Molecular basis of genetic heterogeneity: role of the clinical neurologist.

Advances in molecular genetics have disclosed many different explanations for allelic heterogeneity, how different clinical syndromes arise from mutations in the same gene. The converse, how similar clinical syndromes arise from mutations of different genes on different chromosomes is called locus heterogeneity. Both, however, give rise to some disease-defining mutations, as in childhood spinal muscular atrophy or Duchenne muscular dystrophy. Nevertheless, new problems have been created, including what might be called "diagnosis by the number," diverse syndromes from mutations in the same gene without current explanation, or siblings with different clinical syndromes. These discoveries have transformed the clinical neurology of heritable diseases. They also provide clinicians with new responsibilities and opportunities in defining clinical syndromes and influencing the evolution of our clinical language.