A genome-wide linkage analysis to map the underlying genetic defect was performed in a consanguineous African family with five patients affected with a novel variant of autosomal recessive lower motor neuron disease (LMND), in a study at Hopital Necker Enfants Malades and other centers, Paris, France. In 4 of the 5 patients having a severe phenotype, symptoms appeared during infancy (2 to 3.5 years), with proximal muscle weakness predominating in the lower limbs and early involvement of foot and hand muscles. Paralysis spread to become generalized, except for the cranial nerves, and by age 16 years, patients were tetraplegic with areflexia, contractures, and scoliosis, and required assisted respiratory ventilation. Intelligence was preserved. The mild phenotype in one patient had a delayed onset (11.5 years), a moderate generalized weakness, and a slower course. Genetic testing ruled out linkage to the 5ql3 and 21q22 chromosomal regions and SMN1 and SOD1 loci. This novel LMND variant was assigned to a locus on chromosome lp36. [1]

COMMENT. Studies are underway to identify the gene involved in this novel variant of autosomal recessive LMND. Numerous phenotypes of childhood-onset LMND have been described, the most common being the proximal spinal muscular atrophy (SMA), linked to the SMN1 gene. Kugelberg-Welander disease (SMA type III) has the same range of age at onset (after age of walking) as this novel variety, but the foot and hand paralysis, severe respiratory involvement, and lack of linkage to chromosome 5ql3 that characterize the variant exclude the SMA III diagnosis.