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ataxia syndrome and fragile X premutation: Diagnostic caveats
Journal of Clinical Neuroscience 14 (2007) 245–248 www.elsevier.com/locate/jocn
Short communication
Tremor/ataxia syndrome and fragile X premutation: Diagnostic caveats D.Z. Loesch b
a,*
, L. Litewka b, A. Churchyard c, E. Gould a, F. Tassone d, M. Cook
b
a School of Psychological Science, La Trobe University, Bundoora, Melbourne, Victoria 3086, Australia Department of Clinical Neuroscience and Neurological Research, St Vincent’s Hospital & University of Melbourne, Fitzroy, Victoria, Australia c Southern Health Network, Victoria, Australia d Biochemistry and Molecular Medicine, University of California at Davis, CA, USA
Received 1 November 2005; accepted 9 January 2006
Abstract The fragile X-associated tremor/ataxia syndrome (FXTAS) is a newly discovered late-onset neurodegenerative disorder caused by a premutation in the FMR1 X-linked gene. We present examples of a discrepancy between obvious brain changes observed on MRI, and minimal clinical neurological manifestations in three older carriers of this premutation. This discrepancy occurred in three of nine carriers ascertained in an unbiased manner. If the systematic follow-up studies of adult carriers confirm this trend, this will have an impact on early diagnosis of neurological involvement and possible prevention. If MRI changes precede clinical manifestation of FXTAS this may explain the low detection rate of fragile X carriers among patients with neurological syndromes associated with tremor/ataxia. Ó 2006 Elsevier Ltd. All rights reserved. Keywords: Fragile X; FMR1 premutation carriers; Tremor/ataxia; Magnetic resonance imaging; Neurodegeneration
1. Introduction The fragile X-associated tremor/ataxia syndrome (FXTAS) is a newly discovered late-onset neurodegenerative disorder.1 It is caused by a small expansion of a CGG repeat located in the 5’ untranslated region of the FMR1 X-linked gene,2 from the normal (6– 40) to the expanded (55–200) range, defined as premutation.3,4 The diagnostic criteria of FXTAS comprised intention tremor and ataxia, cognitive decline, and the presence of white matter lesions of the middle cerebellar peduncles (MCP).1,5 Other changes revealed by magnetic resonance imaging (MRI) include widespread cerebellar and cerebral white matter and cortical atrophy, and a significant reduction of cerebral, cerebellar, and cerebral cortex volumes.5–9 A loss of cerebrum volume was significantly associated with the size of CGG repeat.9 The neurohistological
*
Corresponding author. Tel.: +61 3 94791382; fax: +61 3 94791956. E-mail address: [email protected] (D.Z. Loesch).
0967-5868/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2006.01.015
changes were ubiquitin-positive intranuclear inclusions abundant in both neuronal and astrocytic nuclei throughout the brain.10 The elevation of FMR1 mRNA, and a slight reduction of this gene’s protein (FMRP), was demonstrated in blood lymphocytes.11,12 A model, which assumes that an expanded repeat in an RNA transcript exerts a toxic ‘gain-of-function’ effect on cellular metabolism,13 has been considered an explanation for neurodegenerative changes.1,7,10 This model is different from the mechanism involved in fragile X syndrome (FXS) which is associated with intellectual deficit,14 and is caused by a CGG-repeat expansion in excess of 200 repeats on transmissions from daughters of premutation carriers to their offspring.4 These expansions result in silencing of the FMR1 gene, with subsequent gross deficiency of FMRP leading to neurodevelopmental anomaly.15 Based on an estimated prevalence of premutation carriers of 1 in 823 in the general male population,3 and a high (50%) prevalence of obvious tremor/ataxia spectrum among ageing male premutation carriers,7,8 it has been
246
D.Z. Loesch et al. / Journal of Clinical Neuroscience 14 (2007) 245–248
claimed that this condition may be one of the more common single-gene forms of tremor/ataxia in older men, and should thus be considered in their differential diagnosis.7 The earliest screening study of spinocerebellar ataxia (SCA) male patients who were negative for SCA genetic testing showed a significant excess (3/59 patients) of premutation carriers compared with a control series.16 But no significant excess was found in another similar study, where only one individual with premutation was identified among 167 SCA male patients aged >50 years and negative for the relevant genes.17 Screening of 71 patients with essential tremor, 55 patients with SCA, 15 patients with multiple system atrophy (MSA), and 26 patients with atypical parkinsonism failed to detect any FMR1 premutation carriers.18 In another study of 77 Caucasians with a clinical diagnosis of MSA, one male and one female carrying premutation were identified among 55 patients with rapidly progressing cerebellar ataxia and autonomic failure, but none were detected in 22 patients with predominant parkinsonism.19 In the same study, none of the 19 patients with olivopontocerebellar atrophy, or 27 patients with non-specific cerebellar ataxia with cerebellar atrophy, was identified as a FMR1 premutation carrier. This lower than expected yield of premutation among various tremor/ataxia syndromes may be attributed to inadequate information on the broader spectrum of clinical manifestations of FXTAS. The aim of this study is to fill this gap by reporting unusual manifestations in older carriers of FMR1 premutation, with particular emphasis on the relationship between clinical neurological and MRI changes.
2.1. Case 1
2. Case series
2.3. Case 3
All aspects of this study were approved by the ethics committees of La Trobe University, the Royal Children’s Hospital in Melbourne, and the Institutional Board of the University of California at Davis. All participants signed an approved informed consent form. Our observations are based on nine men aged > 50 years carrying a premutation in the FMR1 gene. These men were identified through their descendants diagnosed with FXS, and ascertained irrespective of neurological status. All participants underwent comprehensive neurological and MRI testing, and the results from eight individuals were reported earlier.9 Three individuals in our sample showed close correspondence between the clinical neurological symptoms and MRI status: the most severely affected patient manifested both neurological involvement typical of MSA, and advanced typical MRI white matter changes, including MCP sign; whereas two others were unaffected on both clinical and MRI examination.8,9 Three individuals manifested atypical parkinsonism associated with uncharacteristic MRI changes, as detailed in earlier publications.8,9 Three remaining individuals (presented below) manifested negligible clinical neurological involvement, but obvious white matter changes in MRI.
A man, aged 63, identified through his nephews diagnosed with FXS, suffered from episodes of fatigue with occasional falls over the last 2 years. Otherwise, his medical history was uneventful. Prior to our examination he was seen by a neurologist and reported normal, apart from a ‘slightly positive Romberg test’. On examination, we found slight intention tremor and dysmetria (but no swerve) of the left hand, and moderate body sway while standing with eyes closed. Free walking and tandem walking were normal. His blood pressure was within normal limits, and he did not show any orthostatic hypotension. His IQ was within the normal limits (full scale = 112), he had 99 CGG repeats, and his mRNA level was elevated (2.85). MRI demonstrated a typical bilateral MCP lesion, mild on the right, but marked on the left (Fig. 1).
A 67-year-old grandfather of a boy with FXS had a history of hypertension, hypercholesterolemia, and coronary heart disease. He did not report any neurological problems, and was not seen by a neurologist prior to our testing. On examination, apart from some unsteadiness with eyes closed, mild impairment of writing, and a mild postural and action left hand tremor, his neurological status was normal. His IQ (Wechsler scale) was above normal (full scale = 118), his FMR1 CGG repeat size was 57, and mRNA level showed a five-fold increase (5.99) relative to the normal standard.12 His MRI showed a mild symmetrical MCP lesion, as well as marked symmetrical periventricular white matter changes extending into the subcortical white matter.9 2.2. Case 2 A 53-year-old grandfather of a girl with FXS had a history of dyslexia, asthma and hypertension. For the last 7 years he has suffered from fibromyalgia and anxiety, but did not experience any neurological or memory problems, and had not been seen by a neurologist. On examination we found no neurological abnormalities. His IQ was within the normal limits (full scale = 108), he had 56 CGG repeats, and he had a two-fold increase in mRNA level (2.34). His MRI showed age-unrelated florid symmetrical white matter changes throughout the corona radiata, as well as minimal changes within the MCP.8
3. Discussion The first clinical descriptions of FXTAS based on premutation carriers pre-selected for obvious neurological involvement indicated that the severity of clinical manifestations generally corresponded to the degree of MRI changes.1,5
D.Z. Loesch et al. / Journal of Clinical Neuroscience 14 (2007) 245–248
247
Fig. 1. White matter MRI changes in middle cerebellar peduncles characteristic of fragile x-associated tremor/ataxia syndrome (T2-weighted hyperintense signal within the middle cerebellar peduncle–MCP sign) in Case 3.
In our sample of nine carriers ascertained through their descendants affected with FXS, and recruited irrespective of neurological involvement, only three patients showed close correspondence between clinical features and MRI status, while three other individuals (presented here) manifested an obvious discrepancy between advanced MRI changes and minimal clinical neurological manifestations. One possible reason for this discrepancy is that the MRI anomalies could be explained by other aetiologies, as reviewed elsewhere.20 This is especially relevant in Case 2, where massive periventricular white matter changes were not associated with either increased T2-weighted signal intensity of the middle cerebellar peduncles or tremor/ataxia symptoms. Furthermore, this individual had a history of untreated hypertension, one of the risk factors associated with these types of MRI changes.20 However, the relatively young age of this individual, no history of either ischaemic cerebrovascular or heart disease, or inflammatory process, the severity of MRI changes combined with elevated levels of mRNA, as well as the presence of anxiety and autonomic dysfunction earlier reported in the FXTAS patients,5 all suggest that fragile X premutation is the most likely factor causing, or contributing to the MRI changes observed in Case 2. Clearly, the differential diagnosis is less relevant to the interpretation of MRI signs in Cases 1 and 3, which show the characteristic pattern of abnormalities reported in FXTAS, especially T2 hyperintensities of the MCP. The MCP lesion may develop in a number of other rare disorders, such as olivopontocerebellar atrophy, various forms of autosomal dominant cerebrospinal ataxias or of spinocerebellar degeneration, as well as in Wilson’s disease.6 However, the MCP lesion is usually associated with a number of other MRI anomalies and clinical neurological pre-
sentations, which are characteristic of these respective syndromes, but do not normally occur in fragile X premutation carriers. In the most recent examples of fragile X premutation-unrelated MCP lesion in two unspecified forms of ataxia,21 the pattern of associated clinical manifestations was also not fully consistent with the pattern seen in the affected fragile X premutation carriers. But, in our patients 1 and 3, MRI changes characteristic of FXTAS were associated with subtle but typical clinical manifestations in the form of imbalance and intention tremor. Apart from clinical considerations, the likelihood of the random occurrence of both fragile X premutation and typical MRI changes, in addition to subtle but typical clinical manifestations, in one and the same individual, is negligible. Our findings, although based on a small sample, suggest that MRI changes precede obvious clinical manifestations in some, still unknown, proportion of carriers of an FMR1 premutation. If these findings are confirmed by a more appropriate longitudinal study of larger samples, they will have important implications for early diagnosis of neurological involvement, as well as for revision of the selection criteria used in screening neurological patients. The observed discrepancy between MRI changes and clinical abnormalities could also explain the lower than expected detection rate of premutation carriers in screening of neurological conditions associated with tremor/ataxia.16–19 Cases showing advanced white matter degeneration on MRI, performed as part of our research, would normally not have been referred either to a neurology specialist, or for clinical MRI testing, because of the lack of obvious clinical neurological abnormalities. Thus they would not have been included in any tremor/ataxia groups targeted for premutation screening. At the other end of the spectrum, patients with a well advanced form of the disease, might fall into a
248
D.Z. Loesch et al. / Journal of Clinical Neuroscience 14 (2007) 245–248
‘stroke’ category, and could therefore also be missed in a premutation screening involving only clear-cut tremor/ ataxia syndromes. Our observation that MRI changes precede obvious clinical manifestations in some patients with fragile X-related tremor/ataxia also suggests that neurodegeneration in these individuals may have progressed over a long period. Gradual loss of brain tissue allows for compensation at the clinical level, resulting in minimal neurological impairment, even in the presence of pronounced MRI changes. The abundance of intranuclear inclusions throughout the brain found in well advanced stages of FXTAS10 is consistent with this hypothesis. Although the postulated slow progression of this condition contradicts initial clinical descriptions of FXTAS patients in which fast progression was implicated,1,5 these patients were preselected for severe neurological involvement, consistent with the terminal stage of this condition. In conclusion, we recommend that follow-up clinical and MRI studies be conducted in large samples of adult carriers of the fragile X premutation in order to capture the full spectrum and explain the natural history of neurological involvement in the FMR1 premutation, and to establish the onset of neurodegenerative changes more accurately. Acknowledgement This work was supported by National Institute of Child Health and Human Development grant HD36071 to Dr D. Loesch for the study of genotype-phenotype relationship associated with the fragile X gene and National Medical Research Council of Australia grant No 330400 to Drs D. Loesch, M. Cook and F. Tassone. We thank the study participants and their families for their contributions. Premutation carriers were identified in fragile X families initially diagnosed through the Victorian Genetic Health Services of the Royal Children’s Hospital in Melbourne. References 1. Hagerman RJ, Leehey M, Heinrichs W, et al. Intention tremor, Parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology 2001;57:127–30. 2. Verkerk AJ, Pieretti M, Sutcliffe JS, et al. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 1991;3165:905–14.
3. Dombrowski C, Levesque S, Morel ML, et al. Premutation and intermediate-size FMR1 alleles in 10572 males from the general population: loss of AGG interruptions is a late event in the generation of fragile X syndrome alleles. Hum Mol Genet 2002;11:371–8. 4. Fu YH, Kuhl DPA, Pizzuti A, et al. Variation of the CGG repeat X site results in genetic instability. Resolution of Sherman paradox. Cell 1991;67:1047–58. 5. Jacquemont S, Hagerman RJ, Leehey M, et al. Fragile X premutation tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlates. Am J Hum Genet 2003;72:869–78. 6. Brunberg JA, Jacquemont S, Hagerman RJ, et al. Fragile X premutation carriers: characteristic MR imaging findings in adult males with progressive cerebellar and cognitive dysfunction. Am J Neuroradiol 2002;23:1757–66. 7. Jacquemont S, Hagerman RJ, Leehey MA, et al. Penetrance of the fragile X-associated tremor/ataxia syndrome in a premutation carrier population. JAMA 2004;291:460–9. 8. Loesch DZ, Churchyard A, Brotchie P, et al. Evidence for, and a spectrum of neurological involvement in fragile X premutation: FXTAS and beyond. Clin Genet 2005;67:412–7. 9. Loesch DZ, Litewka L, Brotchie P, et al. Magnetic resonance imaging study in older fragile X premutation male carriers. Ann Neurol 2005;58:326–30. 10. Greco CM, Hagerman RJ, Tassone F, et al. Neuronal intranuclear inclusions in a new cerebellar tremor/ataxia syndrome among fragile X carriers. Brain 2002;125:1760–71. 11. Tassone F, Hagerman RJ, Taylor AK, et al. Clinical involvement and protein expression in individuals with the FMR1 premutation. Am J Med Genet 2000;91:144–52. 12. Tassone F, Hagerman RJ, Taylor AK, et al. Elevated levels of FMR1 mRNA in carrier males: a new mechanism of involvement in fragile X syndrome. Am J Hum Genet 2000;66:6–15. 13. Galvao R, Mendes-Soares L, Camara J, et al. Triplet repeats, RNA secondary structure and toxic gain-of-function models for pathogenesis. Brain Res Bull 2001;56:191–201. 14. Hagerman RJ. The physical and behavioural phenotype. In: Hagerman RJ, Hagerman PJ, editors. Fragile X Syndrome. Diagnosis, Treatment and Research. third ed. Baltimore: John Hopkins University Press; 2002. p. 3–109. 15. Pieretti M, Zhang F, Fu Y-H, et al. Absence of expression of the FMR-1 gene in fragile X syndrome. Cell 1991;66:817–22. 16. Macpherson J, Waghorn A, Hammans S, et al. Observation of an excess of fragile X premutations in a population of males referred with spinocerebellar ataxia. Hum Genet 2003;112:619–20. 17. Milunsky JM. Fragile X carrier screening and spinocerebellar ataxia in older males. Am J Med Genet 2003;125A:320. 18. Tan EK, Zhao Y, Puong KY, et al. Fragile X premutation alleles in SCA, ET and parkinsonism in an Asian cohort. Neurology 2004;63:362–3. 19. Biancalana V, Toft M, Le Ber I, et al. FMR1 premutations associated with fragile X-associated tremor/ataxia syndrome in multiple system atrophy. Arch Neurol 2005;62:962–6. 20. Ketonen LM. Neuroimaging of the aging brain. Neurol Clin N Am 1998;16:581–98. 21. Storey E, Billimoria P. Increased T2 signal in the middle cerebellar peduncles on MRI is not specific for fragile X premutation syndrome. J Clin Neurosci 2005;12:42–3.
Short communication
Tremor/ataxia syndrome and fragile X premutation: Diagnostic caveats D.Z. Loesch b
a,*
, L. Litewka b, A. Churchyard c, E. Gould a, F. Tassone d, M. Cook
b
a School of Psychological Science, La Trobe University, Bundoora, Melbourne, Victoria 3086, Australia Department of Clinical Neuroscience and Neurological Research, St Vincent’s Hospital & University of Melbourne, Fitzroy, Victoria, Australia c Southern Health Network, Victoria, Australia d Biochemistry and Molecular Medicine, University of California at Davis, CA, USA
Received 1 November 2005; accepted 9 January 2006
Abstract The fragile X-associated tremor/ataxia syndrome (FXTAS) is a newly discovered late-onset neurodegenerative disorder caused by a premutation in the FMR1 X-linked gene. We present examples of a discrepancy between obvious brain changes observed on MRI, and minimal clinical neurological manifestations in three older carriers of this premutation. This discrepancy occurred in three of nine carriers ascertained in an unbiased manner. If the systematic follow-up studies of adult carriers confirm this trend, this will have an impact on early diagnosis of neurological involvement and possible prevention. If MRI changes precede clinical manifestation of FXTAS this may explain the low detection rate of fragile X carriers among patients with neurological syndromes associated with tremor/ataxia. Ó 2006 Elsevier Ltd. All rights reserved. Keywords: Fragile X; FMR1 premutation carriers; Tremor/ataxia; Magnetic resonance imaging; Neurodegeneration
1. Introduction The fragile X-associated tremor/ataxia syndrome (FXTAS) is a newly discovered late-onset neurodegenerative disorder.1 It is caused by a small expansion of a CGG repeat located in the 5’ untranslated region of the FMR1 X-linked gene,2 from the normal (6– 40) to the expanded (55–200) range, defined as premutation.3,4 The diagnostic criteria of FXTAS comprised intention tremor and ataxia, cognitive decline, and the presence of white matter lesions of the middle cerebellar peduncles (MCP).1,5 Other changes revealed by magnetic resonance imaging (MRI) include widespread cerebellar and cerebral white matter and cortical atrophy, and a significant reduction of cerebral, cerebellar, and cerebral cortex volumes.5–9 A loss of cerebrum volume was significantly associated with the size of CGG repeat.9 The neurohistological
*
Corresponding author. Tel.: +61 3 94791382; fax: +61 3 94791956. E-mail address: [email protected] (D.Z. Loesch).
0967-5868/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2006.01.015
changes were ubiquitin-positive intranuclear inclusions abundant in both neuronal and astrocytic nuclei throughout the brain.10 The elevation of FMR1 mRNA, and a slight reduction of this gene’s protein (FMRP), was demonstrated in blood lymphocytes.11,12 A model, which assumes that an expanded repeat in an RNA transcript exerts a toxic ‘gain-of-function’ effect on cellular metabolism,13 has been considered an explanation for neurodegenerative changes.1,7,10 This model is different from the mechanism involved in fragile X syndrome (FXS) which is associated with intellectual deficit,14 and is caused by a CGG-repeat expansion in excess of 200 repeats on transmissions from daughters of premutation carriers to their offspring.4 These expansions result in silencing of the FMR1 gene, with subsequent gross deficiency of FMRP leading to neurodevelopmental anomaly.15 Based on an estimated prevalence of premutation carriers of 1 in 823 in the general male population,3 and a high (50%) prevalence of obvious tremor/ataxia spectrum among ageing male premutation carriers,7,8 it has been
246
D.Z. Loesch et al. / Journal of Clinical Neuroscience 14 (2007) 245–248
claimed that this condition may be one of the more common single-gene forms of tremor/ataxia in older men, and should thus be considered in their differential diagnosis.7 The earliest screening study of spinocerebellar ataxia (SCA) male patients who were negative for SCA genetic testing showed a significant excess (3/59 patients) of premutation carriers compared with a control series.16 But no significant excess was found in another similar study, where only one individual with premutation was identified among 167 SCA male patients aged >50 years and negative for the relevant genes.17 Screening of 71 patients with essential tremor, 55 patients with SCA, 15 patients with multiple system atrophy (MSA), and 26 patients with atypical parkinsonism failed to detect any FMR1 premutation carriers.18 In another study of 77 Caucasians with a clinical diagnosis of MSA, one male and one female carrying premutation were identified among 55 patients with rapidly progressing cerebellar ataxia and autonomic failure, but none were detected in 22 patients with predominant parkinsonism.19 In the same study, none of the 19 patients with olivopontocerebellar atrophy, or 27 patients with non-specific cerebellar ataxia with cerebellar atrophy, was identified as a FMR1 premutation carrier. This lower than expected yield of premutation among various tremor/ataxia syndromes may be attributed to inadequate information on the broader spectrum of clinical manifestations of FXTAS. The aim of this study is to fill this gap by reporting unusual manifestations in older carriers of FMR1 premutation, with particular emphasis on the relationship between clinical neurological and MRI changes.
2.1. Case 1
2. Case series
2.3. Case 3
All aspects of this study were approved by the ethics committees of La Trobe University, the Royal Children’s Hospital in Melbourne, and the Institutional Board of the University of California at Davis. All participants signed an approved informed consent form. Our observations are based on nine men aged > 50 years carrying a premutation in the FMR1 gene. These men were identified through their descendants diagnosed with FXS, and ascertained irrespective of neurological status. All participants underwent comprehensive neurological and MRI testing, and the results from eight individuals were reported earlier.9 Three individuals in our sample showed close correspondence between the clinical neurological symptoms and MRI status: the most severely affected patient manifested both neurological involvement typical of MSA, and advanced typical MRI white matter changes, including MCP sign; whereas two others were unaffected on both clinical and MRI examination.8,9 Three individuals manifested atypical parkinsonism associated with uncharacteristic MRI changes, as detailed in earlier publications.8,9 Three remaining individuals (presented below) manifested negligible clinical neurological involvement, but obvious white matter changes in MRI.
A man, aged 63, identified through his nephews diagnosed with FXS, suffered from episodes of fatigue with occasional falls over the last 2 years. Otherwise, his medical history was uneventful. Prior to our examination he was seen by a neurologist and reported normal, apart from a ‘slightly positive Romberg test’. On examination, we found slight intention tremor and dysmetria (but no swerve) of the left hand, and moderate body sway while standing with eyes closed. Free walking and tandem walking were normal. His blood pressure was within normal limits, and he did not show any orthostatic hypotension. His IQ was within the normal limits (full scale = 112), he had 99 CGG repeats, and his mRNA level was elevated (2.85). MRI demonstrated a typical bilateral MCP lesion, mild on the right, but marked on the left (Fig. 1).
A 67-year-old grandfather of a boy with FXS had a history of hypertension, hypercholesterolemia, and coronary heart disease. He did not report any neurological problems, and was not seen by a neurologist prior to our testing. On examination, apart from some unsteadiness with eyes closed, mild impairment of writing, and a mild postural and action left hand tremor, his neurological status was normal. His IQ (Wechsler scale) was above normal (full scale = 118), his FMR1 CGG repeat size was 57, and mRNA level showed a five-fold increase (5.99) relative to the normal standard.12 His MRI showed a mild symmetrical MCP lesion, as well as marked symmetrical periventricular white matter changes extending into the subcortical white matter.9 2.2. Case 2 A 53-year-old grandfather of a girl with FXS had a history of dyslexia, asthma and hypertension. For the last 7 years he has suffered from fibromyalgia and anxiety, but did not experience any neurological or memory problems, and had not been seen by a neurologist. On examination we found no neurological abnormalities. His IQ was within the normal limits (full scale = 108), he had 56 CGG repeats, and he had a two-fold increase in mRNA level (2.34). His MRI showed age-unrelated florid symmetrical white matter changes throughout the corona radiata, as well as minimal changes within the MCP.8
3. Discussion The first clinical descriptions of FXTAS based on premutation carriers pre-selected for obvious neurological involvement indicated that the severity of clinical manifestations generally corresponded to the degree of MRI changes.1,5
D.Z. Loesch et al. / Journal of Clinical Neuroscience 14 (2007) 245–248
247
Fig. 1. White matter MRI changes in middle cerebellar peduncles characteristic of fragile x-associated tremor/ataxia syndrome (T2-weighted hyperintense signal within the middle cerebellar peduncle–MCP sign) in Case 3.
In our sample of nine carriers ascertained through their descendants affected with FXS, and recruited irrespective of neurological involvement, only three patients showed close correspondence between clinical features and MRI status, while three other individuals (presented here) manifested an obvious discrepancy between advanced MRI changes and minimal clinical neurological manifestations. One possible reason for this discrepancy is that the MRI anomalies could be explained by other aetiologies, as reviewed elsewhere.20 This is especially relevant in Case 2, where massive periventricular white matter changes were not associated with either increased T2-weighted signal intensity of the middle cerebellar peduncles or tremor/ataxia symptoms. Furthermore, this individual had a history of untreated hypertension, one of the risk factors associated with these types of MRI changes.20 However, the relatively young age of this individual, no history of either ischaemic cerebrovascular or heart disease, or inflammatory process, the severity of MRI changes combined with elevated levels of mRNA, as well as the presence of anxiety and autonomic dysfunction earlier reported in the FXTAS patients,5 all suggest that fragile X premutation is the most likely factor causing, or contributing to the MRI changes observed in Case 2. Clearly, the differential diagnosis is less relevant to the interpretation of MRI signs in Cases 1 and 3, which show the characteristic pattern of abnormalities reported in FXTAS, especially T2 hyperintensities of the MCP. The MCP lesion may develop in a number of other rare disorders, such as olivopontocerebellar atrophy, various forms of autosomal dominant cerebrospinal ataxias or of spinocerebellar degeneration, as well as in Wilson’s disease.6 However, the MCP lesion is usually associated with a number of other MRI anomalies and clinical neurological pre-
sentations, which are characteristic of these respective syndromes, but do not normally occur in fragile X premutation carriers. In the most recent examples of fragile X premutation-unrelated MCP lesion in two unspecified forms of ataxia,21 the pattern of associated clinical manifestations was also not fully consistent with the pattern seen in the affected fragile X premutation carriers. But, in our patients 1 and 3, MRI changes characteristic of FXTAS were associated with subtle but typical clinical manifestations in the form of imbalance and intention tremor. Apart from clinical considerations, the likelihood of the random occurrence of both fragile X premutation and typical MRI changes, in addition to subtle but typical clinical manifestations, in one and the same individual, is negligible. Our findings, although based on a small sample, suggest that MRI changes precede obvious clinical manifestations in some, still unknown, proportion of carriers of an FMR1 premutation. If these findings are confirmed by a more appropriate longitudinal study of larger samples, they will have important implications for early diagnosis of neurological involvement, as well as for revision of the selection criteria used in screening neurological patients. The observed discrepancy between MRI changes and clinical abnormalities could also explain the lower than expected detection rate of premutation carriers in screening of neurological conditions associated with tremor/ataxia.16–19 Cases showing advanced white matter degeneration on MRI, performed as part of our research, would normally not have been referred either to a neurology specialist, or for clinical MRI testing, because of the lack of obvious clinical neurological abnormalities. Thus they would not have been included in any tremor/ataxia groups targeted for premutation screening. At the other end of the spectrum, patients with a well advanced form of the disease, might fall into a
248
D.Z. Loesch et al. / Journal of Clinical Neuroscience 14 (2007) 245–248
‘stroke’ category, and could therefore also be missed in a premutation screening involving only clear-cut tremor/ ataxia syndromes. Our observation that MRI changes precede obvious clinical manifestations in some patients with fragile X-related tremor/ataxia also suggests that neurodegeneration in these individuals may have progressed over a long period. Gradual loss of brain tissue allows for compensation at the clinical level, resulting in minimal neurological impairment, even in the presence of pronounced MRI changes. The abundance of intranuclear inclusions throughout the brain found in well advanced stages of FXTAS10 is consistent with this hypothesis. Although the postulated slow progression of this condition contradicts initial clinical descriptions of FXTAS patients in which fast progression was implicated,1,5 these patients were preselected for severe neurological involvement, consistent with the terminal stage of this condition. In conclusion, we recommend that follow-up clinical and MRI studies be conducted in large samples of adult carriers of the fragile X premutation in order to capture the full spectrum and explain the natural history of neurological involvement in the FMR1 premutation, and to establish the onset of neurodegenerative changes more accurately. Acknowledgement This work was supported by National Institute of Child Health and Human Development grant HD36071 to Dr D. Loesch for the study of genotype-phenotype relationship associated with the fragile X gene and National Medical Research Council of Australia grant No 330400 to Drs D. Loesch, M. Cook and F. Tassone. We thank the study participants and their families for their contributions. Premutation carriers were identified in fragile X families initially diagnosed through the Victorian Genetic Health Services of the Royal Children’s Hospital in Melbourne. References 1. Hagerman RJ, Leehey M, Heinrichs W, et al. Intention tremor, Parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology 2001;57:127–30. 2. Verkerk AJ, Pieretti M, Sutcliffe JS, et al. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 1991;3165:905–14.
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