Evaluation of clinical, laboratory, and molecular genetic features of patients with biotinidase deficiency.

Biotinidase deficiency (BD) is an autosomal recessive inherited metabolic disorder which results from the inability of biotin-dependent carboxylase enzymes to function due to the release and absorption of biotin, leading to neurological and cutaneous findings. In the present study, evaluation of demographic characteristics, clinical findings, laboratory results, molecular genetic characteristics, and genotype-phenotype correlations of cases with BD. Two hundred forty-seven cases were included in the study who were admitted to the Department of Pediatric Metabolism of Ankara Bilkent City Hospital after being identified with potential BD through the Newborn Screening Program (NBS), during family screening or based on suspicious clinical findings, or following the detection of a pathogenic variant in a BTD genetic analysis during the period of October 2020 and February 2022. The medical files of the cases were reviewed retrospectively. An analysis of the admission routes of all cases to our clinic revealed 89.5% NBS, 5.7% family screening, and 4.9% suspicious clinical findings suggestive of BD. Complete enzyme deficiency was identified in 19.8%, partial enzyme deficiency in 55.1%, and heterogenous enzyme deficiency in 9.7%. The most common pathogenic variants were c.1270G > C (p.Asp424His), c.410G > A (p.Arg137His), and c.38_44delGCGCTGinsTCC (p.Cys13Phefs*36) in BTD gene. The c.1270G > C variant was most common in patients with cutaneous symptoms. The c.410G > A and c.38_44delGCGCTGinsTCC variants were more common in the patients with neurological symptoms. The mean activity level in patients with the c.1270G > C homozygous variant was statistically significantly higher than the mean activity level in the c.1270G > C compound heterozygous patients and the activity level of patients without the c.1270G > C variant. The mean activity level in c.410G > A homozygous patients was statistically significantly lower than the mean activity level of the c.410G > A compound heterozygous patients and the activity level of patients without the c.410G > A variant. In the course of our study, four new pathogenic variants were detected, namely: c.190G > A (p.Glu64Lys), c.249 + 5G > T, c.228delA (p.Val77*), and c.682A > G (p.Ile228Val).     Conclusions: The present study has determined the clinical and genetic spectrum of a large group of patients with BD in a single center. The frequent mutations in our study were similar to those reported in literature, and four novel variants were also described. What is Known: • Biotinidase deficiency is an autosomal recessive, treatable inborn error of metabolism. Two hundred ninety-four pathogenic variants in the BTD gene have been identified and the c.1270G > C variant is the most frequent BTD gene mutation in both Turkey and around the world. What is New: • Four new pathogenic variants (c.190G > A, p.Glu64Lys; c.249 + 5G > T; c.228delA, p.Val77*; and c.682A > G, p.Ile228Val) have been identified. It is believed that the c.38_44delGCGGCTGinsTCC variant is more commonly seen in individuals with ocular issues; however, further genotype-phenotype correlations are needed.

Use of procalcitonin as a biomarker for sepsis in pediatric burns.

Infection and sepsis continue to be the leading cause of morbidity and death in burn injuries. Diagnosing sepsis in burns is challenging as signs and symptoms of sepsis are not specific and overlap with those related to the burn injury. While the use of procalcitonin (PCT) as a biomarker is recommended for diagnosing sepsis in burns, evidence for children with burns is scarce. In this study, we aimed to investigate the role of PCT in distinguishing sepsis in pediatric burns. A prospective observational study was conducted in a single pediatric burn unit. Children hospitalized with burns ≤ 30% of total body surface area were included while patients with chemical burn, inhalation injury, or concomitant chronic diseases were excluded. Patients were classified into three groups for sepsis, systemic inflammatory response syndrome (SIRS), or controls using the American Burn Association (ABA) criteria. The predictive role of C-reactive protein (CRP) and PCT was investigated for distinguishing sepsis. Seventy-two patients were included in the study. The median total body surface area (TBSA) size was 12% (2.0-28.5%), and the median abbreviated burn severity index (ABSI) score was 3 (2-7). The median length of burn unit stay was 9.5 days (1-59 days). Sepsis was diagnosed in 11 patients (15.2%), and SIRS was present in 23 patients (40.0%), whereas 38 patients (52.8%) had neither SIRS nor sepsis (control group). Receiver operating characteristic analysis revealed that CRP and PCT levels distinguished sepsis patients from non-sepsis patients while PCT had a higher positive predictive value (50.0% vs. 45.0%). Optimal cutoff values of CRP and PCT for distinguishing sepsis were 66.75 mg/L and 0.95 ng/mL. CONCLUSIONS: PCT levels could distinguish sepsis in children with burn injuries, performing better than CRP levels. Confirmatory studies are needed to evaluate the development of sepsis and the role of PCT in diagnosing sepsis in pediatric burn patients. WHAT IS KNOWN: • Even though there are excellent criteria for the diagnosis of infection and sepsis in children and several clinical parameters and biomarkers are being studied, it's difficult to diagnose burn wound sepsis in children. WHAT IS NEW: • Data from this study showed that procalcitonin levels performed better than CRP levels as a biomarker for distinguishing sepsis from systemic inflammatory response syndrome (SIRS) in children with burn injuries.

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.

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.

A Novel PUS1 Mutation in 2 Siblings with MLASA Syndrome: A Review of the Literature.

ABSTRACT: Myopathy, lactic acidosis, and sideroblastic anemia (MLASA) is a rare mitochondrial disorder characterized by MLASA. Variable features of this condition include failure to thrive, and developmental delay or intellectual disability. Additional symptoms consist of cognitive impairment, skeletal and dental abnormalities, delayed motor milestones, cardiomyopathy, dysphagia, and respiratory insufficiency. MLASA has previously been associated with mutations in pseudouridylate synthase 1 (PUS1) and YARS2. PUS1 encodes the nuclear PUS1 enzyme, which is located in both the nucleus and the mitochondria. PUS1 converts uridine into pseudouridine in several cytosolic and mitochondrial transfer RNA positions and increases the efficiency of protein synthesis in both compartments.In the present report, we report on 2 Turkish sisters 4 and 11 of years with an MLASA plus phenotype. Both patients have sideroblastic anemia, lactic acidosis, failure to thrive, developmental delay, and chronic diarrhea; in addition, the older sister has strabismus and skeletal anomalies. The sequencing of the PUS1 gene revealed a novel homozygous p.Glu311* mutation. The phenotype of the older sibling is also unique because of the strabismus and skeletal anomalies, when compared with her sister and other previously reported patients with MLASA. The structural differences in the nuclear versus mitochondrial isoforms of PUS1 and modifier genes may be implicated in the variability of the clinical presentations in MLASA. CONCLUSION: This report adds to the growing number of mutations causing complex clinical manifestations of MLASA including lactic acidosis, sideroblastic anemia, chronic diarrhea, and myopathy.

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.

ALG1-CDG: A Patient with a Mild Phenotype and Literature Review.

ALG1-congenital disorder of glycosylation (ALG1-CDG) is an autosomal recessive multisystem disease. We here present a patient with a mild phenotype of ALG1-CDG. A 15-month-old female was referred with hypotonia, failure to thrive, and developmental delay. At 8 months of age, failure to thrive, feeding difficulties and developmental delay became apparent, and an epileptic seizure was observed at 11 months of age. Progressive deterioration and swallowing difficulty were observed. A brain MRI revealed a widening of the cerebrospinal fluid spaces and ventricular system, and decreased protein C, protein S and antithrombin III levels were identified. The isoelectric focusing showed a type 1 pattern. A homozygous c.1076C>T (p.Ser359Leu) variant was found in the ALG1 gene. CDG should be taken into consideration in patients presenting with unexplained multisystem involvement.

Probable Miglustat-Induced Psychosis in a Child With Niemann-Pick Type C.

BACKGROUND: Niemann-Pick disease type C (NP-C) is a neurodegenerative lysosomal disease in which psychiatric symptoms, such as psychosis, can also be observed. Miglustat is indicated in cases with progressive neurological manifestations, and although there have been studies reporting that miglustat completely cures psychosis, it has been recently observed that miglustat may also trigger psychosis. We report on a rare case of probable miglustat-induced psychosis in a patient with NP-C. CASE: A 21-year-old female patient presented with a complaint of social isolation that started at the age of 6 years. During clinical follow-up, the patient's clinical progress deteriorated, and ocular apraxia, ataxia, seizures, and dementia developed at the age of 15 years. A genetic investigation was performed, and a homozygous p.P120S (c.358C > T) variant was detected in the NPC2 gene. Miglustat was initiated at the age of 15 years, and during the 6 months of treatment, psychotic symptoms such as unwarranted anger, suspiciousness, and delusions developed. Consequently, the miglustat was discontinued by the parents of the patient, and the psychosis completely disappeared. The patient has experienced no further psychotic episodes in the approximately 5.5 years following the discontinuation of therapy. CONCLUSION: Although a positive effect of miglustat on neurological and psychiatric symptoms has been reported, there exists a risk of psychosis being triggered. To the best of our knowledge, this is the first case of pediatric NP-C to develop psychosis after miglustat to be reported in literature. Further studies of such cases are needed to understand the impact of miglustat on psychiatric symptoms in NP-C.

Coexistence of Megaconial Congenital Muscular Dystrophy and Cystinuria: Mimicking Hypotonia-Cystinuria Syndrome.

Introduction: Hypotonia-cystinuria syndrome is a contiguous gene deletion syndrome that is characterized by hypotonia, developmental delay, and cystinuria type A. We present a male patient who was admitted to our center with clinical findings of hypotonia-cystinuria syndrome and diagnosed with megaconial congenital muscular dystrophy and cystinuria. Case Presentation: A 16-month-old male patient was admitted with complaints of restlessness and body laxity. It was stated that the patient had hypotonia and growth retardation at the age of 2 months. Physical examination revealed mild hypotonia, growth retardation, and development delay, while laboratory examinations identified elevated serum creatine kinase and elevated dibasic amino acid in urine analysis. Because of the findings of hypotonia, growth retardation, developmental delay, and cystinuria, hypotonia-cystinuria syndrome was considered as a differential diagnosis. However, by chromosomal microarray no contiguous deletion in region 2p21 was found, while a novel homozygous c.225-2A>T pathogenic variant in the CHKB gene and a c.1266_1267delGT heterozygous variant in the SLC7A9 gene inherited from the mother were identified with whole-exome sequencing. The co-occurrence of megaconial congenital muscular dystrophy and cystinuria, mimicking hypotonia-cystinuria syndrome, was confirmed. Conclusion: This case suggests that in countries with a high frequency of consanguineous marriage, even if the molecular genetic analysis results are not compatible with the clinical findings, it should be kept in mind that different genetic diseases may coexist.

A Patient with Recurrent Severe Hypoglycemic Attacks and Mitochondrial Complex III Deficiency, Nuclear Type 3: a Novel UQCRB Variant.

Common causes of hypoglycemia include hyperinsulinism, hormonal deficiencies, fatty acid oxidation disorders, and glycogen storage diseases; however, rare causes should also be considered for the condition. Mitochondrial complex III deficiency shows an autosomal recessive or a mitochondrial inheritance pattern. To date, mitochondrial complex III deficiency, nuclear type 3 attributable to a pathogenic variant of the UQCRB gene (MIM 615158) has been identified in only 2 pediatric patients; both presented with hypoglycemia and lactic acidosis. In this paper, we present a patient with mitochondrial complex III deficiency, nuclear type 3, UQCRB variant associated with acute hypoglycemia and lactic acidosis episodes. The male patient was admitted on the first day of life with tachypnea, metabolic acidosis, and hypoglycemia. Up to 10 years of age, he was admitted 7 times with abdominal pain, vomiting, and fever. His blood tests revealed hypoglycemia, metabolic acidosis, and hyperlactatemia. At 10 years of age, a whole-exome sequencing (WES) analysis was performed identifying a homozygous c.309_313delAGAAA (p.Glu104ArgfsTer10) pathogenic variant of the UQCRB gene. Once the common causes of hypoglycemia are excluded, it is essential to perform a WES analysis for other rare causes. Thus, rare disorders such as mitochondrial complex III deficiency can be diagnosed.

An Atypical Presentation of Mevalonate Kinase Deficiency in Response to Colchicine Treatment.

Mevalonate kinase deficiency (MKD) is a periodic fever syndrome. Nonsteroidal anti-inflammatory drugs, corticosteroids, and anakinra are the most common treatments. However, colchicine is considered insufficient in disease control. In this case report, we present an 8-month-old infant with an atypical presentation of MKD. She had recurrent fever episodes, diarrhea, and lethargy. Elevated mevalonic acid was not detected in the urine. However, the genetic investigation showed a novel pathogenic heterozygous c.925G>C (p.Gly309Arg) variant and a heterozygous c.1129G>A (p.Val377Ile) mutation in the MVK gene. The patient was treated with colchicine for 8 months. During treatment, no further fever episode had been observed. It should be kept in mind that mevalonic acid excretion may not be present in the urine with mild MKD. Colchicine may be a reasonable option in mild MKD patients for a longer duration of treatment due to favorable adverse event profiles.

A Case of Combined Oxidative Phosphorylation Deficiency 35 Associated with a Novel Missense Variant of the TRIT1 Gene.

Combined oxidative phosphorylation deficiency 35 (COXPD35) is a rare autosomal recessive disorder associated with homozygous or compound heterozygous mutations in the tRNA isopentenyltransferase (TRIT1) gene in chromosome 1p34.2. To date, only 10 types of allelic variants in the TRIT1 gene have been previously reported in 9 patients with COXPD35. Herein, we describe a case with a novel homozygous missense variant in TRIT1. A 6-year, 6-month-old boy presented with global developmental delay, microcephaly, intractable seizures, and failure to thrive. The other main clinical manifestations were intellectual disability, spastic tetraparesis, truncal hypotonia, malnutrition, polyuria and polydipsia, ketotic hypoglycemia, dysmorphic facial features, strabismus, bicuspid aortic valve, and nephrolithiasis. The detailed biochemical, radiological, and metabolic evaluations were unremarkable. Chromosomal analysis confirmed a normal male 46,XY karyotype and the array comparative genomic hybridization analysis revealed no abnormalities. We identified a novel homozygous missense variant of c.246G>C (p.Met82Ile) in the TRIT1 gene, and the variant was confirmed by Sanger sequencing. The present case is the first report describing strabismus, ketotic hypoglycemia, nephrolithiasis, and bicuspid aortic valve in TRIT1-related COXPD35. This study expands the genotype-phenotype spectrum of TRIT1-related COXPD35.

Serum biotin interference: A troublemaker in hormone immunoassays.

OBJECTIVES: Biotin therapy can affect the results of many immunoassay procedures. The present study investigates biotin's interference on 25-hydroxy vitamin D (25-OHD), parathyroidhormone (PTH) and thyroid-stimulating hormone (TSH) tests using four different assay systems and biotin neutralization. DESIGN AND METHODS: Enrolled in the study were 50 children diagnosed with biotinidase deficiency (BTD) undergoing treatment with biotin (5-20 mg/day) who were subjected to a series of analyses involving 25-OHD (Roche Diagnostics assays, Beckman Coulter assays, HPLC, LC/MS-MS), TSH, PTH (Roche Diagnostics assays, Beckman Coulter assays) and biotin (LC/MS-MS), before and after biotin neutralization with Streptavidin-coated magnetic particles (SMP). RESULTS: The median biotin concentration was found to be 175.2 [94.0-307.1] µg/L. There was no significant difference in the 25-OHD results before and after neutralization with the Beckman Coulter, HPLC and LC-MS/MS assays. In contrast, the median 25-OHD level was seen to decrease from 90.2 [35.9-105.3] ng/mL to 29.1 [22.6-37.6] ng/mL after neutralization with the Roche assay (p < 0.0001). While there was no statistically significant difference in the values recorded before and after neutralization in PTH analysis using Beckman assay, the median PTH levels increased from 7.8 [1.6-21.6] pg/mL to 28.2 [22.5-41.9] pg/mL after neutralization with the Roche assay (p < 0.0001). The cut-off values at which serum biotin interfered in the Roche assay PTH test, with 25-OHD levels determined as 51.4 µg/L and 62.9 µg/L, respectively. A significant increase was detected in the TSH levels analyzed with a Roche assay after neutralization (from 2.36 [1.85-3.00] mIU/L to 2.74 [1.93-3.70] mIU/L, p < 0.0001). CONCLUSIONS: The PTH, 25-OHD and TSH results were found to be affected by high biotin concentrations in Roche assays, leading to a risk of misdiagnosis, although SMP neutralization can suppress any such interference efficiently.

Unmet Needs of Children with Inherited Metabolic Disorders in the COVID-19 Pandemic.

OBJECTIVE: Crucial information is lacking on unmet needs of children with rare inherited metabolic disorders during the coronavirus disease 2019 pandemic from low- and middle-income countries. We aimed to identify the unmet needs of children with rare inherited metabolic disorders from Turkey. MATERIALS AND METHODS: In a cross-sectional observational design, all children with rare inherited metabolic disorders aged 0-18 years followed at Ankara University School of Medicine Department of Pediatrics Pediatric Metabolism Division were recruited and interviewed via phone calls. The Expanded Guide for Monitoring Child Development enabled assessment of unmet needs and environmental context during coronavirus disease 2019 pandemic. Step-wise logistic regression analysis was used to determine independent factors associated with unmet needs. RESULTS: The sample comprised 229 children (54.1% boys) with rare inherited metabolic disorders (36.7% diet-dependent disorders). Most common diagnoses were amino acid metabolism disorders (40.2%). Of all, 29.3% of the mothers reported depression, 25.3% loss of job of family members during the pandemic. All children had unmet needs: at least 73.0% in health care, 96.8% in education, 78.3% in special services/rehabilitation. Having significant developmental delay and/or disability (odds ratio = 2.31, 95% CI: 1.14-4.67) emerged as the only independent factor associated with unmet needs in health care. CONCLUSION: Children with rare inherited metabolic disorders and their families in Turkey experience unmet needs in many domains during coronavirus disease 2019 pandemic. Urgent action is needed to address the unmet needs of children with rare inherited metabolic disorders, especially those who has significant developmental delays and/or disabilities for this pandemic and possible future crisis.

Early neuroimaging findings of infants diagnosed with inherited metabolic disorders in neonatal period: A case-control study.

OBJECTIVE: Most IMDs are diagnosed in the neonatal period and have severe neurological findings. Neuroimaging plays an essential role in the diagnosis. We aim to investigate early cranial MRI findings of newborns suspected with IMDs to determine IMD-related neuroimaging patterns in the early infant period. METHODS: The medical records of a total of 195 infants with suspected IMDs were screened, and 56 patients who underwent a cranial MRI within the first three months of life were included in the study. The 56 patients were categorized into those diagnosed (Group I) and those not diagnosed (Group II) with IMDs. The patient's clinical findings and radiological imaging reports were extracted to a database. RESULTS: The most common IMDs were mitochondrial diseases, urea cycle disorders, and organic acidemias. In the cranial MRI evaluations, the T2-hyperintensity of white matter and the T2-hyperintensity of basal ganglia were higher in Group I. It was found that high lactate/lipid peaks on 1H-MRS (10.68 times), T2-hyperintensity of white matter (5.75 times), and T2-hyperintensity of the basal ganglia (5.71 times) were more likely to be identified in Group I. Furthermore, no difference was noted between the groups in terms of the diffusion restriction of white matter, basal ganglia, cerebellum, and brainstem, and no statistically significant difference was noted in the T2-hyperintensity of the cerebellum and the brainstem. CONCLUSION: Early neuroimaging findings are essential in evaluations of IMDs, so familiarity with neuroimaging findings is essential for diagnosis, especially in countries that lack an expanded neonatal screening program.

A Mild Phenotype of Mitochondrial DNA Depletion Syndrome Type 13 with a Novel FBXL4 Variant.

Mitochondrial DNA depletion syndromes (MDDS) are a group of rare genetic disorders caused by defects in multiple genes involved in mitochondrial DNA maintenance. Among these, FBXL4 gene variants result in encephalomyopathic mtDNA depletion syndrome 13 (MTDPS13), which commonly presents as a combination of failure to thrive, neurodevelopmental delays, encephalopathy, hypotonia, a pattern of mild facial dysmorphisms, and persistent lactic acidosis. To date, 53 pathogenic FBXL4 variants and 100 cases have been described in the literature. In the present case report, we report on a 4.5-year-old boy with MTDPS13 and a novel variant. The patient had a history of antenatal hydrocephalus, severe developmental delay and mental motor retardation with psychomotor delay, severe hypotonia, mild left ventricular hypertrophic cardiomyopathy, mild facial dysmorphism, and elevated lactate levels. Symptoms suggested mitochondrial myopathy; subsequently, whole-exome sequencing was performed and a novel homozygous variant FBXL4 (NM_012160.4): c.486T>G (p.Tyr162Ter) was identified. While most of the patients with FBLX4 gene mutation have severe clinical manifestation and die at a very young age, clinical progress of our case was milder than previously reported. MDDS are very rare and can present with many different clinical signs and symptoms. In this report, we identified a novel pathogenic variant in the FBXL4 gene. This report shows that patients with FBLX4 gene mutations may present with a milder clinical phenotype than previously reported.

Pyruvate carboxylase deficiency type C as a differential diagnosis of diabetic ketoacidosis.

OBJECTIVES: Type C pyruvate carboxylase (PC) deficiency is extremely rare, and has been described in only a few patients in literature to date. Herein, we present the case of a four-year-old patient admitted with diabetic ketoacidosis and diagnosed with type C PC deficiency based on clinical and biochemical findings. CASE PRESENTATION: A Turkish girl was referred to the intensive care unit at the age of three-years with a three-day history of vomiting and abdominal pain. Upon physical examination, the patient was found to be experiencing lethargy, dehydration, and Kussmaul breathing. Hyperglycemia, metabolic acidosis, and ketonemia were detected. Clinical and laboratory findings pointed to a prediagnosis of diabetic ketoacidosis. Intravenous fluid, bicarbonate, and insulin treatments were initiated. Elevated alanine and proline levels were recorded in plasma amino acid analysis, while urinary organic acid level analysis revealed increased lactate, pyruvate, 3-OH-butyrate, and acetoacetate levels. Whole exome sequencing revealed homozygous c.584C>T (p.Ala195Val) mutation in the PC gene. CONCLUSIONS: To date, there have been no reports in literature of type C phenotype patients manifesting with DKA. Our case is the first case with the type C phenotype to be admitted with clinical and laboratory findings of DKA.

A Fatal Case of Opioid Intoxication After Raw Poppy Plant Ingestion.

Papaver somniferum contains many opioids and is frequently used in agriculture. Both the intoxication and the withdrawal of opioids have a wide range of symptoms such as coma, depressed respiration and agitation. Here, a fatal case of opioid intoxication will be presented. A four-year-old female patient was admitted to the pediatric intensive care unit after ingesting raw poppy plants. She had shallow respiration, tachycardia, hypertension and muscle cramps. A high plasma opioid level was measured and bolus intravenous naloxone was administered which resulted in a brief gain of consciousness. She was intubated after a sudden respiratory depression and loss of consciousness 10 hours later. Naloxone infusion was started and continued for two days. She developed disseminated intravascular coagulation and was lost on day twelve. Raw plant ingestion proves difficult to treat since there is less information about the ingredients. Having no consensus on naloxone dosage and intrinsic complications such as hypo- and hypertension, redistribution, rhabdomyolysis and dysmotility disrupts naloxone administration. Ingestion of opioids as plants brings out different complications for the treatment course while deciding on naloxone dosage proves opioid intoxication difficult to treat.