In Wolfram syndrome (WFS), due to the loss of wolframin function, there is increased ER stress and, as a result, progressive neurodegenerative disorders, accompanied by insulin-dependent diabetes. The aim of the study was to evaluate the oral microbiome and metabolome in WFS patients compared with patients with type 1 diabetes mellitus (T1DM) and controls. The buccal and gingival samples were collected from 12 WFS patients, 29 HbA1c-matched T1DM patients (p = 0.23), and 17 healthy individuals matched by age (p = 0.09) and gender (p = 0.91). The abundance of oral microbiota components was obtained by Illumina sequencing the 16S rRNA gene, and metabolite levels were measured by gas chromatography–mass spectrometry. Streptococcus (22.2%), Veillonella (12.1%), and Haemophilus (10.8%) were the most common bacteria in the WFS patients, while comparisons between groups showed significantly higher abundance of Olsenella, Dialister, Staphylococcus, Campylobacter, and Actinomyces in the WFS group (p < 0.001). An ROC curve (AUC = 0.861) was constructed for the three metabolites that best discriminated WFS from T1DM and controls (acetic acid, benzoic acid, and lactic acid). Selected oral microorganisms and metabolites that distinguish WFS patients from T1DM patients and healthy individuals may suggest their possible role in modulating neurodegeneration and serve as potential biomarkers and indicators of future therapeutic strategies.

Alström (ALMS) and Bardet-Biedl syndromes (BBS) are rare ciliopathies characterized by obesity and hyperglycemia that lead to type 2 diabetes, but also other disorders, including neurodegeneration. However, isolated clinical manifestations can be observed in carriers of heterozygous mutations in the ALMS1 and BBS genes. Recently, the influence of oral bacteria on the presence of obesity, type 2 diabetes, and neurodegenerative processes has been widely discussed. The purpose of the research project was to analyze the profile of the microbiome in the oral cavity by sequencing the 16S rRNA gene in ALMS/BBS patients and carriers of causative variants in these genes. Oral mucosal swabs were taken from 8 ALMS/BBS patients, 24 family members, 20 obese patients, and 29 healthy individuals. Streptococcus (30.7%), Haemophilus (18.9%), and Prevotella (11%) were the most common bacteria in the study group. Comparison between groups showed a higher abundance of Prevotella, Enterococcus, Eikenella, Capnocytophaga, Parvimonas, Selenomonas, and Corynobacterium, and a lower abundance of Lactobacillus in the study group compared to other groups. The specific profile of the oral microbiome found in patients with variants in the ALMS1 and BBS genes may enable the identification of the modulatory role of the oral microbiome in these disorders and point to new directions for additional therapy for these patients and heterozygous family members in the future.

Transient neonatal diabetes mellitus (TNDM) is a genetically heterogeneous form of neonatal diabetes characterized by hyperglycemia that remits during infancy with a tendency to recur in later life. This case report presents the history of a male infant with transient neonatal diabetes mellitus. The patient was treated with a continuous subcutaneous insulin infusion (CSII) and a continuous glucose monitoring (CGM) system until the age of 2 months, when the normoglycemia connected with a withdrawal of treatment was noted. The genetic test results excluded the majority of known mutations related to TNDM. This case report focuses on various genetic mutations and the clinical features connected with them that cause TNDM and highlights the difficulties in the diagnostic and therapeutic processes of this disease. CSII and CGM systems seem to be a safe and effective treatment option in TNDM and may be used in the therapy.

Background: WFS1-spectrum disorders are caused by a mutation in the WFS1 gene. The term includes a wide range of rare disorders, from the most severe Wolfram syndrome with autosomal recessive inheritance to milder clinical manifestations with a single causative variant in the WFS1 gene, such as Wolfram-like syndrome, low-frequency sensorineural hearing loss (LFSNHL), isolated diabetes mellitus (DM), nonsyndromic optic atrophy (OA), and isolated congenital cataracts. Methods: The aim of this study was to evaluate genotype–phenotype correlations in Polish patients with WFS1-spectrum disorders. The study group constituted 22 patients (10 F; 12 M), including 10 patients (3 F; 7 M) referred to the Outpatient Clinic for Rare Diseases in Children and Adolescents and Diabetogenetics between 2019 and 2024 with clinical symptoms suggestive of WFS1-spectrum disorders, and 12 of their first-degree relatives (7 F; 5 M) from 10 families in Poland. Molecular testing was performed using tNGS (Targeted Next Generation Sequencing; Illumina) and analyzed for variants in the WFS1 gene. Results: Thirteen different variants in the WFS1 gene were found in 22 individuals (10 patients and family members), including the identification of two new variants (c.1535T>C and c.2485C>G). All patients had hyperglycemia or DM, hearing impairment, OA, or a combination of these symptoms. Four patients in the study group were diagnosed with Wolfram syndrome and all were compound heterozygotes for variants in the WFS1 gene. Conclusions: The evaluation of molecular characteristics in combination with clinical symptoms broadens the understanding of WFS1-spectrum disorders and allows more accurate management and prognosis for patients with this diagnosis.

Variations in several nuclear genes predisposing humans to the development of MODY diabetes have been very well characterized by modern genetic diagnostics. However, recent reports indicate that variants in the mtDNA genome may also be associated with the diabetic phenotype. As relatively little research has addressed the entire mitochondrial genome in this regard, the aim of the present study is to evaluate the genetic variations present in mtDNA among individuals susceptible to MODY diabetes. In total, 193 patients with a MODY phenotype were tested with a custom panel with mtDNA enrichment. Heteroplasmic variants were selected for further analysis via further sequencing based on long-range PCR to evaluate the potential contribution of frequent NUMTs (acronym for nuclear mitochondrial DNA) insertions. Twelve extremely rare variants with a potential damaging character were selected, three of which were likely to be the result of NUMTs from the nuclear genome. The variant m.3243A>G in MT-TL1 was responsible for 3.5% of MODY cases in our study group. In addition, a novel, rare, and possibly pathogenic leucine variant m.12278T>C was found in MT-TL2. Our findings also found the MT-CO1 gene to be over-represented in the study group, with a clear phenotype–genotype correlation observed in one family. Our data suggest that heteroplasmic variants in MT-COI and MT-TL2 genes may play a role in the pathophysiology of glucose metabolism in humans.

Background: Intellectual disability (ID) affects 1–3% of the world population. The number of genes whose dysfunctions cause intellectual disability is increasing. In addition, new gene associations are constantly being discovered, as well as specific phenotypic features for already identified genetic alterations are being described. The aim of our study was to search for pathogenic variants in genes responsible for moderate to severe intellectual disability and epilepsy, using a panel of targeted next-generation sequencing (tNGS) for diagnosis. Methods: The group of 73 patients (ID, n=32; epilepsy, n=21; ID and epilepsy, n=18) was enrolled in the nucleus DNA (nuDNA) study using a tNGS panel (Agilent Technologies, USA). In addition, high coverage mitochondrial DNA (mtDNA) was extracted from the tNGS data for 54 patients. Results: Fifty-two rare nuDNA variants, as well as 10 rare and 1 novel mtDNA variants, were found in patients in the study group. The 10 most damaging nuDNA variants were subjected to a detailed clinical analysis. Finally, 7 nuDNA and 1 mtDNA were found to be the cause of the disease. Conclusions: This shows that still a very large proportion of patients remain undiagnosed and may require further testing. The reason for the negative results of our analysis may be a non-genetic cause of the observed phenotypes or failure to detect the causative variant in the genome. In addition, the study clearly shows that analysis of the mtDNA genome is clinically relevant, as approximately 1% of patients with ID may have pathogenic variant in mitochondrial DNA.