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.

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.

Difficult to think about but easy to treat: scurvy.

OBJECTIVES: Severe vitamin C deficiency, or scurvy, presents as a syndrome of multisystem abnormalities associated with defective collagen synthesis and antioxidative functions. The many clinical features of scurvy lead to frequent misdiagnoses, as they can often point to other diseases, such as vasculitis, venous thrombosis and musculoskeletal disorders. As such, an extensive workup is recommended in cases in which scurvy is suspected. CASE PRESENTATION: A 21-month-old male patient and a 36-month-old female patient presented with difficulty in walking, painful joint movements, irritability, gingival hypertrophy and bleeding. After exhaustive investigations and risky invasive procedures, vitamin C deficiency was diagnosed in both cases, and the symptoms improved dramatically with vitamin C treatment. CONCLUSIONS: The importance of taking a dietary history in pediatric patients is highly recommended. In cases where scurvy is considered, serum ascorbic acid levels should be checked to confirm the diagnosis prior to conducting invasive tests.

SLC35A2-CDG: novel variants with two ends of the spectrum.

OBJECTIVES: Congenital disorders of glycosylation (CDGs) are rare inherited metabolic disorders associated with facial dysmorphism and in the majority of the patients, there is an important neurological impairment. Epilepsy was a main concern in rare forms of the disease. There are two groups of the disease: CDG-I results from the defects in glycan addition to the N-terminal and CDG-II occurs due to defects in the processing of protein bound glycans. SLC35A2-CDG is a rare form of CDG caused by mutations in the X-linked gene that encodes a UDP-Galactose transporter. The manifestations of the disease include seizures, failure to thrive, delayed myelination, and cerebral atrophy. CASE PRESENTATION: We describe herein a severe female child with intractable seizures, microcephaly, growth retardation, hypotonia, global developmental delay, facial dysmorphism, skeletal findings, cerebral/cerebellar atrophy, and thin corpus callosum, and a mildly affected male carrying a novel variant with seizures and mild global developmental delay who were found by whole exome sequencing (WES) for SLC35A2 mutations previously not reported. CONCLUSIONS: Our findings expand the number of reported cases and add novel variants to the repertoire of SLC35A2-CDG.

Management of hypersensitivity reactions to enzyme replacement therapy in children with lysosomal storage diseases.

BACKGROUND: Intravenous recombinant enzyme replacement therapy (ERT) is currently available for 8 lysosomal diseases. Hypersensitivity reactions (HSRs) may be observed during this long-term treatment. OBJECTIVE: To evaluate the frequency and clinical treatment features of ERT HSRs and the management of desensitizations in children. METHODS: Medical records were reviewed retrospectively for patients who received ERT. Those who had experienced HSRs to ERT were included in the study. The demographic characteristics of the patients, culprit enzyme, signs and symptoms, diagnostic tests, management of the reaction, and the protocol employed for the maintenance of ERT were recorded. RESULTS: During the study period, 54 patients received ERT in our institution. A total of 11 patients (20.4%) experienced HSR to ERT. All reactions were of immediate type. The most common symptoms were cutaneous manifestations. A total of 9 patients experienced urticaria, and 2 had anaphylaxis as initial reaction. Patients who had isolated cutaneous symptoms continued their treatments with antihistamines, corticosteroid premedication, slower infusion rate or both. Patients who had recurrent urticaria with these modalities or those who had anaphylaxis continued their ERT with desensitization (n = 8). A total of 3 patients required revisions in desensitization protocols because of recurrent anaphylaxis. CONCLUSION: The reactions that develop during this long-term treatment may be treated by premedication-prolonged infusion, but in some patients, desensitization protocols are necessary for the continuation of therapy. Revisions in desensitization protocols may be required.

A novel etiologic factor of highly elevated cholestanol levels: progressive familial intrahepatic cholestasis.

Background Progressive familial intrahepatic cholestasis type 3 (PFIC3) is an uncommon cholestatic liver disease caused by mutations in the ATP binding cassette subfamily B member 4 (ABCB4) gene. Although PFIC3 is frequently identified in childhood, ABCB4 disease-causing alleles have been described in adults affected by intrahepatic cholestasis of pregnancy, hormone-induced cholestasis, low-phospholipid-associated cholelithiasis syndrome or juvenile cholelithiasis, cholangiocarcinoma and in sporadic forms of primary biliary cirrhosis. Cholestanol is a biomarker which is elevated especially in cerebrotendinous xanthomatosis and rarely in primary biliary cirrhosis (PBC) and Niemann Pick type C. Case presentation Here we report a Turkish patient with compound heterozygous mutations in the ABCB4 gene, who has hepatosplenomegaly, low level of high-density lipoprotein, cholestasis and high level of cholestanol. Conclusion This is the first PFIC3 case with a high cholestanol level described in the literature. There are very few diseases linked to increased cholestanol levels, two of which are CTX and PBC. From this case, we can conclude that a high cholestanol level might be another indicator of PFIC type 3.

A Rare Etiology of 46,XY Disorder of Sex Development and Adrenal Insufficiency: A Case of MIRAGE Syndrome Caused by Mutations in the SAMD9 Gene

Adrenal hypoplasia is a rare congenital disorder. In spite of biochemical and molecular genetic evaluation, etiology in many patients with adrenal hypoplasia is not clear. MIRAGE syndrome is a recently recognized congenital disorder characterized by myelodysplasia, infection, growth restriction, adrenal hypoplasia, genital phenotypes, and enteropathy. Here we present a case of MIRAGE syndrome due to a heterozygous missense variant (c.2920G>A; p.E974K) mutation in the sterile alpha motif domain-containing protein-9 (SAMD9) gene. This report describes the first MIRAGE syndrome patient in Turkey.

Alpha methyl acyl CoA racemase deficiency: Diagnosis with isolated elevated liver enzymes.

Gündüz M, Ünal Ö, Küçükçongar-Yavas A, Kasapkara Ç. Alpha methyl acyl CoA racemase deficiency: Diagnosis with isolated elevated liver enzymes. Turk J Pediatr 2019; 61: 289-291. Alpha methy acyl CoA racemase (AMACR) deficiency is a rare autosomal recessive peroxisomal disorder characterized by cholestatic liver disease in the neonatal period, and variable neurologic symptoms affecting central and peripheral nervous systems in the following years. We report a Turkish patient who was diagnosed with AMACR deficiency with presentation of isolated elevated liver enzymes. The patient was referred for elevated liver enzymes when he was 10 months old. He had no cholestasis history in the neonatal period. Initially, an etiology could not be identified. Ultimately, the patient was diagnosed with AMACR deficiency with previously unreported p.Cys20Tyr (c.596G > A) homozygous pathogenic variant. At last visit, when he was 7.5 years old, his growth, development and neurologic examination were all normal. Biochemical analysis was normal except for mildly elevated AST levels. We suggest that checking VLCFA analysis may be useful in isolated elevated liver enzymes with unknown etiology.