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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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Pedigree of the SCA17 family. Individuals marked with solid black have a molecular diagnosis of SCA17 accompanied by clinical manifestations of neurological disorders. Individuals marked with gray shading have a clinical diagnosis of a neurological disorder, which has not been confirmed on the molecular level. The proband is marked by an arrow.
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Figure 1: Pedigree of the SCA17 family. Individuals marked with solid black have a molecular diagnosis of SCA17 accompanied by clinical manifestations of neurological disorders. Individuals marked with gray shading have a clinical diagnosis of a neurological disorder, which has not been confirmed on the molecular level. The proband is marked by an arrow.

Mentions: No other family member was reported to have symptoms like the proband (Figure 1, III-5); however, the mother (Figure 1, II-4) was diagnosed with multiple sclerosis since the age of 40 with motor deficits and difficulties in coordination as the first signs of disease and only later developed cognitive impairment. She is now severely disabled, wheel chair bound and fully dependent on daily caregivers at age 74. The mother’s brother, living abroad, (Figure 1, II-2) was diagnosed with Parkinson’s disease and the maternal grandfather (Figure 1, I-2) was reported to have died from Parkinson’s disease (Figure 1).


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)

Pedigree of the SCA17 family. Individuals marked with solid black have a molecular diagnosis of SCA17 accompanied by clinical manifestations of neurological disorders. Individuals marked with gray shading have a clinical diagnosis of a neurological disorder, which has not been confirmed on the molecular level. The proband is marked by an arrow.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Pedigree of the SCA17 family. Individuals marked with solid black have a molecular diagnosis of SCA17 accompanied by clinical manifestations of neurological disorders. Individuals marked with gray shading have a clinical diagnosis of a neurological disorder, which has not been confirmed on the molecular level. The proband is marked by an arrow.
Mentions: No other family member was reported to have symptoms like the proband (Figure 1, III-5); however, the mother (Figure 1, II-4) was diagnosed with multiple sclerosis since the age of 40 with motor deficits and difficulties in coordination as the first signs of disease and only later developed cognitive impairment. She is now severely disabled, wheel chair bound and fully dependent on daily caregivers at age 74. The mother’s brother, living abroad, (Figure 1, II-2) was diagnosed with Parkinson’s disease and the maternal grandfather (Figure 1, I-2) was reported to have died from Parkinson’s disease (Figure 1).

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