Showing papers on "Anticipation (genetics) published in 2015"

Congenital and childhood myotonic dystrophy: Current aspects of disease and future directions

Abstract: Myotonic dystrophy type 1 (DM1) is multisystem disease arising from mutant CTG expansion in the non-translating region of the dystrophia myotonica protein kinase gene. While DM1 is the most common adult muscular dystrophy, with a worldwide prevalence of one in eight thousand, age of onset varies from before birth to adulthood. There is a broad spectrum of clinical severity, ranging from mild to severe, which correlates with number of DNA repeats. Importantly, the early clinical manifestations and management in congenital and childhood DM1 differ from classic adult DM1. In neonates and children, DM1 predominantly affects muscle strength, cognition, respiratory, central nervous and gastrointestinal systems. Sleep disorders are often under recognised yet a significant morbidity. No effective disease modifying treatment is currently available and neonates and children with DM1 may experience severe physical and intellectual disability, which may be life limiting in the most severe forms. Management is currently supportive, incorporating regular surveillance and treatment of manifestations. Novel therapies, which target the gene and the pathogenic mechanism of abnormal splicing are emerging. Genetic counselling is critical in this autosomal dominant genetic disease with variable penetrance and potential maternal anticipation, as is assisting with family planning and undertaking cascade testing to instigate health surveillance in affected family members. This review incorporates discussion of the clinical manifestations and management of congenital and childhood DM1, with a particular focus on hypersomnolence and sleep disorders. In addition, the molecular genetics, mechanisms of disease pathogenesis and development of novel treatment strategies in DM1 will be summarised.

Parental age effects, but no evidence for an intrauterine effect in the transmission of myotonic dystrophy type 1

Abstract: Myotonic dystrophy type 1 (DM1) is caused by the expansion of an unstable CTG repeat (g.17294_17296(45_1000)) with more repeats associated with increased disease severity and reduced age at onset. Expanded disease-associated alleles are highly unstable in both the germline and soma. Germline instability is expansion biased, providing a molecular explanation for anticipation. Somatic instability is expansion biased, size- and age-dependent, features that have compromised genotype–phenotype correlations and intergenerational studies. We corrected these confounding factors by estimating the progenitor allele length in 54 father–offspring and 52 mother–offspring pairs in Costa Rican DM1 families. Not surprisingly, we found major parental allele length effects on the size of the allele transmitted, the magnitude of the intergenerational length change, the age at onset in the next generation and the degree of anticipation in both male and female transmissions. We also detected, for the first time, an age-of-parent effect for both male and female transmission. Interestingly, we found no evidence for an intrauterine effect in the transmission of congenital DM1, suggesting previous reports may have been an artefact of age-dependent somatic instability and sampling bias. These data provide new insights into the germline dynamics of the CTG repeat and opportunities for providing additional advice and more accurate risk assessments to prospective parents in DM1 families.

Anticipation in myotonic dystrophy type 1 parents with small CTG expansions

Abstract: Myotonic dystrophy type 1 is the most common form of adult muscular dystrophy and has the world's highest prevalence in the Saguenay-Lac-St-Jean region, due to a founder effect. This autosomal dominant disorder results from an unstable CTG repeat expansion in DMPK. This region of Canada has had a family screening and predictive testing program for this disorder since 1988. Heterozygotes for small expansions (50-100 CTG repeats) can be asymptomatic or minimally affected. The aim of this study was to assess anticipation for these individuals. At the time of this study, the molecular data of 40 individuals and their 76 affected children were available. We compared 76 parent-child pairs. Most offspring (92.1%) had a larger number of repeats than their parent and the median number of repeats in the offspring was 325 (range, 57-2000). The number of CTG repeats was significantly greater when the mutation was transmitted by a father (median, 425 repeats; range, 70-2000), than when it was transmitted by a mother (median, 200 repeats; range, 57-1400). The majority (65.8%) of children also had a more severe phenotype than their parent but the sex of the parent had no significant influence on the severity of the child's phenotype. No congenital phenotype was observed. These results confirm that anticipation is present even when the parent is heterozygous for a small CTG expansion. The parental sex has an impact on the size of the repeat in the next generation, larger increases being transmitted by males with a small expansion.

Whole Exome Sequencing Identifies Mutations in Usher Syndrome Genes in Profoundly Deaf Tunisian Patients

Abstract: Usher syndrome (USH) is an autosomal recessive disorder characterized by combined deafness-blindness. It accounts for about 50% of all hereditary deafness blindness cases. Three clinical subtypes (USH1, USH2, and USH3) are described, of which USH1 is the most severe form, characterized by congenital profound deafness, constant vestibular dysfunction, and a prepubertal onset of retinitis pigmentosa. We performed whole exome sequencing in four unrelated Tunisian patients affected by apparently isolated, congenital profound deafness, with reportedly normal ocular fundus examination. Four biallelic mutations were identified in two USH1 genes: a splice acceptor site mutation, c.2283-1G>T, and a novel missense mutation, c.5434G>A (p.Glu1812Lys), in MYO7A, and two previously unreported mutations in USH1G, i.e. a frameshift mutation, c.1195_1196delAG (p.Leu399Alafs*24), and a nonsense mutation, c.52A>T (p.Lys18*). Another ophthalmological examination including optical coherence tomography actually showed the presence of retinitis pigmentosa in all the patients. Our findings provide evidence that USH is under-diagnosed in Tunisian deaf patients. Yet, early diagnosis of USH is of utmost importance because these patients should undergo cochlear implant surgery in early childhood, in anticipation of the visual loss.

Primary cataract as a key to recognition of myotonic dystrophy type 1.

Abstract: PURPOSE: Primary cataract is often the initial manifestation of the adult-onset type of myotonic dystrophy type 1 (DM1), the most common muscular dystrophy in adults. It is caused by a CTG repeat expansion within the DMPK gene, and anticipation may cause earlier onset and more severe symptoms in subsequent generations. METHODS: We report a family with hereditary cataract, which was initially classified as primary hereditary cataract. After presentation of 2 children with motor development delay and behavioral changes, DM1 was diagnosed. Subsequently, various DM1 features were recognized in older family members. CONCLUSIONS: This report aims to increase awareness among ophthalmologists of the high prevalence of DM1 among young primary cataract patients. Ophthalmologists can play a significant role in early diagnosis, since cataract frequently is the first occasion that patients seek medical attention. Early recognition is crucial since it enables adequate cardiac follow-up and allows counseling of couples of childbearing age.

Modeling diseases of noncoding unstable repeat expansions using mutant pluripotent stem cells.

Abstract: Pathogenic mutations involving DNA repeat expansions are responsible for over 20 different neuronal and neuromuscular diseases. All result from expanded tracts of repetitive DNA sequences (mostly microsatellites) that become unstable beyond a critical length when transmitted across generations. Nearly all are inherited as autosomal dominant conditions and are typically associated with anticipation. Pathologic unstable repeat expansions can be classified according to their length, repeat sequence, gene location and underlying pathologic mechanisms. This review summarizes the current contribution of mutant pluripotent stem cells (diseased human embryonic stem cells and patient-derived induced pluripotent stem cells) to the research of unstable repeat pathologies by focusing on particularly large unstable noncoding expansions. Among this class of disorders are Fragile X syndrome and Fragile X-associated tremor/ataxia syndrome, myotonic dystrophy type 1 and myotonic dystrophy type 2, Friedreich ataxia and C9 related amyotrophic lateral sclerosis and/or frontotemporal dementia, Facioscapulohumeral Muscular Dystrophy and potentially more. Common features that are typical to this subclass of conditions are RNA toxic gain-of-function, epigenetic loss-of-function, toxic repeat-associated non-ATG translation and somatic instability. For each mechanism we summarize the currently available stem cell based models, highlight how they contributed to better understanding of the related mechanism, and discuss how they may be utilized in future investigations.

Phenotype variability and early onset ataxia symptoms in spinocerebellar ataxia type 7: comparison and correlation with other spinocerebellar ataxias

Abstract: The spinocerebellar ataxias (SCA) are a group of neurodegenerative disorders characterized by heterogeneous clinical presentation. Spinocerebellar ataxia type 7 (SCA7) is caused by an abnormal CAG repeat expansion and includes cerebellar signs associated with visual loss and ophthalmoplegia. Marked anticipation and dynamic mutation is observed in SCA7. Moreover, phenotype variability and very early onset of symptoms may occur. In this article, a large series of Brazilian patients with different SCA subtypes was evaluated, and we compared the age of onset of SCA7 with other SCA. From the 26 patients with SCA7, 4 manifested their symptoms before 10-year-old. Also, occasionally the parents may have the onset of symptoms after their children. In conclusion, our study highlights the genetic anticipation phenomenon that occurs in SCA7 families. Patients with very early onset ataxia in the context of a remarkable family history, must be considered and tested for SCA7.

Families with both Hodgkin lymphoma and multiple myeloma in their pedigrees.

Abstract: Reports of familial clustering of hematologic malignancies have appeared for decades, but the cause of this uncommon observation is still unknown. Most modern investigations support a genetic rather than an environmental explanation. Clinically, most pedigrees of families with familial hematologic malignancies demonstrate age of onset anticipation (ie, diagnosis at an earlier age in successive generations). The cause of anticipation is clear in some familial neurologic disorders (eg, trinucleotide repeat expansion in Huntington disease) but unclear in familial hematologic malignancies. In preparation for molecular studies on familial clustering of hematologic malignancies, we collected pedigrees on 738 families. In these families, we observed anticipation in those with familial multiple myeloma, chronic lymphocytic leukemia, or non-Hodgkin lymphoma. Here we present preliminary data on 26 families with both multiple myeloma and Hodgkin lymphoma in their pedigrees, and demonstrate strong evidence for anticipation and predominantly male transmission of these neoplasms. We encourage all health care personnel to ask patients about their family's medical history, to take careful family histories from individuals with uncommon illnesses, and to refer families with clustering of such illnesses for investigation.

Genetic Anticipation in Familial Neuromyelitis Optica: Case and Literature Review.

Abstract: Objectives To describe genetic anticipation in a mother and daughter with antiaquaporin 4 (AQP4) antibody-positive neuromyelitisoptica (NMO). Methods Retrospective case review. Results A woman with onset of transverse myelitis at age 38 was found to have a positive AQP4 antibody during work-up of recurrent symptoms. Subsequently, she developed intermittent episodes of monocular vision loss with optic nerve involvement that were treated with intravenous methylprednisolone and chronic rituximab. Eighteen years after initial presentation, her 78-year-old mother, with a history of recurrent urinary tract infections, also developed monocular vision loss and her anti-AQP4 antibody was positive. Previous reports of genetic anticipation in familial NMO are identified and discussed. Conclusions These cases highlight genetic anticipation in familial NMO. Disease onset can occur with a chronological age difference of as much as 40 years between parent and child. Patients with NMO should be counseled regarding the possibility of subsequent disease onset in family members, particularly parents, with significant differences in calendar or chronological year of onset.

The hidden story behind gender differences in familial amyloid polyneuropathy (FAP) ATTRV30M

Abstract: Background Familial amyloid polyneuropathy (FAP ATTRV30M) is an autosomal dominant systemic amyloidosis, due to a point mutation in the transthyretin (TTR) gene (chr18q12.1). The most frequent one, V30M is associated with several clusters. Among Portuguese families, FAP shows a wide variation in in age-at-onset (AO) [19-82 yrs] and this variability is also apparent between generations. Also, significant differences in AO regarding gender are known in Portuguese series, where women were found to have a later-onset than men. Moreover, mother-son pairs showed larger anticipation (> 10 yrs) while the father-daughter pairs only showed residual anticipation. Therefore, to unravel these gender-related differences in AO, we studied three candidate-genes (AR, HSD17B1 and BGN) linked to sex-steroid hormones or X-linked as genetic modifiers of AO. We also evaluated if mitochondrial DNA (mtDNA) copy number is associated with AO.

The place of pediatrician monitoring these pregnancies, the antenatal consultation, from prematurity to psychosocial apprehension risk

Abstract: At the time of networked care organizations, especially during the existence of vulnerabilities identified such as the existence of maternal or parental psychiatric disorders more broadly, the pediatrician is part of the actors of pregnancy care, anticipation of birth and postnatal support.

Anticipation as a Biological Phenomenon

Abstract: Anticipation means the increased severity and earlier age at onset of a particular disease, or the increased risk for that disease, with every new generation (1).

[Clinical variability of Juvenile Huntington's Disease phenotype].

Abstract: Huntington's disease is rare, genetically determinated, neurodegenerative disorder. It is determined by dynamic mutation of IT15 gene on short arm of 4 chromosome. Characteristic symptomatology include involuntary movements, cognitive decline and wide spectrum of mood and behaviour disorders. It typically becomes noticeable in mid-adult life, but there are reported cases of appaers of symptoms between 2 and 80 year of life. Especially interesting is juvenile Huntington's disease- the Westphal variant with the beginning in childchood (before 20 year of age) because of clinical differences causing diagnostic difficulties. It affects 5-10% of carries of the mutant gene. Symptoms became noticeable before 10 year of age only in 1% of them.

The Myotonic Dystrophies

Abstract: Myotonic dystrophy is a progressive, multi-systemic condition causing muscle weakness and myotonia. Additional symptoms include cataracts, gastrointestinal abnormalities, male reduced fertility, diabetes, and cardiac conduction defects. Myotonic dystrophy type 1 (DM1) is caused by a CTG expansion in the DMPK gene and type 2 (DM2) by a CCTG repeat expansion in the ZNF9 gene. Whereas age of onset correlates with repeat size in DM1 with anticipation, onset and severity do not correlate well with the repeat expansion size in DM2. The non-dystrophic myotonic disorders produce myotonia without muscle weakness. These conditions are caused by mutations in ion channel genes.

Overview of Adult Muscular Dystrophies

Abstract: The muscular dystrophies (MD) are a group of genetic disorders causing deterioration of normal muscle structure. Although MD principally affect skeletal muscles, many forms of MD also affect the heart, smooth muscle, brain, eye, gastrointestinal tract, and reproductive and endocrine systems. The heterogeneity between and within different subtypes of muscular dystrophy causes challenges in genetic diagnosis and prognosis. Many genetic phenomena, such as anticipation, germline mosaicism, and pleiotropy, can be seen in these conditions. This section discusses the clinical presentation, genetics, and genetic counseling issues of several forms of adult muscular dystrophy.

Genetics of Dominant Ataxias

Abstract: Dominant ataxias represent a clinically and genetically heterogeneous group of hereditary disorders comprising autosomal dominant spinocerebellar ataxias (ADCAs, SCAs) and episodic ataxias (EAs). From the clinical point of view, patients with ADCA exhibit a progressive cerebellar syndrome, either isolated or in combination with extra-cerebellar deficits. EAs are characterized by recurrent episodes of dizziness and ataxia, occurring either in a context of interictal neurological deficits or not. Current genetic classification includes 32 SCA loci (numbered from SCA1 to SCA36, plus dentatorubropallidoluysian atrophy DRPLA) and 7 EA loci (numbered from EA1 to EA7). A group of 12 ADCAs are related to an expansion of CAG repeats (polyglutaminopathies) or to repeats outside the coding region. Disease progression and severity are correlated with the repeat size. Anticipation is due to an instability of the expanded allele during transmission. The other ADCAs are due to conventional gene mutations. Overall, the causative gene is identified in about 60 % of dominant ataxias. There is still no cure for this group of disabling degenerative diseases. Current management is symptomatic.

AB181. Telomere shortening is associated with genetic anticipation in Chinese Von Hippel-Lindau disease families

Abstract: Objective Von Hippel-Lindau (VHL) disease is a rare autosomal dominant cancer syndrome. A phenomenon known as genetic anticipation has been documented in some hereditary cancer syndromes, where it was proved to relate to telomere shortening. Because studies of this phenomenon in VHL disease have been relatively scarce, we investigated anticipation in 18 Chinese VHL disease families.

Long anticipation complicates identifying Lynch syndrome in monozygotic twins

Abstract: Anticipation is a term used to express an earlier age of disease onset in successive generations. Patients with Lynch syndrome (LS) harbor mutations in MMR genes that appear to be associated with the phenomenon where disease is diagnosed 5–12 years earlier in mutation carrying children compared with their affected parent. This has the potential to complicate the recognition of LS as defined by the Amsterdam criteria (or iterations of it) in young probands affected by colorectal cancer. In this report, we describe a case of an LS family with an MLH1 mutation (c.1748 del T). The phenomenon of anticipation was observed in the son of a monozygotic twin who developed two colon cancers that were diagnosed at an age 20 years earlier than the first diagnosis of cancer in his mother. Both the mother and her twin went on to simultaneously develop a rectal carcinoma.