Kennedy disease (X-linked recessive bulbospinal neuronopathy): A comprehensive review from pathophysiology to therapy

Abstract

Acknowledgments: the authors thank AFM-Téléthon, Téléthon Biobank, Institut pour la Recherche sur la Moelle épinière et l'Encéphale (IRME), Association pour la Recherche sur la SLA (ARSla) and the University of Padova for their research support.Kennedy disease (X-Linked recessive Bulbospinal Neuronopathy): a comprehensive review from pathophysiology to therapy. AbstractKennedy's disease, also known as spinal and bulbar muscular atrophy (SBMA), is a rare, adult-onset, Xlinked recessive neuromuscular disease. It is caused by expansion of a CAG repeat sequence in exon 1 of the androgen-receptor (AR) gene, encoding a poly-glutamine (polyQ) tract. Poly-Q-expanded AR accumulates in nuclei and initiates degeneration and loss of motor neurons and dorsal root ganglia. The disease has been retained to be a pure lower motor neuron disease for a long time, but recently the presence of important hyper-Creatine-Kinase-emia and of myopathic alterations on muscle biopsy has suggested the presence of a primary myopathy underlying a wide proportion of clinical manifestations. The disease, that affects male adults, is characterized by muscle weakness and atrophy localized proximally in the limbs and by bulbar involvement. Sensory disturbances are associated to the motor phenotype but may be subclinical. The most frequent systemic symptom is gynecomastia related to androgen insensitivity, but other abnormalities, such as heart rhythm and urinary disturbances, have also been reported. The course of the disease is slowly progressive with normal life expectancy. The diagnosis of SBMA is based on genetic testing, with 38 CAG repeats retained to be pathogenic. Even though several therapeutic attempts have been made in mouse models, no effective disease modifying therapy is available but symptomatic therapy is beneficial for the management of weakness, fatigability and bulbar symptoms.

Virtual brain biopsies in amyotrophic lateral sclerosis: Diagnostic classification based on in vivo pathological patterns

“…Such studies should ideally include conditions which are pathologically, clinically or radiologically similar to ALS, for example hereditary spastic paraplegia (HSP), primary lateral sclerosis (PLS), post-polio or Kennedy's patients. (Querin et al, 2017) Another limitation of the study is that no quantitative spinal cord MR indices were included. Spinal measures are likely to improve diagnostic classification further as they have been previously shown to be sensitive longitudinal and prognostic markers in ALS (Agosta et al, 2009b, El Mendili et al, 2015, El Mendili et al, 2014, Bede et al, 2012).…”

Impaired proteostasis in rare neurological diseases

“…Nevertheless, not all proteins require chaperones to fold. Protein aggregates can also be generated as a consequence of (i) mutations that cause conformational changes in the native state of a protein [9,18,[65][66][67][68][69][70][71][72][73][74]; (ii) defects in protein quantity [65,75]; (iii) elongation of certain protein domains [9,[76][77][78]; or (iv) domain truncations [65][66][67]79] ( Figure 3). The E1 enzyme UBA1 is implicated in the aetiology of X-linked infantile spinal muscular atrophy (XL-SMA) [83], and mutations in the E2 enzyme UBE2A result in UBE2A deficiency syndrome [84], whereas the E2 enzyme UBE2K, which can catalyse protein ubiquitination independent of E3 ligases, is a pivotal factor modulating the neurotoxicity of expanded huntingtin in Huntington's disease [85].…”

Physiotherapy in Kennedy’s disease

“…osób [4,6,9]. Jej pierwsze objawy pojawiają się przeważnie przed ukończeniem 40. roku życia, choć wiek osób, u których rozpoznaje się tę chorobę, mieści się w zakresie 18-64 lata [1,2,4,9]. Z uwagi na położenie zmutowanego genu w chromosomie X (Xq11-12) cho roba dotyka wyłącznie osób płci męskiej.…”

“…Z uwagi na położenie zmutowanego genu w chromosomie X (Xq11-12) cho roba dotyka wyłącznie osób płci męskiej. Kobiety są jedynie nosicielkami zmutowanego genu i nie występują wśród nich objawy rdzeniowo-opuszkowego zaniku mięśni [1,2,4,9,10]. Chorzy żyją statystycznie przez około 20 lat od wystąpienia pierwszych objawów klinicznych choroby [4,9,10].…”

“…androgen receptor, AR), powodując brak wrażliwości białka receptorowego na androgeny w wyniku pofałdowania jego struktury i częściowej proteolizy [1-5, 9, 10]. Nagromadzenie nieprawidłowego białka receptorowego jest inicjatorem procesu neurodegeneracyjnego, prawdopodobnie przyczyniając się do zakłócenia w procesie transkrypcji innych białek [1,4,9,11]. Początkowo zakładano, że choroba Kennedy'ego to choroba dolnego neuronu ruchowego, lecz badania ostatnich lat wskazują, że pierwotnie degeneracji ulega tkanka mięśniowa w wyniku interakcji pomiędzy androgenami a nieprawidłowym białkiem receptora (poliQ-AR) [9,11,12].…”