Long-Term Experience with Anaphylaxis and Desensitization to Alglucosidase Alfa in Pompe Disease.

BACKGROUND AND OBJECTIVE: Pompe disease (PD) is an inherited lysosomal storage disease that progresses with glycogen accumulation in many tissues, due to the deficiency of the acid-alpha glucosidase enzyme. Recombinant alglucosidase alfa (rhGAA) is the only disease-specific treatment option, in the form of enzyme replacement therapy (ERT). Anaphylaxis can develop with rhGAA. There is no study evaluating anaphylaxis and its management in PD in the long term. We aimed to evaluate the development of anaphylaxis and rapid drug desensitization (RDD) with rhGAA in children with PD. MATERIALS AND METHODS: All children diagnosed and followed up in our institution with PD over 12 years between January 2009 and September 2021 were evaluated for development of anaphylaxis and RDD with rhGAA from medical records. RESULTS: Fourteen patients, 64% of whom were female and diagnosed with PD (1 juvenile, 13 infantile types) during the study period included in the study. The median age at diagnosis was 3.2 months (1-40 months). The median follow-up time of the patients was 20 months (1-129 months). Thirteen patients were given rhGAA, one died before ERT. Four (30.8%) patients developed moderate to severe anaphylaxis, and RDD was applied with rhGAA. A total of 390 RDDs have been performed so far without any serious breakthrough reactions during all RDDs. CONCLUSIONS: Anaphylaxis with rhGAA is not rare and RDD with rhGAA is safe and effective in the long term.

Hypophosphatasia: is it an underdiagnosed disease even by expert physicians?

INTRODUCTION: Hypophosphatasia (HPP) is caused by mutations in the ALPL that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (ALP). Clinical manifestations range from extreme life-threatening lethal forms to no signs or symptoms at all. MATERIALS AND METHODS: Consecutive 30,000 outpatients and inpatients with ALP data were screened retrospectively, out of which 1000 patients were found to have low levels of ALP more than once. Then, patients were evaluated for the symptoms and signs of HPP with further biochemical and genetic analyses. RESULTS: Thirty-seven patients who had severe musculoskeletal pain, recurrent fractures, and tooth anomalies were then screened with substrate and DNA sequencing analyses for HPP. It was determined that eight patients had variants in the ALPL gene. A total of eight different ALPL variants were identified in eight patients. The variants, namely c.244G > C (p.Gly82Arg), c.1444C > T (p.His482Tyr), c.1487A > G (p.Asn493Ser), and c.675_676insCA (p.Met226GlnfsTer52), had not been previously reported. DISCUSSION: Considering the wide spectrum of clinical signs and symptoms, HPP should be among the differential lists of bone, muscle, and tooth abnormalities at any age.

Beneficial Effects of Modified Atkins Diet in Glycogen Storage Disease Type IIIa.

INTRODUCTION: Glycogen storage disease Type III (GSD III) is an autosomal recessive disease caused by the deficiency of glycogen debranching enzyme, encoded by the AGL gene. Two clinical types of the disease are most prevalent: GSD IIIa involves the liver and muscle, whereas IIIb affects only the liver. The classical dietetic management of GSD IIIa involves prevention of fasting, frequent feeds with high complex carbohydrates in small children, and a low-carb-high-protein diet in older children and adults. Recently, diets containing high amount of fat, including ketogenic and modified Atkins diet (MAD), have been suggested to have favorable outcome in GSD IIIa. METHODS: Six patients, aged 3-31 years, with GSD IIIa received MAD for a duration of 3-7 months. Serum glucose, transaminases, creatine kinase (CK) levels, capillary ketone levels, and cardiac parameters were followed-up. RESULTS: In all patients, transaminase levels dropped in response to MAD. Decrease in CK levels were detected in 5 out of 6 patients. Hypoglycemia was evident in 2 patients but was resolved by adding uncooked cornstarch to diet. CONCLUSION: Our study demonstrates that GSD IIIa may benefit from MAD both clinically and biochemically.

Posterior fossa horns; a new calvarial finding of mucopolysaccharidoses with well-known cranial MRI features

Background/aim: Mucopolysaccharidoses (MPS) are a group of hereditary metabolic diseases. The aim of this study was to share the previously unreported calvarial finding of internal hypertrophy of the occipitomastoid sutures (IHOMS) together with some other well-known cranial MRI findings in this patient series. Materials and methods: A retrospective evaluation was conducted of 80 cranial MRIs of patients who had been diagnosed and followed up with MPS from 2008 to 2019 in our center. Of these patients, 11 had Hurler, 14 had Hunter, 24 had Sanfilippo, 15 had Morquio, 14 had Maroteaux­Lamy, and 2 had Sly disease. The cranial MRIs were assessed in two main groups as parenchymal intradural cranial MRI findings and extradural calvarial findings. Results: The most common parenchymal intradural cranial MRI findings were white matter signal alterations (n = 51, 63%) and perivascular space enlargements (n = 39, 48%). The most common extradural calvarial findings were J-shaped sella (n = 45, 56%) and tympanic effusion (n = 44, 55%). Although IHOMS was defined in a relatively small number of the patients (n = 12, 15%), the prevalence rate was high in MPS type I (n = 6, 54%). Conclusion: The abnormal cranial MRI findings of the MPS patients, including the newly identified IHOMS, may provide diagnostic clues to differentiate the type of the disease in radiological imaging.

The role of IFIH1 gene rs1990760 and rs2111485 single-nucleotide polymorphisms in generalized vitiligo predisposition

Background/aim: Interferon-induced helicase (IFIH1) is a gene locus that has been recently defined as a candidate for susceptibility to generalized vitiligo (GV). The objectives of this study were to assess the association of IFIH1 gene, rs2111485, and rs1990760 single-nucleotide polymorphisms (SNP) with susceptibility to GV and the autoimmune diseases accompanying GV. Materials and methods: We prospectively studied GV patients and frequency-matched healthy controls by age and sex. The genotypes of the participants were determined for rs1990760 and rs2111485 SNPs of IFIH1. Dominant, recessive, and additive models were evaluated for each SNP adjusted for age and sex. Results: The patients and their controls were observed to be in the Hardy­Weinberg equilibrium for SNP1 (2q24.2, rs1990760, IFIH1, T/C) and SNP2 (2q24.2, rs2111485, IFIH1, G/A), respectively (all P > 0.7). For SNP1, every T allel addition was significantly associated with 1.53 times protectiveness in terms of vitiligo risk (P = 0.033). As for SNP2, every G allel addition was associated with 1.42 times protectiveness, close to statistical significance (P = 0.100). Conclusions: We detected that for SNP1, each T allel and for SNP2, each G allel are protective in terms of vitiligo development. Hereby, we confirmed that IFIH1 gene locus has a role in GV susceptibility.

Early severe anemia as the first sign of cystic fibrosis.

UNLABELLED: Severe anemia is reported to occur rarely in patients with cystic fibrosis (CF). This study aimed to determine the factors associated with early severe anemia in infants with CF. This study included 231 infants with CF from 3 pediatric CF centers ten year period that were retrospectively reviewed in terms of severe anemia as the first sign of CF. Factors that could affect anemia, such as age, pancreatic insufficiency, mutations, vitamin A and E, and albumin level were evaluated. Clinical and laboratory findings in CF patients that presented with severe anemia and no respiratory symptoms were compared to those in CF patients that did not present with severe anemia. Severe anemia as the first sign of CF was noted in 17 of 231 patients. Patient age, prolonged PT/INR and the albumin level differed significantly between the 2 groups of patients (P < 0.001). Feeding pattern, pancreatic insufficiency, vitamin E and A levels, and the types of genetic mutations did not differ between the 2 groups. The mean hemoglobin level was 5.59 ± 0.21 g/dL and respiratory symptoms began a mean 6.3 months after diagnosis of CF in the anemia group. CONCLUSION: In early infancy severe anemia in the absence of respiratory symptoms can be the first sign of CF. CF should be considered in the differential diagnosis of severe anemia in infants. Anemia can occur several months before respiratory symptoms in patients with CF and may be caused due to several reasons. WHAT IS KNOWN: • Severe anemia as a first sign is reported to occur rarely in patients with cystic fibrosis. • Although anemia is well known in cystic fibrosis, factors that cause severe anemia are not known clearly. What is New: • This study shows the importance of severe anemia as the first sign of cystic fibrosis. • Anemia can occur several months before respiratory symptoms in patients with CF.

Home sleep study characteristics in patients with mucopolysaccharidosis.

BACKGROUND: Mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage disorders caused by the deficiency of hydrolases involved in the degradative pathway of glycosaminoglycans. In MPS, upper airway obstruction may result from multiple causative factors which may impact severely upon morbidity and mortality. METHODS: We evaluated upper airway obstructive disease and related clinical findings through home sleep study in 19 patients (11 with MPS VI, 4 with MPS I, 4 with MPS II) with MPS followed at Gazi University Pediatric Metabolic Unit. Patients underwent home-based sleep measurements, and sleep respiratory problems were asked in a detailed clinical history. Measurements of apnea, apnea-hypopnea index (AHI), hypopnea index, oxygen desaturation index, and minimal oxygen saturation were obtained through home sleep study. RESULTS: For 19 children, the disorder was normal in 1, mild (AHI=1.5-5/h) in 5, moderate (AHI=5-10/h) in 2, and severe (AHI>10/h) in 11. The prevalence of OSA was 94.7 % (18/19) in patients with MPS. Snoring, witnessed apnea, pectus carinatum, and macroglossia were the main clinical findings. Echocardiograms showed evidence of pulmonary hypertension in 13 patients. CONCLUSION: Home sleep study is a quick and accessible screening test to determine the abnormalities of breathing during sleep and enables clinicians to take necessary action for patients with severe manifestations.

Radiologic findings of Patterson-Lowry rhizomelic dysplasia in two sisters.

We report two sisters who have a rare skeletal abnormality termed Patterson-Lowry rhizomelic dysplasia. The typical findings of these cases on bone survey are isolated shortening and proximal metaphyseal enlargement and cupping of the bilateral humeri. The elder sister also has coxa vara deformity and dysplastic proximal femoral epiphyses on both sides. The younger sister has normal hip joint bones bilaterally, but her proximal femoral epiphyses are smaller than normal. All other bones of the sisters are of normal size and configuration. Our patients are two siblings, and their parents are first degree relatives, suggesting autosomal-recessive (AR) inheritance. The present patients help us to understand the genetic relationships and skeletal variabilities of this rare entity.

BCS1L gene mutation causing GRACILE syndrome: case report.

GRACILE syndrome is a rare autosomal recessive disease characterized by fetal growth retardation, Fanconi type aminoaciduria, cholestasis, iron overload, profound lactic acidosis, and early death. It is caused by homozygosity for a missense mutation in the BCS1L gene. The BCS1L gene encodes a chaperone responsible for assembly of respiratory chain complex III. Here we report that a homozygous mutation c.296C > T (p.P99L), in the first exon of BCS1L gene found in an affected 2-month-old boy of asymptomatic consanguineous parents results in GRACILE syndrome. This genotype is associated with a severe clinical presentation. So far no available treatments have changed the fatal course of the disease, and the metabolic disturbance responsible is still not clearly identified. Therefore, providing prenatal diagnosis in families with previous affected infants is of major importance. Mitochondrial disorders are an extremely heterogeneous group of diseases sharing, in common, the fact that they all ultimately impair the function of the mitochondrial respiratory chain. A clinical picture with fetal growth restriction, postnatal lactacidosis, aminoaciduria, hypoglycemia, coagulopathy, elevated liver enzymes, and cholestasis should direct investigations on mitochondrial disorder.

Advances in Immune Tolerance Induction in Enzyme Replacement Therapy.

Inborn errors of metabolism (IEMs) are a group of genetic diseases that occur due to the either deficiency of an enzyme involved in a metabolic/biochemical pathway or other disturbances in the metabolic pathway including transport protein or activator protein deficiencies, cofactor deficiencies, organelle biogenesis, maturation or trafficking problems. These disorders are collectively significant due to their substantial impact on both the well-being and survival of affected individuals. In the quest for effective treatments, enzyme replacement therapy (ERT) has emerged as a viable strategy for patients with many of the lysosomal storage disorders (LSD) and enzyme substitution therapy in the rare form of the other inborn errors of metabolism including phenylketonuria and hypophosphatasia. However, a major challenge associated with enzyme infusion in patients with these disorders, mainly LSD, is the development of high antibody titres. Strategies focusing on immunomodulation have shown promise in inducing immune tolerance to ERT, leading to improved overall survival rates. The implementation of immunomodulation concurrent with ERT administration has also resulted in a decreased occurrence of IgG antibody development compared with cases treated solely with ERT. By incorporating the knowledge gained from current approaches and analysing the outcomes of immune tolerance induction (ITI) modalities from clinical and preclinical trials have demonstrated significant improvement in the efficacy of ERT. In this comprehensive review, the progress in ITI modalities is assessed, drawing insights from both clinical and preclinical trials. The focus is on evaluating the advancements in ITI within the context of IEM, specifically addressing LSDs managed through ERT.

New perspectives for the treatment and follow-up of glycogen storage disease type V: DL-3-hydroxybutyric acid with modified Atkins diet and quadriceps femoris shear wave elastography.

OBJECTIVES: Glycogen storage disease type V is caused by the mutations in muscle glycogen phosphorylase gene. This is the first report which DL-3-hydroxybutyric acid was used in combination with modified Atkins diet for the treatment of a patient with glycogen storage disease type V and quadriceps femoris shear wave elastography was performed to evaluate the treatment efficacy. CASE PRESENTATION: A 13-year-old girl was referred with fatigue and muscle cramps with exercise and there were no pathological findings in physical examination. Creatine kinase levels with 442 U/L. No phosphorylase enzyme activity was detected in muscle biopsy, a homozygous c.1A>G (p.M1V) pathogenic mutation was found in PYGM gene. She was started on DL-3-hydroxybutyric acid and modified Atkins diet at age 16. Her walking and stair climbing capacity increased, the need for rest during exercise decreased. The stiffness of the quadriceps femoris exhibited a reduction. CONCLUSIONS: DL-3-hydroxybutyric acid and modified Atkins diet may provide an alternative fuel and shear wave elastography may be useful in demonstrating treatment efficacy. More clinical and pre-clinical studies are obviously needed to reach more definite conclusions.

Pterin Profiling in Serum, Dried Blood Spot, and Urine Samples Using LC-MS/MS in Patients with Inherited Hyperphenylalaninemia.

Background: Hyperphenylalaninemia (HPA) is defined as blood phenylalanine (Phe) levels exceeding the normal values (>120 µmol/L or >2 mg/dL) and is caused by a deficiency in the enzyme phenylalanine hydroxylase (PAH). The widespread screening of Phe levels in newborn screening programs has led to a very high number of patients with HPA. Methods: The samples were collected at various ages, not at the point of diagnosis. Nine pterin derivatives, including isoxanthopterin, sepiapterin, xanthopterin, primapterin, biopterin, neopterin, 7,8-dihydrobiopterin, 7,8-dihydroneopterin, and tetrahydrobiopterin (BH4), were analyzed in different HPA classes in serum, dried blood spots (DBS), and urine samples. A total of 18 patients, including six classical phenylketonuria (PKU), eight BH4-responsive PKU, and four mild HPA patients, were included in the study. Results: Among the nine pterin derivatives measured, a significant increase was observed in the levels of isoxanthopterin, biopterin, and 7,8-dihydrobiopterin in serum, dried blood spots (DBS), and urine samples of patients with HPA compared to the control group. However, elevations in isoxanthopterin, biopterin, and 7,8-dihydrobiopterin were observed in all HPA groups, although the extent of elevation varied among the different disease groups. There were also significant differences between HPA subgroups among these high values. Conclusion: In this study, it might be suggested that pterin profiling shows promising potential for its effective utilization in the differential diagnosis of HPA. Pterin profiling demonstrated its efficacy in accurately categorizing patients into distinct subtypes. This approach offers several notable advantages, including the ability to simultaneously screen multiple HPA subtypes through a single test, establish disease decision limits for pterins, shorten the time required for HPA differential diagnosis, reduce the risk of misdiagnosis, and increase overall diagnostic accuracy. This study is the most comprehensive study examining the association between HPA pterin in the literature. In our study, samples obtained from BH4-responsive PKU patients were on treatment. This may have affected the results. Preliminary findings on pterin profiles may need to be replicated in a prospective cohort of samples collected at the time of diagnosis to confirm the results.

Apheresis-inducible cytokine pattern change in children with homozygous familial hypercholesterolemia.

Familial hypercholesterolemia is a genetic disorder that leads to severe atherosclerosis related cardiovascular complications in young adults. Extracorporeal elimination is a method of LDL-lowering procedures effective in patients with homozygous or severe heterozygous FH utilized in cases. The recruitment of leucocytes into the arterial intima is dependent on a cascade of events mediated through a diverse family of adhesion molecules. Several pro-inflammatory adhesion molecules are cleared by various lipid apheresis methods. This study showed that, LDL-apheresis led to several changes in circulating inflammatory factors which induced antiinflammatory and antiatherogenic changes in the plasma profile in homozygous familial hypercholesterolemic patients.

Oxidized low-density lipoprotein levels and carotid intima-media thickness as markers of early atherosclerosis in prepubertal obese children.

OBJECTIVES: Children with obesity have a high cardiovascular risk and an impaired oxidant-antioxidant status, which may lead to endothelial dysfunction and increased carotid intima media thickness (IMT) even in childhood. The aim of this study was to investigate the circulating oxidized low-density lipoprotein (LDL) concentrations and the IMT of carotid arteries in prepubertal obese children, and also to search for its possible association with carotid atherosclerosis. METHODS: Twenty-seven prepubertal obese children (age, 7.48±2.05 years; boys, 59%) and 30 healthy children (age, 7.80±2.19 years; boys, 55%) were included in the study. Serum concentrations of oxidized LDL, total cholesterol, triglyceride, high-density lipoprotein, LDL, and glucose were measured, and carotid IMT was determined by ultrasound. RESULTS: Serum oxidized LDL levels were significantly higher in prepubertal obese children than in healthy children (p<0.01). No significant correlation was observed between oxidized LDL levels and carotid IMT measurements. However, a significant positive correlation was found between oxidized LDL levels and body mass index, total cholesterol, and LDL-cholesterol. CONCLUSION: Our findings revealed that the oxidation of LDL starts early in obese children but the carotid IMT is not significantly affected. Also, oxidized LDL levels are more strongly associated with obesity and dyslipidemia than the carotid IMT in prepubertal children.

Clinical characteristics of adult and paediatric patients with familial hypercholesterolemia: A real-life cross-sectional study from the Turkish National Database.

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is the most common cause of premature atherosclerotic cardiovascular disease (ASCVD). Türkiye is among the countries with the highest rate of ASCVD. However, no population-based study has been published so far on the prevalence of FH, demographic and clinical characteristics, burden of ASCVD, treatment compliance, and attainment of low-density lipoprotein cholesterol (LDL-C) targets. METHODS: We performed a study using the Turkish Ministry of Health's national electronic health records involving 83,063,515 citizens as of December 2021 dating back 2016. Adults fulfilling the diagnostic criteria of definite or probable FH according to the Dutch Lipid Network Criteria (DLNC), and children and adolescents fulfilling the criteria of probable FH according to the European Atherosclerosis Society (EAS) Consensus Panel report formed the study population (n = 157,790). The primary endpoint was the prevalence of FH. RESULTS: Probable or definite FH was detected in 0.63% (1 in 158) of the adults and 0.61% (1 in 164) of the total population. The proportion of adults with LDL-C levels >4.9 mmol/L (190 mg/dL) was 4.56% (1 in 22). The prevalence of FH among children and adolescents was 0.37% (1 in 270). Less than one-third of the children and adolescents, and two-thirds of young adults (aged 18-29) with FH were already diagnosed with dyslipidaemia. The proportion of adults and children and adolescents on lipid-lowering treatment (LLT) was 32.1% and 1.5%, respectively. The overall discontinuation rate of LLT was 65.8% among adults and 77.9% among children and adolescents. Almost no subjects on LLT were found to attain the target LDL-C levels. CONCLUSIONS: This nationwide study showed a very high prevalence of FH in Türkiye. Patients with FH are diagnosed late and treated sub-optimally. Whether these findings may explain the high rates of premature ASCVD in Türkiye needs further investigation. These results denote the urgent need for country-wide initiatives for early diagnosis and effective management of FH patients.

Hypercalcemia in glycogen storage disease type I patients of Turkish origin.

Glycogen storage disease type I (GSD I) is an autosomal recessive disorder caused by defects in the glucose-6-phosphatase complex. Deficient activity in the glucose-6-phosphatase-a (G6Pase) catalytic unit characterizes GSD IA and defects in the glucose-6-phosphate transporter protein (G6PC) characterize GSD IB. The main clinical characteristics involve fasting hypoglycemia, hyperuricemia, hyperlactatemia, and hyperlipidemia. Hypercalcemia arose as an unknown problem in GSD I patients, especially in those with insufficient metabolic control. The aim of the present study was to obtain the prevalence of hypercalcemia and to draw attention to the metabolic complications of GSD I patients, including hypercalcemia in poor metabolic control. Hypercalcemia frequency and the affecting factors were studied cross-sectionally in 23 GSD I pediatric subjects. Clinical diagnosis of GSD I was confirmed in all patients either through documentation of deficient G6Pase enzyme activity levels on liver biopsy samples or through G6PC gene sequencing of DNA. Hypercalcemia was detected in 78.3% of patients with GSD I. Different from the previous report about hypercalcemia in a GSD IA patient who had R83H and 341delG mutations, we could not identify any genotype-phenotype correlation in our GSD I patients. Hyperlactatemia and hypertriglyceridemia correlated significantly with hypercalcemia. Furthermore, no differences in serum calcium concentrations could be demonstrated between patients with optimal metabolic control. We observed hypercalcemia in our series of GSD I patients during acute metabolic decompensation. Therefore, we speculate that hypercalcemia should be considered as one of the problems of GSD I patients during acute attacks. It may be related with prolonged lactic acidosis or may be a pseudohypercalcemia due to hyperlipidemia that can be seen in GSD I patients with poor metabolic control.

Expected or unexpected clinical findings in liver glycogen storage disease type IX: distinct clinical and molecular variability.

OBJECTIVES: To reveal the different clinical presentations of liver glycogen storage disease type IX (GSD IX), which is a clinically and genetically heterogeneous type of glycogenosis. METHODS: The data from the electronic hospital records of 25 patients diagnosed with liver GSD IX was reviewed. Symptoms, clinical findings, and laboratory and molecular analysis were assessed. RESULTS: Of the patients, 10 had complaints of short stature in the initial presentation additionally other clinical findings. Elevated serum transaminases were found in 20 patients, and hepatomegaly was found in 22 patients. Interestingly, three patients were referred due to neurodevelopmental delay and hypotonia, while one was referred for only autism. One patient who presented with neurodevelopmental delay developed hepatomegaly and elevated transaminases during the disease later on. Three of the patients had low hemoglobin A1C and fructosamine values that were near the lowest reference range. Two patients had left ventricular hypertrophy. Three patients developed osteopenia during follow-up, and one patient had osteoporosis after puberty. The most common gene variant, PHKA2, was observed in 16 patients, 10 variants were novel and six variants were defined before. Six patients had variants in PHKG2, two variants were not defined before and four variants were defined before. PHKB variants were found in three patients. One patient had two novel splice site mutations in trans position. It was revealed that one novel homozygous variant and one defined homozygous variant were found in PHKB. CONCLUSIONS: This study revealed that GSD IX may present with only hypotonia and neurodevelopmental delay without liver involvement in the early infantile period. It should be emphasized that although liver GSDIX is thought of as a benign disease, it might present with multisystemic involvement and patients should be screened with echocardiography, bone mineral densitometry, and psychometric evaluation.

N-carbamylglutamate treatment for acute neonatal hyperammonemia in isovaleric acidemia.

Hyperammonemia occurs mainly in patients with branched-chain organic acidemias such as propionic, methylmalonic, and isovaleric acidemias. Its pathophysiological process is mainly via the competitive inhibition of N-acetylglutamate synthetase. Oral carglumic acid (N-carbamylglutamate) administration can correct hyperammonemia in neonates with propionic and methylmalonic acidemias, thus avoiding dialysis therapy. Isovaleric acidemia is an autosomal recessive disease of leucine metabolism due to deficiency of isovaleryl-CoA dehydrogenase. For the first time, we report a neonate with isovaleric acidemia, whose plasma ammonia concentration dropped dramatically after one oral load of carglumic acid. This experience suggests that carglumic acid could be considered for acute hyperammonemia resulting from isovaleric acidemia. However, trials with more patients are needed.

Analysis of acylcarnitine levels by tandem mass spectrometry in epileptic children receiving valproate and oxcarbazepine.

This prospective study was designed to investigate whether or not monotherapy with sodium valproate (VPA) or oxcarbazepine (OXC) affects plasma levels of fatty acylcarnitine esters in children with epilepsy. A total of 56 children with idiopathic partial or generalised epilepsy were included in the study. Patients were assigned to receive either VPA or OXC monotherapy. Free carnitine (C0) and acylcarnitine profiles of the patients were investigated using tandem mass spectrometry at baseline and at six and 18 months after commencement of therapy. For patients receiving VPA or OXC monotherapy, there were no significant differences in plasma levels of C0, compared with baseline, at six and 18 months (p>0.05). Treatment with VPA for six and 18 months correlated with a significant increase in 3-hydroxy-isovalerylcarnitine (C5-OH) (six months: +23%; 18 months: +73%), and significant decreases in the following acylcarnitines: C6-acylcarnitine (six months: -60%; 18 months: -66%), C14-acylcarnitine (six months: -25%; 18 months: -38%), C16-acylcarnitine (six months: -73%; 18 months: -73%), and C18:1-OH-acylcarnitine (six months: -60%; 18 months: -70%), compared with baseline (p<0.05). In patients receiving OXC monotherapy, on the other hand, plasma concentrations (µmol/L) of acylcarnitines (from C2 to C18:1-OH) fell within the normal reference range. The results of this study indicate that there are significant biochemical changes in acylcarnitines in ambulatory children on VPA monotherapy but these are not clinically significant. OXC monotherapy had no effect on acylcarnitine metabolism in ambulatory children.

Two patients from Turkey with a novel variant in the GM2A gene and review of the literature.

OBJECTIVES: GM2 gangliosidosis is a rare form of inborn errors of metabolism including Tay-Sachs disease, Sandhoff disease, and GM2 activator deficiency. GM2 activator protein deficiency is an ultra-rare form of GM2 gangliosidosis. To date, 16 cases of GM2 activator protein deficiency have been reported in the literature, and among them, 11 cases were the infantile form of the disease. Here we report the first two patients from Turkey with the infantile form of the disease with a novel likely pathogenic variant. CASE PRESENTATION: A boy of eight months old presented to the metabolic department with very mild neurological deterioration, although he had achieved early developmental milestones at the appropriate time. The parents also had a daughter who had lost skills progressively before one year of age. The boy was evaluated and bilateral cherry-red spots were found with no abnormality in either metabolic screening including ß-hexosaminidase or cranial magnetic resonance imaging. A novel homozygous likely pathogenic variant in GM2A was detected in a next-generation sequence panel revealing GM2 activator protein deficiency. His sister was investigated after he was diagnosed with GM2 activator deficiency and it was found that she had the same variant as her brother. CONCLUSIONS: This case report emphasizes that in the event of normal ß-hexosaminidase activity, GM2 activator protein deficiency could be underdiagnosed, and further molecular analysis should be performed. To the best of our knowledge, this boy is one of the youngest patient diagnosed with very mild symptoms. With this novel pathogenic variant, these patients have expanded the mutation spectrum of GM2 activator protein deficiency.