Autosomal-dominant Alzheimer's disease has provided significant understanding of the pathophysiology of Alzheimer's disease. The present review summarizes clinical, pathological, imaging, biochemical, and molecular studies of autosomal-dominant Alzheimer's disease, highlighting the similarities and differences between the dominantly inherited form of Alzheimer's disease and the more common sporadic form of Alzheimer's disease. Current developments in autosomal-dominant Alzheimer's disease are presented, including the international Dominantly Inherited Alzheimer Network and this network's initiative for clinical trials. Clinical trials in autosomal-dominant Alzheimer's disease may test the amyloid hypothesis, determine the timing of treatment, and lead the way to Alzheimer's disease prevention.
The aims of this study are: (1) to determine the frequencies of the various genetic forms of retinitis pigmentosa; and (2) to perform segregation analysis on autosomal dominant, autosomal recessive, and X-linked families. The families studied consisted of 2 series of patients at Moorfields Eye Hospital: (1) 426 families seen in the Genetic Clinic; and (2) 289 families seen in the Electrodiagnostic Department. Comparison between the 2 series identified biases of ascertainment, and it was estimated that the combined series included 53% of simplex cases and a minimum of 15% of X-linked families. Segregation analysis of the Genetic Clinic series showed good agreement with expectation in autosomal dominant and X-linked families, but indicated that no more than 70% of all simplex cases were autosomal recessive. The rest of the simplex cases were mildly affected and may represent fresh autosomal dominant mutations, autosomal dominant transmission with reduced penetrance, the heterozygous state of X-linked disease in some of the females, and phenocopies.
The authors report on the genetic characterization of a deletion in the feline CRX gene in the Rdy cat, defining a new large-animal model for Leber congenital amaurosis, retinitis pigmentosa, and cone–rod dystrophy.
To elucidate the gene defect in a pedigree of cats segregating for autosomal dominant rod–cone dysplasia (Rdy), a retinopathy characterized extensively from a clinical perspective. Disease expression in Rdy cats is comparable to that in young patients with congenital blindness (Leber congenital amaurosis [LCA] or retinitis pigmentosa [RP]).
A pedigree segregating for Rdy was generated and phenotyped by clinical ophthalmic examination methods including ophthalmoscopy and full-field flash electroretinography. Short tandem repeat loci tightly linked to candidate genes for autosomal dominant retinitis pigmentosa in humans were genotyped in the pedigree.
Significant linkage was established to the candidate gene CRX (LOD = 5.56, θ = 0) on cat chromosome E2. A single base pair deletion was identified in exon 4 (n.546delC) in affected individuals but not in unaffected littermates. This mutation generates a frame shift in the transcript, introducing a premature stop codon truncating the putative CRX peptide, which would eliminate the critical transcriptional activation region. Clinical observations corroborate previously reported clinical reports about Rdy. Results show that the cone photoreceptor system was more severely affected than the rods in the early disease process.
A putative mutation causative of the Rdy phenotype has been described as a single base pair deletion in exon 4 of the CRX gene, thus identifying the first animal model for CRX-linked disease that closely resembles the human disease. As such, it will provide valuable insights into the mechanisms underlying these diseases and their variable presentation, as well as providing a suitable model for testing therapies for these diseases.
Metachondromatosis (MC) is a rare, autosomal dominant, incompletely penetrant combined exostosis and enchondromatosis tumor syndrome. MC is clinically distinct from other multiple exostosis or multiple enchondromatosis syndromes and is unlinked to EXT1 and EXT2, the genes responsible for autosomal dominant multiple osteochondromas (MO). To identify a gene for MC, we performed linkage analysis with high-density SNP arrays in a single family, used a targeted array to capture exons and promoter sequences from the linked interval in 16 participants from 11 MC families, and sequenced the captured DNA using high-throughput parallel sequencing technologies. DNA capture and parallel sequencing identified heterozygous putative loss-of-function mutations in PTPN11 in 4 of the 11 families. Sanger sequence analysis of PTPN11 coding regions in a total of 17 MC families identified mutations in 10 of them (5 frameshift, 2 nonsense, and 3 splice-site mutations). Copy number analysis of sequencing reads from a second targeted capture that included the entire PTPN11 gene identified an additional family with a 15 kb deletion spanning exon 7 of PTPN11. Microdissected MC lesions from two patients with PTPN11 mutations demonstrated loss-of-heterozygosity for the wild-type allele. We next sequenced PTPN11 in DNA samples from 54 patients with the multiple enchondromatosis disorders Ollier disease or Maffucci syndrome, but found no coding sequence PTPN11 mutations. We conclude that heterozygous loss-of-function mutations in PTPN11 are a frequent cause of MC, that lesions in patients with MC appear to arise following a “second hit,” that MC may be locus heterogeneous since 1 familial and 5 sporadically occurring cases lacked obvious disease-causing PTPN11 mutations, and that PTPN11 mutations are not a common cause of Ollier disease or Maffucci syndrome.
Children with cartilage tumor syndromes form multiple tumors of cartilage next to joints. These tumors can occur inside the bones, as with Ollier disease and Maffuci syndrome, or on the surface of bones, as in the Multiple Osteochondroma syndrome (MO). In a hybrid syndrome, called metachondromatosis (MC), patients develop tumors both on and within bones. Only the genes causing MO are known. Since MC is inherited, we studied genetic markers in an affected family and found a region of the genome, encompassing 100 genes, always passed on to affected members. Using a recently developed method, we captured and sequenced all 100 genes in multiple families and found mutations in one gene, PTPN11, in 11 of 17 families. Patients with MC have one mutant copy of PTPN11 from their affected parent and one normal copy from their unaffected parent in all cells. We found that the normal copy is additionally lost in cartilage cells that form tumors, giving rise to cells without PTPN11. Mutations in PTPN11 were not found in other cartilage tumor syndromes, including Ollier disease and Maffucci syndrome. We are currently working to understand how loss of PTPN11 in cartilage cells causes tumors to form.
Holoprosencephaly (HPE) is a clinically variable and genetically heterogeneous central nervous system (CNS) malformation. Alobar HPE, which is its most severe form, is associated with a poor prognosis. At the milder end of the HPE spectrum microcephaly, hypotelorism, and single central maxillary incisor may be recognised. Currently, four genes have been identified for this condition. These include Sonic Hedgehog (SHH) on chromosome 7q36, which is thought to be responsible for a significant proportion of autosomal dominant HPE. We report an index case with alobar holoprosencephaly caused by an SHH mutation and six members of his family over two generations with this mutation, with a broad range of clinical presentation, including attention deficit hyperactivity disorder (ADHD). The combination of microcephaly, hypotelorism, subtle midline facial anomalies, and ADHD within a sibship should alert the physician to the possible diagnosis of HPE.
Tuberous sclerosis complex (TSC) is an autosomal dominant tumor suppressor syndrome, characterized by hamartomatous growths in the brain, skin, kidneys, lungs, and heart, which lead to significant morbidity. TSC is caused by mutations in the TSC1 or TSC2 genes, whose products, hamartin and tuberin, form a tumor suppressor complex that regulates the PI3K/Akt/mTOR pathway. Early clinical trials show that TSC-related kidney tumors (angiomyolipomas) regress when treated with the mammalian target of rapamycin (mTOR) inhibitor, rapamycin (also known as sirolimus). Although side effects are tolerable, responses are incomplete, and tumor regrowth is common when rapamycin is stopped. Strategies for future clinical trials may include the investigation of longer treatment duration and combination therapy of other effective drug classes.
Here, we examine the efficacy of a prolonged maintenance dose of rapamycin in Tsc2+/- mice with TSC-related kidney tumors. Cohorts were treated with rapamycin alone or in combination with interferon-gamma (IFN-g). The schedule of rapamycin included one month of daily doses before and after five months of weekly doses. We observed a 94.5% reduction in kidney tumor burden in Tsc2+/- mice treated (part one) daily with rapamycin (8 mg/kg) at 6 months ≤ age < 7 months, (part 2) weekly with rapamycin (16 mg/kg) at 7 months ≤ age < 12 months, and (part 3) daily with rapamycin (8 mg/kg) at 12 months ≤ age < 13 months; but we did not observe any improvement with combination IFN-g plus rapamycin in this study. We also used a Tsc2-/- subcutaneous tumor model to evaluate other classes of drugs including sorafenib, atorvastatin, and doxycycline. These drugs were tested as single agents and in combination with rapamycin. Our results demonstrate that the combination of rapamycin and sorafenib increased survival and may decrease tumor volume as compared to rapamycin treatment alone while sorafenib as a single agent was no different than control. Atorvastatin and doxycycline, either as single agents or in combination with rapamycin, did not improve outcomes as compared with controls.
Our results indicate that prolonged treatment with low doses of mTOR inhibitors may result in more complete and durable TSC-related tumor responses, and it would be reasonable to evaluate this strategy in a clinical trial. Targeting the Raf/Mek/Erk and/or VEGF pathways in combination with inhibiting the mTOR pathway may be another useful strategy for the treatment of TSC-related tumors.
We describe a family with a novel, inherited AXIN2 mutation (c.1989G>A) segregating in an autosomal dominant pattern with oligodontia and variable other findings including colonic polyposis, gastric polyps, a mild ectodermal dysplasia phenotype with sparse hair and eyebrows, and early onset colorectal and breast cancers. This novel mutation predicts p.Tyr663X, which is a truncated protein that is missing the last three exons, including the DIX (Disheveled and AXIN interacting) domain. This nonsense mutation is predicted to destroy the inhibitory action of AXIN2 on WNT signaling. Previous authors have described an unrelated family with autosomal dominant oligodontia and a variable colorectal phenotype segregating with a nonsense mutation of AXIN2, as well as a frameshift AXIN2 mutation in an unrelated individual with oligodontia. Our report provides additional evidence supporting an autosomal dominant AXIN2-associated ectodermal dysplasia and neoplastic syndrome.
AXIN2; polyposis; ectodermal dysplasia; oligodontia
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder characterized by progressive involuntary movements, neuropsychiatric disturbances, and cognitive impairment. The use of tetrabenazine (TBZ), a specific inhibitor of vesicular monoamine transporter, is approved for chorea in HD patients. We aimed to review the medical literature concerning the efficacy and tolerability of TBZ in the treatment of HD patients and to report our personal experience about TBZ use in a cohort of HD patients. We searched PubMed (1960 to July 2010) using the following keywords: “tetrabenazine” + “huntington’s disease + chorea”. We included randomized controlled trials, open-label trials, and retrospective studies. We excluded case reports and studies conducted on fewer than 20 patients. In addition, we retrospectively evaluated 2 years’ follow-up of TBZ treatment on motor and cognitive performances and functional abilities in 28 HD patients, compared with 10 patients treated by other neuroleptics (clotiapine). Only four papers fulfilled the requested criteria. In the first study, which included 84 randomized outpatients, TBZ showed a significant improvement of chorea compared with placebo. In the open-label study extension, TBZ confirmed its efficacy on chorea, with a frequent occurrence of withdrawals due to side effects. In a retrospective study of long-term efficacy, 63 patients under TBZ therapy for an average period of 34 months showed a stable effect on chorea, despite a slight reduction of effect over time. In a telephone survey conducted on a total of 118 patients affected by different movement disorders, TBZ showed the most favorable effect for the 28 included HD patients. Our HD patients showed a slight deterioration of motor performances over time that was nonsignificant compared with TBZ or clotiapine treatments. Despite the fact that the global effect of TBZ seems positive in HD, more attention on evaluating symptomatic treatments for cognitive and psychiatric deterioration as well as motor deterioration would alleviate this devastating disorder until a neuroprotective treatment becomes available.
Huntington’s disease; symptomatic treatment; tetrabenazine
The hyper-IgE syndromes are rare, complex primary immunodeficiencies characterized by clinical manifestation diversity, by particular susceptibility to staphylococcal and mycotic infections as well as by a heterogeneous genetic origin. Two distinct entities - the classical hyper-IgE syndrome which is inherited in an autosomal dominant pattern and the autosomal recessive hyper-IgE syndrome have been recognized. The autosomal dominant hyper-IgE syndrome is associated with a cluster of facial, dental, skeletal, and connective tissue abnormalities which are not observable in the recessive type. In the majority of affected patients with autosomal dominant hyper-IgE syndrome a mutation in the signal transducer and the activator of the transcription 3 gene has been identified, leading to an impaired Th17 cells differentiation and to a downregulation of an antimicrobial response. A mutation in the dedicator of the cytokinesis 8 gene has been identified as the cause of many cases with autosomal recessive hyper-IgE syndrome and, in one patient, a mutation in tyrosine kinase 2 gene has been demonstrated. In this paper, the authors provide a review of the clinical manifestations in the hyper-IgE syndromes with particular emphasis on the diversity of their phenotypic expression and present current diagnostic guidelines for these diseases.
A method is presented for estimating the probability of an affected child being born to a clinically unaffected subject who is at risk for having inherited a rare gene for an autosomal dominant disorder of unknown penetrance. The maximal risk is 8.6% for children of persons at 50% risk for having inherited the mutant gene regardless of the true penetrance of the disorder in question. Applications of this maximal risk figure, which should be of benefit in various counselling situations, are summarised.
Migrainous vertigo (episodic vertigo associated with migraine) is sometimes inherited as an autosomal dominant trait. However, neither disease genes nor loci that might be responsible have been reported. We sought to map the genetic locus for familial migrainous vertigo in a 4-generation family and to define the progression of disease in this family.
We studied 23 members in a family in whom migrainous vertigo was inherited as an autosomal dominant trait. Clinical information obtained included case histories and results of otolaryngological, neurologic, audiometric, and imaging evaluations. Genome-wide linkage analysis was performed with Affymetrix Genechip Human Mapping 10K microarrays. Genotyping of family members' DNA with microsatellite markers was used to further assess candidate loci identified from the whole-genome scan.
Of 23 family members, 10 suffered from migrainous vertigo beginning after 35 years of age. Migraine headaches usually preceded the onset of vertigo by 15 to 20 years. Longitudinal audiometric studies over 12 years showed stable, high-frequency sensorineural hearing loss consistent with presbycusis. Low-frequency or fluctuating hearing loss was not observed. The results of vestibular testing and imaging studies were unremarkable. Genetic analysis defined a 12.0 MB interval on chromosome 5q35 between loci rs244895 and D5S2073 that contained the disease gene (logarithm of odds score, 4.21).
We report the first locus for familial migrainous vertigo, which mapped to 5q35.
familial disease; gene; linkage study; migraine; vertigo
Large mammals, including canids and felids, are affected by spontaneously occurring hereditary retinal diseases with similarities to those of humans. The large mammal models may be used for thorough clinical characterization of disease processes, understanding the effects of specific mutations, elucidation of disease mechanisms, and for development of therapeutic intervention. Two well-characterized feline models are addressed in this paper. The first model is the autosomal recessive, slowly progressive, late-onset, rod-cone degenerative disease caused by a mutation in the CEP290 gene. The second model addressed in this paper is the autosomal dominant early onset rod cone dysplasia, putatively caused by the mutation found in the CRX gene. Therapeutic trials have been performed mainly in the former type including stem cell therapy, retinal transplantation, and development of ocular prosthetics. Domestic cats, having large human-like eyes with comparable spontaneous retinal diseases, are also considered useful for gene replacement therapy, thus functioning as effective model systems for further research.
Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder, with multisystem involvement, including cutaneous manifestations of hyperpigmentation and neurofibromas. Multiple cutaneous lesions are often disfiguring and lead to emotional distress and social isolation. Treatment of NF1 is predominantly surgical but alternative treatments should be considered for patients with large numbers of lesions as cold steel excision of multiple lesions can be cumbersome and may not be practical. The authors report a series of patients with multiple neurofibromas successfully treated using a CO2 laser.
Data on CO2 laser treatments, follow-up, and recurrence following treatment was collected retrospectively. A post-treatment telephone survey was carried out to assess patient satisfaction using a standardized set of questions and a scoring tool.
Five of seven patients who underwent CO2 laser treatment of their multiple neurofibromas responded to the post-treatment survey. All five patients (age range 36–56 years, mean age 45.2 years, three men:two women) had multiple variable-sized neurofibromas. The mean number of lesions per patient was 114 (range 20–200 lesions). The mean number of treatment sessions was 2.2 (range 1–4 sessions) and mean follow-up was 14.4 months (range 6–24 months). Three patients (60%) reported no recurrence up to 2 years post-laser treatment. Two patients (40%) had recurrences of a few lesions (≤10% of treated lesions per patient). The mean patient satisfaction score was 9.2 out of 10 (range 8–10). All patients mentioned that they would recommend CO2 laser treatment to others with multiple neurofibromas. Hypopigmentation or depigmentation at treatment sites were the only reported adverse effects.
Based on current results, the authors feel that CO2 laser treatment achieves a high level of patient satisfaction with a low recurrence of treated lesions.
Carbon dioxide laser; Laser; Neurofibroma; Neurofibromatosis; Patient satisfaction
Familial keloids have been reported, having either autosomal dominant or autosomal recessive inheritance. We wished to determine the inheritance pattern and phenotype of keloids among multigenerational families, as a prelude to a positional mapping strategy to identify candidate genes.
We studied three African American families, one Afro-Caribbean family and one Asian-American family. Phenotyping including assessing all patients for the presence, distribution, and appearance of keloids, together with the timing of keloid onset and provocative factors. The clinical trial was registered at clinicaltrials.gov (NCT 00005802).
Age of keloid onset varied considerably within families, but commonly occurred by the second decade. The fraction of affected individuals was 38%, 45%, 62%, 67% and 73% among the five families respectively. Keloid severity and morphology differed within and between families. A novel finding is that certain families manifest keloids in distinct locations, with one family showing an excess of extremity keloids and two families showing an excess of axilla-groin keloids.
Familial keloids appear to most commonly manifest autosomal dominant or semidominant inheritance, and there may be familial patterns of keloid distribution.
Muir-Torre syndrome is characterised by the association of sebaceous tumours of the skin with internal malignancy. In many instances there is a strong family history of cancer and the autosomal dominant mode of inheritance, tumour spectrum, and high incidence of synchronous and metachronous tumours show parallels with the cancer family syndrome or Lynch II syndrome. We report a five generation family with at least two persons displaying the Muir-Torre phenotype, while many other family members have had tumours consistent with cancer family syndrome. The majority of tumours are gastrointestinal, gynaecological, and urological, with several persons having multiple primaries. The prognosis appears to be better than would be expected. Sebaceous tumours are a marker for internal malignancy and should prompt a search for occult cancer in the individual person and family members. In documented Muir-Torre families, at risk persons should be entered into screening programmes similar to those used in the Lynch II syndrome.
A large proportion of patients with autosomal dominant polycystic kidney disease (ADPKD) suffers from polycystic liver disease. Symptoms arise when liver volume increases. The somatostatin analogue lanreotide has proven to reduce liver volume in patients with polycystic liver disease. However, this study also included patients with isolated polycystic liver disease (PCLD). The RESOLVE trial aims to assess the efficacy of lanreotide treatment in ADPKD patients with symptomatic polycystic livers. In this study we present the design of the RESOLVE trial.
This open-label clinical trial evaluates the effect of 6 months of lanreotide in ADPKD patients with symptomatic polycystic livers. Primary outcome is change in liver volume determined by computerised tomography-volumetry. Secondary outcomes are changes in total kidney volume, kidney intermediate volume and renal function. Furthermore, urinary (NGAL, α1-microglobulin, KIM-1, H-FABP, MCP-1) and serum (fibroblast growth factor 23) biomarkers associated with ADPKD disease severity are assessed to investigate whether these biomarkers predict treatment responses to lanreotide. Moreover, safety and tolerability of the drug in ADPKD patients will be assessed.
We anticipate that lanreotide is an effective therapeutic option for ADPKD patients with symptomatic polycystic livers and that this trial aids in the identification of patient related factors that predict treatment response.
Trial registration number
Clinical trials.gov NCT01354405
ADPKD; Urinary biomarkers; Polycystic liver disease; Lanreotide
Autosomal dominant polycystic kidney disease is an inherited disorder that is characterized by the development and growth of cysts in the kidneys and other organs. Urinary protein excretion is usually less than 1 g/24 hours in autosomal dominant polycystic kidney disease, and an association of nephrotic syndrome with this condition is considered rare. There are only anecdotal case reports of autosomal dominant polycystic kidney disease associated with nephrotic syndrome, with focal segmental glomerulosclerosis being the most commonly reported histopathological diagnosis. Nephrotic-range proteinuria in the presence of autosomal dominant polycystic kidney disease, with or without an accompanying decline in renal function, should be investigated by open renal biopsy to exclude coexisting glomerular disease. To the best of our knowledge, this is the first case of autosomal dominant polycystic kidney disease with histologically proven diffuse proliferative glomerulonephritis presenting with nephrotic-range proteinuria. No other reports of this could be found in a global electronic search of the literature.
We report the case of a 35-year-old Indo-Aryan man with autosomal dominant polycystic kidney disease associated with nephrotic syndrome and a concomitant decline in his glomerular filtration rate. Open renal biopsy revealed diffuse proliferative glomerulonephritis. An accurate diagnosis enabled us to manage him conservatively with a successful outcome, without the use of corticosteroid which is the standard treatment and the drug most commonly used to treat nephrotic syndrome empirically.
Despite the reluctance of physicians to carry out a renal biopsy on patients with autosomal dominant polycystic kidney disease, our case supports the idea that renal biopsy is needed in patients with polycystic kidney disease with nephrotic-range proteinuria to make an accurate diagnosis. It also illustrates the importance of open renal biopsy in planning appropriate treatment for patients with autosomal dominant polycystic kidney disease with nephrotic-range proteinuria. The treatment for various histological subtypes leading to nephrotic syndrome is different, and in this modern era we should practice evidence-based medicine and should avoid empirical therapy with its associated adverse effects.
Detailed clinical, ophthalmological, and molecular studies were performed on a multigeneration family in which there were many subjects with type 1 neurofibromatosis, a common autosomal dominant disorder. Affected family members displayed a wide range of clinical findings including, in two subjects, features seen in Noonan syndrome (triangular facies, downward slanting palpebral fissures, micrognathia, short stature, and learning disability). Subjects have been described previously whose features have overlapped with neurofibromatosis and Noonan syndrome, and it has been suggested that these persons might represent a separate condition. DNA haplotype analysis showed linkage of the neurofibromatosis phenotype seen in this family to the proximal long arm of chromosome 17 in the region where the type 1 neurofibromatosis gene has been mapped. These results imply that the Noonan phenotype seen in some patients with type 1 neurofibromatosis might be the result of variable or variant expression of the neurofibromatosis gene on chromosome 17. The possible role of non-specific factors, such as fetal hypotonia, in producing the neurofibromatosis-Noonan phenotype needs further investigation. The availability of closely linked and intragenic molecular markers for neurofibromatosis could potentially be useful in the diagnosis and characterisation of patients and families with atypical forms of neurofibromatosis.
Mutations in the POLG gene have emerged as one of the most common causes of inherited mitochondrial disease in children and adults. They are responsible for a heterogeneous group of at least 6 major phenotypes of neurodegenerative disease that include: 1) childhood Myocerebrohepatopathy Spectrum disorders (MCHS), 2) Alpers syndrome, 3) Ataxia Neuropathy Spectrum (ANS) disorders, 4) Myoclonus Epilepsy Myopathy Sensory Ataxia (MEMSA), 5) autosomal recessive Progressive External Ophthalmoplegia (arPEO), and 6) autosomal dominant Progressive External Ophthalmoplegia (adPEO). Due to the clinical heterogeneity, time-dependent evolution of symptoms, overlapping phenotypes, and inconsistencies in muscle pathology findings, definitive diagnosis relies on the molecular finding of deleterious mutations. We sequenced the exons and flanking intron region from approximately 350 patients displaying a phenotype consistent with POLG related mitochondrial disease and found informative mutations in 61 (17%). Two mutant alleles were identified in 31 unrelated index patients with autosomal recessive POLG-related disorders. Among them, 20 (67%) had Alpers syndrome, 4 (13%) had arPEO, and 3 (10%) had ANS. In addition, 30 patients carrying one altered POLG allele were found. A total of 25 novel alterations were identified, including 6 null mutations. We describe the predicted structural/functional and clinical importance of the previously unreported missense variants and discuss their likelihood of being pathogenic. In conclusion, sequence analysis allows the identification of mutations responsible for POLG-related disorders and, in most of the autosomal recessive cases where two mutant alleles are found in trans, finding deleterious mutations can provide an unequivocal diagnosis of the disease.
POLG; POLG1; Alpers syndrome; PEO; adPEO; arPEO; SANDO; SCAE; ANS; MEMSA; MCHS; mtDNA depletion; liver failure
This clinical report describes a male with autosomal recessive generalized hypoplastic amelogenesis imperfecta. This case is unusual in coronal resorptions prior to tooth eruption. This finding has been reported in some cases of autosomal recessive, autosomal dominant and X linked amelogenesis imperfecta (AI). In reported cases, the defects were usually small and occurred in a maximum of 2 teeth per person. In our case, pre-eruptive coronal resorptions affected three second molar teeth from both jaws. On the other hand; congenitally missing teeth and malocclusion were present in this case. Recall evaluations at 3 month intervals occurred for a period of 2 years and then prosthodontic management began.
Amelogenesis imperfecta; Congenital missing teeth; Pre-eruptive coronal resorption; Malocclusion; Prosthetic restoration
Frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) is a heritable form of FTD, but the gene(s) responsible for the majority of autosomal dominant FTD-ALS cases have yet to be found. Previous studies have identified a region on chromosome 9p that is associated with FTD and ALS.
The authors report the clinical, volumetric MRI, neuropathological and genetic features of a new chromosome 9p-linked FTD-ALS family, VSM-20.
Ten members of family VSM-20 displayed heterogeneous clinical phenotypes of isolated behavioural-variant FTD (bvFTD), ALS or a combination of the two. Parkinsonism was common, with one individual presenting with a corticobasal syndrome. Analysis of structural MRI scans from five affected family members revealed grey- and white-matter loss that was most prominent in the frontal lobes, with mild parietal and occipital lobe atrophy, but less temporal lobe atrophy than in 10 severity-matched sporadic bvFTD cases. Autopsy in three family members showed a consistent and unique subtype of FTLD-TDP pathology. Genome-wide linkage analysis conclusively linked family VSM-20 to a 28.3 cM region between D9S1808 and D9S251 on chromosome 9p, reducing the published minimal linked region to a 3.7 Mb interval. Genomic sequencing and expression analysis failed to identify mutations in the 10 known and predicted genes within this candidate region, suggesting that next-generation sequencing may be needed to determine the mutational mechanism associated with chromosome 9p-linked FTD-ALS.
Family VSM-20 significantly reduces the region linked to FTD-ALS on chromosome 9p. A distinct pattern of brain atrophy and neuropathological findings may help to identify other families with FTD-ALS caused by this genetic abnormality.
Waardenburg syndrome (WS) is caused by autosomal dominant mutations, and is characterised by pigmentary anomalies and various defects of neural crest derived tissues. It accounts for over 2% of congenital deafness. WS shows high variability in expressivity within families and differences in penetrance of clinical traits between families. While mutations in the gene PAX3 seem to be responsible for most, if not all, WS type 1, it is still not clear what accounts for the reduced penetrance of deafness. Stochastic events during development may be the factors that determine whether a person with a PAX3 mutation will be congenitally deaf or not. Alternatively, genetic background or non-random environmental factors or both may be significant. We compared the likelihoods for deafness in affected subjects from 24 families with reported PAX3 mutations, and in seven of the families originally described by Waardenburg. We found evidence that stochastic variation alone does not explain the differences in penetrances of deafness among WS families. Our analyses suggest that genetic background in combination with certain PAX3 alleles may be important factors in the aetiology of deafness in WS.
Clear, transparent, and sufficiently detailed abstracts of conferences and journal articles related to randomized controlled trials (RCTs) are important, because readers often base their assessment of a trial solely on information in the abstract. Here, we extend the CONSORT (Consolidated Standards of Reporting Trials) Statement to develop a minimum list of essential items, which authors should consider when reporting the results of a RCT in any journal or conference abstract.
Methods and Findings
We generated a list of items from existing quality assessment tools and empirical evidence. A three-round, modified-Delphi process was used to select items. In all, 109 participants were invited to participate in an electronic survey; the response rate was 61%. Survey results were presented at a meeting of the CONSORT Group in Montebello, Canada, January 2007, involving 26 participants, including clinical trialists, statisticians, epidemiologists, and biomedical editors. Checklist items were discussed for eligibility into the final checklist. The checklist was then revised to ensure that it reflected discussions held during and subsequent to the meeting. CONSORT for Abstracts recommends that abstracts relating to RCTs have a structured format. Items should include details of trial objectives; trial design (e.g., method of allocation, blinding/masking); trial participants (i.e., description, numbers randomized, and number analyzed); interventions intended for each randomized group and their impact on primary efficacy outcomes and harms; trial conclusions; trial registration name and number; and source of funding. We recommend the checklist be used in conjunction with this explanatory document, which includes examples of good reporting, rationale, and evidence, when available, for the inclusion of each item.
CONSORT for Abstracts aims to improve reporting of abstracts of RCTs published in journal articles and conference proceedings. It will help authors of abstracts of these trials provide the detail and clarity needed by readers wishing to assess a trial's validity and the applicability of its results.
The authors extend the CONSORT Statement to develop a minimum list of essential items to consider when reporting the results of a randomized trial in any journal or conference abstract.
To identify the genetic defect in an autosomal dominant isolated ectopia lentis (EL) family.
Detailed family history and clinical data were collected from the family including sixteen patients with isolated EL. Blood samples of nine patients, one normal person and two unknown children’s were collected. Genomic DNA was extracted from leukocytes of peripheral blood. Genotyping was performed by microsatellite markers and logarithm-of-odds (LOD) scores were calculated using the LINKAGE Programs. Mutation screening in the candidate gene, fibrillin-1 (FBN1), was performed by direct sequencing.
Linkage to the FBN1 locus is verified. Mutation screening in FBN1 identified a C>T transition at nucleotide position c.2920. This nucleotide change results in the cysteine substitution for highly conserved arginine at codon 974 (p.R974C). This mutation is identified in all affected individuals but is not found in 50 control healthy people.
A novel mutation of FBN1 results in an arginine to cysteine residue (p.R974C) substitution, which is responsible for the patients with isolated EL in this Chinese family.
The genetic and clinical features of 46 patients in nine families with "pure" hereditary spastic paraplegia are described. Inheritance was autosomal dominant in seven families and autosomal recessive in two. In dominant kinships, five families corresponded to type I with onset below 35 years, and two to type II with onset over 35 years. In early onset dominant families, in spite of apparent complete penetrance before 20, variable expression and incomplete penetrance occurred. Irrespective of genetic type, serial evaluation revealed that the main symptom consisted of slowly progressive spastic gait, extremely variable in severity, associated in some patients with decreased vibratory sense and micturition disorders generally as late features. In dominant families, the disease tended to be more severe in late onset cases. No patient had symptoms in the upper limbs and plantar responses were flexor in six symptomatic patients. Central motor conduction time studied by transcranial magnetic stimulation was always normal in the upper limbs and increased in the lower limbs in five of the eight patients on whom it was performed. Monomorphic and stereotyped clinical pattern in this series does not support the concept of multisystem involvement of the central nervous system as a hallmark of the disease.