Gynecomastia. Description. Spinal bulbar muscular atrophy, or Kennedy disease, is a rare X-linked recessive motor neuron disease characterized by proximal ...
Chapter 69
Spinal Bulbar Muscular Atrophy, Kennedy Disease
Keywords Tongue weakness and fasciculations • Rhinolalia • Androgen receptor • Gynecomastia
Description Spinal bulbar muscular atrophy, or Kennedy disease, is a rare X-linked recessive motor neuron disease characterized by proximal and bulbar muscle weakness [1]. The onset of symptoms occurs between 30 and 60 years of age, with tremor, muscle cramps, muscle twitching, fatigue, and slurred speech. Patients develop weakness and wasting of the limb and bulbar muscles, dysarthria, dysphonia, hanging jaw, tongue atrophy, and chewing difficulty. Other clinical features include gynecomastia and hypogonadism, leading to infertility and impotence. Disease progression is slow, 1/3 of patients became wheelchair bound 20 years after diagnosis, and some patients may be unable to swallow or breathe. Intellectual impairment is minimal to none. SBMA is caused by an unstable expansion of a CAG triplet repeat (40–62 repeats) in exon 1 of the AR gene, encoding the androgen receptor (Table 69.1) [2]. The expanded stretch of polyglutamines within the androgen receptor results in misfolding and proteolysis of the mutated receptor, rendering it insensitive to androgen hormones. In the nucleus, AR fragments aggregate, cause dysregulation of the transcription of various other proteins, and lead to motor neuron degeneration. The diagnosis is based on: clinical examination elevated levels of CK, testosterone, progesterone, FSH, and LH; EMG findings of reduced nerve conduction velocities or reduced nerve action potential amplitudes; acute or chronic denervation and reinnervation; and genetic analysis [3, 4].
C. Angelini, Genetic Neuromuscular Disorders: A Case-Based Approach, DOI 10.1007/978-3-319-07500-6_69, © Springer International Publishing Switzerland 2014
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308 Table 69.1 Genetic data
a
69 Spinal Bulbar Muscular Atrophy, Kennedy Disease Disease symbol Disease MIM # Gene symbol Gene MIM # Protein Chromosome locus Inheritance
SBMA 313200 AR 313700 Androgen receptor Xq12 X-linked recessive
b
c
Fig. 69.1 Patient 1 shows slight calf hypertrophy (a), gynecomastia (b), and tongue atrophy (c)
Case Report Patient 1 This man had one affected cousin (Fig. 69.1); at age 54, he started complaining of cramps and myalgia, and EMG showed diffused denervation including bulbar district. At age 56 years, he had proximal upper arm weakness, atrophic tongue with tongue fasciculation, rhinolalia, and mild dysphagia. His CK was 1,664 U/L. EMG showed mixed neurogenic and myogenic changes with pseudomyotonic discharges. He had absent somatosensory evoked potentials. At age 60 years, he walked with the aid of a cane and had Gowers’ sign, difficulty in finger extension, fasciculation in the lower limbs, dysarthria, and difficulty chewing. At age 64 years, he could
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walk a few steps with support. At age 68, he was wheelchair bound and had dysphagia, dysphonia, and restrictive respiratory insufficiency. Patient 2 This is the 32-year-old daughter of patient 1 (obligate carrier) who complained of intermittent cramps and myalgia in her lower extremities for few years. She had bilateral mild calf hypertrophy and a slight finger tremor. Her deep tendon reflexes were absent. Skeletal muscle strength by MRC scale was normal in all muscle groups tested. CK was normal. EMG did not reveal any abnormal motor units; there was a unilateral reduction of sensory action potential of the median nerve with normal conduction velocity.
Laboratory Exams Patient 1 Muscle biopsy showed the feature of chronic neurogenic changes with secondary myopathic features [3]. Genetic analysis of the AR gene showed >550 repeats. Patient 2 A muscle biopsy showed a few angulated fibers and some whorled lobulated fibers and other fibers with internal nuclei [3].
Conclusion The combination of adult-onset, limb-girdle symptoms in males, perioral fasciculations, sensory neuropathy, and abnormal voice suggests the diagnosis of Kennedy disease. Progression is slow and life expectancy is near normal. The lack of sensation and the impairment of dorsal root ganglion cells were expanded AR aggregates cause neuronal dysfunction. Weakness is progressive but patients remain ambulatory.
Key Points • This disorder is found in weak men with gynecomastia and tongue weakness. • Female carriers might have mild myopathy.
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69 Spinal Bulbar Muscular Atrophy, Kennedy Disease
References 1. Kennedy WR, Alter M, Sung JH. Progressive proximal spinal and bulbar muscular atrophy of late onset: a sex-linked recessive trait. Neurology. 1968;18:671–80. 2. La Spada AR, Wilson EM, Lubahn DB, Harding AE, Fischbeck KH. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature. 1991;352:77–9. 3. Sorarù G, D’Ascenzo C, Polo A, Palmieri A, Baggio L, Vergani L, Gellera C, Moretto G, Pegoraro E, Angelini C. Spinal and bulbar muscular atrophy: skeletal muscle pathology in male patients and heterozygous females. J Neurol Sci. 2008;264:100–5. 4. Querin G, D’Ascenzo C, Peterle E, Ermani M, Bello L, Melacini P, Morandi L, Mazzini L, Silani V, Raimondi M, Mandrioli J, Romito S, Angelini C, Pegoraro E, Sorarù G. Pilot trial of clenbuterol in spinal and bulbar muscular atrophy. Neurology. 2013;80:2095–8.
