Showing papers on "Anticipation (genetics) published in 2008"

Mitotic and meiotic stability of the CAG repeat in the X-linked spinal and bulbar muscular atrophy gene

Abstract: X-linked spinal and bulbar muscular atrophy (SBMA) occurs due to an expansion of the trinucleotide repeat (CAG)n in the androgen receptor gene. Anticipation is relatively rare in SBMA in contrast to spinocerebellar ataxia type 1 (SCAl), and dentatorubral and pallidoluysian atrophy (DRPLA) which show obvious paternal anticipation. The differences in the CAG repeat number were compared among sperm, leukocytes and skeletal muscles of SBMA patients. In SBMA, the sperm of most patients and the skeletal muscle of all patients showed the same repeat number as their leukocytes, whereas the increase in the repeat number from leukocytes to sperm was evident in SCA1 and DRPLA patients. The higher mosaicism level in sperm compared with leukocytes was common in SBMA, SCA1 and DRPLA, and the level of sperm was lower in SBMA than in SCA1 and DRPLA. Thus, spermatogenesis was suggested to be strongly associated with paternal anticipation. The mosaicism level was smaller in SBMA than in other (CAG)n expanded disorders, and smallest in the SBMA carrier females. These findings demonstrate that the CAG repeat in SBMA is relatively stable in mitotic and meiotic, processes, and there is a possibility that the lower mosaicism level of the carrier females compared with the SBMA patients is associated with X-linked recessive inheritance.

An autosomal dominant genetically heterogeneous variant of rolandic epilepsy and speech disorder.

Abstract: We report a three generation pedigree with 11 of 22 affected with a variant form of rolandic epilepsy, speech impairment, oromotor apraxia, and cognitive deficit. The core features comprised nocturnal rolandic seizures, interictal centrotemporal spike waves with early age of onset and late age of offset. The transmission of the phenotype was consistent with autosomal dominant inheritance, with variable expressivity but no evidence of anticipation. We found evidence that the seizure and speech traits may be dissociated. No abnormalities were found by cytogenetic analysis. Linkage analysis excluded loci at 11p, 15q, 16p12, and Xq22 for related phenotypes, suggesting genetic heterogeneity.

A genetic and statistical study of some sex‐related factors in Huntington's disease

Abstract: From an analysis of published sibships containing at least one subject with Huntington's disease, evidence was obtained from segregation ratios derived from several hypothetical modes of ascertainment that single-membered sibships are less likely to be recorded than those containing at least two affectcd persons and that the probability of reporting a sibship is proportional to the number of affected siblings Familial sex-limitation and partial sex-linkage could not be detected in the sample Investigation of parental and grandparcntal lines ol transmission revealed that patrilineal descent predominated for all subjccts except unaffected daughters Mcan ages at onset and death wcrc independent of the 5ex of the subject or the tranymitting parent On the other hand, the offspring of affected males suffered from the disorder for a shorter period of time than offspring of affccted females Ages at onsct and death varied significantly from generation to generation, presumably because parents are ofren ascertained through their children in the literature and the phenomenon of anticipation thereby arises Onset age was earlier in members of small sihships than in those of large sibships This could be related to the earlier onset age of parents producing small families compared with those producing large families

Does proximal myotonic myopathy show anticipation

Abstract: Proximal myotonic myopathy (DM2, PROMM) has not been reported in patients younger than 18 years, and apparent lack of congenital and childhood forms is thought to be one of the distinctive clinical characteristics of this trait. We now describe a 2-year-old boy, the youngest member of a family with a history for myotonia in 2 generations. The patient's 35-year-old mother was diagnosed with DM2 of late juvenile onset. She developed aggravating myotonic symptoms during pregnancy. Remarkably few intrauterine child movements were noticed. After birth the child showed general muscular hypotonia with delayed statomotoric development (sitting and crawling at 13 months, first lifting into standing position at 18 months). Muscle reflexes were normal. In the CL3N58 region of ZNF9, DM2-typical unstable expanded CCTG arrays of about 14.5 kb (about 2,500 repeats) were detected both in the mother and the patient by Southern blotting. Expansion of the DM1-specific DMPK CTG repeat was excluded. © 2008 Wiley-Liss, Inc.

Very early onset Huntington's disease: genetic mechanism and risk to siblings.

Abstract: A study of very early onset Huntington's disease (VEOHD) has shown that at least 38% of gene-carrying sibs also develop symptoms before the age of 10, thus improving the genetic risk for those sibs who remain healthy. The prevalence of VEOHD among sibs shows that mutation during spermatogenesis is most unlikely to account for these uncommon cases. The data suggest that two mechanisms contribute to VEOHD: modification by many genes (individually of small effect), and an epigenetic mechanism occurring when transmission is through a series of males.

Enfermedad de Steinert. Presentación de un paciente

Abstract: Myotonic dystrophy (DM) or Steinert's disease is the most common muscular dystrophy in adults, and is the second most common muscular dystrophy after Duchenne muscular dystrophy. It is an autonomus dominant genetic disorder affecting one of each 8000 individuals. Onset is usually in the second or third decade and the life span of affected individuals is typically six decades. It is characterized by weakness and muscular atrophy of the voluntary muscles of the eyes, face, neck, arms and legs, myotonia, posterior subcapsular iridescent cataracts, nervous conduction defects, endocrine changes, cognitive deficit and frontal bald. Muscles related to involuntary activities such as swallowing and breathing, as well as those surrounding the internal organs such as the upper and lower digestive tracts, the urinary bladder, and the uterus may also be affected as the disease progresses in an individual. The disease shows the genetic phenomenon of potentialization and anticipation. We show a patient´s case, that arrived to our clinic suffering from muscular atrophy for more than fifteen years. Because of clinical features the diagnosis of Steinert´s diseases was suspected. A review of the most common clinical features of this disease was done. The patient was examined by the neurologist, ophthalmologist, neurophysiologist, genetics and family doctors and it was found that the clinical and neurophysiological features indicated the presence of the Steiner´s disease. All studies made sure the diagnose of Steinert´s disease. It was found during the medical interview that his father and his older brother suffered from the same symptoms of the disease, which had begun around the forty years. Both of them died because of other causes.

[Anticipation in bipolar disorder: A comparison between two generations].

Abstract: OBJECTIVE: The genetic phenomenon of anticipation is a pattern of inheritance that includes earlier age at onset and increased severity of symptoms in succeeding generations, and is a feature of some neurodegenerative diseases. This phenomenon is suggested to occur in bipolar disorder (BP) as well. METHOD: Anticipation in children with BP type 1 (s2) (n = 31) and their parents (s1) (n = 31) not-consecutive generations-was assessed by analyzing clinical characteristics and prognoses. RESULTS: Age at onset of BP type 1 in s2 (mean: 19.3 +/- 4.2 years) occurred earlier than in s1 (mean: 29.5 +/- 10.2 years) (u = 345, P < 0.001). There was a direct negative correlation between the s1 and s2 cases (r = -0.554, P < 0.001). The total number of episodes in s1 (13.9 +/- 12.3) was greater than in s2 (8.7 +/- 7), which had a higher frequency of episodes (0.6 +/- 0.3 and 1.5 +/- 1.2) (u = 357, P < 0.001). There was a direct correlation between total episodes and the frequency of manic episodes between s1 and s2 (r = 0.312, P < 0.001 and r = 0.365, P < 0.001, respectively). We observed that 72.7% of BP type 1 parents that had episodes with psychotic features had offspring that had episodes with psychotic features. CONCLUSIONS: Results of this study show that age at onset was earlier and the frequency of episodes was greater in s2 BP type 1 cases. In addition, episodes with psychotic features might be a marker for genetic anticipation.

Molecular and genetic analysis of spinocerebellar ataxia type 10 (SCA10)

Abstract: Spinocerebellar ataxia type 10 (SCA10) is a dominantly inherited neurodegenerative disease caused by expansion of the ATTCT pentanucleotide repeat in intron 9 of a novel gene, ATXN10, on chromosome 22q13.3. It is clinically characterized by progressive ataxia, seizures, and anticipation, which can vary within and between families. The length of the expanded ATTCT repeats is highly unstable on paternal transmission and shows a variable degree of somatic and germline instabilty, revealing complex SCA10 genetic mechanisms. Moreover, the purity of the expanded repeat element may be a disease modifier. ATTCT repeats have been recently shown to form unpaired DNA structure and may serve as an aberrant DNA replication origin, potentially contributing to repeat instability and cell death. How this untranslated ATTCT expansion leads to neurodegeneration has been still controversial. We discuss several possible pathogenic mechanisms for SCA10, and growing number of evidence indicates a gain-of-function RNA mechanism, similar to the myotonic dystrophies caused by non-coding CTG or CCTG repeat expansions.

PERINATAL/NEONATAL CASE PRESENTATION Pregnancy and active Huntington disease: a rare combination

Abstract: Huntington disease (HD) is an adult-onset autosomal dominant disorder characterized by progressive deterioration of intellectual function, bradykinesia, rigidity and progressive chorea. It is rare, occurring with a prevalence of approximately 4 to 8 per 100 000 worldwide. Affected individuals have an increase in the number of CAG (cytosine-adenine-guanine) triplet repeats in the Huntingtin gene on chromosome 4. Individuals with inherited disease have more than 35 repeats, whereas normal individuals will have 10 to 35 CAG repeats. The age of symptom onset, on average at age 40, correlates with the number of repeats. Patients with paternal inheritance may experience anticipation and have a dramatic increase in the number of repeats, and may therefore have an earlier disease onset. Although symptomatic HD patients are rarely encountered during pregnancy due to its late onset, the shift toward older maternal age means obstetricians will more likely encounter pregnant patients with HD. A search of the entire PubMed literature (January 1966 to August 2007; search terms: Huntington disease and pregnancy) yielded 203 reports focusing mainly on prenatal diagnosis and counseling among healthy individuals at risk for HD. However, none of these reports focused on care issues relevant to our patient with a pregnancy complicated by advanced HD. We therefore describe the illustrative complicated course of our patient and discuss related issues and others that may arise in the care of such patients.