Biomedical subjects

Paul Hagerman

Publications and source records attributed to Paul Hagerman.

6 recordsLinked to original sources

PubMed2006

Autism spectrum disorders and attention-deficit/hyperactivity disorder in boys with the fragile X premutation.

Fragile X syndrome (FXS) is caused by a full mutation expansion (>200 CGG repeats) in the FMR1 gene that results in a deficiency of the fragile X mental retardation protein. Although most individuals with the premutation (55-200 CGG repeats) are considered unaffected by FXS, recent case studies have documented children with the premutation who have cognitive deficits, behavioral problems, and/or autism spectrum disorders. The objective of this study was to compare the prevalence of autism spectrum disorders (ASD) and attention-deficit hyperactivity disorder (ADHD) symptoms in boys with the premutation who presented as probands, in brothers with the premutation who did not present as probands, and in normal brothers of premutation and/or full mutation carriers. Participants included 43 male children: 14 probands who presented to clinic, 13 nonprobands who were identified through cascade testing (routine genetic testing of family members after identification of a proband) and confirmed to have the premutation, and a control group of 16 male siblings of individuals with the fragile X premutation or full mutation who were negative for the FMR1 mutation. Participants came from 1 of 2 collaborative sites: University of California, Davis and La Trobe University in Australia. Parents completed the Conners' Global Index-Parent Version for assessing symptoms of ADHD and the Social Communication Questionnaire (SCQ) for identifying symptoms of ASD. Children who were in the ASD range on the SCQ (n = 13) underwent further evaluation with either the Autism Diagnostic Observation Schedule-Generic (n = 10) or the Autism Diagnostic Interview-Revised (n = 3). A final diagnosis of ASD included clinical assessment utilizing DSM-IV-TR criteria in addition to the standardized assessments. There was a higher rate of ASD in boys with the premutation presenting as probands (p < 0.001) or nonprobands (p < .04) compared with sibling controls without the premutation. In addition, probands had a significant increase in ADHD symptoms compared with controls (p < .0001). Of the probands, 93% had symptoms of ADHD and 79% had ASD. In the nonproband premutation group, 38% had symptoms of ADHD and 8% had ASD. Thirteen percent of sibling controls had symptoms of ADHD and none had ASD. IQ scores were similar in all 3 groups (p = .13), but the use of psychotropic medications was significantly higher in probands with the premutation compared with that in controls (p < .0001). Developmental problems have been observed in premutation carriers, particularly those who present clinically with behavioral difficulties. Although this study is based on a small sample size, it suggests that premutation carriers, even those who do not present clinically, may be at increased risk for an ASD and/or symptoms of ADHD. If the premutation is identified through cascade testing, then further assessment should be carried out for symptoms of ADHD, social deficits, or learning disabilities.

Adolescent↗

PubMed2006

Dementia with mood symptoms in a fragile X premutation carrier with the fragile X-associated tremor/ataxia syndrome: clinical intervention with donepezil and venlafaxine.

The authors present a case of a patient with dementia with mood symptoms and multiple neurological manifestations of fragile X-associated tremor/ataxia syndrome (FXTAS). Despite a gradually deteriorating neurological course, he was managed for 2 years with combination therapy of donepezil and venlafaxine, which resulted in improvement and relative stabilization of his psychiatric status. Psychiatrists are hereby alerted to the description of a novel dementia syndrome that may respond to pharmacological intervention commonly used for other dementias.

Aged↗

PubMed2005

An enhanced polymerase chain reaction assay to detect pre- and full mutation alleles of the fragile X mental retardation 1 gene.

Several diagnostic strategies have been applied to the detection of FMR1 gene repeat expansions in fragile X syndrome. Here, we report a novel polymerase chain reaction-based strategy using the Expand Long Template PCR System (Roche Diagnostics, Mannheim, Germany) and the osmolyte betaine. Repeat expansions up to approximately 330 CGGs in males and up to at least approximately 160 CGGs in carrier women could be easily visualized on ethidium bromide agarose gels. We also demonstrated that fluorescence analysis of polymerase chain reaction products was a reliable tool to verify the presence of premutation and full mutation alleles both in males and in females. This technique, primarily designed to detect premutation alleles, can be used as a routine first screen for expanded FMR1 alleles.

Alleles↗

PubMed2003

Transformation and normalization of oligonucleotide microarray data.

MOTIVATION: Most methods of analyzing microarray data or doing power calculations have an underlying assumption of constant variance across all levels of gene expression. The most common transformation, the logarithm, results in data that have constant variance at high levels but not at low levels. Rocke and Durbin showed that data from spotted arrays fit a two-component model and Durbin, Hardin, Hawkins, and Rocke, Huber et al. and Munson provided a transformation that stabilizes the variance as well as symmetrizes and normalizes the error structure. We wish to evaluate the applicability of this transformation to the error structure of GeneChip microarrays. RESULTS: We demonstrate in an example study a simple way to use the two-component model of Rocke and Durbin and the data transformation of Durbin, Hardin, Hawkins and Rocke, Huber et al. and Munson on Affymetrix GeneChip data. In addition we provide a method for normalization of Affymetrix GeneChips simultaneous with the determination of the transformation, producing a data set without chip or slide effects but with constant variance and with symmetric errors. This transformation/normalization process can be thought of as a machine calibration in that it requires a few biologically constant replicates of one sample to determine the constant needed to specify the transformation and normalize. It is hypothesized that this constant needs to be found only once for a given technology in a lab, perhaps with periodic updates. It does not require extensive replication in each study. Furthermore, the variance of the transformed pilot data can be used to do power calculations using standard power analysis programs. AVAILABILITY: SPLUS code for the transformation/normalization for four replicates is available from the first author upon request. A program written in C is available from the last author.

Algorithms↗

PubMed2003

Tremor and ataxia in fragile X premutation carriers: blinded videotape study.

Fragile X premutation carriers do not have typical fragile X syndrome (FXS) although late-onset progressive action tremor and gait disorder with CNS atrophy was recently reported in male carriers. We compared tremor, gait disorder and parkinsonian signs in FXS premutation subjects (age 50 or more) and a similar control population, using a standardized videotaping protocol. Videotapes were rated using standard scales for tremor (CRST), ataxia (ICARS), and parkinsonian signs (UPDRS) by an investigator blinded to premutation status. Compared to all other groups pooled (n = 30), the male premutation carrier group (n = 7) had significantly higher scores on the CRST (p = 0.0008), ICARS (p = 0.001), and UPDRS (p = 0.0094). On the CRST, rest, postural and kinetic tremor scores were all higher in the male carriers. The elevated total UPDRS and ICARS scores mainly resulted from markedly higher scores for tremor and limb ataxia, respectively. The female carrier (n = 14) and control groups (n = 8) did not differ on any measure. The FMR1 premutation is associated with increased levels of CGG repeat-containing FMR1 mRNA, which may predispose to these symptoms by interfering with nuclear mechanisms. Given the relatively high population frequency of the FMR1 premutation, this mutation may be a significant cause of late-onset "idiopathic" progressive tremor.

Aged↗

PubMed2002

Reduced FMR1 mRNA translation efficiency in fragile X patients with premutations.

The Fragile X mental retardation gene (FMR1) contains a polymorphic trinucleotide CGG repeat in the 5' untranslated region (UTR) of the FMR1 messenger. We have characterized three lymphoblastoid cell lines derived from unrelated male carriers of a premutation that overexpress FMR1 mRNA and show reduced FMRP level compared to normal cells. The analysis of polysomes/mRNPs distribution of mRNA in the cell lines with a premutation shows that the polysomal association of FMR1 mRNA, which is high in normal cells, becomes progressively lower with increasing CGG repeat expansion. In addition, we could detect a very low level of FMR1 mRNA in a lymphoblastoid cell line from a patient with a full mutation. In this case, FMR1 mRNA is not at all associated with polysomes, in agreement with the complete absence of FMRP. The impairment of FMR1 mRNA translation in patients with the Fragile X syndrome with FMR1 premutation is the cause of the lower FMRP levels that leads to the clinical involvement.

Cell Line↗