Vuopala et al. (1995) described 15 infants from 11 Finnish families with a phenotype of lethal arthrogryposis and anterior horn motor neuron loss. The clinical presentation was the fetal akinesia deformation sequence (FADS) with multiple contractures and facial ... Vuopala et al. (1995) described 15 infants from 11 Finnish families with a phenotype of lethal arthrogryposis and anterior horn motor neuron loss. The clinical presentation was the fetal akinesia deformation sequence (FADS) with multiple contractures and facial anomalies. The phenotype was uniform with low-set ears, hypoplastic jaw, short neck, and contractures. Malpositions in the extremities were moderate, distal, and inwardly spiral. The mean gestational age was 34 weeks, with 8 infants being born at term. Most of the cases were perinatal lethal; 3 infants were stillborn, 5 died within 1 hour, 6 died within a few days, and 1 survived for 20 days. Skeletal muscles were affected in all infants, but the severity of pathologic findings varied. A tibialis muscle sample from one infant showed severe neurogenic atrophy. Muscle spindles were shaped normally with a normal number and differentiation of intrafusal fibers. The size and shape of the spinal cord at different levels were normal but the anterior horn motor neurons were degenerated and diminished in number. The families came from different parts of Finland, and no geographic clustering was observed. Vuopala et al. (1995) differentiated LAAHD from the lethal congenital contracture syndrome (LCCS1; 253310), also prevalent in Finland. LCCS is always fatal during the fetal period, presenting with severe hydrops and intrauterine growth retardation. The spinal cord is macroscopically thinned because of an early reduction of the anterior horn and a paucity of anterior horn cells. The skeletal muscles are extremely hypoplastic, even difficult to locate. Infants with LAAHD survive longer than those with LCCS, and when present, hydrops and intrauterine growth retardation are mild and the macroscopic findings of the central nervous system and skeletal muscles are normal. Furthermore, birthplaces of ancestors of affected individuals do not show clustering in the northeast part of Finland, as is the case with LCCS.
To investigate whether LCCS1 and LAAHD represent allelic disorders, Nousiainen et al. (2008) screened 9 unrelated families with LAAHD for mutations in the GLE1 gene (603371) and identified 12 individuals with mutations. All 12 cases were compound heterozygotes: ... To investigate whether LCCS1 and LAAHD represent allelic disorders, Nousiainen et al. (2008) screened 9 unrelated families with LAAHD for mutations in the GLE1 gene (603371) and identified 12 individuals with mutations. All 12 cases were compound heterozygotes: 6 were heterozygous for the LCCS1 major Finnish mutation (Fin(Major); 603371.0001) and a missense point mutation in exon 13 (603371.0003), and the remaining 6 carried the Fin(Major) mutation and a missense mutation in exon 16 (603371.0004). The authors investigated an additional patient who had been diagnosed initially with severe infantile spinal muscle atrophy (see 253300) but carried no SMN gene deletion. This patient was also a compound heterozygote for Fin(Major) and the exon 16 missense mutation. Autopsy revealed typical neurogenic muscular atrophy and loss of anterior horn cells of the spinal cord. Nousiainen et al. (2008) concluded that homozygosity for the Fin(Major) mutation results in a more severe phenotype than does compound heterozygosity.