X-linked Bulbospinal Neuronopathy

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Abstract
SINCE THE first report in 1968 on a slowly progressive form of a X-linked spinal and bulbar muscular atrophy and the discovery of its molecular background in 1991, Kennedy disease (KD) has increasingly drawn attention.1,2 The disease is commonly described by slowly progressive proximal and bulbar weakness, muscular atrophy, ubiquitous fasciculations with predominance of facial muscles, and additional symptoms including gynecomastia (GM) and postural tremor. Kennedy disease is caused by an expansion of a polymorphic tandem CAG repeat in the first exon of the androgen receptor gene encoding a polyglutamine stretch.2,3 Some investigations described a weak correlation between age of onset of KD and the CAG-repeat length, with the onset of KD being described in the fourth to fifth decades of life.3-6 A 2001 publication reports a strictly defined border between normal and disease-causing alleles.7 Since clinical symptoms overlap with other neuromuscular disorders, for example, amyotrophic lateral sclerosis or spinal muscular atrophies, and clinical signs are nonspecific in early stages of the disease, KD was possibly misdiagnosed or underdiagnosed.8 After genetic testing became available, the number of case reports documented phenotypic variability.4,9 Even asymptomatic carriers of mutations have been described.10 Thus, the clinical diagnosis of KD may still be difficult. Defining the phenotypic spectrum of KD—in particular distribution of paresis, disease onset and characteristic symptoms—is, therefore important for the differential diagnosis, as it also is with regard to life expectancy, genetic counseling, and the increasing costs for diagnostic procedures, in particular genetic testing. Furthermore, for present and upcoming neuroprotective therapy studies, knowledge of the phenotype and identification of possible "markers" of early disease stages are relevant. There is ongoing discussion about whether CAG-repeat length influences clinical phenotype including onset and severity of typical and additional symptoms.