Pantothenate kinase‐associated neurodegeneration (PKAN) is an autosomal recessive disorder characterized by iron accumulation in the brain, because of mutations in the PANK2 gene. Phenotypic and ...genotypic characteristics of 11 patients from five Mexican families with PKAN disease are reported. Sequencing of PANK2 confirmed the diagnosis. The 11 patients had dysarthria associated with dystonia and Parkinsonism in six. Brain magnetic resonance imaging (MRI) showed the ‘eye‐of‐the‐tiger’ sign in all patients. Three different mutations were identified, a novel one (p.A469P) and two (p.G219V and p.N404I) very rare. Homozygous sibs for the p.G219V mutation had a severe disease progression with early death. Dystonia predominated in the p.A469P/p.N404I compound heterozygous patients. Homozygous for p.N404I showed Parkinsonism, tics and personality and speech disorders. Early and late disease onset and variable expression was present in carriers of the different identified mutations. The ‘eye‐of‐the‐tiger’ is an excellent neuroimaging hallmark to predict PANK2 mutations. We detected a ‘cluster’ of patients harboring the p.N404I mutation, strongly suggesting a founder effect for this mutation. This is the first familial clinical‐genetic PKAN disease study accomplished in Mexico.
Lamellar ichthyosis (LI) is an autosomal recessive congenital ichthyosis characterized by generalized dry skin and severe scaling. It is caused by biallelic mutations in the TGM1 gene, however ...molecular data from non-Caucasian populations are limited. Results of genetic-molecular analysis of a group of LI pedigrees originating from two close small populations from south Mexico are presented. LI affected individuals belonging to 9 apparently unrelated families were studied. Exome sequencing or Sanger sequencing in probands from each family was carried out. Furthermore, DNA from 294 unaffected subjects from one of the communities were Sanger sequenced to determine the carrier frequency of the c.427C > T TGM1 variant. Five different TGM1 pathogenic variants, either in homozygous or in compound heterozygous state, were demonstrated in affected subjects. The two most common variants were c.427C > T (p.Arg143Cys) and c.1159+1G > T. A novel c.1645+1G > T TGM1 pathogenic allele was recognized. Carrier frequency analysis identified a total of 23 individuals heterozygous for the c.427C > T variant, predicting a prevalence of 78 carriers per 1000 inhabitants in the community. A high TGM1 allelic heterogeneity with 5 different LI-causing alleles in a limited geographic area was demonstrated. While the occurrence of homozygosity for a founder mutation is expected in small populations with high frequency of a particular autosomal recessive disorder, the occurrence of multiple pathogenic alleles has been previously described, a situation known as the Reúnion paradox. Our results expand the current knowledge of the mutational spectrum of TGM1-linked LI.
Abstract Pantothenate kinase-associated neurodegeneration (PKAN) disease is an autosomal recessive neurodegenerative disorder with iron storage in the brain due to PANK2 gene mutations. Brain ...magnetic resonance imaging (MRI) shows the typical “eye-of-the-tiger” sign. The aim of the present study was to describe clinical, MRI and molecular findings in a 26-year-old male with atypical PKAN disease in whom, brain MRI scans showed bilateral pallidal T2-hypointensity with a small central region of T2-hyperintensity, resembling the “eye-of-the-tiger” typical image. Genetic analysis identified two mutations in PANK2 : c.1561G>A and c.1663G>A, being the latter never described before. Due to limited phenotype–genotype correlation among patients with movement disorders, if “eye-of-the-tiger” brain MRI is present, PANK2 mutations investigation are needed to confirm PKAN disease.
Inherited retinal diseases (IRDs) represent a spectrum of clinically and genetically heterogeneous disorders. Our study describes an IRD patient carrying
ABCA4
and
USH2A
pathogenic biallelic ...mutations as a result of paternal uniparental disomy (UPD) in chromosome 1. The proband is a 9-year-old girl born from non-consanguineous parents. Both parents were asymptomatic and denied family history of ocular disease. Clinical history and ophthalmologic examination of the proband were consistent with Stargardt disease. Whispered voice testing disclosed moderate hearing loss. Next-generation sequencing and Sanger sequencing identified pathogenic variants in
ABCA4
(c.4926C>G and c.5044_5058del) and
USH2A
(c.2276G>T). All variants were present homozygously in DNA from the proband and heterozygously in DNA from the father. No variants were found in maternal DNA. Further analysis of single nucleotide polymorphisms confirmed paternal UPD of chromosome 1. This is the first known patient with confirmed UPD for two recessively mutated IRD genes. Our study expands on the genetic heterogeneity of IRDs and highlights the importance of UPD as a mechanism of autosomal recessive disease in non-consanguineous parents. Moreover, a long-term follow-up is essential for the identification of retinal features that may develop as a result of
USH2A
-related conditions.
A novel method to detect DNA mutations based on gold nanoparticles is described. This bioconjugate was prepared by conjugation of the TGFBI gene on the surface of gold nanoparticles. The surface ...plasmon resonance band observed in the ultraviolet–visible spectrum of the gold nanoparticles showed a shift to a lower energy after the surface was covered with the TGFBI gene. Surface-enhanced infrared spectroscopy (SEIRAS) showed the absorption bands of the bioconjugate due to their proximity to the nanoparticles. The SEIRAS effect was able to detect small and specific changes in the sequence of the TGFBI gene using interactions of the bioconjugates. The study was performed on patients clinically diagnosed with lattice corneal dystrophy (LCD). To our knowledge, this is the first report of FTIR spectroscopy employed to analyse this gene. We used genotyping results previously obtained by next-generation DNA sequencing technology to ensure that the analysed samples had the mutation. Our results show highly reproducible signals, which could be used for analytical studies of mutations in the genome.
We report a female patient with craniofrontonasal syndrome (CFNS) who in addition showed other cranial and extracranial midline defects including partial corpus callosum agenesis, ocular ...melanocytosis, pigmentary glaucoma, duplex collecting system, uterus didelphys, and septate vagina. She was found to have a novel pathogenic variant in exon 5 of EFNB1, c.646G>T (p.Glu216*) predicted to cause premature protein truncation. From our review, we found at least 39 published CFNS patients with extracranial midline defects, comprising congenital diaphragmatic hernia, congenital heart defects, umbilical hernia, hypospadias, and less frequently, sacrococcygeal teratomas, and internal genital anomalies in females. These findings support that the EFNB1 mutations have systemic consequences disrupting morphogenetic events at the extracranial midline. Though these are not rigorously included as midline defects, we found at least 10 CFNS patients with congenital anomalies of the kidney and urinary tract, all females. Additionally, uterus didelphys and ocular melanocytosis observed in our patient are proposed also as a previously unreported EFNB1‐related midline defects. In addition, this case may be useful for considering the intentional search for genitourinary anomalies in future patients with CFNS, which will be helpful to define their frequency in this entity.
Craniofrontonasal syndrome (CNFS) is an X-linked disorder caused by mutations in the EFNB1 gene in which, paradoxically, heterozygous females are more severely affected than hemizygous males. In this ...paper, the clinical and molecular studies of a female subject with CFNS are described. A novel de novo c.473T>C (p.M158T) mutation in exon 3 of EFNB1 was demonstrated in this patient. The M158 residue of the Ephrin-B1 protein is highly conserved between species. Our results expand the mutational spectrum exposed by CNFS.
Familial amyloidosis of the Finnish type (FAF) is an inherited amyloidosis arising from mutations in the gelsolin protein (GSN). The disease includes facial paralysis, loose skin, and lattice corneal ...dystrophy. To date, FAF has been invariably associated with substitution of Asp214 in GSN. We describe the clinical, histopathological, and genetic features of a family with FAF due to a novel GSN mutation.
Five affected adult individuals in a three-generation FAF pedigree were included in the study. Histopathological analysis was performed on an eyelid skin biopsy from one patient. Genetic analysis included next-generation sequencing (NGS) and Sanger sequencing for confirmation of the
variant. Several tools for in silico analysis of pathogenicity for the novel variant and to predict the effect of the amino acid replacement on protein stability were used.
Three older adult affected patients exhibited corneal lattice dystrophy, cutis laxa, and facultative peripheral neuropathy. Two younger adult individuals presented only with corneal amyloid deposits. NGS identified a heterozygous
c.1631T>G transversion, predicting a novel p.Met544Arg mutation. All in silico tools indicated that p.Met544Arg is deleterious for GSN functionality or stability.
The results expand the molecular spectrum of GSN-linked systemic amyloidosis. The novel p.Met544Arg pathogenic variant is predicted to affect gelsolin function, presumably by impairing a potential calcium-sensitive, actin-binding region.
Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is an autosomal dominant entity characterized by eyelid malformations and caused by mutations in the forkhead box L2 (FOXL2) gene. Clinical ...and genetic analyses of large cohorts of BPES patients from different ethnic origins are important for a better characterization of FOXL2 mutational landscape. The purpose of this study is to describe the phenotypic features and the causal FOXL2 variants in a Mexican cohort of BPES patients. A total of 12 individuals with typical facial findings were included. Clinical evaluation included palpebral measurements and levator function assessment. The complete coding sequence of FOXL2 was amplified by PCR and subsequently analyzed by Sanger sequencing. A total of 11 distinct FOXL2 pathogenic variants were identified in our cohort (molecular diagnostic rate of 92%), including 5 novel mutations. Our results broaden the BPES-related mutational spectrum and supports considerable FOXL2 allelic heterogeneity in our population.
•First molecular analysis of FOXL2 gene in Mexican cohort with BPES syndrome•92% of all patients had heterozygous pathogenic variant.•Five novel mutations were identified.•Two changes identified may be associated to POF.
Purpose: Best disease is an autosomal dominant retinal degeneration characterized by the presence of yellow lesions in the macula causing decreased central visual acuity at later stages. Best disease ...is caused by heterozygous mutations in BEST1, a gene located at chromosome 11q13. In the present study, we describe the clinical and molecular analysis of two multigenerational families with Best disease and correlate the optical coherence tomography (OCT) findings in asymptomatic and symptomatic subjects carrying BEST1 mutations.
Methods: Two Mexican families with 3 affected generations each were studied. Probands underwent full ophthalmologic examination including fundus examination, fluorescent angiography (FAG), and electro-oculogram (EOG). Fourier-domain 3D OCT was performed in a number of symptomatic and asymptomatic subjects from these two pedigrees. PCR amplification and automated nucleotide sequencing of the 11 exons of the BEST1 gene in genomic DNA were also performed.
Results: Eighteen members of family 1 were molecularly tested. Seven subjects, including 4 young asymptomatic patients, carried a W24C heterozygous mutation in BEST1. OCT imaging in a 6-year-old asymptomatic patient carrying this mutation did not demonstrate retinal lesions. Fifteen subjects from family 2 were molecularly tested. Four patients, including 2 asymptomatic subjects, carried a heterozygous Q293K BEST1 mutation. OCT imaging in an asymptomatic 8-year-old individual with the Q293K mutation demonstrated bilateral subfoveal lesions and unilateral serous retinal detachment. Symptomatic patients showed severe retinal lesions by OCT.
Conclusions: Our results add to the clinical, imaging, and molecular knowledge of Best disease and suggest that OCT can recognize retinal lesions in some asymptomatic carriers of BEST1 mutations as early as 8 years of age.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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