Mechanisms of pathogenesis and molecular targets in spinal and bulbar muscular atrophy

Published on June 30, 2016   19 min
0:00
Hello and welcome to all listeners, my name is Carlo Rinaldi, I'm a Neurologist at University of Oxford. In the next 30 minutes or so, I'll be discussing the mechanism of pathogenesis and molecular targets in a disease called spinal and bulbar muscular atrophy or SPMA.
0:18
I will first give some background on when and how the disease was discovered, followed by the etiology and an update regarding the most recent understanding of the disease pathogenesis. I will then talk about the main histological and clinical features which helps clinicians with the diagnosis and which are the diseases that most frequently SPMA is diagnosed with. I will then discuss some of the most promising therapeutic strategies currently being tested in preclinical studies in animal models and in clinical trials.
0:51
SPMA goes under in many names, Kennedy's disease, X-linked spinal muscular atrophy type 1, X-linked spinal and bulbar muscular atrophy, spinal bulbar muscular atrophy, and spinal and bulbar muscular atrophy just to name some. Kennedy's disease comes from the name of the neurologist that described the disease in the late '60s.
1:14
Although Kennedy's disease was the name of William Kennedy, the first reports of this disease were likely published by Kurland who described in a typical form of lower motor neurons in a Japanese family in 1957. Following the reports by Kurland, additional descriptions of patients with X-linked spino-bulbar muscular atrophy in the absence of corticospinal tract involvement appeared in the literature. In 1968, Dr. Kennedy reported his experience with two large families at the Mayo Clinic in Rochester, Minnesota. And the designation of Kennedy disease was first introduced into French literature in 1979. Kennedy's initial cardinal attributes of the syndrome were most limited to a bulbar and spinal muscular atrophy of late onset with prominent fasiculations, predominantly in the lower phase with the typical tract of an X-linked trait.
2:10
The underlying genetic defect in Kennedy's disease was later found in Fishbeck's laboratory in 1991 as an abnormal expansion of a CAG repeat in the first exon of androgen receptor gene, encoding for a polyglutamine tract in the androgen receptor protein. As you can see here in the picture, there is an agarose gel of PCR products obtained by the amplification of the AR CAG repeat from two unrelated SBMA pedigrees. Affected individuals have enlarged fragments, where their unaffected brothers have fragment sizes within the normal range. Obligate carrier females have both an enlarged fragment and a normal fragment.
2:51
SBMA is inherited in an X-linked manner. Males who inherit the mutant gene are affected, females who inherit the mutant gene are carriers and usually not affected. Sometimes they might show some symptoms like cramps, fasciculations and sometimes CK, creatine kinase elevation in the blood. Affected males pass the disease causing allele to each daughter and carrier females have a 50% chance of transmitting the CAG trinucleotide repeat expansion to each child.
3:23
The cause of SBMA then is an expansion of a trinucleotide CAG repeat which encodes the polyglutamine tract in the first exon of the androgen receptor gene. The CAG repeat within androgen receptor ranges in size from 9 to 36 in normal subjects and from 38 to 68 in SBMA patients. An allele of 37 CAG trinucleotide repeats can manifest reduce penetrance. Following the discovery of the genetic mutation, many reports emerged demonstrating genotype-phenotype correlations between younger age onset and increased polyglutamine repeat length.
3:60
So here in this cartoon, you can see the genetic localization of androgen receptor in the long arm of the X chromosome. So the squares in the androgen receptor genes are the exons, which are only eight. And the androgen receptor protein is translated, it is a member of the steroid and nuclear receptors super family, which is composed of over a hundred members and continues to grow. Androgen receptor is mainly expressed in the androgen target tissues such as prostate, skeletal muscle, liver and central nervous system with highest expressional levels observed in the prostrate, adrenal gland, and epididymis. Physiologically, functional androgen receptor is responsible for male sexual differentiation in-utero and for male puberal changes. In adult males, androgen is mainly responsible for maintaining libido, spermatogenesis, muscle mass and strength, bone mineral density and erythropoiesis. The protein has 919 amino acids and three major functional domains. The N terminal domain, NTD in the picture, which serves as modulatory function, the DNA binding domain or DBD in purple and the ligand binding domain or LBD, which is encoded by the last five exons.
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Mechanisms of pathogenesis and molecular targets in spinal and bulbar muscular atrophy

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