapy reduces insulin dosage by inhibiting insulin resistance and weight gain. It helps decrease daily insulin dosage variability, which may prevent hypoglycemia. Also, metformin reduces creatinine, preventing renal failure in the long term.

Effects of omega-3 supplementation on endothelial function, vascular structure, and metabolic parameters in adolescents with type 1 diabetes mellitus: A randomized clinical trial.

Background: Vascular dysfunction is a major complication of diabetes mellitus that leads to cardiovascular disease (CVD). This study aimed to examine the effects of omega-3 consumption on endothelial function, vascular structure, and metabolic parameters in adolescents with type 1 diabetes mellitus (T1DM). Methods: In this randomized, double-blind, placebo-controlled clinical trial, 51 adolescents (10-18 years) with T1DM completed the study. Patients received 600 mg/day [containing 180 mg eicosapentaenoic acid (EPA) and 120 mg docosahexaenoic acid (DHA)] of omega-3 or placebo for 12 weeks. Flow-mediated dilation (FMD), carotid intima-media thickness (CIMT), high-sensitivity C-reactive protein (hs-CRP), erythrocyte sedimentation rate (ESR), triglycerides (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), total cholesterol, blood urea nitrogen (BUN), creatinine, fasting blood sugar (FBS), hemoglobin A1C (HbA1c), homeostatic model assessment for insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), serum insulin (SI), urine albumin-creatinine ratio (uACR), blood pressure, and anthropometric indices were assessed at the baseline and after the intervention. Results: Following supplementation, omega-3 significantly increased FMD (3.1 ± 4.2 vs. -0.6 ± 4%, p = 0.006) and decreased TG (-7.4 ± 10.7 vs. -0.1 ± 13.1 mg/dl, p = 0.022) in comparison with the placebo group. However, no significant difference was observed regarding CIMT (-0.005 ± 0.036 vs. 0.003 ± 0.021 mm, p = 0.33). Although hs-CRP was significantly decreased within the omega-3 group (p = 0.031); however, no significant change was observed compared to placebo group (p = 0.221). Omega-3 supplementation had no significant effect on other variables. Conclusion: Given the elevation in FMD and reduction in TG, omega-3 supplementation can improve vascular function and may reduce the risk of cardiovascular disease in adolescents with T1DM patients.

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.

Assessment of Anthropometric Indices in Patients with Phenylketonuria.

OBJECTIVES: Dietary phenylalanine restriction is the main treatment of phenylketonuria (PKU, OMIM 261600). There are a number of studies which have demonstrated growth retardation in these patients, and some are in contrast. This study was performed to assess the growth parameters of treated PKU patients. MATERIALS & METHODS: This cross-sectional study was performed between 2015 and 2017 to compare growth indices in PKU patients in our clinics with normal age and sex matched controls. Weight, height, head circumference (HC), weight for height and BMI (weight/height2) were measured and converted into Z-scores. We assessed differences between patients and controls' anthropometric indexes in all patients and separately in patients who were diagnosed by newborn screening program and patients who were diagnosed after presentation of clinical manifestations in comparison with age and sex-matched controls. Also, this difference was assessed separately in patients aged two years and less. Correlations between pretreatment plasma phenylalanine concentrations mean plasma phenylalanine concentrations and anthropometric parameters were analyzed in the patients. RESULTS: Overall, 209 under-treatment PKU patients (103 males, 106 females; mean age 9.29 ± 8.7 years) and 216 controls (109 males and 107 females; mean age 8.98 ± 8.62 years) matched in terms of age, sex and birth weight were enrolled in this study. In general, 130 patients were diagnosed by newborn screening and 79 were diagnosed when they became symptomatic before the screening program. A significant difference (p=0.000) was found only in HC z-score and weight for height z-score in comparison with the control group, when we assessed all patients. We did not find any significant differences in any of the anthropometric indexes between cases and controls who were aged 2 years old and less. Head circumference SDS and weight for height SDS were significantly different when patients and controls who were more than 2 years old were compared. Mean HC was significantly lower in patients, while BMI SDS, weight SDS, and weight for height SDS were significantly higher in PKU patients in comparison with the control group when patients who were diagnosed in newborn screening were assessed. Head circumference SDS, BMI, height SDS and difference between patients' height SDS and mid parental height SDS had significantly lower mean scores in comparison with those of the control group, while mean weight SDS was significantly higher compared to controls when patients who were diagnosed after clinical presentation were assessed. Mean phenylalanine was not correlated with anthropometric indices, while there was a correlation between pretreatment phenylalanine and HC. CONCLUSION: Disparities in anthropometric indexes changes observed in different studies may be due to diverse diet protocols, availability of various specific products and micronutrient substitutes.

Cost-effectiveness analysis of enzyme replacement therapy (ERT) for treatment of infantile-onset Pompe disease (IOPD) in the Iranian pharmaceutical market.

Infantile-onset Pompe disease (IOPD) or acid maltase deficiency is a rare metabolic disorder. It is caused by a deficiency in functioning of the enzyme acid alpha-glucosidase and leads to the accumulation of glycogen in the liver, heart, muscle, and other tissues. Myozyme is an effective drug, but it imposes a heavy financial burden on societies and healthcare systems. Therefore, this study was conducted to analyze the cost-effectiveness of Myozyme compared to conventional therapy for the treatment of IOPD. PubMed, Scopus, Web of Science, and Cochrane library databases were searched on December 2018 to identify the effectiveness of Myozyme versus conventional therapy. Then, a cost-effectiveness and a cost utility study were conducted in patients suffering from IOPD. In this cost effectiveness and cost utility analysis, Markov and decision tree models were used for modeling. Model parameters were obtained from international data, and the perspective of the payer was considered. Every cycle was one year; the model was run for 22 cycles. TreeAge pro 2011 was used for analysis. Finally, one-way and probabilistic sensitivity analyses were performed. Two papers were included and 39 patients were evaluated as the treatment group in both studies. Results revealed the effectiveness of Myozyme. Results also revealed a wide range of adverse reactions. Enzyme replacement therapy (ERT) resulted in 4.21038 quality-adjusted life years (QALY) per $381,852. The incremental cost per QALY was $96,809 and the incremental cost per life years gained (LYG) was 74,429 over a 22-year time horizon. Sensitivity analysis indicated the robustness of the results. Myozyme is effective for IOPD and could increase the life expectancy of patients significantly. However, since the calculated incremental cost per QALY was 17 times higher than the GDP per capita of Iran, Myozyme is not cost effective in Iran.

Non-progressive Nonimmune Hydrops Fetalis Caused by a Novel Mutation in GUSB Gene.

Objectives: Mucopolysaccharidosis type VII (MPS VII) or Sly syndrome is a rare autosomal recessive disorder caused by deficiency of ß-glucuronidase enzyme, which is involved in degradation of glycosaminoglycans. The lack of ß-glucuronidase in this lysosomal storage disorder is characterized by various manifestations such as nonimmune hydrops fetalis, spinal deformity, organomegaly, dysostosis multiplex, intellectual disability, and eye involvement. It is caused by a mutation in GUSB gene located on chromosome 7 q11. The current study reported an Iranian female with MPS VII and a novel mutation (c.542G>T, p.Arg181Leu) in GUSB gene.

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.

Mutation Analysis of the IDUA Gene in Iranian Patients with Mucopolysaccharidosis Type 1: Identification of Four Novel Mutations.

Background and Purpose: Mucopolysaccharidosis 1 (MPS1) is an autosomal recessive disorder of a lysosomal enzyme called alpha-l-iduronidase caused by mutations in the IDUA gene. This enzyme is responsible for the degradation of the mucopolysaccharides, heparan sulfate, and dermatan sulfate. Based on clinical features and enzyme deficiency, MPS1 is divided into three subtypes, including a severe subtype (Hurler syndrome), an intermediate subtype (Hurler-Scheie syndrome), and an attenuated subtype (Scheie syndrome). The objective of this study was to characterize the mutation profiles of 17 Iranian patients with MPS1 and characterize the clinical features associated with their genotypes. Materials and Methods: Polymerase chain reaction-based sequencing of the IDUA gene was carried out for 10 patients with clinical diagnoses of MPS1 and 50 healthy controls. To estimate the impact of newly identified variants on the structure and function of the encoded alpha-l-iduronidase, in silico analyses was performed. Results: Eight genetic variations were detected, including five missense mutations (p.M1L, p.G51D, p.G134V, p.S157P, p.D301E), two nonsense mutations (p.W402* and p.Y343*), and one deletion (p.GFLNYY197-202), among which p.G134V, p.S157P, p.D301E, and p.GFLNYY197-202 were novel variations that had not been previously reported. Conclusion: After combining the results of the two previous IDUA gene studies performed on Iranian MPS1 patients and the results obtained from the current study, it is inferred that despite the presence of a number of previously known mutations, about half of the detected variations were unique in Iranian patients.

A Novel Frameshift Mutation Associated with Hurler's Syndrome: A Case Report.

Mucopolysaccharidosis 1 (MPS1) is a rare inherited lysosomal storage disorder resulting from the absence or reduction of lysosomal alpha-l-iduronidase due to mutations in the IDUA gene. Three major clinical manifestations have been established including Hurler's or severe type (OMIM 607914), Hurler-Scheie or intermediate type (MIM 607914) and Scheie's or attenuated type (MIM 607016). In the present study, a patient whose disease was diagnosed by biochemical and enzymatic assay was studied in our laboratory. Molecular analysis implemented by PCR-sequencing of all 14 exons and exon-intron junctions confirmed a novel deleterious mutation in a homozygous state. The result of this study has broadened the genotypic spectrum of MPS1 patients, assisting in a more effective approach for carrier testing and counseling.

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.

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.

A Study on the Humoral and Complement Immune System of Patients with Organic Acidemia.

Patients with organic acidemia are prone to different infections, which lead to acidosis episodes. Some studies have evaluated the status of immune system in acidotic phase in these patients, but to the best of our knowledge no study has evaluated the immune system in non-acidotic phase of the disease. In this study, thirty-one patients with organic acidemia were enrolled. For evaluation of humoral immunity, serum IgA, IgG, IgE, IgM, isohemaggltuinin titer, anti tetanus and anti diphtheria IgG were measured. For screening of complement deficiencies, serum C3, C4, and CH50 were assessed. Eleven patients had Maple Syrup Urine Disease (MSUD), 10 had methylmalonic acidemia, 5 had isovaleric acidemia, 4 had glutaric aciduria, and 1 had propionic acidemia. Serum IgM level was less than normal in 2 patients. Serum isohemagglutinin titer was less than 1:8 in 2 other patients. IgA, IgE, and IgG were within normal range for all patients. Anti tetanus and anti diphtheria IgG levels were low in two patients with MSUD. No significant relationship was found between any of the measured parameters and history of recurrent admissions, recurrent infections and the type of their diseases. Five patients had high C3 level, 4 had high C4 level, and 5 had high CH50 percentage. Totally, 10 patients had high complement level, but no remarkable connection was noted between the type of the disease and complement level. Minor insignificant deficiencies in humoral immunity in non-acidotic phase of organic acidemia were found. Some components of complement system showed increase in some patients, which might be due to decreased pH in extracellular fluid.

Family social status and dietary adherence of patients with phenylketonuria.

OBJECTIVE: There are several problems associated to the management of patients with phenylketonuria (PKU). Social status could be one of the affecting factors on dietary adherence in these patients. The aim of this study was to evaluate family social status and dietary adherence of PKU patients in Iranian population. METHODS: In a cross-sectional study, we studied 105 Iranian PKU patients (born 1984 to 2010), treated and followed at Mofid Children's Hospital, Tehran. Social status was defined by number of children in family, number of affected children in family, maternal and paternal education, marital and employment status of the parents. Age at diagnosis and duration of treatment were also recorded. Mean plasma phenylalanine level was considered as a sign of dietary adherence in PKU patients and was calculated considering the phenylalanine measurements throughout at least one year. FINDINGS: Mean plasma phenylalanine concentration was 5.9±3.6 mg/dl in patients <12 years old and 13.1±3.9 mg/dl in patients >12 years old. Blood phenylalanine concentrations in 47.6% of patients were in normal age-related reference range. There was a significant association between divorced and unemployed parents, and higher levels of blood phenylalanine concentration (P=0.02 and P=0.03 respectively). There was a significant positive correlation between number of affected children in the family (r=0.43, P<0.001), age at diagnosis (r=0.2, P=0.03), treatment duration (r=0.7, P=<0.001) and blood phenylalanine concentrations. There was no significant relation between parental education, family size and dietary adherence. CONCLUSION: Social status affects dietary adherence to some extent. We suggest exploring care-givers dietary knowledge as the next step to improve dietary compliance in these patients.

Genome-wide homozygosity analysis reveals HADH mutations as a common cause of diazoxide-responsive hyperinsulinemic-hypoglycemia in consanguineous pedigrees.

CONTEXT AND OBJECTIVE: Recessive mutations in the hydroxyacyl-CoA dehydrogenase (HADH) gene encoding the enzyme 3-hydroxyacyl-CoA dehydrogenase are a rare cause of diazoxide-responsive hyperinsulinemic hypoglycemia (HH) with just five probands reported to date. HADH deficiency in the first three identified patients was associated with detectable urinary 3-hydroxyglutarate and raised plasma 3-hydroxybutyryl-carnitine levels, but two recent cases did not have abnormal urine organic acids or acylcarnitines. RESEARCH DESIGN AND METHODS: We studied 115 patients with diazoxide-responsive HH in whom the common genetic causes of HH had been excluded. No patients were reported to have abnormal acylcarnitines or urinary organic acids. Homozygosity mapping was undertaken in probands from 13 consanguineous pedigrees to search for regions harboring mutations that are identical by descent. RESULTS: HADH sequencing was performed after genome-wide single nucleotide polymorphism analysis revealed a large shared region of homozygosity spanning the HADH locus in six unrelated probands. Homozygous mutations were identified in three of these patients and in a further two probands from consanguineous families. HADH analysis in the remainder of the cohort identified mutations in a further six probands for whom consanguinity was not reported, but who originated from countries with high rates of consanguinity. Six different HADH mutations were identified in 11/115 (10%) patients tested. CONCLUSION: HADH mutations are a relatively common cause of diazoxide-responsive HH with a frequency similar to that of GLUD1 and HNF4A mutations. We recommend that HADH sequence analysis is considered in all patients with diazoxide-responsive HH when recessive inheritance is suspected.