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Degenerative Diseases of the Nervous System
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
James A. Mastrianni, Elizabeth A. Harris
Five of the eight neurologic disorders caused by an increase in the number of CAG repeats result in spinocerebellar ataxia (Table 16.14). The other three are spinal and bulbar muscular atrophy (SBMA or Kennedy's disease), HD, and DRPLA. These disorders are characterized by autosomal dominant or X-linked inheritance, onset in midlife, a progressive course, anticipation, preponderance of unstable repeats from the paternal chromosome, and correlation of increased CAG repeats with earlier age at symptom onset. The abnormal proteins in each disorder are expressed in a wide range of tissues and are not limited to the affected brain regions.
Severe male factor infertility: Genetic consequences and recommendations for genetic testing
Published in David K. Gardner, Ariel Weissman, Colin M. Howles, Zeev Shoham, Textbook of Assisted Reproductive Techniques, 2017
Katrien Stouffs, Willy Lissens, Sara Seneca
Kennedy’s disease or spinal and bulbar muscular atrophy is a neuromuscular disease causing muscular weakness that is associated with testicular atrophy and leads to oligozoo- spermia or azoospermia. It is an X-linked disease caused by an expanded (CAG) trinucleotide repeat in the transactivation domain of the androgen receptor gene (61, 62). If treated with ICSI, genetic counseling is again indicated. However, point mutations in the androgen receptor gene might result in androgen insensitivity through impaired binding of dihydrotestosterone to the receptor, which will interfere with sexual development. The resulting syndrome is testicular feminization or androgen insensitivity syndrome, causing a (partial) female phenotype (63, 64). The presenting problem here will not (only) be male infertility. Patients with an autosomal recessive 5a-reductase deficiency and therefore unable to synthesize dihydrotestosterone from testosterone may theoretically present at the clinic with azoospermia and pseudohermaphroditism (65, 66).
Scientific Basis of Male Hypogonadism
Published in Anthony R. Mundy, John M. Fitzpatrick, David E. Neal, Nicholas J. R. George, The Scientific Basis of Urology, 2010
Thang S. Han, Pierre-Marc G. Bouloux
Original research on X-linked spinal and bulbar muscular atrophy (Kennedy’s disease) suggested a mutation at the N-terminus of the AR gene exon 1, involving amplification of CAG (polyglutamine) repeats as the underlying cause (77), probably because of the neurotoxicity of the polyglutamine-expanded gene products (78). Subsequent studies have identified a number of candidate genes for this CAG triplet polymorphism of the AR (79). It appears that a normal length of CAG repeats is between 8 and 35. Abnormally shorter sequences or longer sequences than this range are associated with increased risk of diseases that are androgen dependent (Table 6) (80–86). This relationship has been explained by the fact that the length of the CAG repeats of the AR determines the transactivation activity of the receptor (87), such that shorter CAG repeats are associated with stronger and longer CAG repeats with weaker activation of the transcription triggered by the AR. The underlying mechanism may lie in the unfolded state of the sequence when it exceeds a critical length (87,88).
Primary lateral sclerosis natural history study – planning, designing, and early enrollment
Published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2023
Hiroshi Mitsumoto, Grace Jang, Ikjae Lee, Zachary Simmons, Alexander V. Sherman, Daragh Heitzman, Eric Sorenson, Ken Cheung, Jinsy Andrews, Matthew Harms, Neil A. Shneider, Regina Santella, Sabrina Paganoni, Senda Ajroud-Driss, J. Americo M. Fernandes, Katherine M. Burke, Kelly Gwathmey, Ali A. Habib, Nicholas J. Maragakis, David Walk, Christina Fournier, Terry Heiman-Patterson, James Wymer, Frank Diaz, Stephen N. Scelsa, Lauren Elman, Angela Genge, Stephen A. Goutman, Ghazala Hayat, Omar Jawdat, Wendy S. Johnston, Nanette C. Joyce, Edward J. Kasarskis, Yaz Y. Kisanuki, Catherine Lomen-Hoerth, Michael T. Pulley, Jaimin S. Shah, Christen Shoesmith, Lorne Zinman
We initiated this study knowing that PLS is an exceedingly rare disease, but the measures we have taken to overcome this have not been successful as quickly as we had planned. We have publicized the study with help of the Spastic Paraplegia Foundation, the ALS Association and the Northeast ALS Consortium. Our PLS COSMOS study took 5 years for 5 sites to recruit roughly 50 participants with “definite” PLS (5 years after symptom onset in this particular study) (33). Recruitment was aided by our simultaneous, ongoing ALS COSMOS study (35). The PLS natural history study has many more sites (30) to compensate for the rarity of PLS and the shorter timeline for recruitment. Based on the PLS-COSMOS study, we calculated that it would take ∼1.7 years to enroll 100 participants. Superimposed upon this, participants with early and probable PLS (50% of our participants) have been more difficult to identify than those with well-established PLS. A clinical trial in Japan for spinal and bulbar muscular atrophy required more than 5 years to recruit the required number of participants for study completion, demonstrating the need for extended periods of recruitment for very rare disorders (48). In the absence of prolonged recruitment periods and extended timelines for funding, studies of rare neurodegenerative diseases will continue to face serious logistical difficulties.
The validity of the International Physical Activity Questionnaire (IPAQ) for adults with progressive muscle diseases
Published in Disability and Rehabilitation, 2022
Sarah F. Roberts-Lewis, Claire M. White, Mark Ashworth, Michael R. Rose
However, concerns remain over potential activity-related exacerbations of muscle disease [4,9]. World Health Organisation (WHO) activity recommendations seem generally applicable and safe [1] for many other neuromuscular diseases. For example, those originating from neuromuscular junction pathology, such as Myasthenia Gravis [10], or nervous system pathologies, such as peripheral neuropathies [11,12] and Spinal and Bulbar Muscular Atrophy [12]. However, there is less evidence regarding safe activity dosage for adults with muscle disease [3]. The reciprocal relationship between activity and muscular gene expression [13] means that, in muscle disease, greater understanding and precision is required for measurement, and evidence-based prescription, of physical activity throughout disease progression [3,14].
Assessment of dysarthria with Frenchay dysarthria assessment (FDA-2) in patients with Duchenne muscular dystrophy
Published in Disability and Rehabilitation, 2022
Nanako Hijikata, Michiyuki Kawakami, Ayako Wada, Maki Ikezawa, Kentaro Kaji, Yasuhiro Chiba, Miyuki Ito, Eri Fujino, Tomoyoshi Otsuka, Meigen Liu
As in the original version [9], five disorder groups were included: upper motor neuron lesions, mixed upper and lower motor lesions, extrapyramidal lesions, cerebellar lesions, and lower motor lesions. The 22 participants for the reliability study included 10 patients with cerebrovascular accident (CVA), four with amyotrophic lateral sclerosis (ALS), four with Parkinson’s disease (PD), two with spinocerebellar degeneration (SCD), and two with spinal and bulbar muscular atrophy (SBMA). The 50 participants for the validity study included 10 patients with CVA, 10 with ALS, 10 with PD, 11 with SCD or multi-system atrophy type C (MSA-C), and 9 with SBMA. They were recruited during hospitalization in National Hospital Organization Higashisaitama National Hospital for recovery phase rehabilitation, short-term evaluation, or respite care between November 2017 and January 2019. All patients were referred to the Department of Rehabilitation Medicine and determined to be dysarthric on the initial examination by a physiatrist with 15 years of experience in CVA and NMD rehabilitation. The exclusion criteria for CVA patients were the presence of aphasia on examination or infratentorial lesions on computed tomography and/or magnetic resonance imaging.