Neuropathology of PolyQ Diseases

Most of the polyQ disease proteins are widely expressed within and outside of the brain. However, expansion of the polyQ tract results in an essentially neuronal-specific phenotype in patients. Moreover, each of the polyQ diseases is distinguished by a unique profile of selective neurodegeneration that can be evinced radiographically or by postmortem analysis (Fig. 1). Although the pathological relevance remains controversial, the polyQ disease brain is characterized by the presence of...

Fragile X Syndrome

FXS is the leading heritable form of mental retardation (Hagerman and Hagerman 2002a), with a prevalence for cognitive impairment of approximately 1 4000 men and 1 6000 women (Turner et al. 1992 Sherman 2002). FXS is almost always due to expansion of a trinucleotide d(CGG) repeat in the 5'-UTR of the FMR1 gene (Verkerk et al. 1991 Pieretti et al. 1991 Oberle et al. 1991 Yu et al. 1991 Fu et al. 1991). FMR1 alleles with more than 200 d(CGG) repeats generally become hypermethylated in the...

Other Extracerebellar Signs and Symptoms

Some SCA10 patients of Mexican origin have additional phenotypes beyond cerebellar degeneration and epileptic seizures (Grewal et al. 1998, 2002 Lin and Ashizawa 2003 Matsuura et al. 1999, 2000 Rasmussen et al. 2001). More extra-cerebellar signs and non-neuronal involvement have been observed in some families. Variable degrees of pyramidal signs, including hyperreflexia, leg spasticity and Babinski's sign, were reported. Affected individuals often complain of mild sensory loss in distal lower...

Modulating Specific Downstream Targets

In some disorders very specific changes in gene expression have been noticed that may be relevant for disease symptoms. For example, altered group 1 metabotropic glutamate (mGluR) receptor signaling is seen in both Fmrl knockout mice (Huber et al. 2002) and in the polyQ disorders (Anborgh et al. 2005). Accordingly, drugs that target these receptors may have promise in alleviating disease symptoms. An mGluR5 antagonist, 2-methyl-6-(phenylethynyl)pyridine (MPEP), decreased audiogenic seizures and...

The Myotonic Dystrophies an Overview

Myotonic dystrophy (dystrophia myotonica, DM) is a dominantly inherited neuromuscular disease that is characterized by a distinctive combination of clinical features, including skeletal muscle myotonia and weakness wasting, cardiac muscle arrhythmias and conduction defects, unusual ocular cataracts, insulin insensitivity, male hypogonadism, balding and hypogammaglobulinemia (Harper 2001). Moreover, the genetic basis of DM is novel because this disease is caused by the expansion of different,...

HDL2 and SCA12 Clinical Phenotype

At least at the level of individual patients, HDL2 is clinically indistinguishable from HD most individuals with HDL2 were initially diagnosed as having HD, often by clinicians experienced in the differential diagnosis of movement disorders. HDL2 cases generally appear to have one of two presentations, though these presentations probably reflect opposite ends of a continuum rather than discrete disease subtypes (Table 1). The first HDL2 presentation is similar to the juvenile onset or Westphal...

HDL2 and SCA12 Pathological Phenotype

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...

Genetics and Clinical Presentation of the Myotonic Dystrophies DM1 Versus DM2 Disease Many Similarities but Significant

Prior to discussing disease models for DM pathogenesis, it is important to distinguish between the clinical presentations of types 1 and 2. Another related disorder with severe frontotemporal dementia, myotonia and DM-type cataracts, but no genetic linkage to DMPK or ZNF9, has been suggested as a candidate for DM type 3 (DM3) (Le Ber et al. 2004). However, the molecular basis for this disease, and its relationship to DM1 and DM2, is still obscure and therefore discussion of this disease will be...