PURPOSE:The ERBB4 gene encodes a tyrosine kinase receptor for neuregulins and EGF family members, and plays a crucial role in various neurobiological processes. At present, the phenotypic manifestations of genetic variants that disrupt ERBB4 gene function (null variants) are not well established. METHODS:A search for new patients with null variants in ERBB4 was initiated through an international data-sharing collaboration via GeneMatcher, and by searching the databases Decipher and ClinVar. Diagnosis had been performed using chromosomal microarray analysis, whole-exome sequencing, or whole-genome sequencing. RESULTS:Twenty-four new patients from 13 unrelated families with null variants in ERBB4 were identified. Genetic findings included single- or multiple-exon deletions in eight families, a reciprocal translocation disrupting ERBB4 in one family, and sequence variants in four. Variants arose de novo in four probands, were inherited in eight, and had an unknown inheritance pattern in one. Co-segregation of variants with clinical manifestations was observed within families. The predominant clinical features included neurodevelopmental disorders (intellectual disability, neurodevelopmental delay, autism spectrum disorder, and attention deficit hyperactivity disorder), speech delay, challenging behaviors, hypotonia, psychiatric conditions and seizures. CONCLUSION:This study represents the largest case series of patients with neurological disorders and null variants in the ERBB4 gene. Our findings support haploinsufficiency as the most plausible pathophysiological mechanism underlying ERBB4-related disorders and broaden the spectrum of associated phenotypes. Autism spectrum disorders and psychiatric manifestations have emerged as frequent, previously underrecognized features. Penetrance appears to be high but incomplete, and expressivity is highly variable, with a tendency toward intrafamilial phenotypic conservation.

Okur-Chung neurodevelopmental syndrome (OCNDS; OMIM #617062) is an ultra-rare autosomal dominant disorder caused by heterozygous CSNK2A1 variants encoding CK2α; although the CSNK2A1 Foundation registry lists more than 350 diagnosed individuals worldwide, individual-level phenotypic data have been published for far fewer, and reports from Türkiye remain scarce. We retrospectively studied nine unrelated Turkish probands (4 F/5 M; 11 months to 23 years) from nine medical genetics centers across four geographic regions of Türkiye, diagnosed by exome sequencing (ES; n = 8) or chromosomal microarray (n = 1). A PRISMA 2020-compliant systematic review (inception-April 2026) provided an individual-level comparator pooled with our cohort (n = 61). Six distinct CSNK2A1 alterations were identified: the recurrent p.(Lys198Arg) p + 1 loop hotspot in 4/9 probands (44.4%); novel/rare p.(Arg195Gln) and p.(Asp156His) missense changes; two nonsense variants (p.(Tyr182Ter), p.(Arg333Ter)); and one ~537 kb heterozygous 20p13 contiguous deletion (arr[GRCh37] 20p13(61568_598427)x1). This proband also represents 20p13 deletion syndrome; previously reported cases of that entity were compared with our cohort. Core OCNDS features (developmental delay, intellectual disability, hypotonia, dysmorphism, behavioral disturbance) occurred at frequencies comparable to those in the pooled literature. Adult-onset obesity with type 2 diabetes (2/9) and hypogonadism (2/9), both essentially unreported in the predominantly pediatric pooled literature, were observed in two adolescent/young-adult males (one with p.(Lys198Arg), one with the 20p13 deletion). This series consolidates Lys198 as a recurrent hotspot across ethnically diverse cohorts, extends the structural-variant spectrum with the first Turkish CSNK2A1 contiguous-gene deletion, and supports adult-onset metabolic-reproductive complications as under-recognized OCNDS features. Systematic adolescent and adult metabolic-endocrine surveillance is recommended regardless of variant class.

Background: A two-year-old female patient was referred to our clinic due to speech and gait disturbances, strabismus, vacant staring, truncal hypotonia, and spasticity in the extremities. The patient had a history of a complicated delivery resulting in perinatal asphyxia. Electrocardiogram (ECG), echocardiogram (ECHO) and abdominal ultrasound findings reported no abnormalities. Previously performed spinal muscular atrophy (SMA) test, chromosomal microarray and karyotype analyses yielded normal results. On clinical examination, facial dysmorphic features included: prominently low-set ears, strabismus, downslanting palpebral fissures, micrognathia, and tapering fingers. Methods: To elucidate the patient’s phenotype, trio exome sequencing was performed using DNA samples of the patient and her parents. Analysis revealed a homozygous variant in the AMPD2 gene (NM_001368809.2) c.353 + 11 C > T, with both parents identified as heterozygous carriers. The phenotype was found to be partially consistent with pontocerebellar hypoplasia type 9 (PCH9), a condition associated with the AMPD2 gene. The variant was suspected to create a novel splicing site; therefore, blood samples were collected from the patient and her parents for RNA extraction. Subsequent cDNA analyses via gel electrophoresis and Sanger sequencing confirmed the alternative splicing event. Quantitative PCR study was applied to evaluate expression. Conclusions: This study designates the early-onset phenotype of PCH9 in a patient carrying a splice-altering variant in AMPD2. It also highlights the feasibility of functional studies in evaluating intronic variants of uncertain significance. Functional validation of such variants, which are often challenging to classify, can provide critical insights for clinical decision-making for the patient and further reproductive planning for the family.

Objective: This study aimed to describe the clinical, laboratory, and genetic characteristics of children with genetically confirmed glucokinase maturity-onset diabetes of the young (GCK-MODY) in a single-center pediatric retrospective study. Methods: In this study, the clinical, laboratory, and genetic results of 20 children under 18 years of age who were diagnosed with GCK-MODY genetically in the Department of Pediatric Endocrinology during 2012-2020 were retrospectively analyzed. Results: The most frequent presenting complaints were polyuria–polydipsia (n=6, 30%) and intermittent hyperglycemia (n=5, 25%). The median interval between initial evaluation and genetic diagnosis was 3.5 years (0.25-8.42). Before genetic confirmation, 35% (n=7) of the patients had been followed as having type 1 diabetes and were therefore treated with insulin. Mean HbA1c was 6.2% ± 0.63%, and diabetes-related autoantibodies were negative in all the patients with available results. Genetic testing identified missense variants in 95% and a frameshift variant in 5%. According to the pathogenicity assessment, 75% of variants were likely pathogenic missense variants, 20% were pathogenic missense variants, and 5% were pathogenic frameshift variants. The most common variant was c.943C>T (p.Leu315Phe), found in 45% of patients. Conclusion: Diagnostic delay and inappropriate treatment were common before recognition of GCK-MODY, and many cases were identified after incidentally detected hyperglycemia. Lack of screening among relatives indicates limited awareness of this condition. In children with atypical diabetes presentations, careful evaluation and timely genetic testing are essential to prevent misdiagnosis, avoid unnecessary therapy, and ensure appropriate long-term clinical management.

In this eight-year study, children with unclassified inborn errors of immunity (IEI) who have no pathogenic variants in targeted next-generation sequencing (tNGS) were re-evaluated by using singleton whole exome sequencing (sWES) and followed-up at least five years. They were also investigated if they had affected family members or not. In addition, all patients had detailed immunological and clinical work-up. In 2017, 108 children with probable diagnosis of IEI had tNGS and pathogenic variants were detected in 38 (35.1

Reduced serum IgM is increasingly encountered in adults evaluated for inborn errors of immunity (IEI), yet its clinical relevance and diagnostic utility remain uncertain. While some patients meet criteria for selective IgM deficiency (SIgMD), others remain unclassified, reflecting significant diagnostic heterogeneity. This study aimed to characterize adult IEI patients with low serum IgM and to assess the prognostic value of IgM levels for clinical outcomes. Among 378 adult IEI patients followed at a tertiary immunology center, 43 individuals (11.4

BACKGROUND:Xeroderma pigmentosum (XP) is a rare DNA damage repair disorder. Seven distinct complementation groups and an XP variant form have been identified; however, limited literature exists on the genotype-phenotype correlation in XP. OBJECTIVES:To explore the manifestations of XP variants in patients from Türkiye. METHODS:Our multicentric investigation involved 69 patients with XP from 52 unrelated families across 12 centres in Türkiye. Clinical examinations and genetic tests were conducted to assess the correlation between variants and disease characteristics. RESULTS:Of the XP groups, XP-C was the most prevalent (n = 38; 55%), followed by XP-variant (n = 15; 22%), XP-E (n = 8; 12%), XP-D (n = 4; 6%), XP-A (n = 3; 4%) and XP-G (n = 1; 1%). XP-B and XP-F were not identified. Median patient age at diagnosis was 9 years (interquartile range 2-19), although this varied significantly according to complementation group, with XP-D and XP-V diagnoses occurring later. Genetic analyses revealed 30 novel variants, including one in a patient with XP/Cockayne syndrome complex. Despite the link of XP-D to neurological degeneration, none of the patients showed neuropathy, while three patients with XP-E had neurological involvement. Notably, 26% (n = 18) of patients reported no consanguinity, yet a significant proportion (n = 11/18) had distant family members with XP. CONCLUSIONS:We found unique clinical patterns and diversity among complementation groups in Turkish patients with XP. Future investigations should focus on functional characterization of the novel variants, preferably through assays like unscheduled DNA synthesis, to determine their potential impact on DNA repair mechanisms and their implications for improved patient care.

OBJECTIVE:Syndromic craniosynostosis is caused by pathogenic variants in genes regulating suture development. This study aims to investigate clinical and molecular characteristics in syndromic craniosynostosis. MATERIALS AND METHODS:This retrospective descriptive study included 53 patients from 40 families with syndromic craniosynostosis. Molecular testing was performed in 22 families. RESULTS:The study included Saethre-Chotzen (n=14), Apert (n=12), Crouzon (n=11), Pfeiffer (n=4), Muenke (n=4), and Carpenter (n=1) syndromes, Crouzon syndrome with acanthosis nigricans (n=2), craniosynostosis with dental anomalies (n=2), craniosynostosis type 4 (n=2), and hypochondroplasia with craniosynostosis (n=1). Genetic etiology was identified in 20 families involving six genes: FGFR1 (Pfeiffer), FGFR2 (Apert, Crouzon, Pfeiffer), FGFR3 (Crouzon with acanthosis nigricans, Muenke), TWIST1 (Saethre-Chotzen), ERF (Craniosynostosis type 4), and IL11RA (Craniosynostosis with dental anomaly). Additionally, a FGFR3 variant causing hypochondroplasia was identified in a patient with multisuture synostosis. Familial inheritance was identified in 25%, but not in Apert syndrome. Brachycephaly (28.3%) was the most common cranial abnormality, followed by plagiocephaly (22.6%). Apert syndrome was characterized by frequent cardiac anomalies, cleft palate, developmental delay, and a higher rate of surgical intervention. In contrast, Crouzon, Pfeiffer, Saethre-Chotzen, and Muenke syndromes showed favorable outcomes, although a fatal course was observed in a patient with Crouzon syndrome with acanthosis nigricans. Rare etiologies included ERF-related craniosynostosis with mild craniofacial findings and IL11RA-related craniosynostosis with intrafamilial phenotypic heterogeneity. CONCLUSION:This study describes clinical features of well-defined syndromes such as Apert, Crouzon, and Pfeiffer; reports craniosynostosis in hypochondroplasia; and documents rare ERF- and IL11RA-related forms, highlighting the importance of combining clinical and molecular diagnostics.

Background and Objectives: Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1INH) is a rare autosomal dominant disorder caused by mutations in the SERPING1 gene and is characterized by considerable clinical variability among affected individuals. Although genotype–phenotype correlations have been reported, data from populations with high consanguinity rates remain limited. Therefore, this study aimed to construct pedigrees of HAE-C1INH families harboring SERPING1 mutations and to investigate whether mutation type is associated with phenotypic characteristics, particularly age at disease onset and C1 inhibitor functional activity. Materials and Methods: Eleven HAE-C1INH probands and their families were followed up at the Allergy and Immunology Department of Internal Medicine, Ege University Faculty of Medicine. Of the 295 family members identified through pedigree construction, 109 had symptoms compatible with HAE-C1INH, and 53 of these symptomatic individuals had both a confirmed SERPING1 genetic result and an available C1-INH functional measurement. Pedigrees were created using the Progeny Pedigree Drawing Software (Progeny Genetics LLC, Delray Beach, FL, USA). Demographic data, disease characteristics, C1-INH function levels, and SERPING1 mutation types were obtained from patient files. Results: A total of 295 individuals (151 males and 144 females) from 11 HAE-C1INH families were identified through pedigree construction. The analytical cohort comprised 53 symptomatic individuals, of whom 7 (13.2%) were homozygous for the variant. Among heterozygous patients (n = 46), 27 (58.7%) had missense mutations, 7 (15.2%) had nonsense mutations, 7 (15.2%) had large deletions, and 5 (10.9%) had frameshift deletion mutations. Patients carrying missense mutations had significantly higher median C1-INH functional activity (28.5%) than those with other mutation types (14.1%) (p = 0.026), and the median age of disease onset was significantly later in the missense group (20 years) than in the non-missense group (8 years) (p < 0.001). Annual HAE attack frequency was also lower in the missense group (median, 12 vs. 48 attacks per year; p = 0.009). Conclusions: Exploratory individual-level analyses showed higher residual C1-INH functional activity and later symptom onset among individuals carrying missense SERPING1 variants than among those carrying pooled non-missense loss-of-function variants. However, familial clustering and the small number of independent families limit the strength and generalizability of these findings.

Myopathy with extrapyramidal signs (MPXPS) is a rare, autosomal-recessive, multisystem disorder caused by biallelic loss-of-function (LOF) variants in MICU1, the calcium-sensing gatekeeper of the mitochondrial calcium uniporter. We clinically and genetically characterized seven affected individuals from six Iranian-Turkish consanguineous families and combined these data with 54 previously published cases (total of 62). The targeted neuromuscular assessment, along with muscle biopsy and exome sequencing, identified six pathogenic MICU1 variants, including c.355C>T; p.Arg119*, c.493 + 1G>A, c.508C>T; p.Gln170*, c.547C>T; p.Gln183*, c.1226C>G; p.Ser409*, and c.553C>T; p.Arg185*. Notably, we report one adult-onset patient whose symptoms began at age 29 and progressed more rapidly than those in childhood-onset cases. A separate pedigree contained monozygotic twins who exhibited an indistinguishable clinical course, emphasizing the consistency of the genotype-driven phenotype. Across the combined cohort, the mean age at onset was 5.9 ± 7.3 years (median = 3 years); 61.5% presented before age 5, while 9.5% manifested after 15 years. Deep phenotyping of 61 patients from different ethnic backgrounds revealed that common symptoms included learning difficulties (72%), myopathy (51%), and speech impairments (51%). Functional studies targeting MCU modulation may provide future therapeutic options.

BACKGROUND:This study investigated the relationship between circulating tumor DNA (ctDNA) parameters and metabolic parameters from FDG PET/CT in advanced breast cancer (ABC) patients. METHODS:In this retrospective single-center study, 47 ABC patients who underwent both liquid biopsy and FDG PET/CT were analyzed. RESULTS:Results showed that 27 patients (57.4%) had detectable ctDNA. Patients with detectable ctDNA demonstrated significantly higher whole-body metabolic tumor volume (WB-MTV) (p = 0.002) and whole-body total lesion glycolysis (WB-TLG) (p = 0.006) compared to those without ctDNA, while no significant difference was found in SUVmax or SUVmean. A moderate correlation was observed between variant allele frequency (VAF) values and metabolic parameters: maximum VAF correlated with SUVmax, WB-MTV, and WB-TLG (r = 0.407, p = 0.005; r = 0.457, p = 0.001; r = 0.415, p = 0.004, respectively). Mean VAF correlated with SUVmax, WB-MTV, and WB-TLG (r = 0.406, p = 0.005; r = 0.446, p = 0.002; r = 0.404, p = 0.005, respectively). The total VAF correlated with SUVmax, WB-MTV, and WB-TLG (r = 0.394, p = 0.006; r = 0.465, p = 0.001; r = 0.430, p = 0.003, respectively). When excluding patients without detectable ctDNA, the correlation between VAF values and WB-MTV, WB-TLG disappeared, while the correlation with SUVmax persisted. Total alteration number in ctDNA showed a moderate correlation with WB-MTV and WB-TLG (r = 0.563, p < 0.001; r = 0.459, p = 0.001, respectively). Correlation with WB-MTV remained significant when excluding patients without detectable ctDNA (r = 0.500, p = 0.008). CONCLUSIONS:These findings suggest that metabolic tumor burden correlates with ctDNA detection and characteristics, potentially offering complementary information for disease monitoring, treatment selection, and response assessment in ABC. The combined use of these parameters may improve prognostic evaluation and guide personalized treatment strategies.

Adenylate cyclase 3 (ADCY3) gene alterations have been found to be associated with obesity. However, few patients with homozygous mutations have been reported so far, and the follow-up procedure and treatment options have not been clarified. A 10-month-old female presented with increased appetite and weight gain. She was born from a consanguineous marriage. Weight, height, head circumference measurements and standard deviation scores (SDS) were 19 kg (+6.98 SDS), 82 cm (+3.53 SDS), and 49 cm (+3.07 SDS), respectively. Laboratory tests revealed a fasting glucose level of 103 mg/dL (5.7 mmol/L), insulin level of 25.39 µIU/mL, and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) value of 6.43. Whole-exome sequencing revealed a novel, homozygous c.1102G>A(p.Asp368Asn) variant in ADCY3. Her parents and healthy sister were heterozygous for the variant. At the age of 2.5 years, neurodevelopmental delay was observed. At the age of 3.5 years, the patient's weight, height, and body mass index values were 49.5 kg (+8.16 SDS), 111 cm (+2.59 SDS), and 40.18 kg/m2 (+6.48 SDS), respectively. Signs of Blount's disease and acanthosis nigricans were distinctive, and she had hyperphagia. She was undergoing speech therapy. Homozygous ADCY3 variants may present with early onset, severe obesity, insulin resistance, and neurodevelopmental delay in children. Severe complications may occur even at young ages. More data regarding the follow-up process and treatment of these patients are needed.

Abstract Introduction Familial hypocalciuric hypercalcemia (FHH) is a rare group of autosomal dominant disorders that result from genetic defects leading to reduced calcium-sensing receptor (CASR) activity. The gold standard for diagnosis of FHH is to detect a heterozygous mutation that causes a loss of function in CaSR gene activity by sequence analysis. Isolated cases have documented the rare coexistence of FHH and Primary hyperparathyroidism (PHPT). Herein, we would like to describe a patient with concurrent FHH and PHPT. Clinical Case A 59-year-old woman with no active complaints was referred for evaluation following the detection of hypercalcemia during routine examinations. Her laboratory results revealed serum calcium (Ca) of 11.1 mg/dl (8.4-10.2), phosphorus (P) of 2.57 mg/dl (2.5-4.5), parathormone (PTH) of 120 ng/dl (15-65), 25-Hydroxyvitamin D of 27 ng/ml (30-70), and 24-hour urine calcium of 128 mg (100-300 mg). Initial suspicion of primary hyperparathyroidism led to a neck ultrasound, which did not identify any mass lesions in the parathyroid origin. However, parathyroid scintigraphy indicated a suspicious area of hyperfunctioning parathyroid adenoma on the left. Additionally, neck ultrasonography revealed multinodular goiter. As a result, the patient underwent total thyroidectomy and parathyroidectomy, with a preoperative diagnosis of parathyroid adenoma and multinodular goiter. Pathological examination revealed a parathyroid lipoadenoma, 1 cm in diameter, with adipocyte and chief cell proliferation. papillary microcarcinoma was detected in the left lobe. Postoperatively, laboratory examination demonstrated serum Ca was 11 mg/dl (8.4-10.2), P was 2.63 mg/dl (2.5-4.5), PTH was 112 ng/dl (15-65), and 24-hour urine calcium was 56 mg/dL (100-300 mg). In the follow-op period, neck USG, sestamibi scan, neck and thorax CT did not reveal any parathyroid adenoma. Due to the suspicion of familial hypocalciuric hypercalcemia, a genetic test was performed. It revealed heterozygous CASR c.665G>A (p.Gly222Glu) and heterozygous c.2027 C>G (p.Thyr676Arg) potential pathogenic variants, leading to the diagnosis of familial hypocalciuric hypercalcemia. Conclusion Although parathyroidectomy is generally not curative or advised for typical cases of FHH, it is crucial to acknowledge the potential link between PHPT and FHH, as well as the role of CASR mutations in the development of some PHPT cases. Since having FHH does not rule out the possibility of a parathyroid adenoma and there can be similarities in the clinical features of both conditions. It is important to consider the possibility of coexisting PHPT and FHH in patients presenting with hypercalcemia, hypophosphatemia, high PTH levels, and low urinary calcium excretion. After surgery, patients might still show mild to moderate hypercalcemia, and further invasive interventions should be avoided; it should not be presumed that the parathyroid exploration was unsuccessful.

BACKGROUND:Familial hypercholesterolemia (FH) is a genetic disorder characterized by impaired clearance of low-density lipoprotein cholesterol (LDL-C), leading to severe hypercholesterolemia and increased risk of premature cardiovascular disease (CVD). Our study aims to describe and compare the clinical, biochemical, and genetic profiles of pediatric patients diagnosed with FH based on LDL-C levels exceeding 400 mg/dL (10.4 mmol/L) and confirmed by biallelic pathogenic variants in low-density lipoprotein receptor (LDLR) or low-density lipoprotein receptor adapter protein-1 (LDLRAP1) genes. METHODS:This retrospective cohort study included 39 pediatric patients diagnosed with FH at a tertiary care center. Clinical data were analyzed, including age at diagnosis, family history, lipid profile, presence of xanthomas, and cardiovascular complications. Molecular analysis was conducted using next-generation sequencing (NGS) and Sanger sequencing to confirm pathogenic variants. Statistical comparisons were performed between the LDLR and LDLRAP1 variant groups regarding lipid profiles, treatment response, and cardiovascular outcomes. RESULTS:Among 39 patients, 32 and 7 had pathogenic variants in LDLR and LDLRAP1 genes, respectively. Genetic analysis identified 27 unique pathogenic variants in LDLR (including 5 novel mutations) and 4 in LDLRAP1 causal for autosomal recessive hypercholesterolemia (ARH), highlighting the molecular diversity of FH. Compared to the LDLR variant group, LDLRAP1 variant patients had significantly lower untreated LDL-C levels (640.0 ± 155.6 mg/dL [16.6 ± 4.0 mmol/L] vs 506.9 ± 130.1 mg/dL [13.1 ± 3.4 mmol/L], P = .026] and showed a superior response to lipid-lowering therapy (LLT), with a greater percentage (70.6% ± 12.0%) reduction in LDL-C levels (P = .015). While xanthomas were present in 62.5% of LDLR variant patients, they were less frequent (42.9%) in the LDLRAP1 group (P = .107). Cardiovascular complications were observed exclusively in LDLR variant patients. Fourteen patients required lipoprotein apheresis (LA), and one underwent liver transplantation due to severe aortic stenosis. CONCLUSION:This study highlights the importance of genetic testing in differentiating classical semidominant homozygous FH from ARH, given their phenotypic overlap but distinct treatment responses. LDLRAP1 variant patients with ARH exhibit better LDL-C reductions with conventional LLT, suggesting a milder phenotype. Early diagnosis, aggressive LLT, and novel treatments are essential to mitigate cardiovascular risk. Future studies with larger cohorts and long-term follow-ups are needed to refine treatment strategies for pediatric FH.

Objectives: This study aimed to expand our understanding of the genetic basis of Parkinson's disease (PD) by investigating individuals diagnosed with early onset PD (EOPD) or those with a suspected genetic predisposition to PD. Patients and methods: Thirty patients (18 females, 12 males; mean age: 33.2 +/- 6.4 years; range, 15 to 48 years) diagnosed with EOPD between January 2018 and December 2019 were included in the study. A targeted next-generation sequencing analysis was conducted on 10 genes (SNCA, LRRK2, VPS35, PARK2, PINK1, PARK7, ATP13A2, PLA2G6, FBXO7, DNAJC6) known to be associated with PD etiology. Additionally, the MLPA method was used to investigate eight genes (SNCA, PARK7, LRRK2, ATP13A2, PINK1, GCH1, PRKN, and UCHL1) for large deletions and duplications. Results: Mutations in PD-associated genes were identified in seven out of the 30 patients included in the study. Four patients exhibited mutations in the PRKN gene: three had defined deletion mutations (exon 5 deletion, exon 2 deletion, and exon 3 and 4 deletion), and one had a splice site mutation newly identified in this study (c.1083+1delG). Two patients displayed a point mutation in the PLA2G6 gene (c.1705C>T), and one patients had a point mutation in the PINK1 gene (c.1247C>T). The clinical and genetic characteristics of these patients were analyzed to explore genotype-phenotype correlations. Conclusion: This study is one of the few in T & uuml;rkiye to examine the molecular etiology of EOPD. The identified mutations in the PRKN, PLA2G6, and PINK1 genes provide valuable insights into genotype-phenotype correlations in PD cases and contribute to the existing literature.

Background/Objectives: Mucopolysaccharidosis type II (MPS II) is an inherited metabolic disorder characterized by progressive neurologic and extra-neurologic findings. We aimed to explore the age at symptom onset and at diagnosis as well as contribute to the phenotype–genotype association with new observations of MPS II based on a broad series of patients in Turkey. Methods: The presented study was retrospective and descriptive. Data on molecular analysis results, the age of onset and diagnosis, diagnostic delays, neurologic and extra-neurologic symptoms, enzyme and urine glycosaminoglycan (GAG) level results, brain magnetic resonance imaging, echocardiography, and electromyography were reviewed. Results: A total of 46 MPS II patients from 40 families were involved. The mean diagnosis age was 40.1 ± 46.8 months, and the diagnostic delay was 19.7 ± 40.4 months. While the mean age of diagnosis of the first cases in the families was 45 ± 24 months, the mean age of diagnosis of the second cases was 14 ± 15 months. The mean age at diagnosis was 42 ± 18 months in the patient group born before 2010, while it was 28 ± 22 months in the patient group born in 2010 and after. The last measurement of the height SDS value showed a significant difference (p = 0.004) between the groups that started ERT before the age of three and those who began ERT at the age of three and above. Five patients showed an attenuated phenotype without neurologic involvement. The sequencing of the IDS gene revealed 25 distinct variants, with 8 novel variants that have yet to be documented in the existing literature. Conclusions: The findings from the observations of this Turkish MPS II cohort emphasize that the actual prevalence of MPS II is probably underestimated and that it has a broad spectrum of clinical phenotypes, even without neurological impairment. In children, specific warning signs—including a coarse facial appearance, abdominal distension, speech delays, and macrocephaly—should raise suspicion and prevent delays in diagnosis. Conducting urine GAG and enzyme analyses is crucial for cases with clinical suspicion. Our data showed that the age of diagnosis tended to decrease over the years.