Biomedical subjects

Tiziano Pramparo

Publications and source records attributed to Tiziano Pramparo.

17 recordsLinked to original sources

PubMed2025

Smith-Lemli-Opitz syndrome: Clinical, biochemical, and genetic insights with emerging treatment opportunities.

Smith-Lemli-Opitz syndrome (SLOS), also known as RSH syndrome, is an inborn error of cholesterol biosynthesis first described in 1964. Since then, significant advances have been made in understanding its pathophysiology, both during fetal development and postnatally. Cholesterol is a crucial lipid in the body, especially in the central nervous system, which accounts for nearly 25% of the body's total cholesterol. Cholesterol deficiency in SLOS can lead to congenital malformations and severe neurodevelopmental disabilities. The biochemical and genetic bases of SLOS have been elucidated. Reduced or absent 7-dehydrocholesterol reductase enzymatic activity results not only in cholesterol deficiency but also in accumulation of 7-dehydrocholesterol, 8-dehydrocholesterol, and toxic oxysterol metabolites, which contribute to the pathophysiology of SLOS and correlate variably with the severity of its clinical symptoms. Despite decades of research, the clinical recognition of SLOS remains challenging because of the condition's multisystemic nature and noteworthy phenotypic variability. This review provides an up-to-date summary of major research advances in the study of SLOS with a focus on clinical manifestations and biochemical and genetic findings, which, taken together, facilitate recognition and diagnostic confirmation. Additionally, we recap past and current efforts in therapeutic development and offer guidance for disease management.

Humans↗

PubMed2007

A patient with duplication (7)(p22.1pter) characterized by array-CGH.

Approximately 40 patients with terminal duplication of the distal short arm of chromosome 7 have been reported, the smallest being dup(7)(p21). We report here on a patient with a smaller duplication, dup(7)(p22.1), detected on G-banding and characterized by array-CGH. We establish phenotype-karyotype correlations with the reported patients with other 7p duplications.

Abnormalities, Multiple↗

PubMed2006

Cortical dysplasia of the left temporal lobe might explain severe expressive-language delay in patients with duplication of the Williams-Beuren locus.

We report on a new duplication case of 7q11.23, reciprocal of the Williams-Beuren (WB) deletion. The patient, a 13-year-old girl, was ascertained within an array-CGH screening of patients with epilepsy and neuronal migration defects. Similarly to the first reported patient, she showed serious difficulties in expressive language in the absence of severe mental retardation and marked dysmorphic features. Magnetic resonance imaging (MRI) of the brain revealed an abnormal development of the cerebral cortex in the left temporal lobe, which showed a simplified gyral pattern, and increased cortical thickness. This finding, which might explain poor language development, suggests that the WB critical region might harbour a dosage-sensitive gene controlling the molecular machinery of neuronal migration, with regional specificity and lateralization. It will be important to confirm our findings in newly diagnosed patients with dup(7)(q11.23). We expect to detect many more patients with the same duplication using widespread clinical implementation of high-resolution genome analysis.

Chromosomes, Human, Pair 7↗

PubMed2006

Identification and molecular modelling of a novel familial mutation in the SRY gene implicated in the pure gonadal dysgenesis.

SRY gene is responsible for initiating male sexual differentiation. The protein encoded by SRY contains a homeobox (HMG) domain, which is a DNA-binding domain. Mutations of the SRY gene are reported to be associated with XY pure gonadal dysgenesis. The majority of these are de novo mutations affecting only one individual in a family. Only a small subset of mutations is shared between the father and one or more of his children. Most of these familial mutations are localized within the HMG box and only two are at the N-terminal domain of the SRY protein. Herein, we describe a young girl with pure gonadal dysgenesis and her father carrying a novel familial mutation in the SRY gene at codon number 3. This mutation is resulting in a serine (S) to leucine (L) substitution. The secondary structure of the SRY protein was carried out by protein modelling studies. This analysis suggests, with high possibility, that the N-terminal domain of the SRY protein, where we found the mutation, could form an alpha-helix from amino acid in position 2 to amino acid in position 13. The secondary structure prediction and the chemical properties of serine to leucine substitution stands for a potential disruption of this N-terminal alpha-helix in the SRY protein. This mutation could have some role in impeding the normal function of the SRY protein.

Adolescent↗

PubMed2006

Subtelomeric trisomy 21q: a new benign chromosomal variant.

The diagnosis of a subtelomeric rearrangement has immediate impact on counseling, particularly in the case of familial rearrangements. However, the existence of subtelomeric imbalances with absent phenotypic effects may hamper genetic counseling, particularly when the rearrangement has not been previously described. We report on a new subtelomeric polymorphism, consisting of a familial subtelomeric rearrangement of chromosome 19 resulting in distal trisomy for 21q, detected in a child with Angelman Syndrome (AS) due to an UBE3A mutation. This report shows that new, previously unknown, benign subtelomeric variants may complicate the correct clinical diagnosis.

Angelman Syndrome↗

PubMed2006

Chromosomal rearrangements in Xq and premature ovarian failure: mapping of 25 new cases and review of the literature.

BACKGROUND: Chromosomal rearrangements in Xq are frequently associated with premature ovarian failure (POF) and have defined a POF 'critical region'. Search for genes responsible for the disorder has been elusive. METHODS: We report mapping of novel breakpoints of X;autosome-balanced translocations and interstitial deletions and a review of published X chromosome rearrangements. RESULTS: All the novel POF-associated rearrangements were mapped outside and often very distant from genes. The majority mapped to a gene-poor region in Xq21. In the same region, deletions were reported in women who apparently did not have problems conceiving. Expression analysis of genes flanking breakpoints clustered in a 2-Mb region of Xq21 failed to demonstrate ovary-specific genes. CONCLUSIONS: Our results excluded most of the possible explanations for the POF phenotype and suggested that POF should be ascribed to a position effect of the breakpoints on flanking genes. We also showed that while the X breakpoint may affect X-linked genes in the distal part of Xq, from Xq23 to Xq28, interruption of the critical region in Xq21 could be explained by a position effect of the Xq critical region on genes flanking the autosomal breakpoints.

Adult↗

PubMed2005

Direct duplication 12p11.21-p13.31 mediated by segmental duplications: a new recurrent rearrangement?

We describe the characterization of an interstitial duplication of 12p, dup(12)(p11.21p13.31), by array-CGH and FISH in a patient with mental retardation and dysmorphic features. The sequence analysis of the breakpoints revealed the presence of homologous low copy repeats (LCRs) flanking the duplication region, thus suggesting that they have mediated the rearrangement. Pip-maker analysis showed that a third cluster of homologous LCRs lie distally to the two mediating the 12p duplication. We hypothesize that this duplication might be a new recurrent rearrangement and that, thanks to the different orientations of the homologous regions lying within each cluster, the three clusters are responsible for at least some of the several 12p aneuploidies reported in the literature such as direct and inverted duplications, deletions and supernumerary analphoid chromosomes. Moreover, we excluded that polymorphic inversions between these three clusters are present in the normal population.

Abnormalities, Multiple↗

PubMed2005

Loss-of-function mutation of the AF9/MLLT3 gene in a girl with neuromotor development delay, cerebellar ataxia, and epilepsy.

The human AF9/MLLT3 gene is a common fusion partner for the MLL gene in translocations t(9;11)(p22;q23) associated with acute myeloid leukemia and acute lymphocytic leukemia. The exact function of the gene is still unknown, although a mouse knock-out model points to a role as a controller of embryo patterning. We report the case of a constitutional translocation t(4;9)(q35;p22) disrupting the AF9/MLLT3 gene in a girl with neuromotor development delay, cerebellar ataxia and epilepsy. Array-CGH analysis at 1 Mbase resolution did not reveal any additional deletions/duplications. We hypothesize a loss-of-function mutation of the AF9/MLLT3 gene, and a possible role for the FAT gene on chromosome 4, in the genesis of the proband's severe neurological phenotype.

Base Sequence↗

PubMed2005

Microphthalmia with linear skin defects (MLS) syndrome: clinical, cytogenetic, and molecular characterization of 11 cases.

The microphthalmia with linear skin defects (MLS) syndrome (MIM 309801) is a severe and rare developmental disorder, which is inherited as an X-linked dominant trait with male lethality. In the vast majority of patients, this syndrome is associated with terminal deletion of the Xp22.3 region. Thirty-five cases have been described to date in the literature since the first description of the syndrome in the early 1990s. We now report on the clinical, cytogenetic, and molecular characterization of 11 patients, 7 of whom have not been described previously. Seven of these patients have chromosomal abnormalities of the short arm of the X-chromosome, which were characterized and defined by fluorescence in situ hybridization (FISH) analysis. Intriguingly, one of the patients displays an interstitial Xp22.3 deletion, which to the best of our knowledge is the first reported for this condition. Finally we report on the identification and molecular characterization of four cases with clinical features of MLS but apparently normal karyotypes, verified by FISH analysis using genomic clones spanning the MLS minimal critical region, and with genome-wide analysis using a 1 Mb resolution BAC microarray. These patients made it possible to undertake mutation screening of candidate genes and may prove critical for the identification of the gene responsible for this challenging and intriguing genetic disease.

Abnormalities, Multiple↗

PubMed2005

Reciprocal translocations: a trap for cytogenetists?

We report four cases of subjects with phenotypic abnormalities and mental retardation associated with apparently balanced translocations, two inherited and two de novo, which showed, by molecular analysis, a hidden complexity. All the cases have been analyzed with different molecular techniques, including array-CGH, and in two of them the translocation breakpoints have been defined at the level of base pairs via studies in somatic hybrids containing single derivative chromosomes. We demonstrated that all the translocations were in fact complex rearrangements and that an imbalance was present in three of them, thus accounting for the phenotypic abnormalities. In one case, a Prader-Willi subject, we were not able to determine the molecular cause of his phenotype. This study, while confirming previous data showing unexpected complexity in translocations, further underscores the need for molecular investigations before taking for granted an apparently simple cytogenetic interpretation.

Abnormalities, Multiple↗

PubMed2005

8.5 Mb deletion at distal 5p in a male ascertained for azoospermia.

We report on a 5p- azoospermic male not showing the clinical features diagnostic for the cri-du-chat syndrome but for a breathy, raspy voice. The 5p deletion breakpoint, determined by fluorescent in situ hybridization (FISH) analysis with BAC clones, maps 8.5 Mb far from the short arm telomere in 5p15.31. Genotype/phenotype correlations in this subject, including his neuropsychological assessment, led us to define that the gene for the cat-like cry and one gene responsible for mild mental retardation with speech delay map both in the distal 8.5 Mb of chromosome 5 short arm.

Adult↗

PubMed2005

A 2.3 Mb duplication of chromosome 8q24.3 associated with severe mental retardation and epilepsy detected by standard karyotype.

Chromosome duplications are found in about 2% of subjects with a typical chromosomal phenotype but their frequency is likely to be higher, as suggested by the first array-CGH data. According to the orientation of the duplicated segment, duplications may be in tandem or inverted. The latter are usually associated with a distal deletion. We studied a de novo 2.3 Mb inverted duplication of 8q24.3 without apparently associated deletion in a subject with profound psychomotor retardation, idiopathic epilepsy and growth delay. In spite of its small size, the presence of the rearrangement was suspected on standard karyotypes (approximately 400 bands) and later confirmed by Fluorescent in situ hybridization (FISH) analysis. We hypothesize that the GRINA gene, a glutamate binding subunit of NMDA receptor ion channel lying within the duplicated segment, may be responsible for the epilepsy. This paper confirms that small subtelomeric de novo duplications may be responsible for mental retardation, facial dysmorphisms and/or congenital malformations, although their presence may be overlooked by FISH analysis.

Child↗

PubMed2004

A susceptibility gene for premature ovarian failure (POF) maps to proximal Xq28.

Terminal deletions of the long arm of the human X chromosome have been described in women with premature ovarian failure (POF). We report here the molecular characterization of an inherited deletion in two affected women and in their mother. The two daughters presented secondary amenorrhea at 17 or 22 years respectively, while the mother was fertile. She had four children, but she eventually had premature menopause at 43 years of age. The fine molecular analysis of the deletion showed that the three women carried an identical deletion. We conclude that the phenotypic difference within the family must be attributed to genetic or environmental factors and not to the presence of different extent deletions. By comparison with other deletions in the region, we map a susceptibility gene for POF to 4.5 Mb, in the distal part of Xq.

Adolescent↗

PubMed2004

Inverted duplications: how many of them are mosaic?

The best-known situation indissolubly linked to mosaicism is the uniparental disomy where a trisomic or monosomic zygote develops at least one cell line with 46 chromosomes. The mosaicism normal/abnormal cell lines may remain confined to placenta or persist in the embryo. Here, we describe a second situation that might also be indissolubly linked to a mosaic condition or at least to a confined placental mosaicism. We analysed the case of a mosaicism del(8p)/inv dup(8p) found in prenatal diagnosis. We had already demonstrated that the first product of the abnormal meiotic recombination at the basis of the inv dup rearrangements is a dicentric chromosome. Its breakage leads to the formation of a deleted and an inv dup chromosome. Although we had previously assumed that the dicentric underwent a breakage at meiosis II so that the zygote inherited the inv dup chromosome, our findings and those of others indeed indicate that the dicentric may be inherited in the zygote and that it might persist as such in early postzygotic stages, then undergoing different breakages in different cells leading to different abnormal chromosomes, either deleted or duplicated. Selection versus the most viable cell line(s) results either in a confined placental mosaicism with the inv dup cell line as the only one present in the embryo or in children with both the deleted and the inv dup cell lines. Phenotype/karyotype relationships in inv dup rearrangements must also take into account the influence of the other abnormal cell line during embryogenesis.

Aborted Fetus↗

PubMed2003

Reciprocal translocation associated with multiple exostoses in seven members of a three generation family and discovered through an infertile male.

We report a four generations family with multiple exostoses segregating with a reciprocal translocation t(8;19)(q24.11;q13.13) in 8 members of three generations. FISH investigations detected a breakage of the dosage-sensitive EXT1 gene. Although three members of the family died perinatally from unknown causes and one carrier had four spontaneous abortions, the translocation was discovered only when the cytogenetic analysis was requested in an affected male because of oligozoospermia. In fact, it is well known that infertile males may be carriers of reciprocal or Robertsonian translocations with a higher frequency than the general population. This family stresses the importance of requesting the cytogenetic analysis in all cases in which a dominant disease segregates with repeated miscarriages and/or newborn deaths of unknown cause.

Adult↗

PubMed2003

TBX1 is required for inner ear morphogenesis.

TBX1 is thought to be a critical gene in the pathogenesis of del22q11/DiGeorge syndrome (DGS). Morphological abnormalities of the external ear and hearing impairment (conductive or sensorineural) affect the majority of patients. Here we show that homozygous mutation of the mouse homolog Tbx1 is associated with severe inner ear defects that prevent the formation of the cochlea and of the vestibulum. Consistent with phenotypic abnormalities, Tbx1 is expressed early in otocyst development in the otic epithelium and in the periotic mesenchyme. Tbx1 loss-of-function blocks inner ear development at early otocyst stage and after neurogenesis. Analysis of chimeras suggests that Tbx1 function is required in the otic epithelium cell autonomously, but abnormalities of the periotic mesenchyme indicate that the pathogenesis of the inner ear phenotype is complex. We propose a model where Tbx1 is required for expansion of a subpopulation of otic epithelial cells, which is required to form the vestibular and auditory organs. Our data suggest that Tbx1 deletion in del22q11 patients may cause not only external and middle ear defects but also sensorineural and vestibular phenotypes observed in these patients.

Animals↗

PubMedDate not supplied

Narrowing the deleted region associated with the 15q21 syndrome.

Interstitial deletions of chromosome 15q, not involving the PWS/AS region, are uncommon and poorly characterized. Few cases defined at the cytogenetic level have been reported with 15q21 deletions and characteristic facial dysmorphisms are present in all them. We report on the molecular characterization by array-CGH of a new patient with a 15q21 deletion and on the redefinition of a second patient previously studied with multicolor banding. The two deletions resulted to be similar and involve about 12 and 8 Mb, respectively. Our study might promote to delineate a better genotype-phenotype correlation associated with 15q21 deletions.

Abnormalities, Multiple↗