Atrofia muscular espinal y bulbar: enfermedad de Kennedy. Aspectos clínicos y genéticos / Spinal and bulbar muscular atrophy (SBMA): Kennedy's disease. Clinical and genetic aspects

La atrofia muscular espinal y bulbar es una enfermedad neurológica caracterizada por degeneración gradual de la motoneurona inferior, que resulta en debilidad muscular, atrofia y fasciculaciones. Es una entidad de etiología genética con mecanismo de herencia ligado al cromosoma X recesivo, por lo que afecta a varones, en la que se produce una expansión del triplete CAGn en el gen del receptor de andrógenos. Se manifiesta por signos de insensibilidad a los andrógenos (ginecomastia e infertilidad). A partir de los 20-30 años, aproximadamente, comienzan los signos de afectación de la motoneurona inferior a nivel espinal con calambres y temblor de acción y posteriormente debilidad muscular. En la evolución se evidencia compromiso bulbar. Se presenta el caso clínico-genealógico de un varón de 32 años con temblores en quien se confirma molecularmente la enfermedad de Kennedy. Este es el primer caso, hasta nuestro conocimiento, reportado en Uruguay. Se destaca la importancia de plantear dicha afección en un paciente joven con "temblores" cuando aún no es ostensible la debilidad muscular. La historia familiar es de capital importancia. La presencia de fasciculaciones en el estudio eléctrico a nivel perioral es muy sugestiva de esta patología. La confirmación molecular es importante para el asesoramiento genético.

Spinal and bulbar muscular atrophy (SBMA) is a neurological disease characterized by the progressive degeneration of the inferior motor neurones, what results in muscle weakness, atrophy and fasciculations. It possesses a genetic etiology with X-linked recessive inheritance mode, and thus affects men. There is an abnormal expansion of the CAG polyglutamine encoding repeat within the androgen receptor gene. It is noticed by signs of androgen insentistivity (gynecomastia and infertility). At 20-30 years old approximately signs of compromise of the lower motor neurones in the spine are seen in cramps and action tremor followed by muscle weakness, evidencing bulbar involvement in the evolution. The study presents the ciínical-genealogical case of a 32 year-old male with tremor, whose Kennedy disease was confirmed with molecules. This is the first case reported in Uruguay as far as we know. The importance of considering this condition is pointed out in a young patient with "tremor" when muscle weakness is not evident yet. Family history is key. The presence of fasciculation in the electrical study strongly suggests this condition. Molecular confirmation is important for genetic advice purposes.

A atrofia muscular bulbo-espinal (BSMA) é uma doença neurológica caracterizada pela degeneração gradual do neurônio motor inferior causando fraqueza muscular, atrofia e fasciculações. É uma entidade de etiologia genética com mecanismo de herança ligada ao cromossoma X recessivo, afetando por isso a indivíduos do sexo masculino, nos quais se observa a expansão do triplete CAGn no gene do Receptor de Andrógenos (RA). Manifesta-se pela ausência de sensibilidade aos andrógenos (ginecomastia e infertilidade); a partir dos 20-30 anos aproximadamente começam a manifestar-se os sinais de afetação do neurônio motor inferior na região espinal com câimbras e tremor de ação e posteriormente debilidade muscular. Em sua evolução observa-se compromisso bulbar. Apresenta-se o caso clínico - genealógico de um indivíduo de sexo masculino de 32 anos com tremores, no qual foi realizado diagnóstico molecular de doença de Kennedy. Este é o primeiro caso informado no Uruguai, que seja de nosso conhecimento. Destaca-se a importância da suspeita desta afecção em um paciente jovem com "tremores" mesmo quando a debilidade muscular ainda não é ostensível. A história familiar é fundamental. A presença de fasciculações no estudo elétrico na região perioral é muito sugestiva desta patologia. A confirmação molecular é importante para o assessoramento genético.

X-linked spinal and bulbar muscular atrophy (Kennedy's disease): the first case described in the Brazilian Amazon / Atrofia muscular bulboespinhal ligada ao cromossomo X (doença de Kennedy): o primeiro caso descrito na Amazônia brasileira

ABSTRACT The X-linked spinal and bulbar muscular atrophy (Kennedy's disease) is a rare X-linked, recessive, lower motor neuron disease, characterized by weakness, atrophy, and fasciculations of the appendicular and bulbar muscle. The disease is caused by an expansion of the CAG repetition in the androgen receptor gene. Patients with Kennedy's disease have more than 39 CAG repetitions. We report a case of 57-year-old man, resident of Monte Dourado (PA, Brazil) who complained of brachiocrural paresis evolving for 3 years along with fasciculations and tremors of extremities. In addition, he also developed dysarthria, dysphagia, and sexual dysfunction. The patient clinical picture included gait impairment, global hyporeflexia, proximal muscle atrophy of upper limbs, deviation of the uvula to right during phonation and tongue atrophy with fasciculations. The patient reported that about 30 years ago he had undergone gynecomastia surgery. His electroneuromyography suggested spinal muscular atrophy, and nuclear magnetic resonance imaging showed tapering of the cervical and thoracic spinal cord. Patient's creatine kinase level was elevated. In view of the findings, an exam was requested to investigate Kennedy's disease. The exam identified 46 CAG repetitions in the androgen receptor gene, which confirmed the diagnostic suspicion. This was the first case of Kennedy's disease diagnosed and described in the Brazilian Amazon. To our knowledge only other four papers were published on this disease in Brazilian patients. A brief review is also provided on etiopathogenic, clinical and diagnostic aspects.

RESUMO A atrofia muscular bulboespinhal ligada ao cromossomo X (doença de Kennedy) é uma rara doença de neurônio motor inferior, recessiva, ligada ao X, e caracterizada por fraqueza, atrofia e fasciculações da musculatura apendicular e bulbar. É causada por uma expansão da repetição CAG no gene do receptor de androgênio. Pacientes com doença de Kennedy apresentam mais de 39 repetições CAG. O paciente deste relato era do sexo masculino, 57 anos, morador de Monte Dourado (PA, Brasil), com queixa de paresia braquiocrural há 3 anos, acompanhada de fasciculações e tremores de extremidades. Em seguida, ele desenvolveu disartria, disfagia e disfunção sexual. Também apresentava comprometimento da marcha, hiporreflexia global, atrofia muscular proximal dos membros superiores, desvio da úvula para direita à fonação e atrofia de língua com fasciculações. Foi realizada cirurgia para tratamento de ginecomastia há 30 anos. A eletroneuromiografia sugeriu quadro de atrofia muscular espinhal. Imagens de ressonância magnética demonstraram afilamento da medula espinhal cervical e torácica. A creatina quinase estava elevada. Diante dos achados, solicitou-se investigação para doença de Kennedy, e foram identificadas 46 repetições CAG no gene do receptor de androgênio, o que confirmou a suspeita diagnóstica. Este foi o primeiro caso de doença de Kennedy diagnosticado e descrito na Amazônia brasileira. Existem, além deste relato, apenas outros quatro trabalhos publicados sobre a doença em pacientes do Brasil. Também realizamos breve revisão de aspectos etiopatogênicos, clínicos e diagnósticos.

Clinical Characteristics and Genotype-Phenotype Correlation of Korean Patients with Spinal and Bulbar Muscular Atrophy

PURPOSE: Spinal and bulbar muscular atrophy (SBMA) is an X-linked motor neuron disease characterized by proximal muscle weakness, muscle atrophy, and fasciculation. Although SBMA is not uncommon in Korea, there is only one study reporting clinical characteristics and genotype-phenotype correlation in Korean patients. MATERIALS AND METHODS: In this study, age at the onset of symptoms, the score of severity assessed by impairment of activities of daily living milestones, and rate of disease progression, and their correlations with the number of CAG repeats in the androgen receptor (AR) gene, as well as possible correlations among clinical characteristics, were analyzed in 40 SBMA patients. RESULTS: The median ages at onset and at diagnosis were 44.5 and 52.5 years, respectively, and median interval between onset and diagnosis and median rate of disease progression were 5.0 years and 0.23 score/year, respectively. The median number of CAG repeats in the AR gene was 44 and the number of CAG repeats showed a significant inverse correlation with the age at onset of symptoms (r=-0.407, p=0.009). In addition, patients with early symptom onset had slower rate of disease progression. CONCLUSION: As a report with the largest and recent Korean cohort, this study demonstrates clinical features of Korean patients with SBMA and reaffirms the inverse correlation between the age at disease onset and the number of CAG repeats. Interestingly, this study shows a possibility that the rate of disease progression may be influenced by the age at onset of symptoms.

Enfermedad de Kennedy en el Perú: Primeros casos con diagnóstico molecular / Kennedy disease in Peru: First cases with molecular diagnosis

La enfermedad de Kennedy es un trastorno neurodegenerativo de herencia recesiva ligada al cromosoma X, de inicio en la adultez, caracterizado por degeneración progresiva de las neuronas motoras espinales, debido a una mutación dinámica del gen del receptor de andrógeno. Se presentan tres familias (cinco casos) con temblor, calambres, debilidad muscular generalizada lentamente progresiva con atrofia, afectación de músculos bulbares y alteraciones endocrinas. El estudio neurofisiológico demostró compromiso de segunda motoneurona. El análisis molecular mostró una expansión anormal de tripletes citosina-adenina-guanina en el gen de receptor de andrógeno en todos los casos. Todos los pacientes cursaron con una presentación clínica típica de la enfermedad siendo los primeros casos de enfermedad de Kennedy con diagnóstico molecular realizado en el Perú.

Kennedy’s disease is an X-linked recessive disorder with onset in adulthood, characterized by progressive degeneration of spinal motor neurons due to a dynamic mutation in the androgen receptor gene. We report three families (five cases) characterized by progressive weakness involving both limbs and bulbar muscles, atrophy, tremor, cramps and endocrinologic disturbances; the neurophysiological studies demonstrated second motor neuron impairment. The molecular analysis identified abnormal CAG repeats expansion in the androgen receptor gene (AR) in all cases. Clinical features were consistent with other previous reports. These are the first Peruvian cases of Kennedy´s disease with confirmed molecular diagnosis.