HDL2 and SCA12 Pathological Phenotype

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HDL2 neuroimaging consistently reveals prominent caudate atrophy, moderate atrophy of the cerebral cortex, and little abnormality in other brain structures. HDL2 and HD MRI images cannot be distinguished from each other (Fig. 1). Examination of the first autopsied HDL2 case (Fig. 2) was notable for mild atrophy of cortical gray matter, ventricular dilatation, and severe atrophy of the head of the caudate and the putamen. Severe neuronal degeneration and reactive astrocytosis, with vacuolation of the neuropil, was observed throughout the caudate, with more severe involvement of dorsal than ventral regions and a selective loss of medium-sized neurons. Degeneration was somewhat less marked in the putamen, with the same dorsal-to-ventral gradient. Neuronal loss and astrocytosis was more moderate in the globus pallidus, and moderate neuronal degeneration accompanied by pigment incontinence was observed in the substantia nigra, but no Lewy bodies. No fi amyloid deposits or neurofibrillary tangles were detected. Immunohistochemically, the key finding was the presence of intranuclear aggregates that stained with 1C2 (somewhat specific for expanded polyglutamine tracts) and anti-ubiquitin antibodies, but not anti-huntingtin antibodies. Inclusions were more common in the cortex than in the striatum. TorsinA (Walker et al. 2002) and TATA-box binding protein (TBP) have also been detected in these inclusions.

Fig. 1 Huntington's disease-like 2 (HDL2) is indistinguishable from Huntington's disease (HD) by MRI scan. a, d HDL2 case, MRI at age 36, 10-year disease duration. b, e Typical HD case, age 48 years, 12-year disease duration. c, f Normal control, age 43 years. Note the atrophy of the striatum and cerebral cortex in the HDL2 and HD cases, with relative sparing of the cerebellum and brain stem. (Reprinted with permission, Annals of Neurology, copyright 2001; Margolis et al. 2001)

Fig. 1 Huntington's disease-like 2 (HDL2) is indistinguishable from Huntington's disease (HD) by MRI scan. a, d HDL2 case, MRI at age 36, 10-year disease duration. b, e Typical HD case, age 48 years, 12-year disease duration. c, f Normal control, age 43 years. Note the atrophy of the striatum and cerebral cortex in the HDL2 and HD cases, with relative sparing of the cerebellum and brain stem. (Reprinted with permission, Annals of Neurology, copyright 2001; Margolis et al. 2001)

Fig. 2 HDL2 pathology. a Gross pathology, with prominent striatal atrophy (arrow) and moderate cortical atrophy. b Microscopic pathology of the caudate, with neuronal degeneration, astrocytic gliosis, and vacuolization. c Intranuclear inclusions stained by the 1C2 antibody (arrow). (Reprinted with permission, Annals of Neurology, copyright 2001; Margolis et al. 2001)

Fig. 2 HDL2 pathology. a Gross pathology, with prominent striatal atrophy (arrow) and moderate cortical atrophy. b Microscopic pathology of the caudate, with neuronal degeneration, astrocytic gliosis, and vacuolization. c Intranuclear inclusions stained by the 1C2 antibody (arrow). (Reprinted with permission, Annals of Neurology, copyright 2001; Margolis et al. 2001)

Recent evidence suggests that nuclear RNA inclusions may also be present in HDL2 brain (see below). A total of four HDL2 brains have now been examined in some detail, with consistent findings.

Cerebellar Atrophy Myotonia

Fig. 3 Spinocerebellar ataxia type 12 neuroimaging. MRI of a 59-year-old woman demonstrating moderate cerebral cortical and cerebellar atrophy affecting the vermis and lateral cerebellar hemispheres. (Reprinted with permission, Neurology, copyright 2001, Lippincott Williams & Wilkins; O'Hearn et al. 2001)

Fig. 3 Spinocerebellar ataxia type 12 neuroimaging. MRI of a 59-year-old woman demonstrating moderate cerebral cortical and cerebellar atrophy affecting the vermis and lateral cerebellar hemispheres. (Reprinted with permission, Neurology, copyright 2001, Lippincott Williams & Wilkins; O'Hearn et al. 2001)

The variability of SCA12 neuroimages is consistent with the variability in the SCA12 phenotype. MRI of most affected individuals reveals atrophy of the cerebral cortex and less marked atrophy of the cerebellum, with somewhat greater atrophy in the vermis than in the hemispheres; atrophy in other brain regions is less consistent (Fig. 3). A single SCA12 brain has come to autopsy. This brain was characterized by bilateral diffuse moderate atrophy of the cerebral cortex, most prominent in the parietal lobe; mild atrophy of the cerebellum, pons, and corpus calosum; and mild ventricular enlargement. Microscopic examination revealed moderate loss of Purkinje cells and mild neuronal loss in the substantia nigra, dentate nucleus, and inferior olivary nucleus. Neuronal intranuclear inclusions staining for ubiquitin and resembling Marinesco bodies were found in substantia nigra neurons and, more rarely, in Purkinje cells and motor cortical neurons. No Lewy bodies, neuronal tangles, or inclusions staining for tau or with 1C2 were detected (O'Hearn et al. 2004).

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