Scientific Basis of Male Hypogonadism
Anthony R. Mundy, John M. Fitzpatrick, David E. Neal, Nicholas J. R. George in The Scientific Basis of Urology, 2010
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).
Severe male factor infertility: Genetic consequences and recommendations for genetic testing
David K. Gardner, Ariel Weissman, Colin M. Howles, Zeev Shoham in Textbook of Assisted Reproductive Techniques, 2017
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).
Degenerative Diseases of the Nervous System
Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw in Hankey's Clinical Neurology, 2020
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.
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.
Chitotriosidase as biomarker for early stage amyotrophic lateral sclerosis: a multicenter study
Published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2021
Petra Steinacker, Emily Feneberg, Steffen Halbgebauer, Simon Witzel, Federico Verde, Patrick Oeckl, Philip Van Damme, Nayana Gaur, Elizabeth Gray, Julian Grosskreutz, Claude G. Jardel, Mykyta Kachanov, Jens Kuhle, Foudil Lamari, Aleksandra Maceski, Maria Del Mar Amador, Benjamin Mayer, Claudia Morelli, Susanne Petri, Koen Poesen, Joost Raaphorst, François Salachas, Vincenzo Silani, Martin R. Turner, Marcel M. Verbeek, Alexander E. Volk, Jochen H. Weishaupt, Patrick Weydt, Albert C. Ludolph, Markus Otto
As disease comparison group we included 30 patients with other motoneuron diseases (oMND: N = 16 primary lateral sclerosis (PLS); N = 9 spinal muscular atrophy, N = 5 spinal and bulbar muscular atrophy, and furthermore 41 patients with ALS mimicking diseases (disease controls, DCon). The ALS mimic diagnoses were as follows: N = 12 polyneuropathy, N = 8 peripheral mononeuropathy, N = 2 brachial plexopathy, N = 2 radiculopathy, N = 2 myopathy, N = 1 juvenile parkinsonism, N = 1 lipid storage disease, N = 3 spastic paraplegia, N = 3 fasciculation syndromes, N = 1 cerebrovascular disease, N = 2 myelopathy, N = 4 no neurological diagnosis. A group of 43 participants who had no signs of neurodegeneration or acute or chronic inflammation of the brain served as control group (Con).
Prolonged distal latency of the median motor nerve is associated with poor prognosis in amyotrophic lateral sclerosis
Published in Neurological Research, 2021
Masayuki Sato, Takumi Nakamura, Kazuaki Nagashima, Yukio Fujita, Yoshio Ikeda
Findings of motor NCS in patients with ALS typically showed no abnormality or slight abnormalities, including decreased conduction velocity or amplitude of compound muscle action potential (CMAP). Distal latency (DL) of CMAP in ALS exhibits basically normal values [8]. However, obvious abnormalities in motor NCS have been reported in patients with ALS [9,10]. In particular, prolonged DL of the median motor nerve is frequently reported in a subset of patients with ALS [11]. Previous studies have shown that prolonged median motor DL (MMDL) is a specific finding in ALS compared to other motor neuron diseases such as spinal muscular atrophy (SMA), spinal and bulbar muscular atrophy (SBMA), and axonal neuropathy [12,13]. It has been reported that motor DLs of patients with SBMA were mildly prolonged compared to control subjects, and those with SMA were usually within normal range [14–16]. However, the frequency of SBMA patients with prolonged motor DLs was lower than that of ALS patients [12]. Distal axonal degeneration in dying-back pattern may contribute to prolongation of motor DL in patients with ALS [17]. Neuropathological findings of superoxide dismutase 1 (SOD1) mutant mouse and ALS patients who died at an earlier stage suggested that motor neuron pathology began from distal to proximal portions of axons [18]. NCS is routinely assessed in clinical settings for the differential diagnosis of ALS. The clinical significance of prolonged MMDL found in patients with ALS has not been fully elucidated. The present study aimed to clarify the clinical importance of NCS characteristics in patients with ALS.
Related Knowledge Centers
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