Huntington’s Disease Complicated by Traumatic Subarachnoid Bleeding and Subdural Hematoma

Though Huntington’s Disease (HD) is frequently complicated by falls and consecutive Traumatic Brain Injury (TBI) with Subdural Hematoma (SDH), traumatic Subarachnoid Bleeding (SAB) has not been reported as a complication of HD. A 67yo female with HD due to a CAG-repeat expansion of 43 repeats, diagnosed 18 months earlier, was admitted after a fall with a Glasgow-Coma Scale (GCS) score of 3. Cerebral CT on admission revealed bilateral SDH and SAB. No aneurysm could be detected on conventional angiography. After extubation, she was non-responsive to verbal requests and typical choreatic movement recurred. Tiaprid, olanzapine, and tetrabenazine were of limited effect. This case shows that falls in HD may not only cause SDH but rarely traumatic SAB. TBI in HD may worsen the phenotype and may increase the risk of a poor outcome.

The Spectrum of Common Mutations in CFTR, AR Gene, and the Y Chromosome Microdeletions and Karyotyping Abnormalities in Phenotypic Male with Very Severe Oligozoospermia

Male infertility due to very severe oligozoospermia has been associated with a number of genetic risk factors.This association in patients with sperm concentration lower than 1× 106 ml are not yet fully studied.The present study aims to investigate the distribution of the mutations in the CFTR gene, the CAG repeat expansion of the AR gene as well as Y chromosome microdeletions and karyotyping abnormalities in very severe oligozoospermia patients from the Iranian population. In the present case-control study 200 severe oligozoospermia and 200 fertile males were enrolled. All patients karyotyped for diagnosis of the chromosomal abnormalities using routine. Microdeletions were evaluated using multiplex PCR. Five common CFTR mutations were genotyped using the ARMS-PCR technique. The CAG repeat expansion in the AR gene was evaluated for the number of repeats in each patient using sequencing. Overall, 4% of cases have a numerical and structural abnormality. 7.5% of patients had a deletion in one of the AZF regions on Yq, and 3.5% had a deletion in two regions. F508del was the most common (4.5%) CFTR gene mutation, G542X, and W1282X were detected with 1.5% and 1% respectively. One patient was found to have AZFa microdeletion and F508del in heterozygote form; one patient had AZFb microdeletion with F508del. F508del was seen as compound heterozygous with G542X in one patient and with W1282X in the other patient. The difference in the mean of the CAG repeat in the AR gene in patients and controls were statistically significant (P = 0.04). Our study shows that ICSI in couples with very severe oligozoospermia can lead to an increase in children who are at risk of unbalanced chromosomal complement, male infertility due to transmission of Y-chromosomal microdeletion , AR- CAG repeat and cystic fibrosis if both partners carry the CFTR gene mutation. Genetic testing and counseling before considering ICSI is suggested for these couples.

Polyglutamine-expanded ataxin-3: a target engagement marker for Spinocerebellar ataxia type 3 in peripheral blood

Spinocerebellar ataxia type 3 is a rare neurodegenerative disease, caused by a CAG repeat expansion leading to polyglutamine elongation in the ataxin-3 protein. While no curative therapy is yet available, preclinical gene silencing approaches to reduce polyglutamine-toxicity demonstrate promising results. In view of upcoming clinical trials, quantitative and easily accessible molecular markers are of critical importance as pharmacodynamic and particularly as target engagement markers. We developed a novel ultrasensitive immunoassay to measure specifically polyQ-expanded ataxin-3 in plasma and cerebrospinal fluid. Statistical analyses revealed a correlation with clinical parameters and a stability of polyglutamine-expanded ataxin-3 during conversion from the pre-ataxic to the ataxic phase.

The genetics of Huntington’s disease

This chapter describes the nature of the genetic mistake. The genetic code, or DNA molecule, is wound up onto structures called chromosomes. The gene for HD is located on chromosome 4. As we have two copies of our genes the chromosomes are in pairs. Only one copy of the HD has to be abnormal to cause the condition. This results in a pattern of inheritance called autosomal dominant and both males and females can be affected. Genes code for proteins; the protein encoded by the HD gene is called huntingtin. Proteins are made of building blocks called amino acids. The gene for HD has an expansion of the genetic code for glutamine. Therefore, abnormal huntingtin has an expansion of the number of glutamines. The genetic code for glutamine is CAG so the mistake in the gene is sometimes called a CAG repeat expansion disorder or in referring to the protein it is called a polyglutamine repeat expansion. The gene is in one part of the cell and the protein-making machinery is in another part of the cell so a chemical messenger is required which is called RNA. Explaining this is important for understanding some current clinical trials

Promotion of somatic CAG repeat expansion by Fan1 knock-out in Huntington’s disease knock-in mice is blocked by Mlh1 knock-out

Recent genome-wide association studies of age-at-onset in Huntington’s disease (HD) point to distinct modes of potential disease modification: altering the rate of somatic expansion of the HTT CAG repeat or altering the resulting CAG threshold length-triggered toxicity process. Here, we evaluated the mouse orthologs of two HD age-at-onset modifier genes, FAN1 and RRM2B, for an influence on somatic instability of the expanded CAG repeat in Htt CAG knock-in mice. Fan1 knock-out increased somatic expansion of Htt CAG repeats, in the juvenile- and the adult-onset HD ranges, whereas knock-out of Rrm2b did not greatly alter somatic Htt CAG repeat instability. Simultaneous knock-out of Mlh1, the ortholog of a third HD age-at-onset modifier gene (MLH1), which suppresses somatic expansion of the Htt knock-in CAG repeat, blocked the Fan1 knock-out-induced acceleration of somatic CAG expansion. This genetic interaction indicates that functional MLH1 is required for the CAG repeat destabilizing effect of FAN1 loss. Thus, in HD, it is uncertain whether the RRM2B modifier effect on timing of onset may be due to a DNA instability mechanism. In contrast, the FAN1 modifier effects reveal that functional FAN1 acts to suppress somatic CAG repeat expansion, likely in genetic interaction with other DNA instability modifiers whose combined effects can hasten or delay onset and other CAG repeat length-driven phenotypes.