Comprehensive analyses of phenylalanine hydroxylase variants and phenotypic characteristics of patients in the eastern region of Türkiye.

OBJECTIVES: Phenylalanine hydroxylase (PAH) is predominantly a hepatic enzyme that catalyzes phenylalanine (Phe) into tyrosine, which is the rate-limiting step in Phe catabolism. Biallelic variants in the PAH gene cause PAH enzyme deficiency. Phenylketonuria (PKU) is an autosomal recessive disorder that causes neurologic, behavioral, and dermatological findings. PKU could be divided clinically into three types based on the blood Phe levels: classic phenylketonuria (cPKU), mild-moderate phenylketonuria (mPKU), and mild hyperphenylalaninemia (MHP). This study aimed to determine the phenotypic and genotypic characteristics of Turkish PKU patients in the eastern region of Türkiye. METHODS: Demographic characteristics, serum Phe levels, treatments, and PAH variants of 163 patients with PKU and hyperphenylalaninemia (HPA) were retrospectively evaluated. Blood Phe levels of the patients were analyzed with the high-performance liquid chromatography method. For PAH gene analysis, next-generation sequencing was performed. RESULTS: Of the 163 patients included in the study, 38 (23.3 %) had cPKU, 16 (9.8 %) had mPKU, and 109 (66.9 %) had MHP. Homozygous variants in the PAH gene were detected in 66 (40.5 %) of the patients, while compound heterozygous variants were detected in 97 (59.5 %) patients. Two novel and 35 recurrent variants in the PAH gene were detected. Of the two novel variants, one was missense (p.Phe351Leu) and the other was frameshift (p.Met276Cysfs*65). The most frequently detected variants were p.Thr380Met (18 %), p.Arg261Gln (16.8 %), and p.Ala300Ser (12.8 %). All patients with the homozygous c.1066-11G>A variant exhibited cPKU phenotype. The c.898G>T (p.Ala300Ser), c.1139C>T (p.Thr380Met), and c.1208C>T (p.Ala403Val) variants were statistically related to mild phenotype. On the other hand, c.592_613del (p.Tyr198Serfs*136), c.1028A>G (p.Tyr343Cys), and c.782G>A (p.Arg261Gln) variants were more frequently detected in the cPKU group. CONCLUSIONS: Our study, conducted with patients from the eastern region of Türkiye, demonstrates the genetic heterogeneity in the Turkish population. Simultaneously, our research contributes to genotype-phenotype correlation and expands the genotypic spectrum by identifying novel variants.

A novel Mecom gene mutation associated with amegakaryocytic thrombocytopenia in a premature infant.

BACKGROUND: Hereditary bone marrow failure syndromes are a category of biologically different syndromes that can cause cytopenia in at least one hematopoietic cell lineage. CASE: We present a 29-week-old male infant who had a low Apgar Score, advanced delivery room resuscitation, widespread petechial rash, and ecchymoses at birth, without any dysmorphic features. Initial laboratory tests revealed bicytopenia (platelet count 7x10 3 /uL, hemoglobin of 3.9 g/dL, neutrophil 2.0x103 /uL) with findings of disseminated intravasculer coagulation (DIC). Imaging studies demonstrated accompanying left-sided congenital pulmonary airway malformation. On the second postnatal week pancytopenia occurred and the bone marrow findings were consistent with congenital amegakaryocytic thrombocytopenia. Further evaluations for differential diagnosis of pancitopenia were performed and the results of congenital viral infections, metabolic and immunologic tests were negative. While supportive treatments were in progress, haploidentical bone marrow transplantation (BMT) was performed from the father at 84th day due to unavailability of HLA-matched relative or nonrelative donor. Whole exome sequencing revealed a novel heterozygous frameshift variation (c.1242dupT [p. Thr538fs]) in exon 8 of the MECOM gene and validated by Sanger sequencing. No variation was detected in the parents genetic analysis. CONCLUSIONS: In this report, we present a patient with congenital bone marrow failure successfully treated with haploidentic BMT and describe a novel, de novo pathogenic variant in MECOM gene.

A rare cause of hydrops fetalis in two Gaucher disease type 2 patients with a novel mutation.

Gaucher disease type 2 is the most progressive and the rarest form of Gaucher disease, defined as the acute neuronopathic type. We presented two GD2 patients who died before three months of age due to severe septicemia, respiratory and liver failure. One was homozygous for a novel GBA variant c.590 T > A (p.197 K), and the second homozygous for the known GBA mutation c.1505G > A (p.R502H). Ichthyosis, hydrops fetalis, apnea, myoclonic seizures, and hepatosplenomegaly occurred in both patients, but hypertrophic cardiomyopathy was observed only in the second and unilateral cataract in the first patient. Due to the disease's early and rapid neurological progression, we did not administer ERT to our patients. It is strongly believed that early diagnosis is essential, and prenatal diagnosis makes genetic counselling possible for future pregnancies.

Vitamin D receptor gene polymorphisms in ocular surface squamous cell neoplasms.

PURPOSE: To investigate vitamin D receptor polymorphisms in ocular surface squamous cell neoplasm and to evaluate the relationship between the identified polymorphisms and susceptibility to ocular surface squamous cell neoplasm and the clinical course. MATERIALS AND METHODS: A totala of 70 patients with ocular surface squamous cell neoplasm (study group) and 75 healthy age and gender-matched individuals (control group) were included in the study. Vitamin D receptor FokI and BsmI polymorphisms were examined. The relationships between histopathological diagnosis, recurrence rates, tumor stage, and identified polymorphisms were investigated. RESULTS: Histopathologically, 43 of the cases were squamous cell carcinoma and 27 of the cases were conjunctival intraepithelial neoplasia. The frequency of FokI (FF, Ff, ff) and BsmI (BB, Bb, bb) polymorphism genotype of vitamin D receptor gene were similar in the groups. The frequency of polymorphism (heterozygous or homozygous) for BsmI (Bb and bb) was significantly higher (p = 0.046) in the study group, while no difference was found between the groups in terms of polymorphic carriers (heterozygous or homozygous) for FokI. There was no correlation between tumor stage, recurrence-polymorphism frequency, and patient age-polymorphism frequency. CONCLUSION: It is known that active vitamin D inhibits the growth of cancer cells by binding to vitamin D receptor with regulation of genes responsible for cell proliferation. The presence of BsmI polymorphism in vitamin D receptor, in particular bb genotype and b allele, appears to be associated with the susceptibility of ocular surface squamous cell neoplasm. BsmI gene polymorphisms of vitamin D receptor might play an effective role in the formation, progression, and in the course of ocular surface squamous cell neoplasm.