Early onset and novel features in a spinal and bulbar muscular atrophy patient with a 68 CAG repeat

Abstract

Spinal and bulbar muscular atrophy (SBMA) is an X-linked neuromuscular disease caused by a trinucleotide (CAG) repeat expansion in the androgen receptor gene. Patients with SBMA have weakness, atrophy, and fasciculations in the bulbar and extremity muscles. Individuals with CAG repeat lengths greater than 62 have not previously been reported. We evaluated a 29 year old SBMA patient with 68 CAGs who had unusually early onset and findings not seen in others with the disease. Analysis of the androgen receptor gene confirmed the repeat length of 68 CAGs in both peripheral blood and fibroblasts. Evaluation of muscle and sensory function showed deficits typical of SBMA, and in addition the patient had manifestations of autonomic dysfunction and abnormal sexual development. These findings extend the known phenotype associated with SBMA and shed new insight into the effects of the mutated androgen receptor.

The clinical application of preimplantation genetic diagnosis for the patient affected by congenital contractural arachnodactyly and spinal and bulbar muscular atrophy

“…However, the age of disease onset correlates inversely with the CAG repeat length, i.e., greater CAG repeat lengths correspond to earlier disease onset [29]. Christopher Grunseich et al reported a 29-year-old patient with SBMA who had 68 CAG repeats in the AR gene and who had presented weakness since age 18 [14]. In our study, the father (II-2), 37 years old, had 53 CAG repeats (Fig.…”

“…Spinal and bulbar muscular atrophy (SBMA; MIM 313200), also known as Kennedy's disease, is an Xlinked recessive and adult-onset motor neuron disease characterized by slowly progressive weakness and atrophy in the limb and bulbar muscles [13,14]. SBMA is caused by an expansion of trinucleotide cytosine adenine guanine (CAG) repeats in exon 1 of the androgen receptor (AR) gene on chromosome Xq11-12 [15].…”

Non-neural phenotype of spinal and bulbar muscular atrophy: results from a large cohort of Italian patients

“…Patients affected with SBMA usually do not report symptoms that may suggest autonomic dysfunction; nevertheless, the subclinical involvement of both the orthosympathetic and parasympathetic nervous systems has been reported 39. Moreover, one single patient, carrying the longest CAG repeat ever found (68 triplets), reported autonomic dysfunctions such as decreased sweating and difficulties with ejaculation 4. In our SBMA cohort, we have studied Sympathetic Skin Response (SSR) and our preliminary findings are consistent with a prolonged latency of the potential (unpublished data).…”

“…1 The AR CAG repeat ranges in size from 9 to 36 in healthy respondents but from 38 to 68 in patients with SBMA. [2][3][4] SBMA is characterised by loss of lower motor neurons in the spinal cord and brainstem, leading to progressive limb and bulbar muscle weakness and atrophy. SBMA affects adult males with onset usually between 30 and 50 years.…”

The Role of the Protein Quality Control System in SBMA

“…The molecular basis of the disease is associated with an expansion of a CAG triplet repeat sequence, that codes for the amino acid glutamine (Q), located in exon 1 of the androgen receptor (AR) gene (La Spada, et al, 1991). In the normal population, this CAG repeat is comprised between 9 and 37 repeats (average=22), but in SBMA patients, expansions of more than 38 (up to 68) repeats (Fratta, et al, 2014a,Grunseich, et al, 2014a) results in disease. The CAG repeat codes for a polyglutamine (polyQ) tract, which is located in the N-terminal transactivation domain of the AR (ARpolyQ) protein.…”