Last Updated: March 3, 2023
Introduction to Spinobulbar Muscular Atrophy
Spinobulbar muscular atrophy (SBMA) is an adult onset, slowly progressive motor neuropathy that results from the expansion of a CAG trinucleotide repeat in exon 1 of the androgen receptor (AR) gene. SBMA is also known as Kennedy disease (KD) and spinal and bulbar muscular atrophy, X-linked 1 (SMAX1).
SBMA is an X-linked recessive form of spinal muscular atrophy and as such occurs almost exclusively in males. In normal individuals the CAG repeat ranges from 9–36 and in affected individuals it ranges from 38–62. SBMA represents the prototypical adult onset neurodegenerative disease caused by expansion of a trinucleotide repeat.
Molecular Biology of SBMA
The androgen receptor gene (symbol AR: also identified as NR3C4), alternatively known as the dihydrotestosterone receptor, is located on the X chromosome (Xq12) and spans more than 90 kb encompassing 11 exons that generate five alternatively spliced mRNAs, each of which encode distinct protein isoforms.
The AR protein belongs to the class of nuclear receptors called activated class I steroid receptors, which also includes the glucocorticoid receptor (GCCR or GR, also identified as NR3C1), the progesterone receptor (PGR or PR, also identified as NR3C3) and the mineralocorticoid receptor (MR, also identified as NR3C2). These receptors recognize canonical androgen response elements (AREs), which are inverted repeats of 5’–TGTTCT–3′. The major domains of AR include N- and C-terminal activation domains, which are designated activation function-1 (AF-1) and AF-2, a ligand-binding domain, and a polyglutamine tract.
Mutations in the AR gene are also associated with the androgen insensitivity syndrome (AIS, formerly known as the testicular feminization syndrome, TFM), and in Kennedy spinal and bulbar muscular atrophy.
Clinical Features of SBMA
SBMA is and adult onset neuronopathy and as such is associated with age of onset seen as usually occurring in the third to fifth decade of life. However, earlier involvement has been reported. The disorder is characterized by slowly progressive limb and bulbar muscle (muscles of mouth and throat) weakness with fasciculations (muscle twitching), and muscle atrophy. The motor weakness and wasting spreads throughout the distal musculature as well as the face. Muscle cramps occur in up to 70% of SBMA patients and these may precede the onset of muscle weakness by 10 years or more. Eventual involvement of the peripheral limb muscles results in the reduction or loss of deep tendon reflexes. Atrophy of the muscles served by the cranial nerves of the bulbar region [glossopharyngeal nerve (cranial nerve IX), vagus nerve (cranial nerve X), and hypoglossal nerve (cranial nerve XII)] result in facial muscle sagging, seen most clearly in the lower lip, speech difficulties and difficulty swallowing. The muscle twitching can be sever in the tongue which can interfere with sleep.
Because the defect causing SBMA is in the androgen receptor some patients exhibit defects in male sex characteristics including late hypogonadism (presenting as testicular atrophy and gynecomastia) and late sterility. However, these patients do not manifest the full symptoms of androgen insensitivity syndrome (testicular feminization) that are found in AR loss-of-function mutations. In addition, deletion of the AR in humans does not lead to motor neuron disease. One additional feature this disease is that females harboring homozygous expansion of the polyglutamine tract show only very mild symptoms of SBMA.
These observations indicate that manifestation of SBMA is related high androgen levels. Recent experiments in mice, in which a polyglutamine expanded form of the AR is expressed, show binding of androgen as well as translocation of the hormone-receptor complex to the nucleus and that these processes are required for the onset of motor neuron disease. In another experiment, mice expressing a human AR with 112 glutamines in the polyglutamine tract developed a disease with many of the features of SBMA. When these mice were surgically castrated, thus depleting androgen production, motor neuron function was partially restored.
Currently there is no effective treatment for the motor neuronopathy of SBMA.