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Increased T2 signal in the middle cerebellar peduncles on MRI is not specific for fragile X premutation syndrome
Journal of Clinical Neuroscience (2005) 12(1), 42–43 0967-5868/$ - see front matter ª 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2004.07.006
Clinical study
Increased T2 signal in the middle cerebellar peduncles on MRI is not specific for fragile X premutation syndrome Elsdon Storey1,2 FRACP DPHIL, Phiroz Billimoria2 MD MRCP FRACP 1 Department of Medicine (Neuroscience), Monash University (Alfred Hospital Campus), Melbourne, Australia, 2Department of Neuroscience, Alfred Hospital, Melbourne, Australia
Summary The fragile X premutation tremor/ataxia syndrome (FXTAS) is a recently described adult-onset neurodegenerative disorder, in which ataxia, tremor, cognitive decline, parkinsonism, neuropathy and autonomic dysfunction occur in various combinations. It is reported to display a characteristic MRI appearance, with increased T2 signal in the middle cerebellar peduncles and around the dentate nuclei. Diagnostic criteria have been proposed on the basis of these clinical and radiological features, presupposing that a CGG expansion has been demonstrated. We present three cases in which MRI and clinical findings suggested the possibility of FXTAS, although only one was confirmed on genetic testing. The phenotypic overlap with multiple system atrophy of cerebellar type (MSA-C) and the importance of genetic confirmation are emphasised. ª 2004 Elsevier Ltd. All rights reserved. Keywords: fragile X premutation, multiple system atrophy, MRI, middle cerebellar peduncles
INTRODUCTION The fragile X premutation tremor/ataxia syndrome (FXTAS) is characterised by progressive ataxia, tremor and cognitive decline in various combinations, with additional features of parkinsonism, neuropathy, and autonomic dysfunction.1,2 Criteria for definite, probable and possible FXTAS have recently been formulated, based on MRI and clinical features.2 Importantly, the criteria presuppose a CGG repeat size of 55–200.2 FXTAS typically develops in men over 50 years of age, but two manifesting female carriers (presumably resulting from skewed X-inactivation) with onset ages of 32 and 52 have recently been reported.3 The clinical features of FXTAS clearly overlap those of a number of other disorders, such as multiple system atrophy of cerebellar type (MSA-C),4 spinocerebellar ataxias with disguised dominance (especially SCA’s 2, 3 and 17), and even essential tremor. A definitive diagnosis is important in these patients, however, as their daughters’ male offspring are potentially at risk for the full fragile X syndrome. A characteristic pattern of MRI abnormalities has been reported in FXTAS: T2 hyperintensity in the middle cerebellar peduncles and around the dentate nuclei, with mild-moderate cerebellar and cerebral atrophy and mild pontine atrophy, and patchy and confluent T2 hyperintensities in the deep white matter in some cases.5 As pointed out by Brunberg et al.,5 however, this pattern of MRI changes is not specific for fragile X premutation syndrome, and can also be seen in MSA-C and in a recently reported adult-onset recessive ataxia with additional characteristic thalamic lesions.6 Three cases illustrating the lack of specificity of middle cerebellar peduncle T2 hyperintensities are outlined below. Case 1 A 61 year old man presented with a 2 year history of right arm postural and kinetic tremor, extending to affect the left arm 1 year
Received 15 June 2004 Accepted 7 July 2004 Correspondence to: Elsdon Storey, Department of Neuroscience, Alfred Hospital, Commercial Road, Melbourne, Vic. 3004, Australia. Tel.: +613 9276 2552; Fax: +613 9276 2458; E-mail: [email protected]
42
later. Examination revealed moderate postural and kinetic tremor, with no evidence of ataxia apart from mild overshoot on ballistic tracking. His MRI, shown in Fig. 1A, suggested a diagnosis of FXTAS, which was subsequently confirmed on direct genetic testing with a CGG repeat number of 96. This finding triggered predictive genetic testing of several members of his wider family. Case 2 A 53 year old woman presented with a 3 year history of progressive ataxia and sphincteric dysfunction. She also reported orthostatic shoulder and neck discomfort, suggestive of postural hypotension.7 Examination revealed moderate cerebellar dysarthria and limb ataxia, with slightly saccadic visual smooth pursuit, mild asymmetric extrapyramidal rigidity, and severe postural hypotension with a systolic drop from 172 recumbent to 84 after standing for 3 min. In the light of her MRI appearance (Fig. 1B), FXTAS was excluded by direct genetic testing. Case 3 A 43 year old man, the offspring of a non-consanguineous union, presented with an approximately 20 year history of ataxia, dysarthria and distal weakness. His family history was unrevealing. Examination revealed severe cerebellar dysarthria, normal eye movements apart from hypermetric saccades, moderate sensorineural deafness, areflexia with marked distal amyotrophy to the knees and wrists, and impaired two-point discrimination at the great toes. His MRI is shown in Fig. 1C and D. The differential diagnosis of presumed recessive ataxia with neuropathy is extensive,8 but the MRI abnormalities were not typical of any of the reported entities. Friedreich’s ataxia was further excluded by direct genetic testing, and FXTAS was considered possible on MRI grounds, despite his age of onset, but was also excluded by direct genetic analysis. This may represent a previously unreported, presumably recessive, form of ataxia. DISCUSSION The MRI findings in Case 1 suggested the diagnosis of FXTAS, which was subsequently confirmed genetically. Jacquemont
Increased T2 signal in the middle cerebellar peduncles on MRI
43
Fig. 1 (A) Axial FLAIR image at the level of the middle cerebellar peduncles in Case 1. Symmetrical hyperintensities are seen in the peduncles and around the dentate nuclei. (B) Axial FLAIR image at the level of the middle cerebellar peduncles in Case 2. Similar, although less prominent, symmetrical hyperintensities are seen. (C) Axial FLAIR image at the level of the middle cerebellar peduncles in Case 3. In addition to the symmetrical hyperintensities there is pontine and cerebellar atrophy. (C) Axial FLAIR image in Case 3 showing patchy, asymmetric cerebral white matter hyperintensities.
et al.2 have suggested that a ‘definite’ diagnosis of FXTAS can be made on the basis of the major radiological feature (MRI white matter lesions in the middle cerebellar peduncles) and one of two major clinical features (gait ataxia or intention tremor), provided that fragile X CGG repeat numbers are between 55 and 200. The patient described in Case 2 met the clinical and radiological sections of these diagnostic criteria, and even her female gender did not exclude this possibility.3 It is important to note that patients with MSA-C may also fulfil the clinical and radiological criteria for FXTAS. Confirmation of the latter diagnosis by direct genetic testing is therefore essential. The patient described in Case 3 also met the clinical and radiological diagnostic criteria for ‘definite’ FXTAS, with gait ataxia and middle cerebellar peduncle T2 hyperintensities. He also fulfilled one of the two minor MRI criteria, displaying cerebral white matter lesions but not moderate to severe generalised atrophy. However, his age of onset is considerably less than any reported to date. Again, FXTAS was excluded by direct genetic testing. The diagnosis remains uncertain; he may have a novel recessive ataxia.
CONCLUSION While the criteria for FXTAS suggested by Jacquemont et al.2 are useful, their inclusion criterion of a fragile X CGG expansion of between 55 and 200 must be followed strictly if diagnostic errors ª 2004 Elsevier Ltd. All rights reserved.
are to be avoided. MSA-C, in particular, may show extensive clinical and radiological overlap with FXTAS.
REFERENCES 1. Hagerman RJ, Leehey M, Heinrichs W, et al.. Intention tremor, parkinsonism, and generalised brain atrophy in male carriers of fragile X. Neurology 2001; 57: 127–130. 2. 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: 869–878. 3. Hagerman RJ, Zhang L, Brunberg J, et al.. Two female cases of the fragile X premutation tremor/ataxia syndrome: cognitive, molecular and radiological studies. Neurology 2003; 60(Suppl.): 331–332. 4. Zhang L, Leehey M, Wheelock V, Tassone F, Hagerman RH, Hagerman PJ. A subtype of multiple system atrophy with cerebellar ataxia (MSA-C): the fragile X-associated tremor/ataxia syndrome (FXTAS). Neurology 2003; 60: A470. 5. Brunberg JA, Jacquemont S, Hagerman RJ, et al.. Fragile X premutation carriers: characteristic MR imaging findings of adult male patients with progressive cerebellar and cognitive dysfunction. Am J Neuroradiol 2002; 23: 1757–1766. 6. Rantamaki M, Krahe R, Paetau A, Cormand B, Mononen I, Udd B. Adult-onset autosomal recessive ataxia with thalamic lesions in a Finnish family. Neurology 2001; 57: 1043–1049. 7. Bannister R. Clinical features of autonomic failure. A. Symptoms, signs, and special investigations. In: Bannister R, editor. Autonomic Failure: A Textbook of Clinical Disorders of the Autonomic Nervous System. 2nd ed.. Oxford: Oxford University Press; 1988. p. 268–269. 8. Koenig M. Rare forms of autosomal recessive neurodegenerative ataxia. Semin Pediatr Neurol 2003; 10: 183–192.
Journal of Clinical Neuroscience (2005) 12(1), 42–43
Clinical study
Increased T2 signal in the middle cerebellar peduncles on MRI is not specific for fragile X premutation syndrome Elsdon Storey1,2 FRACP DPHIL, Phiroz Billimoria2 MD MRCP FRACP 1 Department of Medicine (Neuroscience), Monash University (Alfred Hospital Campus), Melbourne, Australia, 2Department of Neuroscience, Alfred Hospital, Melbourne, Australia
Summary The fragile X premutation tremor/ataxia syndrome (FXTAS) is a recently described adult-onset neurodegenerative disorder, in which ataxia, tremor, cognitive decline, parkinsonism, neuropathy and autonomic dysfunction occur in various combinations. It is reported to display a characteristic MRI appearance, with increased T2 signal in the middle cerebellar peduncles and around the dentate nuclei. Diagnostic criteria have been proposed on the basis of these clinical and radiological features, presupposing that a CGG expansion has been demonstrated. We present three cases in which MRI and clinical findings suggested the possibility of FXTAS, although only one was confirmed on genetic testing. The phenotypic overlap with multiple system atrophy of cerebellar type (MSA-C) and the importance of genetic confirmation are emphasised. ª 2004 Elsevier Ltd. All rights reserved. Keywords: fragile X premutation, multiple system atrophy, MRI, middle cerebellar peduncles
INTRODUCTION The fragile X premutation tremor/ataxia syndrome (FXTAS) is characterised by progressive ataxia, tremor and cognitive decline in various combinations, with additional features of parkinsonism, neuropathy, and autonomic dysfunction.1,2 Criteria for definite, probable and possible FXTAS have recently been formulated, based on MRI and clinical features.2 Importantly, the criteria presuppose a CGG repeat size of 55–200.2 FXTAS typically develops in men over 50 years of age, but two manifesting female carriers (presumably resulting from skewed X-inactivation) with onset ages of 32 and 52 have recently been reported.3 The clinical features of FXTAS clearly overlap those of a number of other disorders, such as multiple system atrophy of cerebellar type (MSA-C),4 spinocerebellar ataxias with disguised dominance (especially SCA’s 2, 3 and 17), and even essential tremor. A definitive diagnosis is important in these patients, however, as their daughters’ male offspring are potentially at risk for the full fragile X syndrome. A characteristic pattern of MRI abnormalities has been reported in FXTAS: T2 hyperintensity in the middle cerebellar peduncles and around the dentate nuclei, with mild-moderate cerebellar and cerebral atrophy and mild pontine atrophy, and patchy and confluent T2 hyperintensities in the deep white matter in some cases.5 As pointed out by Brunberg et al.,5 however, this pattern of MRI changes is not specific for fragile X premutation syndrome, and can also be seen in MSA-C and in a recently reported adult-onset recessive ataxia with additional characteristic thalamic lesions.6 Three cases illustrating the lack of specificity of middle cerebellar peduncle T2 hyperintensities are outlined below. Case 1 A 61 year old man presented with a 2 year history of right arm postural and kinetic tremor, extending to affect the left arm 1 year
Received 15 June 2004 Accepted 7 July 2004 Correspondence to: Elsdon Storey, Department of Neuroscience, Alfred Hospital, Commercial Road, Melbourne, Vic. 3004, Australia. Tel.: +613 9276 2552; Fax: +613 9276 2458; E-mail: [email protected]
42
later. Examination revealed moderate postural and kinetic tremor, with no evidence of ataxia apart from mild overshoot on ballistic tracking. His MRI, shown in Fig. 1A, suggested a diagnosis of FXTAS, which was subsequently confirmed on direct genetic testing with a CGG repeat number of 96. This finding triggered predictive genetic testing of several members of his wider family. Case 2 A 53 year old woman presented with a 3 year history of progressive ataxia and sphincteric dysfunction. She also reported orthostatic shoulder and neck discomfort, suggestive of postural hypotension.7 Examination revealed moderate cerebellar dysarthria and limb ataxia, with slightly saccadic visual smooth pursuit, mild asymmetric extrapyramidal rigidity, and severe postural hypotension with a systolic drop from 172 recumbent to 84 after standing for 3 min. In the light of her MRI appearance (Fig. 1B), FXTAS was excluded by direct genetic testing. Case 3 A 43 year old man, the offspring of a non-consanguineous union, presented with an approximately 20 year history of ataxia, dysarthria and distal weakness. His family history was unrevealing. Examination revealed severe cerebellar dysarthria, normal eye movements apart from hypermetric saccades, moderate sensorineural deafness, areflexia with marked distal amyotrophy to the knees and wrists, and impaired two-point discrimination at the great toes. His MRI is shown in Fig. 1C and D. The differential diagnosis of presumed recessive ataxia with neuropathy is extensive,8 but the MRI abnormalities were not typical of any of the reported entities. Friedreich’s ataxia was further excluded by direct genetic testing, and FXTAS was considered possible on MRI grounds, despite his age of onset, but was also excluded by direct genetic analysis. This may represent a previously unreported, presumably recessive, form of ataxia. DISCUSSION The MRI findings in Case 1 suggested the diagnosis of FXTAS, which was subsequently confirmed genetically. Jacquemont
Increased T2 signal in the middle cerebellar peduncles on MRI
43
Fig. 1 (A) Axial FLAIR image at the level of the middle cerebellar peduncles in Case 1. Symmetrical hyperintensities are seen in the peduncles and around the dentate nuclei. (B) Axial FLAIR image at the level of the middle cerebellar peduncles in Case 2. Similar, although less prominent, symmetrical hyperintensities are seen. (C) Axial FLAIR image at the level of the middle cerebellar peduncles in Case 3. In addition to the symmetrical hyperintensities there is pontine and cerebellar atrophy. (C) Axial FLAIR image in Case 3 showing patchy, asymmetric cerebral white matter hyperintensities.
et al.2 have suggested that a ‘definite’ diagnosis of FXTAS can be made on the basis of the major radiological feature (MRI white matter lesions in the middle cerebellar peduncles) and one of two major clinical features (gait ataxia or intention tremor), provided that fragile X CGG repeat numbers are between 55 and 200. The patient described in Case 2 met the clinical and radiological sections of these diagnostic criteria, and even her female gender did not exclude this possibility.3 It is important to note that patients with MSA-C may also fulfil the clinical and radiological criteria for FXTAS. Confirmation of the latter diagnosis by direct genetic testing is therefore essential. The patient described in Case 3 also met the clinical and radiological diagnostic criteria for ‘definite’ FXTAS, with gait ataxia and middle cerebellar peduncle T2 hyperintensities. He also fulfilled one of the two minor MRI criteria, displaying cerebral white matter lesions but not moderate to severe generalised atrophy. However, his age of onset is considerably less than any reported to date. Again, FXTAS was excluded by direct genetic testing. The diagnosis remains uncertain; he may have a novel recessive ataxia.
CONCLUSION While the criteria for FXTAS suggested by Jacquemont et al.2 are useful, their inclusion criterion of a fragile X CGG expansion of between 55 and 200 must be followed strictly if diagnostic errors ª 2004 Elsevier Ltd. All rights reserved.
are to be avoided. MSA-C, in particular, may show extensive clinical and radiological overlap with FXTAS.
REFERENCES 1. Hagerman RJ, Leehey M, Heinrichs W, et al.. Intention tremor, parkinsonism, and generalised brain atrophy in male carriers of fragile X. Neurology 2001; 57: 127–130. 2. 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: 869–878. 3. Hagerman RJ, Zhang L, Brunberg J, et al.. Two female cases of the fragile X premutation tremor/ataxia syndrome: cognitive, molecular and radiological studies. Neurology 2003; 60(Suppl.): 331–332. 4. Zhang L, Leehey M, Wheelock V, Tassone F, Hagerman RH, Hagerman PJ. A subtype of multiple system atrophy with cerebellar ataxia (MSA-C): the fragile X-associated tremor/ataxia syndrome (FXTAS). Neurology 2003; 60: A470. 5. Brunberg JA, Jacquemont S, Hagerman RJ, et al.. Fragile X premutation carriers: characteristic MR imaging findings of adult male patients with progressive cerebellar and cognitive dysfunction. Am J Neuroradiol 2002; 23: 1757–1766. 6. Rantamaki M, Krahe R, Paetau A, Cormand B, Mononen I, Udd B. Adult-onset autosomal recessive ataxia with thalamic lesions in a Finnish family. Neurology 2001; 57: 1043–1049. 7. Bannister R. Clinical features of autonomic failure. A. Symptoms, signs, and special investigations. In: Bannister R, editor. Autonomic Failure: A Textbook of Clinical Disorders of the Autonomic Nervous System. 2nd ed.. Oxford: Oxford University Press; 1988. p. 268–269. 8. Koenig M. Rare forms of autosomal recessive neurodegenerative ataxia. Semin Pediatr Neurol 2003; 10: 183–192.
Journal of Clinical Neuroscience (2005) 12(1), 42–43