Molecular characterization of a large cohort of mucopolysaccharidosis patients: Iran Mucopolysaccharidosis RE-diagnosis study (IMPRESsion).

Mucopolysaccharidoses (MPSs) are rare, heterogeneous inborn errors of metabolism (IEM) diagnosed through a combination of clinical, biochemical, and genetic investigations. The aim of this study was molecular characterization of the largest cohort of Iranian MPS patients (302 patients from 289 unrelated families), along with tracking their ethnicity and geographical origins. 185/289 patients were studied using an IEM-targeted NGS panel followed by complementary Sanger sequencing, which led to the diagnosis of 154 MPS patients and 5 non-MPS IEMs (diagnostic yield: 85.9%). Furthermore, 106/289 patients who were referred with positive findings went through reanalysis and confirmatory tests which confirmed MPS diagnosis in 104. Among the total of 258 MPS patients, 225 were homozygous, 90 harbored novel variants, and 9 had copy number variations. MPS IV was the most common type (34.8%) followed by MPS I (22.7%) and MPS VI (22.5%). Geographical origin analysis unveiled a pattern of distribution for frequent variants in ARSB (c.430G>A, c.962T>C [p.Leu321Pro], c.281C>A [p.Ser94*]), GALNS (c.319G>A [p.Ala107Thr], c.860C>T [p.Ser287Leu], c.1042A>G [p.Thr348Ala]), and IDUA (c.1A>C [p.Met1Leu], c.1598C>G [p.Pro533Arg], c.1562_1563insC [p.Gly522Argfs*50]). Our extensive patient cohort reveals the genetic and geographic landscape of MPS in Iran, which provides insight into genetic epidemiology of MPS and can facilitate a more cost-effective, time-efficient diagnostic approach based on the region-specific variants.

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 prevalence of zinc deficiency in morbidly obese patients before and after different types of bariatric surgery.

BACKGROUND: The prevalence of obesity is considered to be increased worldwide. Lack of mineral elements is one of the essential side effects of bariatric surgery as a trending treatment for obesity. We aimed to assess zinc deficiency among morbidly obese patients before and following different types of bariatric surgical procedures. METHODS: In the present retrospective cohort study, 413 morbidly obese patients (body mass index (BMI) ≥ 40 kg/m2 or BMI ≥ 35 kg/m2 with a complication or risk factor, e.g., diabetes mellitus) were enrolled who received bariatric surgery, aged between 18 and 65 years old, and had a negative history of active consumption of alcohol and illicit drugs. Patients were assigned into three groups of bariatric surgeries: mini-gastric bypass, Roux-en-Y gastric bypass (RYGB), and sleeve gastrectomy (SG). We recorded baseline clinical and demographic characteristics and zinc serum levels during the preoperative and postoperative follow-up periods at three, six, and 12 months after the operation. RESULTS: All patients with a mean age of 40.57 ± 10.63 years and a mean preoperative BMI of 45.78 ± 6.02 kg/m2 underwent bariatric surgery. 10.2% of the bariatric patients experienced zinc deficiency before the surgery, and 27.1% at 1 year after the surgery. The results showed that 27.7% of mini-gastric bypass patients, 29.8% of RYGB, and 13.3% of SG experienced zinc deficiency 12 months following surgery. We observed no statistical differences in the preoperative and postoperative zinc deficiency between different types of surgeries. CONCLUSION: A high prevalence of preoperative zinc deficiency among morbidly obese patients who underwent bariatric surgery was observed, which increased during the postoperative periods. We recommend assessing zinc serum levels and prescribing zinc supplements before the bariatric operation to alleviate the prevalence of zinc deficiency after the operation.

Inherited non-alcoholic fatty liver disease and dyslipidemia due to monoallelic ABHD5 mutations.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is a multifactorial condition and the most common liver disease worldwide, affecting more than one-third of the population. So far there have been no reports on mendelian inheritance in families with NAFLD. METHODS: We performed whole-exome or targeted next-generation sequencing on patients with autosomal dominant NAFLD. RESULTS: We report a heritable form of NAFLD and/or dyslipidemia due to monoallelic ABHD5 mutations, with complete clinical expression after the fourth decade of life, in 7 unrelated multiplex families encompassing 39 affected individuals. The prevalence of ABHD5-associated NAFLD was estimated to be 1 in 1,137 individuals in a normal population. CONCLUSION: We associate a Mendelian form of NAFLD and/or dyslipidemia with monoallelic ABHD5 mutations. LAY SUMMARY: Non-alcoholic fatty liver disease (NAFLD) is a common multifactorial disorder with a strong genetic component. Inherited forms of NAFLD have been suspected but, their molecular pathogenesis has not been disclosed. Here we report a heritable form of NAFLD with clinical expression after 40 years of age, associated with monoallelic ABHD5 mutations.

Vaginal bleeding imitated rape in a 6-year old girl, a case report about granulosa cell tumor as a reason of peripheral precocious puberty.

INTRODUCTION: Although female victims of sexual child abuse present with symptoms such as local pain and vaginal bleeding, however, before any definitive diagnosis a comprehensive physical examination along with a detailed history related to vaginal bleeding should be taken from the patient. Undoubtedly, we must not forget that only one of the causes of vaginal bleeding is rape. Therefore, before making a final diagnosis, other causes of this symptom must be carefully examined. CASE PRESENTATION: The patient was a 6-years-old female who was hospitalized for notable generalized abdominal distention, acute lower abdomen pain associated with nausea and mild fever lasting 5 days progressively worsening, thelarche and vaginal bleeding. Ultrasound examination showed that multilocular-solid masses located in right side of abdomen which led to surgery and mass excision. Histopathology diagnosis was a juvenile granulosa cell tumor of the ovary. DISCUSSION: Among the various causes of peripheral premature puberty, granulosa cell tumor (GCT) is rare but very important. Since in the two age groups - prepuberty and menopause - we don't expect to see vaginal bleeding, the occurrence of this disorder especially in association with breast enlargement in prepubertal group, need to appropriate imaging including pelvic ultrasound and bone age determination also laboratory data such as level of sex hormones and tumor markers to avoid misdiagnosis. CONCLUSION: We report the case of a granulosa cell tumor patient with vaginal bleeding that a complete history and examination provides the right path to a diagnosis.

Pseudodendritic keratitis in citrullinemia; a report of an unusual and novel ocular finding in this metabolic disorder.

Purpose: To report a 15 year old girl with citrullinemia type 1 and 2 accompanied by neurologic signs and symptoms and a novel ocular complaint in cornea like tyrosinemia type 2. Observations: A 15 year old female was admitted with decreased consciousness and neurologic signs and symptoms. Citrulinemia was discovered through metabolic testing. Later genetic studies revealed mutations in both ASS1 and SLC25A13 genes. Two years after the first presentation, the patient was re-admitted with complaints of bilateral photophobia and tearing. Biomicroscopic examination revealed bilateral corneal haziness with pseudodendritic lesions like tyrosinemia type 2 that were subsided with protein restriction and the use of urea cycle disease (UCD) formula. Conclusions and importance: Citrullinemia is the inherited autosomal recessive disorder of urea cycle that leads to ammonia and accumulation of other toxic substances in the blood. Two types of Citrullinemia have been defined. Citrullinemia type 1, caused by deficiency or reduction in argininosuccinate synthetase enzyme activity due to damaging mutation in ASS1 gene. Citrullinemia type 2 as another subtype is caused by the absence or dysfunction of the mitochondrial membrane carrier protein (SLC25A13), also called CITRIN. Pseudodendritic keratitis is a rare condition that may be seen with tyrosinemia type 2. The association of this ocular complaint with citrullinemia has not been described previously. Awareness of this phenomenon may improve the diagnosis and management of citrullinemia patients.

A Novel Mutation in the OXCT1 Gene Causing Succinyl-CoA:3-Ketoacid CoA Transferase (SCOT) Deficiency Starting with Neurologic Manifestations.

Succinyl-CoA:3-oxoacid CoA-transferase (SCOT) deficiency is an inborn error of ketone body utilization characterized by intermittent ketoacidosis crises. This study reports the first Iranian patient with SCOT deficiency who presented with seizure and hypotonia at birth. Accordingly, she was consequently re-hospitalized due to hypotonia and respiratory distress. Laboratory tests revealed hyperammonemia, ketonuria, and metabolic acidosis. Besides, the plasma glucose level was normal without any other abnormality. Despite treatment with high-dose bicarbonate, severe acidosis persisted. Poor response to treatment raised a significant diagnostic challenge among specialists until genetic investigation identified a homozygous nonsense mutation (c.79G>T; p.Gly27*) in the OXCT1 gene (NM_000436), causing SCOT deficiency. Genetic studies help clinicians achieve a definite diagnosis of such metabolic disorders. In this case, the accurate and early diagnosis of SCOT deficiency opened new therapeutic possibilities, including frequent carbohydrate-rich meals and low fat and protein diet. Moreover, our findings expand the mutational and clinical spectrum of SCOT deficiency.

Methenyltetrahydrofolate synthease deficiency (MTHFS deficiency): Novel mutation and brain MRI findings: A case report and glance to other cases.

This is a case report of Methenyl Tetrahydrofolate synthetase deficiency (MTHFS deficiency) characterized by global developmental delay, cerebral hypomyelination, severe spastic tonicity in extremities, and microcephaly. Mutation in the MTHFS gene was reported in the Whole Exome Sequencing (WES) and confirmed with Sanger sequencing of parents. It is of great significance to report since it would be the first case of MTHFS mutation reported from Iran and the fourth throughout the world with novel mutation and brain imaging.

Placenta derived Mesenchymal Stem Cells transplantation in Type 1 diabetes: preliminary report of phase 1 clinical trial.

INTRODUCTION: Type 1 Diabetes Mellitus (T1DM) is an auto immune reaction against insulin secreting beta cells. Exogenous insulin administration is the only standard treatment for T1DM. However, despite tight glycemic control many patients will develop chronic life-threatening complications. Recently, stem cell transplantation has been suggested as a novel treatment for eliminating the beta cell damage and promoting their regeneration by modulating auto-immunity. To our knowledge; this is the first preliminary report of placenta derived MSCs (PLMSCs) transplantation in juvenile T1DM. METHOD: An Open label non-randomized phase 1 clinical trial was designed to evaluate the safety of PLMSCs transplantation in new onset juvenile T1DM (IRCT20171021036903N2). PLMSCs were manufactured in our clean room facility using a Xeno-free/GMP compliant protocol. The first series of patients (n = 4) received one dose of1 × 106 PLMSCs/kg intravenously. Diabetic clinical and laboratory parameters and side effects were evaluated weekly for the first month, monthly for 6 months, and then every 3 month till 1 year. RESULTS: Serious adverse events were not seen during 1 year follow-up. Partial remission and hypoglycemic attacks were happened one month after transplantation in two patients. ZnT8-Ab decreased till month 3 and then increased again in all patients. Anti Gad-Ab decreased till month 3 of follow up then increased. DISCUSSION: This preliminary report of our phase I clinical trial demonstrated the short term safety of PLMSCs transplantation in juvenile T1DM. To prove the long term safety and probable efficacy of this treatment more investigations are needed. TRIAL REGISTRATION: Iranian Registry of Clinical Trials: IRCT20171021036903N2.

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.

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.