Molecular Syndromology最新文献

Introduction: Peroxisome biogenesis disorders (PBDs) encompass a group of diseases marked by clinical and genetic heterogeneity. Phenotypes linked to PBDs include Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum disease (IRD), rhizomelic chondrodysplasia punctata type 1, and Heimler syndrome. PBD phenotypes manifest through hypotonia, developmental delay, facial dysmorphism, seizures, liver dysfunction, sensorineural hearing loss, and retinal dystrophy.

Methods: The proband underwent comprehensive clinical evaluation, followed by whole-exome sequencing (WES) coupled with copy number analysis (CNV), aimed at identifying potential disease-causing variants aligning with the observed phenotype.

Results: Our findings detail an individual exhibiting developmental delay, hearing loss, visual impairment, hepatomegaly, and splenomegaly, attributed to a biallelic deletion of exon 4 in the PEX26 gene. The WES analysis of the index case did not uncover any pathogenic/likely pathogenic single-nucleotide variations that could account for the observed clinical findings. However, the CNV data derived from WES revealed a homozygous deletion in exon 4 of the PEX26 gene (NM_001127649.3), providing a plausible explanation for the patient's clinical features. The exon 4 region of PEX26 encodes the transmembrane domain of the protein. The transmembrane domain plays a crucial role in anchoring the protein within lipid bilayers, and its absence can disrupt proper localization and functioning. As a result, this structural alteration may impact the protein's ability to facilitate essential cellular processes related to peroxisome biogenesis and function.

Conclusion: The index patient, which presented with hearing loss, retinal involvement and hepatic dysfunction in adolescence age, has atypical clinical course that can be considered unusual for Zellweger syndrome (ZS) and IRD phenotypes, and its rare genotypic data (in-frame single exon deletion) expands the PBD disease spectrum. This study revealed for the first time that PEX26 protein transmembrane domain loss exhibits an unusual course with clinical findings of IRD and ZS phenotypes. WES studies, incorporating CNV analyses, empower the identification of novel genetic alterations in genes seldom associated with gross deletion/duplication variations, such as those in the PEX26 gene. This not only enhances diagnostic rates in rare diseases but also contributes to broadening the spectrum of causal mutations.

Introduction: Inherited 5-oxoprolinase (OPLAH) deficiency is a rare inborn condition characterized by 5-oxoprolinuria. The inherited condition of 5-oxoprolinuria, or pyroglutamic aciduria, is primarily caused by mutations in the genes that encode glutathione synthetase (GSS) and 5-oxoprolinase (OPLAH), which are enzymes involved in the gamma-glutamyl cycle in glutathione metabolism. We report a 3-year-old male patient with epilepsy and speech difficulty diagnosed as primary 5-oxoprolinuria due to a novel OPLAH gene mutation.

Case presentation: A 3-year-old boy who was delivered at full term in an uncomplicated birth to consanguineous parents presented with epilepsy at the age of 2 years. He did not speak fluently. He was using 5-10 words with decreased language fluency. His past medical history revealed postnatal macrocephaly, hydrocephalus, and well-controlled epilepsy with levetiracetam. Progressive cerebral atrophy, hypomyelination, ventriculomegaly, and corpus callosum hypoplasia were striking features in brain MRI. A urine sample was sent for organic acid analysis by gas chromatography-mass spectrometry (GC-MS); quantitation of 5-oxoproline by stable isotope dilution gave a value of 177.9 mmol/mol creatinine (reference values 25.8-92.2). Molecular genetic analysis of the OPLAH gene revealed a novel homozygous variant (OPLAH (NM_017570.5): c.1909C>T p.Arg637Trp).

Conclusion: We conclude that inherited 5-oxoprolinase deficiency is not a benign biochemical condition, and patients with 5-oxoprolinuria should be screened for it. The nature of this inherited metabolic disorder must be determined through long-term observation. We wish to emphasize the significance of molecular genetic analysis in symptomatic patients with persistently elevated levels of 5-oxoproline in the urine, as measured by organic acid analysis.

Introduction: Sanfilippo syndrome or mucopolysaccharidosis type 3 (MPS-3) is a rare condition and its epidemiological data are still not defined. MPS-3 is linked to a deficiency in enzymes involved in heparan sulfate degradation. This biomolecule is neurotoxic and its accumulation underlies the severe central nervous system degeneration observed in this disease.

Methods: Here, we describe 15 Turkish patients with MPS-3A or MPS-3B subtypes. Clinical data upon the diagnosis and during the follow-up as well as molecular characterization are reported.

Results: Two and ten distinct variants were identified in SGSH and NAGLU gene sequences, respectively. Six variants (NAGLU NM_000263.3:c.532-?_c.764+?del, NAGLU NM_000263.3: c.509G>T, NAGLU NM_000263.3: c.700C>G, NAGLU NM_000263.3:c.507_516 del, NAGLU NM dises_000263.3: c.1354 G>A, NAGLU NM_000263.3: c.200T>C) have been previously published and 6 are novel (SGSH NM_000199.4: c.80T>G, SGSH NM_000199.4: c.7_16del, NAGLU NM_000263.3: c.224_235del, NAGLU NM_000263.3: c.904G>T, NAGLU NM_000263.3: c.626C>T, NAGLU NM_000263.3: c.1241A>G). SGSH NM_000199.4:c.7_16del variation might be caused by a founder effect.

Conclusion: Due to the high rate of consanguinity in Turkey, the incidence of Sanfilippo syndrome might be higher compared to other populations worldwide. Our results contribute to the characterization of rare diseases in Turkey and to improve our knowledge of the clinical, molecular, and epidemiological aspects of MPS-3 disease.