Randi Hagerman, M.D.

 Randi  Hagerman, M.D.


  • Professor
  • Pediatrics

Genotype-Phenotype Relationships in Fragile X Syndrome

Research Summary

A central focus of my research is on genotype- phenotype relationships in fragile X syndrome. Fragile X is the leading inherited cause of mental retardation, but it also causes learning disabilities and emotional problems in those who do not have mental retardation. Our previous research has demonstrated that variations in the FMR1 gene are significantly correlated with clinical involvement. We presently utilize a quantitative immunocytochemical technique to quantify the level of protein produced from the FMR1 gene in any given patient. Correlations between FMRP and IQ level have been significant in both males and females affected by fragile X syndrome. We are also interested in secondary gene effects which can modify the clinical presentation. We are currently funded by NICHD to study genotype-phenotype relationships with a focus on autism in children, and emotional difficulties in adults with fragile X. Although autism is associated with fragile X, we are studying whether additional genetic effects could be additive and worsen the expression of social deficits in fragile X.

We have recently identified a new syndrome in older male carriers who have the premutation for fragile X. The premutation consists of 50-200 CGG repeats within the FMR1 gene. We have recently reported intension tremor, ataxia, cognitive deficits and a peripheral neuropathy in a limited number of male carriers who are older than 50. We are presently carrying out epidemiological studies to characterize the prevalence of this syndrome among carriers of fragile X. We are also carrying out neuropathological studies with Dr. Claudia Greco in individuals who have suffered from this disorder during their life. Further molecular studies including the presence of elevated messenger RNA are being carried out by Dr. Paul Hagerman and Dr. Flora Tassone in collaboration with us. We are also assessing the possibility of secondary gene effects working in conjunction with the FMR1 premutation to lead to this syndrome.

The treatment of children and adults with neurodevelopmental disorders is also a focus of our research. We are carrying out a study of the use of melatonin to treat individuals with autism, fragile X, or other neurodevelopmental disorders who have a sleep disturbance. Additional psychopharmacological trials will be set up through the M.I.N.D. Institute including the use of ampakines to treat cognitive deficits in individuals with autism, fragile X, and other developmental disabilities. In the future, we hope to utilize both psychophysiological measures and neuroimaging studies to characterize the treatment outcome of children in a variety of psychopharmacological protocols.

Select Publications

Simon JA, Keenan JM, Pennington BF, Taylor AK, Hagerman RJ. (2001) Discourse processing in women with fragile X syndrome: Evidence for a deficit establishing coherence. Cognitive Neuropsychology 18(1),1-18

Mangeot SD, Miller LJ, McIntosh DN, McGrath-Clark J, Simon J, Hagerman RJ, Goldson E. (2001) Sensory modulation dysfunction in children with attention-deficit-hyperactivity disorder. Developmental Medicine & Child Neurology 43:399-406

Tassone F, Hagerman RJ, Taylor AK, Hagerman PJ. (2001) A majority of fragile X males with methylated, full mutation alleles have significant levels of FMR1 messenger RNA. J Med Genet. 38:0-3

Hagerman RJ, Leehey M, Heinrichs W, Tassone F, Wilson R, Hills J, Grigsby J, Gage B, Hagerman PJ. (2001) Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology 57:127-130

Simon JA, Keenan JM, Pennington BF, Taylor A, Hagerman RJ. (2001) Discourse processing in women with fragile X syndrome: Coherence. Cognitive Neuropsychology 18:1-18.

Bennetto L, Pennington BF, Porter D, Taylor AK, Hagerman RJ. (2001) Profile of cognitive functioning in women with the fragile X mutation. Neuropsychology 15:290-299.

Gould EL, Loesch DZ, Martin MJ, Hagerman RJ, Armstrong SM, Huggins RM. (2000) Melatonin profiles and sleep characteristics in boys with fragile X syndrome: A preliminary study. Am J Med Genet 95:307-315.

Tassone F, Hagerman RJ, Chamberlain WD, Hagerman PJ. (2000b) Transcription of the FMR1 gene in individuals with fragile X syndrome. Am J Med Genet (Semin. Med. Genet.) 97:195-203.

Tassone F, Hagerman RJ, Loesch D, Lachiewicz A, Taylor A, Hagerman PJ. (2000a) Fragile X males with unmethylated full mutation trinucleotide repeat expansion have elevated levels of FMR1 messenger RNA. Am J Med Genet 94:232-236.

Tassone F, Hagerman RJ, Taylor AK, Mills JB, Harris SW, Gane LW, Hagerman PJ. (2000) Clinical Involvement and Protein Expression in Individuals with the FMR1 Premutation. Am J Med Genet 91:144-152.

Tassone F, Hagerman RJ, Taylor AK, Gane LW, Godfrey T, Hagerman PJ. (2000b) Elevated levels of FMR1 messenger RNA in carrier males: A new mechanism of involvement in fragile X syndrome. Am J Human Genet 66:6-15.