Alternative titles; symbols
SNOMEDCT: 717964007; ORPHA: 247604;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q33.1 | Primary lateral sclerosis, juvenile | 606353 | Autosomal recessive | 3 | ALS2 | 606352 |
A number sign (#) is used with this entry because of evidence that juvenile primary lateral sclerosis (PLSJ) is caused by homozygous mutation in the gene encoding alsin (ALS2; 606352) on chromosome 2q33.
Juvenile amyotrophic lateral sclerosis-2 (205100) and infantile-onset ascending spastic paralysis (IAHSP; 607225) are allelic disorders with overlapping phenotypes.
See also adult-onset PLS (611637), which occurs sporadically or shows autosomal dominant inheritance.
Although primary lateral sclerosis is similar to amyotrophic lateral sclerosis (ALS; 105400), they are considered to be clinically distinct progressive paralytic neurodegenerative disorders. Following a period of diagnostic confusion, the clinical distinction between ALS and PLS became clear and diagnostic criteria established (Pringle et al., 1992). PLS is characterized by degeneration of the upper motor neurons and the corticospinal and corticobulbar tracts, whereas ALS is a more severe disorder characterized by degeneration of both the upper and lower motor neurons. A diagnosis of PLS is essentially one of exclusion (Sotaniemi and Myllyla, 1985; Younger et al., 1988; Yang et al., 2001).
Stark and Moersch (1945) defined primary lateral sclerosis as a disease of lateral columns of the spinal cord, the corticospinal tracts. In a review of 60 cases, including 17 familial cases, the authors concluded that it was a slowly progressive disorder restricted to involvement of the pyramidal tracts and clinically characterized primarily by spasticity, hyperreflexia, and extensor plantar responses.
Lerman-Sagie et al. (1996) reported a consanguineous Kuwaiti family in which 3 sons developed progressive spastic paralysis of the lower extremities in infancy with subsequent involvement of the upper extremities and bulbar muscles. Cognition was spared. The authors noted the phenotypic overlap with hereditary spastic paraplegia, but concluded that the disorder in this family was consistent with primary lateral sclerosis. Shaw (2001) classified this family as having primary lateral sclerosis because of the lack of evidence of denervation.
Mintchev et al. (2009) reported a consanguineous Cypriot family in which 3 members had juvenile primary lateral sclerosis. Onset was at age 2 years in all patients, with leg spasticity, bulbar paresis, and prominent saccadic gaze paresis. One patient became wheelchair-bound at age 50 years, the second never achieved ambulation, and the third remained ambulatory at age 16. Lower motor neuron symptoms were not apparent.
PLS is usually a sporadic disorder of adult middle age. However, it has been described in children, and is then referred to as juvenile PLS, and in families in a pattern consistent with autosomal recessive inheritance (Gascon et al., 1995; Lerman-Sagie et al., 1996).
In affected members of the Kuwaiti family reported by Lerman-Sagie et al. (1996), Hadano et al. (2001) identified a homozygous mutation in the ALS2 gene (606352.0004).
Yang et al. (2001) identified a homozygous deletion in the ALS2 gene (606353.0002) in 3 affected members of a consanguineous Saudi Arabian family with PLSJ.
In affected members of a consanguineous Cypriot family with juvenile-onset PLS, Mintchev et al. (2009) identified a homozygous mutation in the ALS2 gene (606353.0013).
Gascon, G. G., Chavis, P., Yaghmour, A., Stigsby, B., Shums, A., Ozand, P., Siddique, T. Familial childhood primary lateral sclerosis with associated gaze paresis. Neuropediatrics 26: 313-319, 1995. [PubMed: 8719747] [Full Text: https://doi.org/10.1055/s-2007-979781]
Grunnet, M. L., Leicher, C., Zimmerman, A., Zalneraitis, E., Barwick, M. Primary lateral sclerosis in a child. Neurology 39: 1530-1532, 1989. [PubMed: 2812336] [Full Text: https://doi.org/10.1212/wnl.39.11.1530]
Hadano, S., Hand, C. K., Osuga, H., Yanagisawa, Y., Otomo, A., Devon, R. S., Miyamoto, N., Showguchi-Miyata, J., Okada, Y., Singaraja, R., Figlewicz, D. A., Kwiatkowski, T., and 9 others. A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nature Genet. 29: 166-173, 2001. Note: Erratum: Nature Genet. 29: 352 only, 2001. [PubMed: 11586298] [Full Text: https://doi.org/10.1038/ng1001-166]
Lerman-Sagie, T., Filiano, J., Smith, D. W., Korson, M. Infantile onset of hereditary ascending spastic paralysis with bulbar involvement. J. Child. Neurol. 11: 54-57, 1996. [PubMed: 8745388] [Full Text: https://doi.org/10.1177/088307389601100114]
Mintchev, N., Zamba-Papanicolaou, E., Kleopa, K. A., Christodoulou, K. A novel ALS2 splice-site mutation in a Cypriot juvenile-onset primary lateral sclerosis family. Neurology 72: 28-32, 2009. [PubMed: 19122027] [Full Text: https://doi.org/10.1212/01.wnl.0000338530.77394.60]
Pringle, C. E., Hudson, A. J., Munoz, D. G., Kiernan, J. A., Brown, W. F., Ebers, G. C. Primary lateral sclerosis: clinical features, neuropathology and diagnostic criteria. Brain 115: 495-520, 1992. [PubMed: 1606479] [Full Text: https://doi.org/10.1093/brain/115.2.495]
Shaw, P. J. Genetic inroads in familial ALS. Nature Genet. 29: 103-104, 2001. [PubMed: 11586285] [Full Text: https://doi.org/10.1038/ng1001-103]
Sotaniemi, K. A., Myllyla, V. V. Primary lateral sclerosis: a debated entity. Acta Neurol. Scand. 71: 334-336, 1985. [PubMed: 4003039] [Full Text: https://doi.org/10.1111/j.1600-0404.1985.tb03210.x]
Stark, F. M., Moersch, F. P. Primary lateral sclerosis: a distinct clinical entity. J. Nerv. Ment. Dis. 102: 332-337, 1945.
Yang, Y., Hentati, A., Deng, H.-X., Dabbagh, O., Sasaki, T., Hirano, M., Hung, W.-Y., Ouahchi, K., Yan, J., Azim, A. C., Cole, N., Gascon, G., Yagmour, A., Ben-Hamida, M., Pericak-Vance, M., Hentati, F., Siddique, T. The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis. Nature Genet. 29: 160-165, 2001. Note: Erratum: Nature Genet. 29: 352 only, 2001. [PubMed: 11586297] [Full Text: https://doi.org/10.1038/ng1001-160]
Younger, D. S., Chou, S., Hays, A. P., Lange, D. J., Emerson, R., Brin, M., Thompson, H., Jr., Rowland, L. P. Primary lateral sclerosis: a clinical diagnosis reemerges. Arch. Neurol. 45: 1304-1307, 1988. [PubMed: 3196189] [Full Text: https://doi.org/10.1001/archneur.1988.00520360022005]