Linkage study

Motor neuron diseases (MNDs) are an etiologically heterogeneous group of disorders that are characterized by muscle weakness and/or spastic paralysis, which results from the selective degeneration of lower motor neurons (LMNs) and/or upper motor neurons (UMNs), respectively Until recently, attention was focused mainly on the pathogenic processes that result from mutations in superoxide dismutase 1 (SOD1) and that underlie a fraction of familial amyotrophic lateral sclerosis (FALS) cases. However, exciting recent progress has been made in identifying mutations in other genes that underlie a range of MNDs, particularly ALS and hereditary spastic paraplegia (HSP). Studies of these genes in cell-based systems and animal models have implicated several additional cellular processes in MND pathogenesis, including RNA processing, membrane trafficking and axonal transport, and mitochondrial function. Furthermore, in the case of ALS, some of these genes are mutated in sporadic forms of the disease. Although additional predisposing genes remain to be identified, the insights gained should accelerate further gene discovery and, ultimately, are hoped to provide routes for the development of much-needed new therapies. Amyotrophic lateral sclerosis ALS is the most common adult-onset MND, is usually fatal within five years of onset and is characterized by the degeneration of UMNs and LMNs. Approximately 5-10% of patients with ALS have a family history, and these patients most frequently inherit the disease in an autosomal dominant manner. Family-based linkage studies have led to the identification of twelve loci and eight genes for FALS, as well as three loci for ALS with frontotemporal dementia (FTD) (TABLE 2). Although these findings have provided valuable insights, they only explain a small fraction of all ALS cases. The majority of ALS cases have no obvious family history and are referred to as sporadic ALS (SALS). Initial hypotheses about the causes of SALS mainly considered environmental factors; more recently, suggestions have been made about the involvement of epigenetics (BOX 1). However, increasing evidence suggests that genetic factors also contribute to SALS. In the following sections we review recent progress made in understanding the genetic basis of both FALS and SALS. Mendelian ALS involving SOD1 Our understanding of the molecular and genetic basis of ALS began with the identification of mutations in Linkage study A method of searching for the chromosomal location of a gene by looking for co-segregation of the disease with genetic markers of known chromosomal location within families. Epigenetics Changes in gene expression that are stable through cell division but do not involve changes in the underlying DNA sequence. The beststudied example is cellular differentiation, but environmental factors, such as maternal nutrition, can influence epigenetic programming. Genetics of motor neuron disorders: new insights into pathogenic mechanisms Patrick A. Dion, Hussein Daoud and Guy A. Rouleau Abstract | The past few years have seen the identification of dozens of genes with causal roles in motor neuron diseases (MNDs), particularly for amyotrophic lateral sclerosis and hereditary spastic paraplegia. Although many additional MND genes remain to be identified, the accumulated genetic evidence has already provided new insights into MND pathogenesis, which adds to the well-established involvement of superoxide dismutase 1 (SOD1) mutations. The pathways that have been recently implicated include those that affect RNA processing, axonal transport and mitochondrial function. The functional classes of MND genes identified so far are likely to aid the selection of high-priority candidate genes for future investigation, including those for so-called sporadic cases