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BRIEF COMMUNICATIONS: R. J. Hagerman, M. Leehey, W. Heinrichs, F. Tassone, R. Wilson, J. Hills, J. Grigsby, B. Gage, and P. J. Hagerman Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X Neurology 2001; 57: 127-130 [Abstract] [Full text] [PDF]

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Reply to Munoz

RJ Hagerman, "C Greco, M Leehey, S Jacquemont, P Hagerman"   (24 October 2001)

Adult-onset neurodegeneration in Fragile X syndrome

David G Munoz   (15 October 2001)

Reply to Munoz 24 October 2001
RJ Hagerman M.I.N.D. Institute, UC Davis Medical Center, "C Greco, M Leehey, S Jacquemont, P Hagerman" Send Correspondence to journal: Re: Reply to Munoz randi.hagerman{at}ucdmc.ucdavis.edu RJ Hagerman, et al.	Dear Editor: We are aware of the Desai [1] study of a man with fragile X syndrome (FXS) who also had ALS. This case appears to be the coincidental occurrence of ALS in a patient with FXS. Previous neuropathological reports in FXS have shown limited neuronal cell loss and gliosis [2], although neuronal cell death in the substantia nigra has not previously been reported in FXS. There is evidence, however, of shrinkage of the temporal lobes and dilation of the ventricles with age that is more remarkable in FXS compared to what is seen in controls [3]. Further neuroanatomical studies in those with the full mutation and those with the premutation are needed. There are no reports of neurodegeneration in patients with the full FXS with ALS other than the case reported by Desai [1]. In contrast, the neurological syndrome in older men with the premutation that we reported [4] has been observed in other cases. We have since seen this tremor ataxia syndrome in nine other men and have the medical records on an additional eight cases who died after a neurodegenerative course. Further epidemiology studies are needed to clarify the prevalence of this problem in both men and women with the premutation. It is unclear whether this condition is related to the elevated mRNA in these males but studies are in progress. The neuropathology in this tremor/ataxia syndrome are also being examined. There is no megalencephaly or loss of neurons in the substantia nigra, indicating a different mechanism of pathogenesis than what was reported or discussed by Munoz. References: 1. Desai HB,Donat J, Shokeir MH, Munoz DG. Amyotrophic lateral sclerosis in a patient with fragile X syndrome. Neurology 1990; 40:378-80. 2. Sabaratnam M. Pathological and neuropathological findings in two males with fragile X syndrome. J Intell Disabil Res 2000; 44:81-85. 3. Reiss AL, Abrams MT, Greenlaw R, Freund L, Denckla MB. Neurodevelopmental effects of the FMR-1 full mutation in humans. Nature Medicine 1995; 1:159-67. 4. Hagerman RJ, Leehey M, Heinrichs W, Tassone F, Wilson R, Hills J, Grigsby J, Gage B, Hagerman PJ. Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology 2001; 57:127- 130.
Adult-onset neurodegeneration in Fragile X syndrome 15 October 2001
David G Munoz, Neurologist Hospital Ruber Internacional, Madrid, Spain Send Correspondence to journal: Re: Adult-onset neurodegeneration in Fragile X syndrome dave_munoz{at}yahoo.com David G Munoz	Hagerman et al have described a syndrome characterized by intention tremor, parkinsonism, executive function disturbances, and generalized brain atrophy in male carriers of the fragile X syndrome [1]. Autopsies were not available. It may be of interest to consider a previous report of a progressive neurodegenerative disease of adult onset in a patient with the characteristic fragile X phenotype and cytogenetically proven fragile X chromosome. At age 39 this man developed dysarthria and spasticity, and by age 40 he was anarthic and unable to stand. In addition to muscle atrophy, fasciculations, increased tone and hyperreflexia, examination showed focal and generalized myoclonic jerks. There was generalized slowing on EEG and cerebral atrophy on CT scan. Autopsy, obtained after death at age 41, showed typical features of amyotrophic lateral sclerosis (ALS), along with megalencephaly (1850 g), evidence of neuronal death in the substantia nigra, and loss of small neurons and gliosis in the neostriatum . Clinical and pathological diagnosis was ALS with atypical features [2]. Thus, both male carriers and patients expressing the full fragile X syndrome can develop neurodegenerative diseases as adults and those diseases may not fit neatly into established categories. By analogy with the fragile X patient, it can be predicted that histological examination of the brains of the fragile X carriers reported by Hagerman et al. will show neuronal loss and gliosis in the absence of beta-amyloid, tau, or alpha-synuclein deposition. This raises questions concerning shared pathogenetic mechanisms among the several neurodegenerative diseases and the role of elevated FMR1 messenger RNA in their development. Reference List 1. Hagerman RJ, Leehey M, Heinrichs W, Tassone F, Wilson R, Hills J et al. Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology 2001; 57:127-130. 2. Desai HB, Donat J, Shokeir MH, Munoz DG. Amyotrophic lateral sclerosis in a patient with fragile X syndrome. Neurology 1990; 40:378- 380.