Determination of miR-373 and miR-204 levels in neuronal exosomes in Alzheimer's disease.

BACKGROUND: NLRP3 inflammasome activation has been known to be involved in the etiology and progression of Alzheimer's disease (AD). Furthermore, AD and diabetes mellitus have common pathomechanisms. It has been shown that P2X7R whose expression is increased in brain tissues with AD and plays a role in the activation of NLRP3 inflammasome is suppressed by miR-373 in patients with osteoarthritis. Therefore, the question of whether the suppressive effect of miR-373 on NLRP3 may have a role in the pathophysiology of AD comes to mind. On the other hand, it is known that the miR-204 level increases in response to TXNIP, another NLRP3 inflammasome inducer with high expression in AD. In primary human islets, miR-204 reduces the expression of GLP-1R. It has been discovered that in vivo deletion of miR-204 is protective against diabetes by increasing GLP-1R and insulin secretion. Considering the relationship between miR-204 and TXNIP and the relationship of miR-204 with diabetes suggests investigating the effect of miR-204 on the inflammatory pathway in AD. Based on the common pathophysiological mechanisms between AD and diabetes and the reported changes related to NLRP3 inflammasome, we analyzed miR-373 and miR-204 in neuron-derived serum exosomes in this study. Neuron-derived exosomes in neurodegenerative diseases are considered to be better candidates for developing potential biomarkers. METHODS: The expression levels of miR-204 and miR-373 were investigated in neuron-derived serum exosomes obtained from 15 patients with mild AD, 18 with moderate AD, and 21 cognitively healthy individuals. RESULTS: The miR-204 and miR-373 expressions were significantly decreased in both patient groups compared to the control group. Therefore, we suggest that miR-204 and miR-373 are potential biomarkers for AD. However, due to the preliminary nature of this study, further large-scale studies are needed to support our findings.

Novel RETREG1 (FAM134B) founder allele is linked to HSAN2B and renal disease in a Turkish family.

Hereditary sensory and autonomic neuropathy type 2B (HSAN2B) is a rare autosomal recessive peripheral neuropathy caused by biallelic variants in RETREG1 (formerly FAM134B). HSAN2B is characterized by sensory impairment resulting in skin ulcerations, amputations, and osteomyelitis as well as variable weakness, spasticity, and autonomic dysfunction. Here, we report four affected individuals with recurrent osteomyelitis, ulceration, and amputation of hands and feet, sensory neuropathy, hyperhidrosis, urinary incontinence, and renal failure from a family without any known shared parental ancestry. Due to the history of chronic recurrent multifocal osteomyelitis and microcytic anemia, a diagnosis of Majeed syndrome was considered; however, sequencing of LPIN2 was negative. Family-based exome sequencing (ES) revealed a novel homozygous ultrarare RETREG1 variant NM_001034850.2:c.321G>A;p.Trp107Ter. Electrophysiological studies of the proband demonstrated axonal sensorimotor neuropathy predominantly in the lower extremities. Consistent with the lack of shared ancestry, the coefficient of inbreeding calculated from ES data was low (F = 0.002), but absence of heterozygosity (AOH) analysis demonstrated a 7.2 Mb AOH block surrounding the variant consistent with a founder allele. Two of the four affected individuals had unexplained renal failure which has not been reported in HSAN2B cases to date. Therefore, this report describes a novel RETREG1 founder allele and suggests renal failure may be an unrecognized feature of the RETREG1-disease spectrum.

Phenotypic and molecular characterization of five patients with PIK3CA-related overgrowth spectrum (PROS).

Somatic and germline PI3K-AKT-mTOR pathway pathogenic variants are involved in several segmental overgrowth phenotypes such as the PIK3CA-related overgrowth spectrum (PROS), Proteus syndrome, and PTEN hamartoma tumor syndrome. In this study, we describe five patients with PROS. We identified by high-throughput sequencing four different somatic PIK3CA pathogenic variants in five individuals. The Glu726Lys variant, which was previously reported in megalencephaly-capillary malformation-polymicrogyria (MCAP) syndrome, was identified in two patients with unclassified PROS. The Cys420Arg substitution, which was previously reported in CLOVES, was found in a patient with fibroadipose hyperplasia. Additionally, relatively rare pathogenic variants, His1047Tyr and Tyr1021Cys, were detected in two patients with MCAP. Therefore, we suggest performing deep sequencing of PIK3CA in all patients with suspected PROS, instead of targeted polymerase chain reaction for hotspot pathogenic variants.

Skeletal and molecular findings in 51 Cleidocranial dysplasia patients from Turkey.

Loss or decrease of function in runt-related transcription factor 2 encoded by RUNX2 is known to cause a rare autosomal-dominant skeletal disorder, cleidocranial dysplasia (CCD). Clinical spectrum and genetic findings in 51 CCD patients from 30 unrelated families are herein presented. In a majority of the patients, facial abnormalities, such as delayed fontanel closure (89%), parietal and frontal bossing (80%), metopic groove (77%), midface hypoplasia (94%), and abnormal mobility of shoulders (90%), were recorded following clinical examination. In approximately one-half of the subjects, wormian bone (51%), short stature (43%), bell-shaped thorax (42%), wide pubic symphysis (50%), hypoplastic iliac wing (59%), and chef's hat sign (44%) presented in available radiological examinations. Scoliosis was identified in 28% of the patients. Investigation of RUNX2 revealed small sequence alterations in 90% and gross deletions in 10% of the patients; collectively, 23 variants including 11 novel changes (c.29_30insT, c.203delAinsCG, c.423 + 2delT, c.443_454delTACCAGATGGGAinsG, c.505C > T, c.594_595delCTinsG, c.636_637insC, c.685 + 5G > A, c.1088G > T, c.1281delC, Exon 6-9 deletion) presented high allelic heterogeneity. Novel c.29_30insT is unique in affecting the P1-driven long isoform of RUNX2, which is expected to disrupt the N-terminal region of RUNX2; this was shown in two unrelated phenotypically discordant patients. The clinical findings highlighted mild intra-familial genotype-phenotype correlation in our CCD cohort.

Dual diagnosis of Ochoa syndrome and Niemann-Pick disease type B in a consanguineous family.

OBJECTIVES: Ochoa syndrome (UFS1; Urofacial syndrome-1) is a very rare autosomal recessive disorder caused by mutations in the HPSE2 gene that results bladder voiding dysfunction and somatic motor neuropathy affecting the VIIth cranial nerve. Niemann-Pick disease is a rare autosomal recessive lysosomal storage disorder with systemic involvement resulting from sphingomyelinase deficiency and generally occurs via mutation in the sphingomyelin phosphodiesterase-1 gene (SMPD1). CASE PRESENTATION: Here, we report a 6-year-old girl with symptoms such as urinary incontinence, recurrent urinary tract infections, peculiar facial expression, mainly when smiling, hypertelorism, constipation, incomplete closure of eyelids during sleep and splenomegaly. Homozygote mutations in two different genes responsible for two distinct syndromes were detected in the patient. Homozygous NM_000543.5:c.502G>A (p.Gly168Arg) mutation was found in the SMPD1 gene causing Niemann-Pick disease. In addition, some of the clinical features were due to a novel homozygous mutation identified in the HPSE2 gene, NM_021828.5:c.755delA (p.Lys252SerfsTer23). CONCLUSIONS: Here, we discuss about the importance of considering dual diagnosis in societies where consanguineous marriages are common. Accurate diagnosis of the patient is very important for the management of the diseases and prevention of complications.

Extending Phenotypic Spectrum of 17q22 Microdeletion: Growth Hormone Deficiency.

BACKGROUND: The 17q22 contiguous microdeletion syndrome is a recently described chromosomal disorder. Clinical features are heterogeneous because of variable deletion sizes. Clinical report: We present a child with delayed psychomotor development, dysmorphic features (prominent posterior rotated ears, upturned nose, thin upper lip, smooth philtrum, high palate), vesicoureteral reflux and growth hormone deficiency. 1.53 Mb loss at the 17q22 chromosome region in the proband was the responsible for the phenotype. Conclusion: In the few cases of interstitial 17q22 deletion in the literature, this is the first with growth hormone deficiency. This may contribute to the phenotypic spectrum of 17q22 microdeletion syndrome. As the reported cases increase, we believe that genotype-phenotype correlation will be better illuminated.

Autosomal Recessive Oculodentodigital Dysplasia: A Case Report and Review of the Literature.

Oculodentodigital dysplasia (ODDD) is a rare condition characterized by a typical facial appearance and variable findings of the eyes, teeth, and fingers. ODDD is caused by mutations in the GJA1 gene in chromosome 6q22 and inherited in an autosomal dominant manner in the majority of the patients. However, in recent clinical reports, autosomal recessive ODDD cases due to by GJA1 mutations were also described. Here, we report on a 14-year-old boy with microphthalmia, microcornea, narrow nasal bridge, hypoplastic alae nasi, prominent columnella, hypodontia, dental caries, and partial syndactyly of the 2nd and 3rd toes. These clinical findings were concordant with the diagnosis of ODDD, and a novel homozygous mutation (c.442C>T, p.Arg148Ter) was determined in the GJA1 gene leading to a premature stop codon. His phenotypically normal parents were found to be carriers of the same mutation. This is the third family in the literature in which ODDD segregates in an autosomal recessive manner.