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OBJECTIVE: Metabolic syndrome is an increasingly common disorder, characterized by obesity, high low-density cholesterol level (LDL), triglyceride level (TG), and insulin sensitivity. It is known that both genetic and environmental factors play a role in the etiopathogenesis of metabolic syndrome. It has shown that the m.16189T>C variant that occurs mainly in mitochondrial DNA is associated with this disease. In this study, it was aimed to examine the clinical and laboratory findings of m.16189T>C change detected in patients who applied with suspected mitochondrial disease.MATERIAL AND METHODS: Patients with a change in m.16189T>C among the patients who came to our clinic with the suspicion of mitochondrial disease between 2019-2020 were included in the study. Mitochondrial DNA was isolated from peripheral blood because the clinical and laboratory findings of the patients were suspicious of mitochondrial disease. New generation DNA sequencing and whole mitochondrial genome DNA sequence analysis were performed and patients with m.16189T>C changes were determined and included in the study. Clinical and laboratory findings of these patients were examined in terms of metabolic syndrome.RESULTS: M.16189T>C variant was found in mitochondrial genome analysis in 11 of 55 patients (20%). In the physical examination findings, excessive weight and obesity were not detected in any of the patients. The glucose, LDL, and triglyceride levels of the patients were within the normal range.CONCLUSIONS: This change, which was detected at a high rate in our patient group, could not be associated with metabolic syndrome and was evaluated as a polymorphism. However, it can be predicted that the drugs used by these patients who had a suspicion of mitochondrial disease, their diet, and the pathophysiology of the disease may be the environmental factors affecting the metabolic syndrome., AMAÇ: Metabolik sendrom, obezite, yüksek düzeyde düşük yoğunluklu kolesterol düzeyi (LDL), trigliserit düzeyi (TG) ve insuline duyarlılık ile karakterize olan günümüzde sıklığı giderek artan bir bozukluktur. Metabolik sendromun etiyopatogenezinde hem genetik hem de çevresel nedenlerin rol oynadığı bilinmektedir. Özellikle mitokondriyal DNA’da oluşan m.16189T>C değişikliğinin bu hastalıkla ilişkili olduğu gösterilmiştir. Bu çalışmada mitokondriyal hastalık şüphesi ile başvuran hastalarda saptanan m.16189T>C değişikliğinin klinik ve laboratuvar bulgularının incelenmesi amaçlanmıştır.GEREÇ VE YÖNTEM: Kliniğimize 2019 - 2020 yılları arasında mitokondriyal hastalık şüphesi ile gelen hastalardan m.16189T>C değişikliği olan hastalar çalışmaya alınmıştır. Hastaların klinik ve laboratuvar bulguları mitokondriyal hastalık şüphesi taşıması nedeniyle periferik kandan mitokondriyal DNA izolasyonu yapılmıştır. Yeni nesil DNA dizileme ile tüm mitokondriyal genom DNA dizi analizi yapılarak m.16189T>C değişikliği olan hastalar saptanarak çalışmaya dahil edilmiştir. Bu hastaların klinik ve laboratuvar bulguları metabolik sendrom açısından incelenmiştir.BULGULAR: 1 yıllık süre içinde 55 hastanın 11’inde mitokondriyal genom analizinde m.16189T>C değişikliği saptanmıştır (%20). Fizik muayene bulgularında, hiçbir hastada fazla tartı ve obezite saptanmamıştır. Hastaların glukoz, LDL ve trigliserit düzeyleri normal aralıkta bulunmuştur.SONUÇ: Hasta grubumuzda oldukça yüksek oranda saptanan bu değişikliğin metabolik sendrom ile ilişkisi gösterilememiş ve polimorfizm olarak değerlendirilmiştir. Ancak mitokondriyal hastalık şüphesi ile gelen bu hastaların kullandığı ilaçların, beslenme şekillerinin ve hastalığın patofizyolojisinin bu metabolik sendromu etkileyen çevresel faktörler olabileceği ön görülebilir.

Objectives Fabry disease is an X-linked lysosomal disorder caused by decreased or absent alpha galactosidase enzyme. The enzyme deficiency leads to progressive accumulation of globotriaosylceramide (Gb-3) and its deacetylated form lyso-Gb3 in various tissue lysosomes that results in primarily lysosomal deterioration and subsequently mitochondrial, endothelial, and immunologic dysfunctions. Methods The endocrinological, metabolic, immunological and HLA status of 12 patients were evaluated. Results A total of 11 patients (91.6 %) had immunologic and/or endocrinologic abnormalities. fT4, anti-TPO, and anti-TG levels were increased in 1, 2, and 2 patients, respectively. Three patients had elevated proinflammatory cytokines. ANA profile, p-ANCA and c-ANCA were positive in 1, 1, and 2 patients, respectively. Tissue transglutaminase antibody was negative in all patients however P5 was diagnosed with Celiac disease at the age of 12 and on gluten free diet. All patients had distinct types of HLA apart from 2 patients with anti-TG and anti-TPO positive and there was no relationship between the HLA types and the autoimmunity biomarkers. Conclusions FD may have impact on endocrinologic and immunologic abnormalities even in the patients under ERT, therefore prevalence of these abnormalities may be higher in ERT naïve patients. However, apparently, they are less likely to cause clinical symptoms. Certain HLA alleles may contribute to the direct impact of immunological pathogenesis in FD by developing abnormal autoimmune biomarkers. To the best of our knowledge, this is the first study investigating HLA status of FD patients; therefore further studies are needed to elucidate the underlying mechanism of action.

Objectives Fructose 1,6 bisphosphatase (FBPase) deficiency is a rare autosomal recessively inherited metabolic disease. It is encoded by FBP1, and the enzyme catalyzes the hydrolysis of fructose-1,6-bisphosphate to fructose 6-phosphate. Patients with recurrent episodes of metabolic acidosis, hypoglycemia, hypertriglyceridemia, and hyperketonemia are present. Methods In this study, we describe the clinical, biochemical, and molecular genetic features of six unrelated Turkish patients from six different families who were genetically diagnosed with FBPase deficiency in our clinic between 2008 and 2020. Their clinical and laboratory data were collected retrospectively. Next-generation sequencing (NGS) was performed for the molecular genetic analysis. Results All patients were hospitalized with recurrent hypoglycemia and metabolic acidosis episodes. Three out of six patients were presented in the neonatal period. The mean age at diagnosis was 26 months. NGS revealed a known homozygous gross deletion including exon 2 in three patients (50%), a known homozygous c.910_911dupTT pathogenic variant in one patient (16%), a novel homozygous c.651_653delCAGinsTAA likely pathogenic variant, and another novel homozygous c.705+5G>A splice site variant. Leukocyte FBPase analysis detected no enzyme activity in the patient with homozygous c.705+5G>A splice site variant. Conclusions We identified two novel mutations in this study. One of them is a splice site mutation which is five bases downstream of the exon, and the other one is an indel mutation. Both of the splice site and indel mutations are exceedingly rare in FBP1, and to the best of our knowledge, there are second splice site and indel variants reported in the literature. Exon 2 deletion is the most common mutation consistent with the previous reports in Turkish patients. FBPase is a frequent cause of hypoglycemia and metabolic acidosis, and the widespread use of molecular genetic analysis would contribute to the enlightenment of advanced genetic factors and possible genotype/phenotype correlation.

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.

© 2022Background: Mevalonate kinase (MVK) plays a role in cholesterol and non-sterol isoprenoid biosynthesis and its deficiency-related diseases are caused by bi-allelic pathogenic mutations in the MVK gene, (MVK), which leads to rare hereditary autoinflammatory diseases. The disease may manifest different clinical phenotypes depending on the degree of the deficiency in the enzyme activity. The complete deficiency of the enzyme activity results in the severe metabolic disease called mevalonic aciduria, while a partial deficiency results in a broad spectrum of clinical presentations called hyper-immunoglobulin D syndrome (HIDS). Serum immunoglobulin (Ig) D and urine mevalonic acid levels may be increased during inflammatory attacks of HIDS. Case Presentation: Herein, for the first time in the literature, we present a 6-year-old male patient who suffered from recurrent episodes of fever, polyarthritis, skin rash, diarrhea, abdominal pain, and inflammatory bowel disease-like manifestations with elevated levels of serum IgD, and urine mevalonic acid. Eventually we detected compound heterozygous mutations in the phosphomevalonate kinase (PMVK) gene coding the second enzyme after mevalonate kinase in the mevalonate pathway. Conclusion: For patients presenting with HIDS-like findings, disease exacerbations and persistent chronic inflammation, and having high urinary mevalonic acid and serum IgD levels, raising suspicion in terms of MVK deficiency (MVKD), it is recommended to study all mevalonate pathway enzymes, even if there is no mutation in the MVK gene. It should be kept in mind that novel mutations might be seen such as PMVK gene.

Giriş ve Amaç: Siklik kusma sendromu (SKS) sık görülen gastrointestinal fonksiyonel bir düzensizliktir. Gastrointestinal fonksiyonel düzensizliklerin mitokondriyal polimorfizmlerle ilişkili olduğu gösterilmiştir. Bu çalışmada, m.3010G>A değişikliğini taşıyan hastalarda klinik bulguların incelenmesi amaçlanmıştır. Gereç ve Yöntemler: Kliniğimize mitokondriyal hastalık şüphesi ile gelen 55 hastadan, periferik kandan mitokondriyal DNA izolasyonu yapılmıştır. Yeni nesil DNA dizileme ile tüm mitokondriyal genom DNA dizi analizi yapılarak m.3010G>A değişikliği olan hastalar saptanmıştır. Bu hastalarda klinik bulgular incelenmiştir. Bulgular: Toplam 55 hastada yapılan mitokondriyal genom analizinde altı farklı hastada m.3010G>A değişikliği saptanmıştır. m.3010G>A değişikliği saptanan bu hasta grubunda SKS ile ilgili klinik bulgular saptanmamıştır. Sonuç: Daha önce yapılan çalışmalarda m.3010G>A değişikliğinin SKS ile ilişkili olabileceği gösterilmiş olsa da bizim çalışmamızda katılan hastalarda bu bulgular bulunmamaktadır. Yine de SKS’nin ileri yaşlarda da ortaya çıkabileceği göz önünde bulundurulmalı ve yakın takip edilmelidir.

Sanfilippo type B is a mucopolysaccharidosis (MPS) with a major neuronopathic component characterized by heparan sulfate (HS) accumulation due to mutations in the NAGLU gene encoding for alfa-N-acetyl-glucosaminidase. Enzyme replacement therapy for neuronopathic MPS requires efficient enzyme delivery throughout the brain in order to normalize HS, prevent brain atrophy and potentially delay cognitive decline.In this phase 1/2, open-label study, subjects (n=22) affected with MPS IIIB were treated with tralesinidase alfa administered intracerebroventricularly (ICV). Subjects were monitored for drug exposure, total HS and HS non-reducing end (HS-NRE) levels in both cerebrospinal fluid (CSF) and plasma, anti-drug antibody response, brain, spleen and liver volumes as measured by magnetic resonance imaging and cognitive development as measured by age-equivalent (AEq) scores.In the Part 1 dose escalation (30, 100, and 300 mg) phase, tralesinidase alfa 300 mg was necessary to achieve normalization of HS and HS-NRE in CSF and plasma. In Part 2, tralesinidase alfa 300 mg sustained HS and HS-NRE normalization in the CSF and stabilized cortical grey matter volume (CGMV) over 48 weeks of treatment. Resolution of hepatomegaly and reduction in spleen volume were observed in most subjects. Significant correlations were also established between change in cognitive AEq and plasma drug exposure, plasma HS-NRE level and change in CGMV.ICV administration of tralesinidase alfa effectively normalized HS and HS-NRE as a prerequisite for clinical efficacy. Peripheral drug exposure data suggests a role for the glymphatic system in altering tralesinidase alfa efficacy.gov: NCT02754076.

Aim:Gaucher disease (GD) is the most prevalent hereditary lysosomal storage disorder, affecting multiple organ systems. It is characterized by a deficiency of the enzyme glucocerebrosidase leading to an accumulation of glucosylceramide in lysosomes. The majority of patients present with hepatosplenomegaly, anemia, thrombocytopenia, bleeding tendencies, skeletal pathologies, growth retardation and in severe cases pulmonary disease. The bone manifestations include bone infarcts, avascular bone necrosis, lytic lesions, osteopenia and osteoporosis. This article gives an overview of the bone manifestations of 20 GD patients and reviews the current literature.Materials and Methods:The data of 20 patients with GD who were being followed up in Gazi University Hospital Pediatric Metabolism Unit were retrospectively evaluated. Their demographic information including age, gender, clinical findings, enzyme replacement therapy (ERT) status and duration were recorded. Laboratory analyses including serum calcium, phosphorus, vitamin D, the presence of skeletal findings, and bone mineral density (BMD) Z scores were collected from the patient files. The BMD status of patients was compared with their pre-treatment values.Results:The main symptoms of referral were abdominal distention, cytopenia, bleeding tendency and skeletal findings. All patients had skeletal symptoms. Nineteen patients showed vitamin D deficiency. The medullary involvement of femur and vertebrae was present in 14 (70%), Erlenmeyer flask deformity in 3 (15%), and avascular necrosis in one (5%) patient. Also, one patient (5%) had lytic bone lesions. Ten patients showed osteoporosis (50%), and 8 showed osteopenia (40%) at the time of diagnosis, before the initiation of ERT. The rate of osteoporosis was determined to be 40%, and osteopenia was 35% within the study group after the initiation of ERT.Conclusion:Physicians, including pediatricians, may be unfamiliar with bone pathophysiology and the complexity of the skeletal manifestations of GD. There is a need to enhance awareness and to improve the diagnosis and treatment of skeletal pathology in patients with GD.

The pathophysiology of congenital defects of glycosylation (CDG) is complex and the diagnosis has been a challenge because of the overlapping clinical signs and symptoms as well as a large number of disorders. Isoelectric focusing of transferrin has been used as a screening method but has limitations. Individual enzyme or molecular genetic tests have been difficult to perform. In this study, we aimed to describe CDG patients who were referred to from different departments either without a preliminary diagnosis or suspected to have a genetic disorder other than CDG. The patients were diagnosed mainly with a 450 gene next-generation DNA sequencing panel for inborn errors of metabolism, which also included 25 genes for CDG. A total of 862 patients were investigated with the panel, whereby homozygous (10) or compound heterozygous (4) mutations were found in a total of 14 (1.6%) patients. A total of 13 different mutations were discovered, 10 of them being novel. Interestingly, none of the patients was suspected to have a CDG before referral. This report expands the clinical/laboratory findings in patients with CDG and stresses on the fact that CDG should be in the differential list for pediatric patients presented with nonspecific dysmorphic features and neurological delays/regression. Also, next-generation DNA sequencing with panel approach was noticed to have a significant diagnostic potential in patients presented with nonspecific neurologic and dysmorphic findings.

Objectives Familial hyperphosphatemic tumoral calcinosis is a rare disorder characterized by hyperphosphatemia with recurrent ectopic periarticular calcifications, in addition to other visceral and vascular manifestations, without any inflammatory or neoplastic disorder. The available treatment strategies are limited. Here we report an eight year old female patient with recurrent lesions under the chin, and bilateral hips which are painful and improving of the size of the lesions and hyperphosphatemia. Case presentation The patient was started to the treatment with peroral acetazolamide however the lesion did not regress but a new lesion appeared then we added sevelamer and topical sodium thiosulfate treatment for three months. After the three months of the combination treatment the lesions, there were no pain, no hyperphospahtemia regression/disappearance of the lesions. Conclusions This combination treatment or topical sodium thiosulfate use only may be a novel treatment strategy for the patients prospective controlled trials are needed.

Genetic factors play a major role in the etiopathogenesis of attention-deficit/hyperactivity disorder (ADHD). In this study, we aimed to investigate the relationship between the CDH13 (rs6565113, rs11150556) and LPHN3 (rs6551665, rs6858066, rs1947274, rs2345039) gene polymorphisms and ADHD. We also sought to examine possible relationships between these polymorphisms and the clinical course and treatment response in ADHD. A total of 120 patients (79% boys), aged 6 to 18 years, newly diagnosed (medication-naïve) with ADHD according to the DSM-5 and a group of 126 controls (74% girls) were enrolled in the study. We examined the association between the aforementioned polymorphisms and ADHD. Univariate and multivariate logistic regression analysis were used to evaluate factors influencing the treatment response of ADHD. A significant difference was found between ADHD and control groups in terms of genotype distribution of the LPHN3 rs6551665 and rs1947274 polymorphisms. The results also showed that having the GG genotype of rs6551665 and CC genotype of rs1947274 of the LPHN3 gene was associated with risk for ADHD, and this relationship was more prominent in male participants. In the multivariate logistic regression model established with variables shown to have a significant relationship with treatment response, the presence of the GG genotype of the LPHN3 rs6551665 polymorphism and high severity of ADHD assessed by CGI-S were associated with poor response to treatment. This study is the first study to investigate the relationship between ADHD and these polymorphisms among Turkish adolescents. Our results imply that the LPHN3 rs6551665 and rs1947274 polymorphisms have a significant effect on ADHD in a Turkish population, and support previous observations that the presence of the GG genotype of the LPHN3 rs6551665 polymorphism may be associated with poor response to treatment in ADHD.

This study evaluated the nutritional status of Syrian refugees in the early adolescent period living in different vulnerable settings. Nutritional assessment of Syrian refugee adolescents is often neglected but essential for a healthy physical, pubertal and mental development. Growth parameters of Syrian refugee adolescents going to a public school in an urban area and in a temporary protection center (TPC) were recorded along with the Turkish adolescents. Stunting percentages were similar between the groups (p = 0.811). While the proportion of children with a BMI over 85th percentile were significantly higher among Syrian adolescents living in TPC, Turkish children have the highest percentage of underweight (p = 0.01). Both food insecurity and unhealthy weight gain continue to be major concerns for refugee adolescents after their resettlement to a host country. The findings suggest that nutritional assessment and intervention at early adolescence is critical for Syrian refugees depending on their living conditions.

Objectives Enzyme replacement therapy (ERT) with alglucosidase alfa (rhGAA) has changed the fatal course of infantile Pompe disease, however, development of anti rhGAA antibodies and infusion-associated reactions (IAR) restrict the tolerability and effectiveness of the treatment. Case presentation We describe a successful concomitant immune tolerance induction (ITI) and desensitization protocols in a cross-reactive immunologic material (CRIM) negative 7-month-old male patient. At the age of 5 months and eighth dose of the ERT, the patient developed IAR and his rhGAA specific IgE was negative however, his rhGAA specific IgG titer was as high as 12,800. ITI therapy to suppress antibody formation and a desensitization protocol was devised to be given concomitantly. At the end of 5-week therapy, his fatigue and weakness improved profoundly and a control antidrug antibody level decreased at 800. At the time of the patient’s follow up, he was still on ERT with desensitization at the age of 15 months without any reactions. Conclusions This is the first report in the literature applying concomitant ITI and desensitization protocols in a CRIM negative infantile-onset Pompe disease patient successfully, hence the importance of the case.

To characterize the longitudinal natural history of disease progression in pediatric subjects affected with mucopolysaccharidosis (MPS) IIIB.Sixty-five children with a confirmed diagnosis of MPS IIIB were enrolled into 1 of 2 natural history studies and followed for up to 4 years. Cognitive and adaptive behavior functions were analyzed in all subjects, and volumetric magnetic resonance imaging analysis of liver, spleen, and brain, as well as levels of heparan sulfate (HS) and heparan sulfate nonreducing ends (HS-NRE), were measured in a subset of subjects.The majority of subjects with MPS IIIB achieved an apex on both cognition and adaptive behavior age equivalent scales between age 3 and 6 years. Development quotients for both cognition and adaptive behavior follow a linear trajectory by which subjects reach a nadir with a score25 for an age equivalent of 24 months by age 8 years on average and by 13.5 years at the latest. All tested subjects (n = 22) had HS and HS-NRE levels above the normal range in cerebrospinal fluid and plasma, along with signs of hepatomegaly. Subjects lost an average of 26 mL of brain volume (-2.7%) over 48 weeks, owing entirely to a loss of cortical gray matter (32 mL; -6.5%).MPS IIIB exists along a continuum based on cognitive decline and cortical gray matter atrophy. Although a few individuals with MPS IIIB have an attenuated phenotype, the majority follow predicted trajectories for both cognition and adaptive behavior.ClinicalTrials.gov identifiers NCT02493998, NCT03227042, and NCT02754076.

ObjectiveThere is no applicable and easy procedure to screenoxidative stress in mucopolysaccaridosis (MPS)patients. The aim herein was to show the antioxidativeproperties of free carnitine (FC) and propionylcarnitine(PC) with respect to oxidative markers in MPS anduse a simple and easy method in patient follow-up.Material and MethodsFC and PC were studied as an antioxidativemarker using tandem mass spectroscopy andmalondialdehyde (MDA) was studied as an oxidativemarker in 27 MPS patients and 24 healthy volunteers.ResultsWhile the PC and FC levels were significantlydecreased, the MDA levels were higher in theMPS patients than in the healthy volunteers.Whencompared between the enzyme-treated MPS patientsand untreated MPS patients, there were no significantdifferences between the groups. MDA was found toinversely correlated with PC (r =–0.402, P=0.003).Itwas noteworthy that PC had a significant correlationwith MDA.ConclusionThe findings revealed that the affected patients hadhigher MDA levels and lower PC and FC levels,indicating an imbalance through the oxidative side. Anapplicable method of FC and PC measurement couldbe used to screen patients, considering them as newantioxidative markers in the patient follow-up periodfor the response of enzyme replacement therapy and/or antioxidant drugs., AmaçMukopolisakkaridoz (MPS) hastalarında oksidatifstresi taramak için uygulanabilir ve kolay bir prosedürmevcut değildir. Bu çalışmada amaç, MPS'deki oksidatifbelirteçlere göre serbest karnitin (SK) ve propiyonilkarnitinin(PK) antioksidatif özelliklerini göstermekve hasta takibinde basit ve kolay bir yöntem olarakkullanmaktır.Gereç ve YöntemÇalışmaya, 27 MPS hastasında ve 24 sağlıklı gönüllüdahil edilerek bu hastalarda SK ve PK, antioksidatifbelirteç olarak tandem kütle spektroskopisi kullanılarakçalışıldı ve malondialdehit (MDA), ise oksidatifbelirteç olarak kullanıldı.BulgularMPS hastalarında, PK ve SK seviyeleri önemli ölçüdeazalırken, MDA seviyeleri sağlıklı gönüllülere göredaha yüksek bulundu. Enzim yerine koyma tedavisialan MPS hastaları ile tedavi edilmeyen MPS hastalarıkarşılaştırıldığında, gruplar arasında anlamlı bir farksaptanmadı. Çalışma, MDA'nın PK ile anlamlı orandaters orantılı olduğu bulundu (r = –0.402, P = 0.003).PK'nin MDA ile anlamlı bir korelasyona sahip olmasıdikkat çekiciydi.SonuçMPS hastalarının daha yüksek MDA düzeylerine vedaha düşük PK ve SK düzeylerine sahip olduğunugöstermiştir, buna göre MPS hastalarının oksidatifyönde bir dengesizliğe sahip olduğunu ortaya koymuştur.PK ve SK, MPS hastalarının takibinde uygulanabilirbir yöntem olabilir ve hastaların enzim yerinekoyma ve/veya antioksidan ilaçların tedavilerinin cevabınıngözlemek için yeni biyobelirteçler olarak kullanılabilir.

Fructose 1,6 bisphosphatase (FBPase) deficiency is a rare autosomal recessively inherited metabolic disease. It is encoded byIn this study, we describe the clinical, biochemical, and molecular genetic features of six unrelated Turkish patients from six different families who were genetically diagnosed with FBPase deficiency in our clinic between 2008 and 2020. Their clinical and laboratory data were collected retrospectively. Next-generation sequencing (NGS) was performed for the molecular genetic analysis.All patients were hospitalized with recurrent hypoglycemia and metabolic acidosis episodes. Three out of six patients were presented in the neonatal period. The mean age at diagnosis was 26 months. NGS revealed a known homozygous gross deletion including exon 2 in three patients (50%), a known homozygous c.910_911dupTT pathogenic variant in one patient (16%), a novel homozygous c.651_653delCAGinsTAA likely pathogenic variant, and another novel homozygous c.705+5GA splice site variant. Leukocyte FBPase analysis detected no enzyme activity in the patient with homozygous c.705+5GA splice site variant.We identified two novel mutations in this study. One of them is a splice site mutation which is five bases downstream of the exon, and the other one is an indel mutation. Both of the splice site and indel mutations are exceedingly rare in

BACKGROUND COVID-19 pandemic caused significant modifications such as limiting the number of residents in the clinics, cancelling elective surgical procedures, stopping face to face practical education, and transforming theoretical education into distance learning platforms resulted in alterations in the curriculum. OBJECTIVE We addressed to assess the situation of trainees’ education using an online questionnaire from the trainees’ and directors’ perspective during the pandemic. METHODS The survey platform SurveyMonkey® was used to distribute the survey and to collect responses. We generated a list of multiple-choice questions about how social distancing affected the delivery of medical education, potential compromise in core training and difficulties in conducting clinical research for the thesis. RESULTS A total of 364 trainees among 552 (65.9%) under training at our university hospital and 90% of the directors (37 of 41) responded the survey. Almost 78 percent of the trainees claimed that they have been negatively affected during the pandemic. Although majority of the trainees (60,3%) reported that extension of their education program is not necessary, most of the program directors were in tendency of extending the duration of the speciality training period. The participants predominantly considered that online training would keep on being a part of the training program after the pandemic. CONCLUSIONS Education programs are negatively affected during pandemics. However, authorities should manage this deficiency by a new perspective since present trainees are familiar to use technology-driven virtual sources for their education. After the pandemic, computer-assisted online learning and web-based programs should be integrated into educational curriculum. CLINICALTRIAL The study was approved from the institutional review board of Gazi University Ethics Committee (Approval Number: 2021-276).

Fabry disease results from deficiency of the lysosomal enzyme alpha-galactosidase A. The families of 11 index cases were screened by enzyme and molecular assays. Further clinical and laboratory investigations were carried out in all cases. Including 33 new patients, a total of 28 females (Age 25,82 ± 12,1 Range 8–46) and 16 males (Age 24,56 ± 15,04 Range 2–48) were investigated. Ten different disease-causing variants were found two of them being novel. One patient had co-existing familial mediteranian fever, one had celiac disease and three had rheumatological disorders. Lipoprotein (a) levels were elevated in 17,6%, homocysteine in 22,2%, total and low density cholesterol in 12% and antithrombin 3 levels were elevated in 13,3%. One patient was found to be heterozygous for prothrombin p.G20210A disease-causing variant (5,8%) and two for factor V Leiden disease-causing variant (11,7%). Anticardiolipin IgM antibody was found to be positive in 11,7%. The patients with abnormal cranial imaging were also noticed to have additional risk factors for thrombosis. This study provides the largest data about Fabry patients from Turkey and implies that co-existing risk factors unrelated to Fabry Disease have significant association with the presence of clinical symptoms in females and might cause an early and severe clinical course in males.

Glycogen storage disease type 1a (GSD1a) is an autosomal recessively inherited inborn error of metabolism caused by a mutation in the G6PC gene, which encodes the catalytic subunit of glucose-6-phosphatase-α (G6Pase-α) enzyme. This enzyme plays a role in the final step of gluconeogenesis and glycogenolysis. Patients carrying GSD1a show growth retardation, hypoglycemia, hepatomegaly, hepatic steatosis, hyperlipidemia, hyperuricemia and lactic acidemia. Long-term symptoms include gouty arthritis and uric acid stones, osteoporosis, renal failure, intestinal impairment, cirrhosis and hepatic adenomas, and eventually, hepatocellular carcinoma. Hyperlipidemia is the indicator of poor metabolic control in GSD1a. Patients with variable levels of triglycerides (TGs) have been reported in the literature. We present a case of GSD1a that presented with severe hypertriglyceridemia (HTG) mimicking familial chylomicronemia syndrome.

BACKGROUND The ketogenic diet (KD) is a low-carbohydrate, high-fat diet that has been used as an effective nonpharmacological treatment in many neurological and metabolic disorders for a long time. The effectiveness of the KD is revealed in mitochondrial disorders, mainly in pyruvate dehydrogenase deficiency. CASE REPORT A 4-year-old girl who was diagnosed with an F-box and leucine-rich repeat protein 4 (FBXL4) gene mutation was hospitalized with sepsis. She was first given standard parenteral nutrition (PN) because of gastrointestinal problems. During the disease course, lactic acidosis became prominent and did not respond to pharmacological treatment; standard PN was gradually switched to parenteral KD, and lactate levels decreased after parenteral KD. The patient was discharged with an enteral KD. CONCLUSION This is the first case of mitochondrial depletion syndrome effectively treated with parenteral KD for lactic acidosis.

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 β-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 β-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.

Background: Malnutrition is a serious childhood problem and has been shown to have negative effects on organ sizes in animal studies. Hence, specific size ranges must be determined for solid organs such as the liver in malnourished children. We observed that liver dimensions were interpreted within normal limits radiologically in malnourished children with hepatomegaly on physical examination. Thus, we aimed to show the possibility of differences in clinical and radiological interpretations in malnourished children and to establish the normal radiological dimensions of the liver according to the degree of malnutrition. Methods: Our study was conducted in patients aged 3 months to 3 years with malnutrition and imaging records between January 2008 and March 2020. Interpretations of physical examination results and radiological organ sizes were compared in malnourished children who had hepatomegaly on physical examination. Findings: We identified the inconsistency between the physical examination and radiological findings in detecting hepatomegaly in malnourished patients with hepatomegaly on physical examination. In our study, malnourished children with hepatomegaly but no liver-related diseases were examined, and new percentage values were determined for the radiological dimensions of the liver to be used in evaluating such children (The Gazi-PULSAM Liver Scale). Interpretation: No study has compared physical examination and imaging methods in malnourished children. The normal ranges of liver sizes were defined radiologically using the The Gazi-PULSAM Liver Scale for malnourished children. The Gazi-PULSAM Liver Scale has been shown to be more sensitive in terms of radiological evaluation of hepatomegaly in malnourished children with hepatomegaly on physical examination. Funding: None to declare. Declaration of Interest: The authors declare no conflict of interest. Ethical Approval: This study was approved by Gazi University Clinical Research Ethics Committee.

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.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 β-hexosaminidase or cranial magnetic resonance imaging. A novel homozygous likely pathogenic variant inThis case report emphasizes that in the event of normal β-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.

In this study, the aim was to examine patients with inborn errors of metabolism (IEM) who presented with only autism, without any other findings, to suggest any other neurological and genetic disorders. To investigate IEM, data of the hospital records of 247 patients who were referred from pediatric psychiatric to pediatric metabolism outpatient clinics due to further evaluation of autism spectrum disorders (ASD) were examined. Among them, 237 patients were evaluated for IEM leading to ASDs. Organic acidemias, phenylketonuria, tetrahydrobiopterin and neutrotransmitter disorders, biotinidase deficiency, Smith-Lemni-Opitz syndrome, disorders of cerebral creatine metabolism, urea cycle defects, homocystinuria, purine-pyrimidine metabolism disorders, mitochondrial disorders, cerebrotendinous xantomatosis, mucopolysaccaridosis, and glucose 6 phosphate dehydrogenase deficiency were screened with complete blood counts, complete biochemical analyses, homocysteine levels, an arterial blood gase, and metabolic investigations. Six patients were diagnosed as follows: one with phenylketonuria (PKU), one with cerebral creatine deficiency, one with hypobetalipoproteinemia, one with glycogen storage disease type IX-a, one with dihydropyrimidine dehydrogenase deficiency, and one with succinic semialdehyde dehydrogenase deficiency (SSADHD). Forty-six patients screened for IEM were from consanguineous families, among them, one was diagnosed with FKU and the other was with SSADHD. It would not be expected to find PKU in a 5-year-old patient as a result of newborn screening, but she could not been screened due to being a refugee. The diagnosed diseases were rare presentations of the diseases and furthermore, the diagnosis of hypobetalipoproteinemia and glycogen storage disease type IX-a were surprising with the only presentation of ASDs. LAY SUMMARY: It is well-known that some types of inborn errors of metabolism (IEM) may present with that of autism spectrum disorders (ASDs). This study suggests that in countries where consanguinity marriages are common such as Turkey and refugees whose escaped from neonatal screening are present, patients with ASD should be screened for IEMs. The results can surprise the physicians with a very rare cause of autism that has never been thought. Autism Res 2021, 14: 887-896. © 2021 International Society for Autism Research, Wiley Periodicals LLC.

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. 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. 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. 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.

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.

Aim: Coronary heart disease is one of the most common causes of death around the world. The pathological process of coronary heart disease like atherosclerosis starts in childhood. During this period thrombosis constitutes a high-risk factor. In this study, we investigated the effect of soluble CD40 ligand (sCD40L) and clotting activation on children and adolescents with hypercholesterolemia. Materials and Methods: Plasma levels of sCD40L, P-selectin, 8-hydroxy-2-deoxyguanosine (8-OHdG), and prothrombin fragment 1+2 [(F) 1+2] were determined in thirty-five hypercholesterolemic patients (20 girls and 15 boys; age, median: 13 years) and forty healthy normocholesterolemic subjects (28 girls and 12 boys; age, median: 13 years). Results: No significant differences were observed between the patient group and controls in terms of age, high-density lipoprotein (HDL) cholesterol, 8-OHdG, F1+2 (p>0.05). However, there were significant differences between the two groups with respect to total cholesterol, low-density lipoprotein (LDL) cholesterol, very LDL cholesterol, triglycerides, sCD40L and P-selectin (p0.05). Conclusion: We believe that future prospective studies to determine the increase in the level of sCD40L with a larger sample size of a pediatric population with dyslipidemias may be more helpful in predicting the risk of cardiovascular disease.

Citrullinemia type 1 (CTLN1) is a rare inherited urea cycle disorder, which resulted from the deficiency of argininosuccinate synthetase enzyme. We presented an infant who was hospitalized because of acute losses of tonus and cyanotic hypoventilation attacks lasting approximately 4-5 min. The physical and neurological examinations were normal. Ammonia level was in the normal range. Citrulline levels increased in both blood and urine. The blood sample was sent to mutation analysis, which showed one novel and one known mutation on ASS1 gene sequencing: a heterozygous novel mutation p.A94V (c.281C>T) and a heterozygous mutation p.W179R (c.535C>T). Urea cycle disorders should be considered in the differential diagnosis of unexplained brief apnea or hypoventilation attacks, even though those symptoms do not lead to hyperammonemia during infancy and childhood as seen in our patient. This is the first case in terms of atypical clinical presentation with a new mutation for CTLN1.

Objective To evaluate vitamin D levels and bone mineral density in patients with dietary limitations due to inborn errors of metabolism (IEM) and its correlation with diets. Study design Retrospective study. Place and duration of study Department of Pediatrics, Division of Pediatric Metabolism and Nutrition, Gazi University Hospital, Turkey, from March to Semtember 2016. Methodology The study is a retrospective review of 115 patients. Information about vitamin D status, bone mineral density (BMD) measurement and anthropometric parametres were collected. Patients were divided into two major groups, receiving protein-restricted diets (n=83) and lactose-restricted diets (n=32). Data of 110 healthy children were used as the control group. Results Mean vitamin D level of patients with special diets 28.1 ±14.9 ng/ml while mean level of healthy controls was 26.6 ±12.27 ng/ml. Levels of 26.8% (n=26/97) patients were found to be deficient and 34% (n=33/97) were found to be insufficient. No statistically significant differences were found between vitamin D levels and BMD of patients and healthy controls. BMD was not influenced by vitamin D levels. Conclusion Low BMD may be encountered in IEM, independent of vitamin D levels and revision of diet for adequacy of essential nutrients; and follow-up for dietary compliance is inevitable.

Inherited metabolic diseases are pathologic conditions that generally develop as a result of impairment of the production or breakdown of protein, carbohydrate, and fatty acids. Early determination of hematological findings has a positive effect on the prognosis of metabolic diseases. Three hundred eighteen patients who were being followed-up within the previous 6 months at Department of Pediatric Nutrition and Metabolism, Gazi University, Turkey, were included in the study. The hematological findings were classified under 7 main groups: anemia of chronic disease, iron deficiency anemia, vitamin B12 deficiency anemia, hemophagocytosis, leukocytosis, and thrombocytosis. Nine hundred twenty-two hematological examinations of the 319 patients were included in the study, and 283 hematological findings were determined, 127 anemia of chronic disease, 81 iron deficiency anemia, 56 cytopenia, and 4 vitamin B12 deficiency anemia. Leukocytosis (n=1), thrombocytosis (n=5), and hemophagocytosis (n=9) were also observed. It was determined that, although anemia of chronic disease and nutritional anemia are the most common hematological findings, these may be diagnosed late, whereas neutropenia, thrombocytopenia, pancytopenia, and hemostasis disorders may be diagnosed earlier. Our study is the most comprehensive one in the literature, and we think it would positively contribute to the monitoring and prognosis of congenital metabolic diseases.

Niemann-Pick type C disease (NPC) is an autosomal recessive disorder resulting in accumulation of unesterified lysosomal cholesterol. An 8-year-old girl with NPC disease had a painless, rigid, and fixed mass measuring 3 cm in diameter located on the left angular region of mandibula. The mass biopsy showed lipid-laden phagocytic cells infiltrating the lymph node consistent with Niemann-Pick cells. In NPC, accumulation of cholesterol in tissues could be seen not only in reticuloendothelial and nervous systems, but also in all systems. Our case is important for it being the first case of NPC with submandibular lymphadenopathy characterized with NPC cell infiltration.

Background Chronic renal failure (CRF) is a serious complication of Fabry disease (FD). The aims of the present study were to determine the prevalence of unrecognized FD in Turkish hemodialysis population and to investigate the molecular background. Method Primarily, α-galactosidase A (α-Gal A) activity was investigated on DBS in 1136 patients of both sexes who underwent dialysis for CRF in Turkey. The disease was confirmed by analyzing enzyme activity in leukocyte and GLA gene sequencing in all patients in whom α-Gal A level was 40% of normal or less. Results Mean age of the patients (44.5% female, 52.5% male) was 56.46 ± 15.85 years. Enzyme activity was found low with DBS method in 12 patients (four males, eight females). Two men, but no women, were diagnosed with FD by enzymatic and molecular analysis. In consequence of genetic analysis of a case, a new mutation [hemizygote c.638C>T (p.P214S) missense mutation in exon 5] was identified, which was not described in literature. Family screening of cases identified six additional cases. Conclusion As a result of this initial screening study performed on hemodialysis patients for the first time with DBS method in Turkey, the prevalence of FD was detected as 0.17%. Although the prevalence seems to be low, screening studies are of great importance for detecting hidden cases as well as for identifying other effected family members.

Background The aim of this study was to investigate the quality of life (QoL) of a group of patients with inherited metabolic diseases (IMD) who were treated with restrictive diet. Method A total of 68 patients (35 boys, 51.5%; 33 girls, 48.5%) with IMD (organic acidemia [OA], n = 14; disorder of carbohydrate metabolism [CMD], n = 33; and disorder of amino acid metabolism [AMD], n = 21) and their parents were inteviewed. Both parents completed a QoL Scale for Metabolic Diseases–Parent Form, a KINDL parent questionnaire, and a depression form. All patients aged ≥4 years completed a questionnaire themselves, including the KINDL-Kid and KINDL-Kiddo self-reports. The semi-standardized interviews were carried out with patients and their parents in a clinical setting. Results The patients with bad diet compliance had lower scores for school labeling and perception of disease on both the parent and child questionnaire forms (P < 0.05). The patients were then divided into three groups (OA, CMD, AMD) for further analysis. Differences were seen between groups with regard to scores of physical function and school performance according to QoL Scale for Metabolic Diseases–Parent Form (P < 0.01). According to parent perceptions, the CMD patients had better QoL with regard to emotional wellbeing. Conclusion As negative effects of the disease increased, the QoL of IMD patients and their parents decreased in terms of emotional, physical, and cognitive function. Application of expanded newborn scanning programs, early diagnosis, regular follow up, and family education would lessen the effects of the disease and improve the QoL of both families and children.

INTRODUCTION: Mucopolysaccharidosis is a hereditary lysosomal storage disease, which develops due to a deficiency in the enzymes that play a role in the metabolism of glycosaminoglycans (GAG). The incidence of mucopolysaccharidosis is 1/25,000, with autosomal recessive inheritance (except for MPS II). Mucopolysaccharidosis occurs in seven different types, each with a different congenital deficiency of lysosomal enzymes. In mucopolysaccharidosis patients, even though progression of clinical findings is not prominent, the disease advances and causes death at early ages. Facial dysmorphism, growth retardation, mental retardation, and skeletal or joint dysplasia are the most frequently found symptoms in these patients. OBJECTIVE: The purpose of our study is to present the types of hearing loss types and tympanometric findings of patients with mucopolysaccharidosis referred to our clinic with suspicion of hearing loss. METHODS: After otorhinolaryngological examination, 9 patients with different types of mucopolysaccharidosis, underwent to immittance and audiometric evaluations, performed according to their physical and mental abilities, and ages, in order to determine their hearing thresholds. RESULTS: The audiometric findings of the 9 patients followed with mucopolysaccharidosis were reported separately for each case. CONCLUSION: Based on the high frequency of hearing loss in mucopolysaccharidosis patients, early and detailed audiological evaluations are highly desirable. Therefore, regular and systematic multidisciplinary evaluations are very important. Resumo Introdução: Mucopolissacaridose (MPS) é uma doença hereditária de depósito lisossômico, decorrente da deficiência das enzimas que influenciam o metabolismo dos glicosaminoglicanos (GAGs). A incidência de MPS é de 1/25.000 habitantes, resultante de herança autossômica recessiva (exceto no caso de MPS II). MPS se apresenta na forma de sete tipos diferentes e, em cada tipo, ocorre uma deficiência congênita distinta de enzimas lisossômicas. Embora em pacientes com MPS os achados clínicos não sejam geralmente observados, a doença progride em seu curso natural e costuma levar a óbito pacientes muito jovens. Dismorfismo facial, retardo de crescimento, retardo mental e displasia esquelética ou articular são os sinais e sintomas mais frequentemente observados nesses pacientes. Objetivo: A finalidade do presente estudo foi apresentar os tipos de perda auditiva e os achados timpanométricos de pacientes com MPS encaminhados para nossa clínica com suspeita de perda auditiva. Método: Em seguida ao exame otorrinolaringológico, nove pacientes com diferentes tipos de MPS, foram submetidos a avaliações imitanciométricas e testes audiométricos de acordo com sua faixa etária eficiência física e mental, no intuito de identificar seus limiares auditivos. Resultados: Os achados audiométricos dos nove pacientes acompanhados por MPS foram descritos separadamente para cada caso. Conclusão: Baseado na alta frequência de perda auditiva em pacientes com MPS, avaliação audiológica precoce e detalhada é altamente desejável. Para tanto, é importante que sejam realizados avaliações multidisciplinares periódicas e sistemáticas.

We describe two new hypolipidemic patients with very low plasma triglyceride and apolipoprotein B (apoB) levels with plasma lipid profiles similar to abetalipoproteinemia (ABL) patients. In these patients, we identified two previously uncharacterized missense mutations in the microsomal triglyceride transfer protein (MTP) gene, R46G and D361Y, and studied their functional effects. We also characterized three missense mutations (H297Q D384A, and G661A) reported earlier in a familial hypobetalipoproteinemia patient. R46G had no effect on MTP expression or function and supported apoB secretion. H297Q D384A, and G661A mutants also supported apoB secretion similarly to WT MTP. Contrary to these four missense mutations, D361Y was unable to support apoB secretion. Functional analysis revealed that this mutant was unable to bind protein disulfide isomerase (PDI) or transfer lipids. The negative charge at residue 361 was critical for MTP function as D361E was able to support apoB secretion and transfer lipids. D361Y most likely disrupts the tightly packed middle alpha-helical region of MTP, mitigates PDI binding, abolishes lipid transfer activity, and causes ABL. On the other hand, the hypolipidemia in the other two patients was not due to MTP dysfunction. Thus, in this study of five missense mutations spread throughout MTP's three structural domains found in three hypolipidemic patients, we found that four of the mutations did not affect MTP function. Thus, novel mutations that cause severe hypolipidemia probably exist in other genes in these patients, and their recognition may identify novel proteins involved in the synthesis and/or catabolism of plasma lipoproteins. (C) 2016 Elsevier B.V. All rights reserved.

Hereditary coproporphyria (HCP) is an autosomal dominant acute hepatic porphyria due to the half-normal activity of the heme biosynthetic enzyme, coproporphyrinogen oxidase (CPOX). The enzyme catalyzes the step-wise oxidative decarboxylation of the heme precursor, coproporphyrinogen III, to protoporphyrinogen IX via a tricarboxylic intermediate, harderoporphyrinogen. In autosomal dominant HCP, the deficient enzymatic activity results primarily in the accumulation of coproporphyrin III. To date, only a few homozygous HCP patients have been described, most having Harderoporphyria, a rare variant due to specific CPOX mutations that alter enzyme residues D400-K404, most patients described to date having at least one K404E allele. Here, we describe a Turkish male infant, the product of a consanguineous union, who presented with the Harderoporphyria phenotype including neonatal hyperbilirubinemia, hemolytic anemia, hepatosplenomegaly, and skin lesions when exposed to UV light. He was homoallelic for the CPOX missense mutation, c.980A > G (p.H327R), and had massively increased urinary uroporphyrins I and III (9,250 and 2,910 mu M, respectively) and coproporphyrins I and III (895 and 19,400 mu M, respectively). The patient expired at 5 months of age from an apparent acute neurologic porphyric attack. Structural studies predicted that p.H327R interacts with residue W399 in the CPOX active site, thereby accounting for the Harderoporphyria phenotype.

We report a 13-year-old boy with multisystem involvement secondary to accumulation of amylopectin-like material. He was born to consanguineous parents at full term without any complications and his maternal perinatal history was uneventful. His parents were cousins. He had normal growth and development except for his weight. His sister died from an unexplained cardiomyopathy at the age of 8 years. Our patient's initial symptom was severe heart failure. Since he also had a complaint of muscle weakness, electromyography was performed which showed muscle involvement. The diagnosis was suggested by tissue biopsy of skeletal muscle showing intracellular, basophilic, diastase-resistant, periodic acid-Schiff-positive inclusion bodies and was confirmed by the presence of a completed branching enzyme deficiency. Similar intracytoplasmic inclusion-like bodies were also found in liver biopsy, but very few in number compared with the skeletal muscle. The patient died from an intercurrent infection. Postmortem endomyocardial biopsy revealed the same intracytoplasmic inclusions as described above affecting almost all myocardial cells. Ultrastructural examination of liver biopsy was nondiagnostic; however, myocardium showed prominent, large, intracytoplasmic deposits. Glycogen branching enzyme gene sequence was normal, and thus classical branching enzyme deficiency was excluded. Our patient represents the first molecular study performed on a patient in whom there was multiple system involvement secondary to accumulation of amylopectin-like material. We suggest that this is an as yet undefined and different phenotype of glycogen storage disease associated with multisystemic involvement.