Mitochondrial phosphate-carrier deficiency mimicking infantile-onset Pompe disease.

The mitochondrial phosphate carrier is critical for adenosine triphosphate synthesis by serving as the primary means for mitochondrial phosphate import across the inner membrane. Variants in the SLC25A3 gene coding mitochondrial phosphate carrier lead to failure in inorganic phosphate transport across mitochondria. The critical dependence on mitochondria as an energy source is especially evident in tissues with high-energy demands such as the heart, muscle; defects in the mitochondrial energy production machinery underlie a wide range of primary mitochondrial disorders that present with cardiac and muscle diseases. The characteristic clinical picture of a prominent early-onset hypertrophic cardiomyopathy and lactic acidosis may be an indication for analysis of the SLC25A3 gene. Here, described a patient with suspicion of infantile Pompe disease due to involvement of heart and muscle and high-level of plasma creatinine kinase but finally diagnosed mitochondrial phosphate-carrier deficiency.

A Rare Treatable Cause of Cardiomyopathy: Primary Carnitine Deficiency.

Introduction: Primary carnitine deficiency (PCD) is a rare autosomal recessive disorder caused by loss of function mutations in the solute carrier family 22 member 5 (SLC22A5) gene that encodes a high-affinity sodium-ion-dependent organic cation transporter protein (OCTN2). Carnitine deficiency can result in acute metabolic decompensation or, in a more insidious presentation, cardiomyopathy. Cardiomyopathy associated with PCD often presents with life-threatening heart failure. This presentation also usually includes skeletal muscle myopathy. Early recognition of this disorder and treatment with carnitine can avoid life-threatening complications related to cardiomyopathy. Case Presentation: Herein, we present a 10-month-old male patient with PCD, which was diagnosed while investigating the etiology of dilated cardiomyopathy and confirmed by molecular genetic analysis. Conclusion: Homozygous c.254_265 insGGCTCGCCACC (p.I89Gfs) pathogenic variant of the SLC22A5 gene was detected. With oral L-carnitine supplementation, the free carnitine level increased up to 14 µmol/L and the symptoms disappeared. LVEF increased by 45-70%. We would like to emphasize that this problem is a combination of the metabolic decompensation and the cardiac phenotypes, which are usually separated to either phenotype.

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

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

Assessment of the diagnosis, treatment, and follow-up of a group of Turkish pediatric glycogen storage disease type 1b patients with varying clinical presentations and a novel mutation.

OBJECTIVES: Glycogen storage disease (GSD) type 1b is a multisystemic disease in which immune and infectious complications are present, different from GSD type 1a. Treatment with granulocyte-colony stimulating factor (G-CSF) is often required in the management of neutropenia and inflammatory bowel disease. Recently, an alternative treatment option to G-CSF has been preferred, like empagliflozin. To report on the demographics, genotype, clinical presentation, management, and complications of pediatric patients with glycogen storage disease type 1b (GSD 1b). METHODS: A retrospective analysis of the clinical course of eight patients with GSD type 1b whose diagnosis was confirmed by molecular testing. RESULTS: The mean age at referral was four months. The diagnosis of GSD 1b was based on clinical and laboratory findings and supported by genetic studies. One patient presented with an atypical clinical finding in the form of hydrocephalus at the time of first admission. The first symptom was abscess formation on the scalp due to neutropenia in another patient. Other patients had hypoglycemia at the time of admission. All patients presented suffered from neutropenia, which was managed with G-CSF, except one. Hospitalizations for infections were frequent. One patient developed chronic diarrhea and severe infections, which have been brought under control with empagliflozin. CONCLUSIONS: Neutropenia is an essential finding in GSD 1b and responsible for complications. The coexistence of hypoglycemia and neutropenia should bring to mind GSD 1b. Empagliflozin can be a treatment option for neutropenia, which is resistant to G-CSF treatment.

Caring for a Child with Phenylketonuria: Parental Experiences from a Eurasian Country.

OBJECTIVES: Phenylketonuria (PKU) and mild hyperphenylalaninemia (HPA) are characterized by increased blood phenylalanine concentrations varying from mild to severe. Management of PKU was reported to be time consuming and burdensome for caregivers. This study intended to explore the experiences of families caring for a child with PKU/HPA in a country with a high PKU rate. The aim of this study was to compare parental well-being between parents of children with and without dietary restrictions and to explore the factors associated with parental psychological well-being. METHODS: Participants were interviewed about their experiences, concerns, and challenges related to the disease by using a semistructured questionnaire. After the interview, parents filled out the Beck Depression Inventory and State-Trait Anxiety Inventory-Trait. RESULTS: This study highlighted the adverse psychological, financial, and social effects of the diagnosis and management of the disease regarding the lives of the families of children with PKU/HPA. Although parental anxiety scores of children with and without dietary restrictions were similar, depressive symptom scores were higher in parents of children with dietary restrictions. However, in multiple regression analysis, lower household income and absence of perceived social support were found to be independent factors associated with higher depressive symptom scores. Having a daughter diagnosed with PKU/HPA and lower household income were found to be factors associated with higher anxiety scores. CONCLUSION: This study revealed that income level, perceived social support, and gender of the child were factors associated with psychological well-being of parents caring for children with PKU/HPA. Health care professionals should identify the challenges faced by families and should be aware of risk factors associated with lower parental well-being to achieve better family adjustment and better health outcomes.

The effectiveness of enzyme replacement therapy on cardiac findings in patients with mucopolysaccharidosis.

Background This study aimed to determine cardiac findings in patients with mucopolysaccharidosis (MPS) and to assess the changes in these findings after enzyme replacement therapy (ERT). Methods A retrospective clinical cohort study was conducted on patients who were diagnosed with MPS between 1995 and 2018 in Hacettepe University, Division of Pediatric Metabolism. A total of 96 patients were diagnosed with MPS during the study period. Of these patients, 81 (84.3%) received ERT. Echocardiographic findings of the patients together with the 6-min walking test (6MWT) results before and after ERT were compared. Results Thirty-one participants (38.2%) were female, while 50 (61.8%) were male. The mean age of the participants was 11.97 ± 6.33 years (range: 1.8-30). Five patients (6.2%) had MPS type I, 14 (17.3%) had type II, 28 (34.6%) had type IVa, 33 (40.7%) had type VI and one (1.2%) had type VII. Before ERT, 69.4% of patients had mitral insufficiency (MI; mild: 40.5%, moderate: 16.5%, severe: 12.7%), 35.4% had aortic insufficiency (AI; mild: 22.8%, moderate: 12.7%) and 45.1% had tricuspid insufficiency (TI; mild: 39.2%, moderate: 2.5%). The median duration of the ERT was 3.5 years. The ERT significantly improved left ventricular hypertrophy (LVH), but all other study variables returned non-significant before and after treatment. ERT may improve LVH in MPS. Bearing in mind that MPS is a progressive disease, ERT seems to prevent significant deterioration of this ailment but is not able to reverse the already settled pathologies except for LVH. ERT is not able to reverse the damage, but provides stabilization; so it is best to initiate treatment before cardiac damage.

Cognitive and behavioral impairment in mild hyperphenylalaninemia.

Evinç SG, Pektas E, Foto-Özdemir D, Yildiz Y, Karaboncuk Y, Bilginer-Gürbüz B, Dursun A, Tokatli A, Coskun T, Öktem F, Sivri HS. Cognitive and behavioral impairment in mild hyperphenylalaninemia. Turk J Pediatr 2018; 60: 617-624. As elevated phenylalanine (Phe) is detrimental to brain functions, determining a safe upper limit of blood Phe is important for initiation of treatment plans and setting Phe targets in hyperphenlalaninemic patients. It is accepted that Phe levels below 360 µmol/L does not impair brain function and hence does not require treatment. Therefore, we aimed to compare cognitive functions and attention-related problems among healthy children and untreated patients with hyperphenylalaninemia (HPA). This study included 41 hyperphenylalaninemic patients (`all HPA group`) aged 6-16 years with untreated blood Phe between 240 and 600 µmol/L and 29 healthy controls. `All HPA group` was further divided into 2 subgroups according to their lifetime median blood Phe levels as `Phe 360-600 µmol/L` and `Phe 240-360 µmol/L` groups. Wechsler Intelligence Scale for Children-IV (WISC-IV), Conners` Continuous Performance Test (CPT), Strength and Difficulties Questionnaire (SDQ) and Schedule for Affective Disorders and Schizophrenia for School-Age Children: Present and Lifetime Version (K-SADS-PL) were performed as a comprehensive neurocognitive, attention and behavioral assessment. The study illustrated that `all HPA` patients had significantly lower scores on all WISC-IV indexes compared to controls, except for Working Memory. Both `Phe 360-600 µmol/L` and `Phe 240-360 µmol/L` subgroups had lower Full Scale intelligence quotient (IQ) and Verbal Comprehension scores compared to controls. `All HPA` patients also had longer reaction times and more peer problems than controls, indicating attention deficits and behavioral problems. Since the results demonstrated that children with untreated Phe levels between 240-360 µmol/L are at higher risk for cognitive and attention-related problems, lowering the `safe` upper Phe level should be considered.

A Fanconi-Bickel syndrome patient with a novel mutation and accompanying situs inversus totalis.

Tastemel-Öztürk T, Bilginer-Gürbüz B, Teksam Ö, Sivri S. A Fanconi-Bickel syndrome patient with a novel mutation and accompanying situs inversus totalis. Turk J Pediatr 2017; 59: 693-695. Fanconi-Bickel syndrome is a rare autosomal recessive disorder of carbohydrate metabolism, caused by mutations in the SLC2A2 gene, that codes for the glucose transporter protein 2 (GLUT2). The disease is characterized by proximal renal tubular dysfunction, impaired glucose and galactose utilization, and accumulation of glycogen in the liver and kidney. Signs and symptoms of Fanconi-Bickel syndrome begin in infancy and include failure to thrive, hepatomegaly, hypophosphatemic rickets, and short stature. Here in we report a Turkish Fanconi-Bickel syndrome case who also has situs inversus totalis and a novel mutation that has not been described before.