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.

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.

Two cases of MEGDHEL syndrome diagnosed with hyperammonemia.

OBJECTIVES: MEGDHEL [3-methylglutaconic aciduria (MEG), deafness (D), hepatopathy (H), encephalopathy (E), and Leigh-like disease (L)] syndrome is an autosomal recessive disorder caused by mutations in the serine active site-containing protein 1 (SERAC1) gene. MEGDHEL syndrome is clinically characterized by sensorineural hearing loss, encephalopathy, hepatopathy, 3-methylglutaconic aciduria, and Leigh-like lesions on cranial magnetic resonance imaging. During the neonatal period, it has been reported to present with hypoglycemia, hyperammonemia, impaired liver functions, cholestasis, metabolic acidosis, and sepsis-like clinical findings. However, clinical findings in the neonatal period were reported as a result of the retrospective evaluation of patients diagnosed at an older age. Herein we reported two cases diagnosed as MEGDHEL syndrome during neonatal period in two different clinics with sepsis-like findings, impaired liver functions, and ammonia levels high enough to require dialysis. CASE PRESENTATION: One of the cases was born 37 weeks of gestation with a birth weight of 2,060 g and initially presented with respiratory distress and feeding difficulties. The other case admitted to the neonatal intensive care unit had fed problems together with respiratory distress and circulatory failure within the first 24 h after initiation of parenteral nutrition. CONCLUSIONS: MEGDHEL syndrome should be suspected in patients with sepsis-like clinical features and hyperammonemia.

Evaluation of nutritional status in pediatric patients diagnosed with Covid-19 infection.

AIM: The aim of this study was to evaluate the nutritional status, the nutritional effect on the risk of infection and the severity of the disease, and the contribution of nutrition to the course of the infection in pediatric patients diagnosed with coronavirus disease who required additional nutritional support after hospitalization. METHODS: The body weight, height, body mass index, upper arm circumference, and triceps skinfold thickness of 49 patients aged 1 month to 18 years and diagnosed with Covid-19 and then hospitalized at the Ankara City Hospital, Pediatric Health and Diseases Hospital, Pediatric Infection ward between 15 May and 15 June 2020 were measured. Total protein, albumin, prealbumin, selenium, zinc, ferritin, folate, and selenium, C, D, E, and B12 levels were studied from blood drawn simultaneously from the patients. RESULTS: A total of 49 patients aged 8-18 years were evaluated. The median age was 13 years (age range 8-18). The females made up 53% and the males 47% of the group. No patient needed intensive care admission. Only 3 patients received antibiotic treatment and the others were followed up without treatment. The weight was normal in 75% and the height was normal in 90%. Mid-arm circumference and triceps thickness were normal in 72% of the patients. Vitamin D deficiency was present in 82%, vitamin B12 deficiency in 18%, vitamin C deficiency in 17%, ferritin deficiency in 16%, folate deficiency in 15%, vitamin A deficiency in 13%, and vitamin E deficiency in 7%. CONCLUSION: No patient required intensive care admission. Only 3 patients received antibiotic treatment and the others were followed up without treatment. Malnourishment was present in 3% of the patients while 9% were obese. Vitamin D deficiency was the most common vitamin deficiency while vitamin B12, vitamin C, Ferritin, vitamin A, vitamin E, and Folate deficiency were less common. Selenium and zinc levels were normal in all patients. There was no correlation between anthropometric values and susceptibility to childhood COVID-19 infection or the clinical course. It is possible that vitamin D deficiency increases susceptibility to the infection.

Molecular and clinical findings of Turkish patients with hereditary fructose intolerance.

OBJECTIVES: Hereditary fructose intolerance (HFI) is an autosomal recessive disorder caused by a deficiency in aldolase B that can result in hypoglycemia, nausea, vomiting, abdominal pain, liver and kidney dysfunction, coma, and even death. This study aims to represent the clinical features and molecular genetic analysis data of the patients diagnosed with HFI in our study population. METHODS: The medical records of the 26 patients with HFI were evaluated retrospectively. Age, gender, clinical findings, metabolic crises, and the results of molecular analyses were recorded. RESULTS: The patients with HFI had a good prognosis and the aversion to sugar-containing foods was the main complaint. Seven different variants were identified in the Aldolase B (ALDOB) gene in HFI patients. The most frequent mutations were p.Ala150Pro, p.Ala175Asp had a prevalence of 61 and 30%, respectively, in agreement with the literature and other known variants were found with minor frequencies c.360-363del4(3.8%), p.Asn335Lys(3.8%), and three novel mutations c.113-1_15del4 (3.8%), p.Ala338Val(7.6%), and p.Asp156His(3.8%) were identified at a heterozygous, homozygous, or compound heterozygous level. CONCLUSIONS: This study results revealed three novel mutations in patients with HFI. On the basis of age of presentation, clinical symptoms, and metabolic crisis, there was no clear-cut genotype-phenotype correlation. This article also demonstrates the importance of screening suspected infants in cases of acute liver failure for prompt diagnosis and treatment of HFI.

Malonyl coenzyme A decarboxylase deficiency with a novel mutation.

Malonyl-CoA, a product of acetyl-CoA carboxylase is a metabolic intermediate in lipogenic tissues that include liver and adipose tissue, where it is involved in the de novo fatty acid synthesis and elongation. Malonyl-CoA decarboxylase (MLYCD, E.C.4.1.1.9), a 55-kDa enzyme catalyses the conversion of malonyl-CoA to acetyl-CoA and carbon dioxide, thus providing a route for disposal of malonyl-CoA from mitochondria and peroxisomes, whereas in the cytosol, the malonyl-CoA pool is regulated by the balance of MLYCD and acetyl-CoA carboxylase activities. So far, 34 cases with different MLYCD gene defects comprising point mutations, stop codons, and frameshift mutations have been reported in the literature. Here, we describe the follow-up of a patient affected by malonic aciduria upon neonatal onset. Molecular analysis showed novel homozygous mutations in the MLYCD gene. Our findings expand the number of reported cases and add a novel variant to the repertoire of MLYCD mutations.

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.