Late-onset Pompe disease primarily affects quality of life in physical health domains.

OBJECTIVE: To investigate quality of life in an international population of patients with late-onset Pompe disease. METHODS: Data on quality of life (SF-36), age, sex, disease duration, wheelchair use, and use of artificial ventilation were collected for 210 adults with Pompe disease from Australia, Germany, the Netherlands, the United Kingdom, and the United States. SF-36 scores were compared between countries and related to patient characteristics. In addition, for the Dutch subgroup (n = 51), comparisons with the general population and 1-year follow-up assessments were performed. RESULTS: No significant differences between countries were found for the four physical health scales. Mean scores on the vitality, role functioning-emotional, and mental health scale differed between countries, but these differences were not consistent. Wheelchair use was associated with lower physical and social functioning scores (B = -23.6 and -15.1, p < 0.001), and the use of artificial ventilation with lower physical functioning scores (B = -8.4, p = 0.004). Patients reported significantly poorer quality of life than the general population on the physical functioning, role functioning-physical, general health, vitality, and social functioning scales. No significant differences in SF-36 scores were found between the baseline and 1-year follow-up measurement. CONCLUSIONS: Patients with late-onset Pompe disease are, on average, markedly affected on the physical health domains of quality of life, but score only slightly lower than the general population on the mental health domains.

Cannabinoids reduce levodopa-induced dyskinesia in Parkinson's disease: a pilot study.

The lateral segment of the globus pallidus (GPl) is thought to be overactive in levodopa-induced dyskinesia in PD. Stimulation of cannabinoid receptors in the GPl reduces gamma-aminobutyric acid (GABA) reuptake and enhances GABA transmission and may thus alleviate dyskinesia. In a randomized, double-blind, placebo-controlled, crossover trial (n = 7), the authors demonstrate that the cannabinoid receptor agonist nabilone significantly reduces levodopa-induced dyskinesia in PD.

The selective vulnerability of nerve cells in Huntington's disease.

It is now more than 7 years since the genetic mutation causing Huntington's disease (HD) was first identified. Unstable CAG expansion in the IT15 gene, responsible for disease, is translated into an abnormally long polyglutamine (polyQ) tract near the N-terminus of the huntingtin protein. The presence of expanded polyQ in the mutant protein leads to its abnormal proteolytic cleavage with liberation of toxic N-terminal fragments that tend to aggregate, probably first in the cytoplasm. Subsequent nuclear translocation of the cleaved mutant huntingtin is associated with formation of intranuclear protein aggregates and neurotoxicity, probably involving apoptotic cascades. These processes, which can be experimentally modelled in cultured neuronal and non-neuronal cells, seem to underlie neurodegeneration in HD, and also other polyQ disorders, such as dentatorubro-pallidoluysian degeneration, spinal and bulbar muscular atrophy and the spinocerebellar ataxias. They do not, however, explain why within the corpus striatum and cerebral cortex certain nerve cells are susceptible to disease and others are not. In the human HD brain, vulnerable pyramidal neurones within the deeper layers of the cerebral cortex frequently contain large intranuclear inclusions composed of N-terminal fragments of huntingtin. Such inclusions are, however, rare within neurones of the striatum, even in the medium spiny neurones preferentially lost from this region. While inclusions per se do not seem to be neurotoxic, they may provide a surrogate marker of molecular pathology. Recent studies indicate that the nuclear accumulation of mutant huntingtin interferes with transcriptional events. Of particular importance may be the effect on the genes encoding neurotransmitter receptor proteins, especially those involved with glutamatergic neurotransmission. Such changes may trigger or facilitate a low-grade, chronic excitotoxicity of the glutamatergic cortical projection neurones on their target cells in the striatum, already partly compromised by the toxic effects of the HD mutation. This combination of insults, for anatomical reasons experienced predominantly by striatal projection neurones, would eventually cause their selective demise.

Huntington's disease intranuclear inclusions contain truncated, ubiquitinated huntingtin protein.

Intranuclear inclusion bodies are a shared pathological feature of Huntington's disease (HD) and its transgenic mouse model. Using a panel of antibodies spanning the entire huntingtin molecule, we have investigated the pattern of immunoreactivity within the intranuclear inclusions in the frontal cortex and striatum of patients with HD. The intranuclear inclusions reacted with anti-ubiquitin and antibodies against the N-terminal portion of huntingtin (CAG53b, HP1), but not with HD1 and the 1C2 antibodies that detect the expanded polyglutamine tract nor the more C-terminal antibodies. However, the 1C2, HP1, CAG53b, and HD1 antibodies detected granular cytoplasmic deposits in cortical and striatal neurons that also contained intranuclear N-terminal huntingtin immunoreactivity. These data show a differential intracellular location of truncated huntingtin in the HD brain. Both the cytoplasmic and the nuclear aggregates of the protein fragments could be neurotoxic. The frequency of the cortical intranuclear inclusions correlated with the size of CAG expansion and was inversely related to the age at onset and death. No such correlations were detected for the striatum, which most likely reflects a more advanced neuronal loss accrued by the time of death.