164
Journal of
CLINICAL NEUROMUSCULAR DISEASE
Case Review
Volume 15, Number 4 June 2014
Kennedy Disease With Biphasic Clinical Course and Rapid Progression Pedro María Rodríguez Cruz, MD,* Javier Ricardo Pérez Sánchez, MD,* Irene Catalina Álvarez, MD,*† Alfredo Traba López, MD,‡ and José Luis Muñoz Blanco, MD*†§
Abstract
From the *Department of Neurology, Madrid, Spain; †ALSNeuromuscular Unit, Madrid, Spain; ‡Department of Clinical Neurophysiology, Madrid, Spain; and §Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Hospital General Universitario Gregorio Marañón, Madrid, Spain. P. M. Rodríguez Cruz: conception and design, drafting the article, and article review. J. R. Pérez Sánchez: conception and design, drafting the article, and article review. I. Catalina Alvarez: conception and design and critical review. A. Traba López: neurophysiology studies and critical review. J. L. Muñoz Blanco: critical review, final approval of the version to be published, and guarantor. The authors report no conflicts of interest. Reprints: Pedro Maria Rodriguez Cruz, MD, Servicio de Neurología, Hospital General Universitario Gregorio Marañón, c/Doctor Esquerdo 46, Madrid 28007, Spain (e-mail: rodriguezcruzpm@gmail. com). Copyright © 2014 by Lippincott Williams & Wilkins
We report a case of spinal and bulbar muscular atrophy (SBMA), also known as Kennedy disease, with a 38 CAG-repeat expansion in exon-1 of the androgen receptor gene, presenting with a 2-year history of mild speech difficulty, dysphonia, and occasional choking. Initial clinical features and complementary studies were consistent with SBMA. The disease progression, as assessed by the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised, remained stable over the first 5 years from the onset but showed a rapid decline (from 42 to 24 points) over the next 18 months before his death. In the later stages of the disease, deep tendon reflexes were preserved in limbs and a brisk jaw-jerk reflex and bilateral Hoffmann sign were evident. Survival from disease onset was 78 months. The final cause of death was aspiration pneumonia. The atypical clinical features, evolution, and accelerated disease course are not concordant with the relatively short 38 CAG-repeat expansion in the androgen receptor gene. This may represent either a variant SBMA phenotype, which has not been recorded to date, or the development of amyotrophic lateral sclerosis in a known case of SBMA. Key Words: spinal and bulbar muscular atrophy, Kennedy disease, amyotrophic lateral sclerosis, motor neuron disorders, CAG-repeat expansion, androgen receptor gene
( J Clin Neuromusc Dis 2014;15:164–166)
CASE REPORT A 65-year-old man presented to our facility with a 2-year history of mild speech difficulty, dysphonia, and occasional choking spells. There was no history of weight loss or aspiration pneumonia and no family history of diabetes mellitus or neuromuscular diseases. Neurological examination revealed fasciculations and mild muscular
atrophy in tongue, mentalis, masseters, shoulder girdle, and both quadriceps. Muscle strength and deep tendon reflexes in limbs, plantar responses, and gait were normal. The jaw-jerk reflex and Hoffmann sign were not present initially. Mild dysarthria for lingual consonants was noticed. Exteroceptive and vibratory sensations were impaired symmetrically in distal third of legs and feet. An asymmetric postural tremor in both hands and real gynecomastia were observed. There was no cognitive, oculomotor, or autonomic impairment. Amyotrophic Lateral Sclerosis Functional Rating ScaleRevised (ALSFRS-R) was 45. Creatine kinase, thyroid function, and serum immunofixation showed normal values. There were no alterations in the video-fluoroscopic swallowing study, mammography, and magnetic resonance imaging of the brain, cervical, and dorsal spinal cord. Initial electromyography revealed chronic neurogenic abnormalities with occasional positive sharp waves and fasciculation potentials in cranial muscles (masseter, orbicularis oris) and distal upper limbs. Electroneurography excluded motor conduction blocks. Sensory and motor conduction velocities were normal. Amplitude was reduced in sensory nerve action potentials (SNAP) of median (0.90 mV), cubital (0.23 mV), and sural (1.1 mV) nerves. Somatosensory-evoked potentials from median and posterior tibial nerves were unrecordable. Central motor conduction time was normal except for the right lower limb (16 milliseconds). No mutations were found in SOD-1, TARDBP, FUS, and ANG genes. The study of
Kennedy Disease With Biphasic Clinical Course
Journal of
CLINICAL NEUROMUSCULAR DISEASE Volume 15, Number 4 June 2014
FIGURE 1. Assessment of disease progression in the case reported and the cohort of patients with SBMA followed in our facility (n ¼ 6) using ALSFRS-R.
the androgen receptor gene (ARG) showed a 38 CAG-repeat expansion in exon-1. The disease progression assessed by the ALSFRS-R remained stable over the first 5 years from clinical onset but then showed a rapid decline the next 18 months before this death, including speech, deglutition, and muscle strength in all 4 limbs (from 42 to 24 points). Deep tendon reflexes remained intact in all 4 limbs, and the jaw-jerk reflex and bilateral Hoffmann sign were demonstrated. Plantar responses were flexor. Clonus and hypertonia were absent. Sensory findings were unchanged. The patient survived 78 months from the onset of symptoms. Aspiration pneumonia was the cause of death.
DISCUSSION Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy disease, is a slowly progressive X-linked motor neuron disease caused by a CAG-repeat expansion, between 40 and 62 CAG-repeat size in exon-1 of the ARG.1 However, an expansion beyond 35 repeats is considered to be pathogenic.2
SBMA is misdiagnosed as amyotrophic lateral sclerosis (ALS) in approximately 2% of the cases.3 Nevertheless, no differences were found in the CAG-repeat length of the ARG between ALS and controls.4 We report a case of SBMA with a 38 CAG-repeat expansion associated with atypical clinical features and an unusually truncated survival from disease onset. Initially, this patient had the common clinical findings of SBMA: weakness and wasting of facial, bulbar, and limb muscles; postural tremor in hands; gynecomastia; and sensory axonal neuropathy with significantly reduced SNAP amplitudes.5 The 38 CAGrepeat expansion in exon-1 of the ARG and the specific decrease of SNAP amplitude supported the diagnosis: CAG expansions of the ARG are not present in ALS, and the specific decrease of SNAP amplitude in SBMA has recently shown to be useful for the differential diagnosis of motor neuron disorders.4,6 Afterwards, he developed atypical features taking into account the natural history and clinical characteristics of SBMA. His survival differed from the natural history www.jcnmd.com
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Volume 15, Number 4 June 2014
Rodríguez Cruz et al
of SBMA, where the long-term survival is minimally reduced from age-matched controls and was closer to that obtained from population studies in bulbar onset ALS (mean survival, 33.5 months).7,8 His clinical course during the first 5 years was similar to the population studies in SBMA (mean ALSFRS-R after 13-year follow-up: 37) and to the cohort of patients with SBMA followed in our facility.7,9 Therefore, the overall rate of decline in the ALSFRS-R was faster than expected (Fig. 1). The time interval from the onset of muscular weakness to the appearance of aspiration pneumonia and death in a study of 223 Japanese patients with SBMA was 16 and 22 years, respectively.10 These intervals are greater than the survival time from clinical onset of this patient (6.5 years). The 38 CAG-repeat expansion in the present case was much shorter than the CAG-repeat length correlated with the onset ages of pneumonia and death in previous studies (46.7 6 4.2 and 45.4 6 3 CAG).10 Time to diagnosis was 36 months, which is in between the mean delay for bulbar onset ALS (11 months) and SBMA (60 months).5,8 There was no evidence of raised CK or arreflexia, which are commonly identified in 88% and 93%–100% of patients with SBMA, respectively.5,11 This may be related to the short expansion in the ARG. In the later stages, a positive jaw-jerk reflex and bilateral Hoffmann sign were noted. Although a postmortem study was not performed to confirm that the brisk reflexes were associated with corticospinal tracts fiber loss, it is worth mentioning that the present case could meet the El Escorial diagnostic criteria for “probable ALS” if a previous diagnosis for SBMA had not been given.12 To the best of our knowledge, there are no reports in the literature of genetically confirmed SBMA associated with a significantly reduced survival. The atypical clinical features, evolution, and accelerated disease course are also not concordant with the relatively short 38 CAG-repeat expansion in
© 2014 Lippincott Williams & Wilkins
the ARG. This may represent either a variant SBMA phenotype, which has not been recorded to date, or the development of ALS in a known case of SBMA. ACKNOWLEDGMENTS The authors thank Prof FL Mastaglia, Dr Jithin George, and Dr Rosa Ceballos for their helpful comments. REFERENCES 1. Finsterer J. Perspectives of Kennedy’s disease. J Neurol Sci. 2010;298:1–10. 2. La Spada A. Spinal and bulbar muscular atrophy. Gene Rev. 2011. 3. Parboosingh JS, Figlewicz DA, Krizus A, et al. Spinobulbar muscular atrophy can mimic ALS: the importance of genetic testing in male patients with atypical ALS. Neurology. 1997;49:568–572. 4. Bruson A, Sambataro F, Querin G, et al. CAG repeat length in androgen receptor gene is not associated with amyotrophic lateral sclerosis. Eur J Neurol. 2012;19:1373–1375. 5. Rhodes LE, Freeman BK, Auh S, et al. Clinical features of spinal and bulbar muscular atrophy. Brain. 2009;132:3242–3251. 6. Hama T, Hirayama M, Hara T, et al. Discrimination of spinal and bulbar muscular atrophy from amyotrophic lateral sclerosis using sensory nerve action potentials. Muscle Nerve. 2012;45:169–174. 7. Chahin N, Klein C, Mandrekar J, et al. Natural history of spinal-bulbar muscular atrophy. Neurology. 2008; 70:1967–1971. 8. Wijesekera LC, Mathers S, Talman P, et al. Natural history and clinical features of the flail arm and flail leg ALS variants. Neurology. 2009;72:1087–1094. 9. Rodríguez Cruz PM, Pérez Sánchez JR, CatalinaAlvarez I, et al. Progressive bulbar palsy associated to a pathogenic expression of the androgen receptor gene: clinical features and disease progression compared to six cases of spinal and bulbar muscular atrophy (P-2948). EFNS 16th Congress; September 8–11, 2012; Stockholm, Sweden. 10. Atsuta N, Watanabe H, Ito M, et al. Natural history of spinal and bulbar muscular atrophy (SBMA): a study of 223 Japanese patients. Brain. 2006;129:1446– 1455. 11. Mariotti C, Castellotti B, Pareyson D, et al. Phenotypic manifestations associated with CAG-repeat expansion in the androgen receptor gene in male patients and heterozygous females: a clinical and molecular study of 30 families. Neuromuscul Disord. 2000;10:391–397. 12. Brooks BR. El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis. J Neurol Sci. 1994;124(Suppl):96–107.
Journal of
CLINICAL NEUROMUSCULAR DISEASE
Case Review
Volume 15, Number 4 June 2014
Kennedy Disease With Biphasic Clinical Course and Rapid Progression Pedro María Rodríguez Cruz, MD,* Javier Ricardo Pérez Sánchez, MD,* Irene Catalina Álvarez, MD,*† Alfredo Traba López, MD,‡ and José Luis Muñoz Blanco, MD*†§
Abstract
From the *Department of Neurology, Madrid, Spain; †ALSNeuromuscular Unit, Madrid, Spain; ‡Department of Clinical Neurophysiology, Madrid, Spain; and §Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Hospital General Universitario Gregorio Marañón, Madrid, Spain. P. M. Rodríguez Cruz: conception and design, drafting the article, and article review. J. R. Pérez Sánchez: conception and design, drafting the article, and article review. I. Catalina Alvarez: conception and design and critical review. A. Traba López: neurophysiology studies and critical review. J. L. Muñoz Blanco: critical review, final approval of the version to be published, and guarantor. The authors report no conflicts of interest. Reprints: Pedro Maria Rodriguez Cruz, MD, Servicio de Neurología, Hospital General Universitario Gregorio Marañón, c/Doctor Esquerdo 46, Madrid 28007, Spain (e-mail: rodriguezcruzpm@gmail. com). Copyright © 2014 by Lippincott Williams & Wilkins
We report a case of spinal and bulbar muscular atrophy (SBMA), also known as Kennedy disease, with a 38 CAG-repeat expansion in exon-1 of the androgen receptor gene, presenting with a 2-year history of mild speech difficulty, dysphonia, and occasional choking. Initial clinical features and complementary studies were consistent with SBMA. The disease progression, as assessed by the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised, remained stable over the first 5 years from the onset but showed a rapid decline (from 42 to 24 points) over the next 18 months before his death. In the later stages of the disease, deep tendon reflexes were preserved in limbs and a brisk jaw-jerk reflex and bilateral Hoffmann sign were evident. Survival from disease onset was 78 months. The final cause of death was aspiration pneumonia. The atypical clinical features, evolution, and accelerated disease course are not concordant with the relatively short 38 CAG-repeat expansion in the androgen receptor gene. This may represent either a variant SBMA phenotype, which has not been recorded to date, or the development of amyotrophic lateral sclerosis in a known case of SBMA. Key Words: spinal and bulbar muscular atrophy, Kennedy disease, amyotrophic lateral sclerosis, motor neuron disorders, CAG-repeat expansion, androgen receptor gene
( J Clin Neuromusc Dis 2014;15:164–166)
CASE REPORT A 65-year-old man presented to our facility with a 2-year history of mild speech difficulty, dysphonia, and occasional choking spells. There was no history of weight loss or aspiration pneumonia and no family history of diabetes mellitus or neuromuscular diseases. Neurological examination revealed fasciculations and mild muscular
atrophy in tongue, mentalis, masseters, shoulder girdle, and both quadriceps. Muscle strength and deep tendon reflexes in limbs, plantar responses, and gait were normal. The jaw-jerk reflex and Hoffmann sign were not present initially. Mild dysarthria for lingual consonants was noticed. Exteroceptive and vibratory sensations were impaired symmetrically in distal third of legs and feet. An asymmetric postural tremor in both hands and real gynecomastia were observed. There was no cognitive, oculomotor, or autonomic impairment. Amyotrophic Lateral Sclerosis Functional Rating ScaleRevised (ALSFRS-R) was 45. Creatine kinase, thyroid function, and serum immunofixation showed normal values. There were no alterations in the video-fluoroscopic swallowing study, mammography, and magnetic resonance imaging of the brain, cervical, and dorsal spinal cord. Initial electromyography revealed chronic neurogenic abnormalities with occasional positive sharp waves and fasciculation potentials in cranial muscles (masseter, orbicularis oris) and distal upper limbs. Electroneurography excluded motor conduction blocks. Sensory and motor conduction velocities were normal. Amplitude was reduced in sensory nerve action potentials (SNAP) of median (0.90 mV), cubital (0.23 mV), and sural (1.1 mV) nerves. Somatosensory-evoked potentials from median and posterior tibial nerves were unrecordable. Central motor conduction time was normal except for the right lower limb (16 milliseconds). No mutations were found in SOD-1, TARDBP, FUS, and ANG genes. The study of
Kennedy Disease With Biphasic Clinical Course
Journal of
CLINICAL NEUROMUSCULAR DISEASE Volume 15, Number 4 June 2014
FIGURE 1. Assessment of disease progression in the case reported and the cohort of patients with SBMA followed in our facility (n ¼ 6) using ALSFRS-R.
the androgen receptor gene (ARG) showed a 38 CAG-repeat expansion in exon-1. The disease progression assessed by the ALSFRS-R remained stable over the first 5 years from clinical onset but then showed a rapid decline the next 18 months before this death, including speech, deglutition, and muscle strength in all 4 limbs (from 42 to 24 points). Deep tendon reflexes remained intact in all 4 limbs, and the jaw-jerk reflex and bilateral Hoffmann sign were demonstrated. Plantar responses were flexor. Clonus and hypertonia were absent. Sensory findings were unchanged. The patient survived 78 months from the onset of symptoms. Aspiration pneumonia was the cause of death.
DISCUSSION Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy disease, is a slowly progressive X-linked motor neuron disease caused by a CAG-repeat expansion, between 40 and 62 CAG-repeat size in exon-1 of the ARG.1 However, an expansion beyond 35 repeats is considered to be pathogenic.2
SBMA is misdiagnosed as amyotrophic lateral sclerosis (ALS) in approximately 2% of the cases.3 Nevertheless, no differences were found in the CAG-repeat length of the ARG between ALS and controls.4 We report a case of SBMA with a 38 CAG-repeat expansion associated with atypical clinical features and an unusually truncated survival from disease onset. Initially, this patient had the common clinical findings of SBMA: weakness and wasting of facial, bulbar, and limb muscles; postural tremor in hands; gynecomastia; and sensory axonal neuropathy with significantly reduced SNAP amplitudes.5 The 38 CAGrepeat expansion in exon-1 of the ARG and the specific decrease of SNAP amplitude supported the diagnosis: CAG expansions of the ARG are not present in ALS, and the specific decrease of SNAP amplitude in SBMA has recently shown to be useful for the differential diagnosis of motor neuron disorders.4,6 Afterwards, he developed atypical features taking into account the natural history and clinical characteristics of SBMA. His survival differed from the natural history www.jcnmd.com
165
166
Journal of
CLINICAL NEUROMUSCULAR DISEASE
Volume 15, Number 4 June 2014
Rodríguez Cruz et al
of SBMA, where the long-term survival is minimally reduced from age-matched controls and was closer to that obtained from population studies in bulbar onset ALS (mean survival, 33.5 months).7,8 His clinical course during the first 5 years was similar to the population studies in SBMA (mean ALSFRS-R after 13-year follow-up: 37) and to the cohort of patients with SBMA followed in our facility.7,9 Therefore, the overall rate of decline in the ALSFRS-R was faster than expected (Fig. 1). The time interval from the onset of muscular weakness to the appearance of aspiration pneumonia and death in a study of 223 Japanese patients with SBMA was 16 and 22 years, respectively.10 These intervals are greater than the survival time from clinical onset of this patient (6.5 years). The 38 CAG-repeat expansion in the present case was much shorter than the CAG-repeat length correlated with the onset ages of pneumonia and death in previous studies (46.7 6 4.2 and 45.4 6 3 CAG).10 Time to diagnosis was 36 months, which is in between the mean delay for bulbar onset ALS (11 months) and SBMA (60 months).5,8 There was no evidence of raised CK or arreflexia, which are commonly identified in 88% and 93%–100% of patients with SBMA, respectively.5,11 This may be related to the short expansion in the ARG. In the later stages, a positive jaw-jerk reflex and bilateral Hoffmann sign were noted. Although a postmortem study was not performed to confirm that the brisk reflexes were associated with corticospinal tracts fiber loss, it is worth mentioning that the present case could meet the El Escorial diagnostic criteria for “probable ALS” if a previous diagnosis for SBMA had not been given.12 To the best of our knowledge, there are no reports in the literature of genetically confirmed SBMA associated with a significantly reduced survival. The atypical clinical features, evolution, and accelerated disease course are also not concordant with the relatively short 38 CAG-repeat expansion in
© 2014 Lippincott Williams & Wilkins
the ARG. This may represent either a variant SBMA phenotype, which has not been recorded to date, or the development of ALS in a known case of SBMA. ACKNOWLEDGMENTS The authors thank Prof FL Mastaglia, Dr Jithin George, and Dr Rosa Ceballos for their helpful comments. REFERENCES 1. Finsterer J. Perspectives of Kennedy’s disease. J Neurol Sci. 2010;298:1–10. 2. La Spada A. Spinal and bulbar muscular atrophy. Gene Rev. 2011. 3. Parboosingh JS, Figlewicz DA, Krizus A, et al. Spinobulbar muscular atrophy can mimic ALS: the importance of genetic testing in male patients with atypical ALS. Neurology. 1997;49:568–572. 4. Bruson A, Sambataro F, Querin G, et al. CAG repeat length in androgen receptor gene is not associated with amyotrophic lateral sclerosis. Eur J Neurol. 2012;19:1373–1375. 5. Rhodes LE, Freeman BK, Auh S, et al. Clinical features of spinal and bulbar muscular atrophy. Brain. 2009;132:3242–3251. 6. Hama T, Hirayama M, Hara T, et al. Discrimination of spinal and bulbar muscular atrophy from amyotrophic lateral sclerosis using sensory nerve action potentials. Muscle Nerve. 2012;45:169–174. 7. Chahin N, Klein C, Mandrekar J, et al. Natural history of spinal-bulbar muscular atrophy. Neurology. 2008; 70:1967–1971. 8. Wijesekera LC, Mathers S, Talman P, et al. Natural history and clinical features of the flail arm and flail leg ALS variants. Neurology. 2009;72:1087–1094. 9. Rodríguez Cruz PM, Pérez Sánchez JR, CatalinaAlvarez I, et al. Progressive bulbar palsy associated to a pathogenic expression of the androgen receptor gene: clinical features and disease progression compared to six cases of spinal and bulbar muscular atrophy (P-2948). EFNS 16th Congress; September 8–11, 2012; Stockholm, Sweden. 10. Atsuta N, Watanabe H, Ito M, et al. Natural history of spinal and bulbar muscular atrophy (SBMA): a study of 223 Japanese patients. Brain. 2006;129:1446– 1455. 11. Mariotti C, Castellotti B, Pareyson D, et al. Phenotypic manifestations associated with CAG-repeat expansion in the androgen receptor gene in male patients and heterozygous females: a clinical and molecular study of 30 families. Neuromuscul Disord. 2000;10:391–397. 12. Brooks BR. El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis. J Neurol Sci. 1994;124(Suppl):96–107.
