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Severe and rapidly progressing cognitive phenotype in a SCA17-family with only marginally expanded CAG/CAA repeats in the TATA-box binding protein gene: a case report.

Nielsen TT, Mardosiene S, Løkkegaard A, Stokholm J, Ehrenfels S, Bech S, Friberg L, Nielsen JK, Nielsen JE - BMC Neurol (2012)

Bottom Line: Normally, repeats within this range show reduced penetrance and result in a milder disease course with slower progression and later age of onset.Thus, this case presented with an unusual phenotype.The current case highlights the diagnostic challenge of neurodegenerative disorders and the need for a thorough clinical and paraclinical examination of patients presenting with rapid cognitive decline to make a precise diagnosis on which further genetic counseling and initiation of treatment modalities can be based.

View Article: PubMed Central - HTML - PubMed

Affiliation: Memory Disorders Research Group, Neurogenetics Clinic, Department of Neurology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. troelsn@sund.ku.dk

ABSTRACT

Background: The autosomal dominant spinocerebellar ataxias (SCAs) confine a group of rare and heterogeneous disorders, which present with progressive ataxia and numerous other features e.g. peripheral neuropathy, macular degeneration and cognitive impairment, and a subset of these disorders is caused by CAG-repeat expansions in their respective genes. The diagnosing of the SCAs is often difficult due to the phenotypic overlap among several of the subtypes and with other neurodegenerative disorders e.g. Huntington's disease.

Case presentation: We report a family in which the proband had rapidly progressing cognitive decline and only subtle cerebellar symptoms from age 42. Sequencing of the TATA-box binding protein gene revealed a modest elongation of the CAG/CAA-repeat of only two repeats above the non-pathogenic threshold of 41, confirming a diagnosis of SCA17. Normally, repeats within this range show reduced penetrance and result in a milder disease course with slower progression and later age of onset. Thus, this case presented with an unusual phenotype.

Conclusions: The current case highlights the diagnostic challenge of neurodegenerative disorders and the need for a thorough clinical and paraclinical examination of patients presenting with rapid cognitive decline to make a precise diagnosis on which further genetic counseling and initiation of treatment modalities can be based.

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Related in: MedlinePlus

Brain MRI and18 F-FDG-PET-scan of the proband in the transverse plane. A: The MRI scan included a diffusion weighted sequence (DWI) and a T2* weighted sequence. No focal lesions were observed; however, the cerebellar hemispheres and vermis appeared atrophic (arrow heads). B: 18 F-FDG-PET-scan showing strikingly reduced metabolism in the cerebellum suggesting pathology primarily localized to the cerebellum.
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Figure 2: Brain MRI and18 F-FDG-PET-scan of the proband in the transverse plane. A: The MRI scan included a diffusion weighted sequence (DWI) and a T2* weighted sequence. No focal lesions were observed; however, the cerebellar hemispheres and vermis appeared atrophic (arrow heads). B: 18 F-FDG-PET-scan showing strikingly reduced metabolism in the cerebellum suggesting pathology primarily localized to the cerebellum.

Mentions: I123-FP-CIT DAT SPECT was normal (not shown). Brain MRI showed no focal lesions, but the cerebellar hemispheres and vermis appeared atrophic (Figure 2A). The MRI scan included a diffusion weighted sequence (DWI) and a T2* weighted sequence. There was no sign of restricted diffusion as may be seen in Creutzfeldt-Jakob disease or excessive iron accumulation in the basal ganglia which may be suggestive of other causes of neurodegeneraton. 18 F-FDG-PET-scan showed strikingly reduced metabolism in the cerebellum (Figure 2B) supporting the cerebellar atrophy visualized by MRI, suggesting pathology localized to the cerebellum. Furthermore, slightly decreased metabolism in the left caudate nucleus was observed, although this finding could only be detected by comparison to scans of normal control individuals with subsequent statistical analyses using NeuroQ software (Philips Healthcare).


Severe and rapidly progressing cognitive phenotype in a SCA17-family with only marginally expanded CAG/CAA repeats in the TATA-box binding protein gene: a case report.

Nielsen TT, Mardosiene S, Løkkegaard A, Stokholm J, Ehrenfels S, Bech S, Friberg L, Nielsen JK, Nielsen JE - BMC Neurol (2012)

Brain MRI and18 F-FDG-PET-scan of the proband in the transverse plane. A: The MRI scan included a diffusion weighted sequence (DWI) and a T2* weighted sequence. No focal lesions were observed; however, the cerebellar hemispheres and vermis appeared atrophic (arrow heads). B: 18 F-FDG-PET-scan showing strikingly reduced metabolism in the cerebellum suggesting pathology primarily localized to the cerebellum.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3475097&req=5

Figure 2: Brain MRI and18 F-FDG-PET-scan of the proband in the transverse plane. A: The MRI scan included a diffusion weighted sequence (DWI) and a T2* weighted sequence. No focal lesions were observed; however, the cerebellar hemispheres and vermis appeared atrophic (arrow heads). B: 18 F-FDG-PET-scan showing strikingly reduced metabolism in the cerebellum suggesting pathology primarily localized to the cerebellum.
Mentions: I123-FP-CIT DAT SPECT was normal (not shown). Brain MRI showed no focal lesions, but the cerebellar hemispheres and vermis appeared atrophic (Figure 2A). The MRI scan included a diffusion weighted sequence (DWI) and a T2* weighted sequence. There was no sign of restricted diffusion as may be seen in Creutzfeldt-Jakob disease or excessive iron accumulation in the basal ganglia which may be suggestive of other causes of neurodegeneraton. 18 F-FDG-PET-scan showed strikingly reduced metabolism in the cerebellum (Figure 2B) supporting the cerebellar atrophy visualized by MRI, suggesting pathology localized to the cerebellum. Furthermore, slightly decreased metabolism in the left caudate nucleus was observed, although this finding could only be detected by comparison to scans of normal control individuals with subsequent statistical analyses using NeuroQ software (Philips Healthcare).

Bottom Line: Normally, repeats within this range show reduced penetrance and result in a milder disease course with slower progression and later age of onset.Thus, this case presented with an unusual phenotype.The current case highlights the diagnostic challenge of neurodegenerative disorders and the need for a thorough clinical and paraclinical examination of patients presenting with rapid cognitive decline to make a precise diagnosis on which further genetic counseling and initiation of treatment modalities can be based.

View Article: PubMed Central - HTML - PubMed

Affiliation: Memory Disorders Research Group, Neurogenetics Clinic, Department of Neurology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. troelsn@sund.ku.dk

ABSTRACT

Background: The autosomal dominant spinocerebellar ataxias (SCAs) confine a group of rare and heterogeneous disorders, which present with progressive ataxia and numerous other features e.g. peripheral neuropathy, macular degeneration and cognitive impairment, and a subset of these disorders is caused by CAG-repeat expansions in their respective genes. The diagnosing of the SCAs is often difficult due to the phenotypic overlap among several of the subtypes and with other neurodegenerative disorders e.g. Huntington's disease.

Case presentation: We report a family in which the proband had rapidly progressing cognitive decline and only subtle cerebellar symptoms from age 42. Sequencing of the TATA-box binding protein gene revealed a modest elongation of the CAG/CAA-repeat of only two repeats above the non-pathogenic threshold of 41, confirming a diagnosis of SCA17. Normally, repeats within this range show reduced penetrance and result in a milder disease course with slower progression and later age of onset. Thus, this case presented with an unusual phenotype.

Conclusions: The current case highlights the diagnostic challenge of neurodegenerative disorders and the need for a thorough clinical and paraclinical examination of patients presenting with rapid cognitive decline to make a precise diagnosis on which further genetic counseling and initiation of treatment modalities can be based.

Show MeSH
Related in: MedlinePlus