Clinical, biochemical, and molecular insights into Cerebrotendinous Xanthomatosis: A nationwide study of 100 Turkish individuals.

OBJECTIVE: Cerebrotendinous xanthomatosis (CTX) is an inherited metabolic disorder characterized by progressive neurologic and extraneurologic findings. The aim of this retrospective, descriptive study was to explore the time of presentation and diagnosis, and to expand the phenotype and genotype of CTX, based on a nationwide and comprehensive series of patients in Turkey. METHODS: The demographic, clinical, biochemical and genotypic characteristics of the CTX patients were reviewed. Data on molecular analysis, age of onset and diagnosis, diagnostic delay, neurologic and extraneurologic symptomatology, results of plasma cholestanol levels, brain magnetic resonance imaging and electromyography at the time of diagnosis were reviewed. RESULTS: 100 confirmed CTX patients from 72 families were included. The mean age at diagnosis was 28.16 ± 14.28 years, and diagnostic delay was 18.39 ± 13.71 years. 36 patients were diagnosed in childhood. Frequency of intention tremor (p = 0.069), peripheral neuropathy (p = 0.234) and psychiatric manifestations (p = 0.396) did not differ between two groups, demonstrating the high rate in pediatric patients. Three adult patients showed a milder phenotype without neurologic involvement. Seven patients had normal plasma cholestanol levels despite neurological impairment. Sequencing of the CYP27A1 gene revealed 25 different variants, with a novel c.671_672del variant not previously described in literature. CONCLUSION: Based on the observations of this Turkish CTX cohort, it is emphasized that the true prevalence of CTX is probably underestimated and that it has a wide spectrum of clinical phenotypes even without neurological impairment. In children, abnormal cerebellar findings, peripheral neuropathy and psychiatric findings associated with intellectual disability have been suggested as warning signs to avoid diagnostic delay. In cases of clinical suspicion, molecular analysis is recommended despite normal plasma cholestanol levels, as severe neurologic involvement may occur in CTX patients without elevated cholestanol levels.

Evaluation of the efficacy and associated complications of regional citrate anticoagulation in neonates: experience from a fourth level neonatal intensive care unit.

Continuous kidney replacement therapy (CKRT) use has increased in recent years, but anticoagulation is a challenge for neonates. Regional citrate anticoagulation (RCA) is rarely preferred in neonates because of citrate accumulation (CA) and metabolic complications. We aimed to demonstrate the efficacy and safety of RCA in neonates. We retrospectively analyzed the medical records of 11 neonates treated with RCA-CKRT between 2018 and 2023. The initial dose of RCA was 2.1-3 mmol/l, and then, its dose was increased according to the level of ionized calcium (iCa+2) in the circuit and patients. The total/iCa+2 ratio after-treatment > 2.5 was indicated as CA. We evaluated to citrate dose, CA, circuit lifespan, and dialysis effectivity. The median gestational age was 39 (36.4-41.5) weeks, the median body weight (BW) was 3200 (2400-4000) grams, and the mean postnatal age was 4 (2-24) days. The most common indication for CKRT was hyperammonemia (73%). All neonates had metabolic acidosis and hypocalcemia during CKRT. Other common metabolic complications were hypophosphatemia (90%), hypokalemia (81%), and hypomagnesemia (63%). High dialysate rates with a median of 5765 ml/h/1.73 m2 allowed for a rapid decrease in ammonia levels to normal. Four patients (36.3%) had CA, and seven (63.7%) did not (non-citrate accumulation, NCA). Mean BW, median postnatal age, biochemical parameters, coagulation tests, and ammonia levels were similar between the CA and NCA groups. Low pH, low HCO3, high lactate, and SNAPPE-II scores could be associated with a higher T/iCa ratio. CONCLUSION:  RCA was an efficient and safe anticoagulation for neonates requiring CKRT. Metabolic complications may occur, but they could be managed with adequate supplementation. WHAT IS KNOWN: • Continuous kidney replacement therapy (CKRT) has become popular in recent years due to its successful treatment of fluid overload, electrolyte imbalance, metabolic acidosis, multi-organ failure, and hyperleucinemia/hyperammonemia associated with inborn errors of metabolism. • The need for anticoagulation is the major difficulty in neonatal CKRT. In adult and pediatric patients, regional citrate anticoagulation has been shown to be effective. WHAT IS NEW: • RCA is an effective and safe anticoagulation method for neonates who require CKRT. • Electrolyte imbalances and metabolic acidosis could be managed with adequate supplementation and appropriate treatment parameters such as citrate dose, blood flow rate, and dialysate flow rate.

Characteristics of continuous venovenous hemodiafiltration in the acute treatment of inherited metabolic disorders.

BACKGROUND: Continuous kidney replacement therapies (CKRT) have been reported to be an effective approach to removing toxic metabolites in inborn errors of metabolism (IEM). The present study evaluates efficiency and complications of CKRT in children with IEM. METHODS: Patients diagnosed with IEM who underwent CKRT in pediatric and neonatal intensive care units were analyzed. CKRT were initiated in patients with persistently high blood ammonia levels (≥ 500 µmol/L), blood ammonia levels > 250 µmol/L in the presence of moderate encephalopathy, high blood leucine levels (≥ 1500 µmol/L), and blood leucine levels < 1500 µmol/L in the presence of deteriorating neurological status or persistent metabolic acidosis. RESULTS: Of 22 patients enrolled, nine (40.9%) Maple syrup urine disease (MSUD), eight (36.4%) urea cycle disorders (UCD), and five (22.7%) organic acidemias (OA). Median age was 72.3 [9.9-1040.8] days. In total, 28 dialysis sessions were analyzed [16 (57.1%) continuous venovenous hemodialysis, and 12 (42.9%) continuous venovenous hemodiafiltration]. A significant decrease was noted in leucine levels (from 1608.4 ± 885.3 to 314.6 ± 109.9 µmol/L) of patients with MSUD, while ammonia levels were significantly decreased in patients with UCD and OA (from 1279.9 ± 612.1 to 85.1 ± 21.6 µmol/L). The most frequent complications of CKRT were thrombocytopenia (60.7%), hypotension (53.6%), and hypocalcemia (42.9%). Median age of patients with hypotension treated with vasoactive medications was significantly lower than median age of those with normal blood pressure. CONCLUSION: CKRT is a reliable approach for effective and rapid removal of toxic metabolites in children with IEM, and CKRT modalities can be safely used and are well-tolerated in infants.

Does Metformin Treatment in Pediatric Population Cause Vitamin B12 Deficiency?

BACKGROUND/AIM: There have been no studies to date examining the effect of metformin treatment on vitamin B12 status in children and adolescents. In this prospective study, the effects of metformin on blood vitamin B12, serum methylmalonic acid (MMA), homocysteine and holo-transcobalamin-II (holo-TC-II) levels were assessed in pediatric age group. MATERIALS AND METHODS: This prospective study was conducted at the Pediatric Endocrinology and Adolescent Department between January 2017 and March 2019. Metabolic syndrome and polycystic ovary syndrome diagnosed patients with insulin resistance and/or impaired glucose tolerance, patients with type 2 diabetes mellitus (DM) treated with metformin were enrolled in study. Blood vitamin B12, MMA, homocysteine, holo-TC-II levels and hemogram values were evaluated. RESULTS: Twenty-four patients were enrolled in study. Among these, 15 (62.5%) were female. The mean age of patients was 13.7±2.3 (10-19) years. Sixteen patients were diagnosed with metabolic syndrome and 8 patients were type 2 DM. At 6-month follow-up of all patients, there was no statistically significant difference in terms of vitamin B12, homocysteine, MMA and holo-TC-II levels. A 0.6% decline in vitamin B12 levels were revealed. At 12-month follow-up of 11 patients (45.8%) (6 Type 2 DM, 5 metabolic syndrome), no statistically significant difference was determined in vitamin B12, homocysteine, MMA and holo-TC-II levels. There were 6% decline in vitamin B12 levels and 10.9% increase in homocysteine levels, 5.4% decrease was detected in holo-TC-II level. CONCLUSION: Although no significant changes in the serum vitamin B12, homocysteine, MMA or holo-TC-II levels with metformin therapy were detected, long-term prospective studies with high-dose metformin treatment in pediatric population are needed to confirm our results.

Inherited metabolic disorders in the neonatal intensive care unit: Red flags to look out for.

BACKGROUND: We aimed to assess symptoms, laboratory findings, and radiological abnormalities in patients diagnosed with inherited metabolic disorders (IMDs) in the neonatal intensive care unit. METHODS: A total of 6,150 newborns treated in a third-level neonatal intensive care unit between 2012 and 2020 in Turkey were screened, of which 195 consulted with a suspicion of metabolic disease based on their clinical, laboratory, or radiological findings were included in the present study. RESULTS: The prevalence of IMDs in the patients was 1:94.6. Those consulted in the department of pediatric metabolism were divided into two groups, with the 65 diagnosed with IMDs assigned as Group I, and the 130 patients who were not diagnosed with IMDs as Group II. The most common IMDs were organic acidemias (29.23%) and urea cycle disorders (UCDs) (26.15%). The rates of consanguinity marriage (75.3% vs 37.6%, P < 0.001), siblings diagnosed with an IMD (27.6% vs 3.8%, P < 0.001), and sibling death (56.9% vs 14.6%, P < 0.001) were higher in Group I than in Group II. Hyperammonemia (61.5% vs 18.4%, P < 0.001) was the most common laboratory finding in Group I, and anemia (Group I 60.0% vs 43.0% P = 0.033), metabolic acidosis (53.8% vs 36.9%, P = 0.028) and respiratory alkalosis (16.9% vs 1.5%, P < 0.001) were all higher in Group I. CONCLUSIONS: This retrospective study found that the results of clinical findings and basic laboratory tests could be strong indicators of IMDs, although extensive newborn screening tests and advanced biochemical and genetic tests should be carried out for the diagnosis of IMDs in newborns.

Pros and Cons of Telemedicine for Inherited Metabolic Disorders in a Developing Country During the COVID-19 Pandemic.

Introduction: The COVID-19 pandemic has led to considerable changes in the health care system. Experts suggested that individuals protect themselves through social isolation during the pandemic, and consequently, the importance of telemedicine came to be understood for patients with chronic diseases. Telemedicine started to be used in developing countries where the appropriate infrastructure was lacking earlier. The present study investigates the level of satisfaction of patients with inherited metabolic disorders (IMDs) with telemedicine. Methods: This prospective study was conducted by making use of a new video appointment program that ensures the privacy of the patients in video-based consultations. The sociodemographic characteristics of the patients, their clinical status, their views on the telemedicine system, and their levels of satisfaction were questioned. Results: Overall, 174 patients were included in the study. The most common diagnoses were aminoacidopathies, lipid metabolism disorders, biotinidase deficiency, and lysosomal/peroxisomal diseases. More than half of the parents (67.6%) who lived in another city reported accommodation issues when coming to the hospital, and most believed telemedicine would save them time (93.1%) and money for travel (81.6%). The lack of laboratory and radiological tests (83.9%) was stated as the main disadvantage by most parents. Almost all the parents (96.6%) stated that they would opt for telemedicine if it became available in daily practice. The overall satisfaction rate was 94.6 (±10.1)/100. Conclusions: The present research is the most extensive cohort study to date assessing telemedicine in patients with IMDs and it highlights the importance of telemedicine, especially in developing countries during the COVID-19 pandemic.

Could lysosomal acid lipase enzyme activity be used for clinical follow-up in cryptogenic cirrhosis?

BACKGROUND: Cholesterol ester storage disease (CESD) is one of the rare causes that should be kept in mind in the etiology of cirrhosis. Recent studies detected that significantly reduced lysosomal acid lipase deficiency enzyme (LAL) in patients with cryptogenic cirrhosis (CC). Moreover, studies have evaluated that LAL activity is as effective as scoring systems in assessing the severity of cirrhosis. In this study, we aimed to investigate the CESD with LAL level and mutation analysis of LIPA gene in patients diagnosed with CC and to compare LAL activities between patients with CC and healthy volunteers. METHODS: Laboratory parameters and cirrhosis stage (CHILD and MELD) were recorded for the patient group included in the study. In addition, blood samples were taken from each case included in the study for LAL activity determination and LIPA gene analysis. RESULTS: A statistically significant decrease in LAL activity was found in patients diagnosed with CC compared to the healthy group. LIPA gene analysis did not detect CESD in any patient group. Correlation analysis showed a positive correlation between LAL activity and white blood cell and platelet counts in both healthy volunteers and CC patient groups. In the univariate and multivariate logistic regression analysis of the parameters associated with the MELD of ≥10 in patients with CC, significant relationship was found between the MELD of ≥10 and the LAL activity. DISCUSSION: In our study, LAL activity was significantly lower in CC patients than in the normal population. LAL activity level appears to be a parameter that can be used to assess the severity of cirrhosis.

Neuronal ceroid lipofuscinosis: genetic and phenotypic spectrum of 14 patients from Turkey.

INTRODUCTION AND PURPOSE: Neuronal ceroid lipofuscinoses (NCLs) is a group of congenital metabolic diseases where the neurodegenerative process with the accumulation of ceroid and lipofuscin autofluorescent storage materials is at the forefront. According to the age of presentation, NCLs are classified as congenital, infantile (INCL), late infantile (LINCL), juvenile (JNCL), and adult (ANCL) NCLs. In our study, it was aimed to discuss the clinical and molecular characteristics of our patients diagnosed with NCL. MATERIAL AND METHOD: This is a descriptive cross-sectional study which was conducted in 14 patients from 10 unrelated families who were diagnosed with different types of NCL based on clinical presentation, neuroimaging, biochemical measurements, and molecular analyses, at the department of pediatric metabolism between June 2015 and June 2020. RESULTS: A total of 14 patients were diagnosed with different types of NCL. Of those, 4 patients were diagnosed with NCL7 (4/14; 30%), 3/14 (23%) with NCL1, 3/14 (23%) with NCL2, 2/14 (14.2%) with NCL13, and 1/14 (7.1%) with NCL10. Eleven pathogenic variants were detected, 5 of which are novel (c.721G>T [p.Gly241Ter] and c.301G>C [p.Ala146Pro] in MFDS8 gene; c.316C>T [p.Gln106Ter] in PPT1 gene; c.341C>T [p.Ala114Val] in TPP1 gene; c.686A>T [p.Glu229Val] in CTSD gene) CONCLUSION: This study is one of the pioneer comprehensive researches from Turkey that provides information about disease-causing variants and clinical presentation of different and rare types of NCLs. The identification of novel variants and phenotypic expansion is important for genetic counselling in Turkey and expected to improve understanding of NCLs.

Analysis of hematological parameters in patients treated with ketogenic diet due to drug-resistant epilepsy.

Benefits of the ketogenic diet (KD) in epileptic patients are well known while less is known about the nutritional risks of the diet and its potential impacts on biochemical nutritional status. In this study, we aimed to evaluate the hematological parameters of patients who have drug-resistant epilepsy and are treated with KD. Fifty-three patients with drug-resistant epilepsy (mean age 7.4 ± 4.4 years [2-18], 23 [43.4%] female) were included in the study. Demographic and laboratory data of the patients were retrospectively analyzed at baseline and Month 6 and Month 12 of the treatment. Repeated measures ANOVA (post hoc Bonferroni correction) and Friedman test were used to assess the changes in data during the treatment. Mean hemoglobin levels increased by 0.594 g/dL after 6 months (p = 0.001) and by 0.602 g/dL after 12 months of the treatment (p = 0.002). Mean hematocrit level was found to be significantly increased at Month 6 and 12 of the treatment compared to baseline [F(2,94) = 8.9, p < 0.0001]. An increase in MCV levels was determined with the KD treatment [F(2,94) = 19.7, p < 0.0001]. Mean level of vitamin B12 was found to be significantly increased in Month 12 of treatments compared to Month 6 [F(1.686,72.479) = 3.472, p = 0.035]. There was no significant effect of KD on other hematological parameters (red blood cell, white blood cell and platelet counts, serum iron, total iron-binding capacity, transferrin saturation, and ferritin and folic acid levels). We can conclude that KD increases levels of hemoglobin, hematocrit, MCV, and serum vitamin B12 in patients with intractable epilepsy. Prospective, multi-center, longitudinal studies are needed to confirm our results.

The Effects of Breastfeeding in Infants With Phenylketonuria.

PURPOSE: In the early years of phenylketonuria (PKU) treatment, mothers and healthcare professionals often decide to discontinue breastfeeding after the diagnosis of PKU in infants. It was believed to be the only effective way to monitor the infant's intake and allow for precise titration and measurement of the intake of phenylalanine (Phe). In the early 1980s, with the determination of low concentration of Phe in breast milk, breast milk supplemented with Phe-free formula has become an acceptable dietary treatment for infants with PKU. Today, breastfeeding is encouraged and well established in PKU patients. The aim of the present study is to investigate the prevalence and duration of breastfeeding, the effect of breastfeeding on serum Phe levels, and weight gain in infants with PKU. DESIGN AND METHODS: Data were collected from chart reviews. Medical records of 142 children with PKU diagnosed via the national neonatal screening program were analyzed retrospectively. RESULTS: Of the 41 infants with complete medical records, 40 (97.6%) were breastfed following delivery whereas only one (2.4%) was bottle fed. After the diagnosis, breastfeeding was continued in 25 (61%) infants with phenylalanine-free amino acid based protein substitute. The mean duration of breastfeeding was 7.4±4.0 (1-15) months. Serum Phe concentration of breastfed infants (280±163 µmol/L) was significantly lower than non-breastfed infants (490±199 µmol/L) (p<0.001). Mean monthly weight gain in the first year of life was significantly higher in breastfed patients (493±159 g/month) compared to non-breastfed patients (399±116 g/month) (p=0.046). CONCLUSION: In the first year of life, weight gain and serum Phe levels were more favorable in breastfed infants with PKU compared to non-breastfed infants with PKU.

A novel mutation in the glycine decarboxylase gene in patient with non-ketotic hyperglycinemia.

Non-ketotic hyperglycinemia (NKH) is a rare inborn error of metabolism and is caused by a glycine cleavage system deficiency. Eighty-five percent of patients present with the neonatal type of NKH, the infants initially develop lethargy, seizures, and episodes of apnea, and most often death. Between 60-90% of cases are caused by mutations in the glycine decarboxylase (GLDC). We believed that more mutation reports especially for rare disease as NKH help to evaluate the genotype-phenotype relationship in patients with GLDC. In this study, we describe a case of a neonate admitted to intensive care unit with hypotonia, respiratory failure, lethargy, poor feeding. Due to the history of 2 non-ketotic hyperglycinemia diagnosed male siblings, molecular prenatal diagnosis in patient was performed and a novel c.2963G>A (Arg998Gln) homozygous mutation within the GLDC gene has been detected. We aimed to contribute to mutation knowledge pool of GLDC gene with a novel mutation.

The Effect of Rapid Antigen Detection Test on Antibiotic Prescription Decision of Clinicians and Reducing Antibiotic Costs in Children with Acute Pharyngitis.

We aimed to investigate the effect of rapid antigen detection test (RADT) in the diagnosis of streptococcal pharyngitis, its impact on antibiotic prescription decision of pediatricians and influence on reduction of antibiotic treatment costs in children with pharyngitis. The study group consisted of 223 patients who were diagnosed with pharyngitis by pediatricians. The sensitivity and specificity of RADT were 92.1% (95% Cl: 78.6-98.3%) and 97.3% (95% Cl: 93.8-99.1%), respectively. In the first assessment, before performing RADT, pediatricians decided to prescribe antibiotics for 178 (79.8%) patients with pharyngitis. After learning RADT results, pediatricians finally decided to prescribe antibiotics for 83 (37.2%) patients with pharyngitis, and antibiotic prescription decreased by 42.6%. Antibiotic costs in non-Group A streptococcus pharyngitis, Group A streptococcus pharyngitis and all subjects groups decreased by 80.8%, 48%, and 76.4%, respectively. Performing RADT in children with pharyngitis has an important impact on treatment decision of clinicians, reduction of unnecessary antibiotic prescriptions and antibiotic costs.

Val2Ala mutation in the Atp6v0a4 gene causes early-onset sensorineural hearing loss in children with recessive distal renal tubular acidosis: a case report.

A young female patient born to consanguineous parents was admitted to our clinic at the age of 3 years with a 5-month history of weight loss and recurrent urinary tract infections. Based on clinical findings (delayed growth and O-bein deformity) and laboratory tests (hypokalemia, hyperchloremia, partially compensated metabolic acidosis, alkaline urine and nephrocalsinosis), a diagnosis of distal renal tubular acidosis (dRTA) was made. Then, the audiogram revealed a bilateral sensorineural hearing loss (SNHL). On follow-up, bilateral SNHL progressively worsened requiring the need for hearing aid. The ATP6V0A4 gene mutation analysis showed homozygote Val2Ala mutation. To the best of our knowledge, this is the first report describing a Turkish girl with dRTA who suffered from early-onset SNHL caused by Val2Ala mutation in the ATP6V0A4 gene.

Neuronal ceroid lipofuscinosis type 11 diagnosed patient with bi-allelic variants in GRN gene: case report and review of literature.

OBJECTIVES: Neuronal ceroid lipofuscinosis type 11 (NCL11) is a rare disease that presents with progressive cognitive decline, epilepsy, visual impairment, retinal atrophy, cerebellar ataxia and cerebellar atrophy. We present herein a case of NCL11 in a patient diagnosed with neuromotor developmental delay, epilepsy, bronchiolitis obliterans and hypothyroidism. CASE PRESENTATION: A 4-year-old male patient was admitted to our clinic with global developmental delay and a medical history that included recurrent hospitalizations for pneumonia at the age of 17 days, and in months 4, 5 and 7. Family history revealed a brother with similar clinical findings (recurrent pneumonia, hypothyroidism, hypotonicity, swallowing dysfunction and neuromotor delay) who died from pneumonia at the age of 22 months. Computed tomography of the thorax was consistent with bronchiolitis obliterans, while epileptic discharges were identified on electroencephalogram with a high incidence of bilateral fronto-centro-temporal and generalized spike-wave activity but no photoparoxysmal response. Cranial MRI revealed T2 hyperintense areas in the occipital periventricular white matter and volume loss in the white matter, a thin corpus callosum and vermis atrophy. A whole-exome sequencing molecular analysis revealed compound heterozygous c.430G>A (p.Asp144Asn) and c.415T>C (p.Cys139Arg) variants in the GRN gene. CONCLUSIONS: The presented case indicates that NCL11 should be taken into account in patients with epilepsy and neurodegenerative diseases.

Two Turkish patients with Primary Coenzyme Q10 Deficiency-7: case report and literature review.

OBJECTIVES: Primary Coenzyme Q10 Deficiency-7 (OMIM 616276) results from bi-allelic pathogenic variants in the COQ4 gene. Common clinical findings include hypotonia, seizures, respiratory distress, and cardiomyopathy. In this report, we present two patients diagnosed with Primary Coenzyme Q10 Deficiency-7 along with a review of previously published cases, with the aim being to provide a better understanding of the clinical and laboratory manifestations of the disease. CASE PRESENTATION: A 3-month-and-22-day-old male was admitted to our outpatient clinic due to poor feeding and restlessness. He was born following an uneventful pregnancy to a nonconsanguineous marriage. A physical examination revealed hypotonia, a dolichocephaly, periorbital edema, and long eyelashes. Blood tests revealed metabolic acidosis and elevated serum lactate levels, while the genetic analysis revealed a variant previously reported as pathogenic, c.437T>G (p.Phe146Cys), in the COQ4 gene. Genetic tests were also conducted on both mother and father, and it revealed heterozygous variant, 0.437T>G (p.Phe146Cys), in the COQ4 gene. As a result of these findings, the patient was diagnosed with neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome (Primary Coenzyme Q10 Deficiency-7). A 1-year-old male was admitted to our clinic with complaints of hypotonia, seizures, and feeding difficulties. He was born following an uneventful pregnancy to a nonconsanguineous marriage. On his first day of life, he was admitted to the neonatal intensive care unit due to poor feeding and hypotonia. A physical examination revealed microcephaly, a high palate, poor feeding, weak crying, hypotonia, bilateral horizontal nystagmus, and inability to maintain eye contact. Laboratory findings were within normal limits, while a whole exome sequencing analysis revealed a homozygous variant previously reported as pathogenic, c.458C>T (p.A153V), in the COQ4 gene. The patient was diagnosed with Primary Coenzyme Q10 Deficiency-7. CONCLUSIONS: Primary Coenzyme Q10 Deficiency-7 should be considered in the differential diagnosis of infants presenting with neurological and dysmorphic manifestations.

Metabolic etiologies in children with infantile epileptic spasm syndrome: Experience at a tertiary pediatric neurology center.

OBJECTIVE: Infantile epileptic spasm syndrome (IESS), including West syndrome (WS) and infantile spasm (IS), causes a challenging prognosis, particularly when associated with metabolic etiologies. METHODS: This study, conducted at a tertiary pediatric neurology center, explored the prevalence and clinical features of inborn errors of metabolism in 112 children with IESS over 10 years. RESULTS: Most patients presented with seizures, primarily flexor spasms, and the median age at onset was 5 months. Comprehensive clinical evaluation and neuroimaging revealed structural-acquired causes as the most common etiology. Notably, inborn errors of metabolism were identified in 5.4 % of cases, with six distinct diagnoses including nonketotic hyperglycinemia, pyridoxine-dependent epilepsy, primary coenzyme Q10 deficiency 7, congenital disorder of glycosylation type IIM, 6-pyruvoyl tetrahydrobiopterin synthase deficiency, and argininosuccinate lyase deficiency. The prevalence of inborn errors of metabolism in this cohort was consistent with global variations reported in the literature. Genetic testing, including karyotype analysis and whole exome sequencing, was performed in a subset of cases with no clear diagnosis, revealing abnormalities in approximately 50 % of cases. Adrenocorticotropic hormone emerged as the most frequently prescribed antiseizure medication. CONCLUSION: This study provides insight into the diagnostic challenges associated with IESS and highlights the importance of metabolic investigations, especially in cases without a clear etiology. The findings emphasize the need for further genetic and metabolic studies to enhance prognostic accuracy and guide potential treatment options for children with IESS, particularly in populations with high rates of consanguinity.

Long-term clinical evaluation of patients with alpha-mannosidosis - A multicenter study.

BACKGROUND: Alpha mannosidosis is an autosomal recessive lysosomal storage disorder caused by biallelic pathogenic variants in the MAN2B1 gene. It manifests with clinical features, including intellectual disability, hearing impairment, coarse facial appearance, skeletal anomalies, immunodeficiency, central nervous system involvement, psychiatric comorbidities, corneal opacity, and hepatosplenomegaly. This multicenter study assesses the long-term outcomes of individuals diagnosed with alpha-mannosidosis, examining demographic, clinical, laboratory, and molecular characteristics. METHOD: Sixteen patients diagnosed with alpha-mannosidosis who presented to four pediatric metabolic units were included in the study. The patients' medical records were analyzed and data on demographics, clinical presentation and laboratory findings were recorded. RESULTS: Of the 16 patients (6 females, 10 males) with alpha mannosidosis included in the study, the mean age at the time of diagnosis was 79.4 ± 56.1 (16-208) months, and the mean diagnosis delay time was 57.9 ± 51.9 (4-181) months. Hearing loss was the primary manifestation found in seven out of 16 patients (43.8%), followed by speech delay in 37.8%. On clinical follow-up, 87.5% of patients experienced recurrent infections, mainly in the upper respiratory tract, with 12 requiring the use of a hearing aid. Hepatomegaly was found in six out of 13 patients who received abdominal ultrasonography; two out of 12 patients who underwent echocardiography were found to have mitral valve prolapse (16.6%). Upon neurological evaluation, five patients displayed no neurological manifestation. Delayed language development was observed in nine (56.3%) patients, intellectual disability in eight (50%) patients, and hypertonicity was identified in one (6.3%) patient with the severe form of the disease. Homozygous c.2477C>A (p.Ser826Ter) and homozygous c.967G>A (p.Glu323Lys) novel variants were detected in four patients and one patient, respectively. The most common variant observed in the study was c.2477C>A (p.Ser826Ter). CONCLUSION: The present study identified two novel MAN2B1 variants. An evaluation of the long-term outcome of alpha-mannosidosis, in which the early initiation of enzyme replacement therapy (ERT) may lead to a better clinical outcome, can permit a better analysis of the effect of ERT on the natural progression of the disease.

Is Ultrasonography a Reliable Approach for the Evaluation of Carpal Tunnel Syndrome in Patients With Mucopolysaccharidosis?

BACKGROUND: One of the most common causes of carpal tunnel syndrome (CTS) in childhood is mucopolysaccharidosis (MPS). While ultrasonography (US) can aid in the diagnosis of CTS in adult patients, there is limited experience of this in the pediatric group. We aimed to investigate the results of wrist ultrasonography, which may be a candidate alternative to electrophysiological examination. METHODS: The participants were evaluated for symptoms, physical examination findings, electrophysiological tests and grayscale US. CTS was diagnosed in accordance with the American Academy of Orthopedic Surgeons Management of Carpal Tunnel Syndrome: Evidence-Based Clinical Practice Guideline. RESULTS: Included in the study were 27 MPS patients aged 4.5-32 years and 30 healthy control subjects aged 4.3-26 years. Of the 54 wrists in the MPS group, 30 were diagnosed with CTS. The median cross-sectional area (CSA) at the proximal carpal tunnel, the CSA at the forearm, and the wrist-forearm ratio (WFR) were higher in the wrists of the MPS with CTS group than in those without CTS and the healthy control subjects. The WFR cutoff of ≥1.35, 56.6% (95% CI: 437.4-74.5) sensitivity, and 89.8% (95% CI: 81.0-95.5) specificity were consistent with a diagnosis of CTS (receiver operating characteristics analysis, area under the curve = 0.775, 95% CI: 0.673-0.877). CONCLUSION: Although the US provides results with unsatisfactory specificity and sensitivity, it is a candidate for further investigation for the diagnosis of CTS because it is an innovative, noninvasive, and more accessible method. WFR value may produce more meaningful results than wrist or forearm nerve area measurements.