Alternative titles; symbols
SNOMEDCT: 784341001; ORPHA: 357043; DO: 0060196;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 9q34.13 | Amyotrophic lateral sclerosis 4, juvenile | 602433 | Autosomal dominant | 3 | SETX | 608465 |
A number sign (#) is used with this entry because of evidence that juvenile amyotrophic lateral sclerosis-4 (ALS4) is caused by heterozygous mutation in the senataxin gene (SETX; 608465) on chromosome 9q34.
Juvenile amyotrophic lateral sclerosis-4 (ALS4) is an autosomal dominant disorder characterized by distal muscle weakness and atrophy, normal sensation, and pyramidal signs, with onset of symptoms before the age of 25 years, a slow rate of progression, and a normal life span (summary by Chen et al., 2004).
For a phenotypic description and a discussion of genetic heterogeneity of amyotrophic lateral sclerosis, see ALS1 (105400).
Chance et al. (1998) studied an 11-generation pedigree with a slowly progressive, autosomal dominant form of juvenile ALS, defined as a chronic motor neuron disease characterized by combined upper and lower motor neuron symptoms and signs with onset before age 25 years. The family was originally described by Myrianthopoulos et al. (1964) as having Charcot-Marie-Tooth disease (CMT; see 118200). They had traced ancestors to 17th-century England, and the disorder was documented in 8 generations, including 52 affected persons living in southern Maryland and nearby states. In the study of Chance et al. (1998), diagnosis of early-onset selective upper- and lower-motor-neuron involvement was established by patient history, clinical findings, and results of electrophysiologic tests. Affected persons typically manifested symptoms in the second decade of life (mean age 17 years). They initially had difficulty walking; this was followed by weakness and wasting of small muscles of the hands and distal lower limbs. By the fourth or fifth decade, affected persons had significant proximal weakness and were frequently wheelchair-bound, and by the sixth decade, they had lost useful hand function. Bulbar muscles were not symptomatically involved. Among 49 affected and 34 at-risk individuals, pathologic hyperreflexia was found in 86% of affected individuals, and 17% had extensor plantar responses. In many affected individuals, weakness of the toe and foot extensor muscles prevented interpretation of the plantar response. Forty-four of 49 subjects tested had normal sensory examinations; 5 older individuals (mean age, 51 years) had slight elevation of the vibratory threshold in the feet.
Rabin et al. (1999) reported the clinical and electrodiagnostic findings in 49 affected members and the neuropathologic findings in 2 autopsies of the Maryland family reported by Chance et al. (1998). Motor conduction studies, performed in 8 affected members, showed reduced evoked amplitudes and normal conduction parameters. Sensory conduction studies (8 individuals), quantitative sensory testing (4 individuals), and intracutaneous sensory fibers in skin biopsies (6 individuals) were normal in all patients tested. Electromyography (8 individuals) showed distal more than proximal chronic partial denervation and reinnervation. Postmortem spinal cord tissue demonstrated atrophic spinal cords with marked loss of anterior horn cells and degeneration of corticospinal tracts, as well as loss of neurons in the dorsal root ganglia and degeneration of the posterior columns. Axonal spheroids were present in the gray matter of the spinal cord, the dorsal root entry zones, and the peripheral nerves. Motor and sensory roots, as well as peripheral nerves, showed significant axonal loss. Swellings were prominent around motor neurons, probably representing changes in presynaptic terminals.
De Jonghe et al. (2002) reported 3 unrelated families with a familial disorder that they diagnosed as distal hereditary motor neuropathy (dHMN). In 2 families, the age at onset was generally less than 6 years, whereas in the third family, some patients had a later onset, including 2 with adult onset. In all families, there was distal lower limb weakness and atrophy with later involvement of the upper limbs. Bulbar muscles were spared and sensory abnormalities were absent. Most patients had brisk reflexes, and 8 of 18 had extensor plantar responses. Two families had pes cavus. De Jonghe et al. (2002) explained their diagnosis of dHMN by the distal distribution of affected muscles, the absence of sensory abnormalities, and the pattern of disease progression. They also noted the phenotypic similarities to the kindred reported by Chance et al. (1998).
By way of clinical characterization, Chen et al. (2004) stated that individuals affected with ALS4 usually have an onset of symptoms at less than 25 years of age, a slow rate of progression, and a normal life span.
Chance et al. (1998) performed a genomewide search in an 11-generation kindred with juvenile ALS and found a lod score of 18.8 at theta = 0.00 with D9S1847. Analysis of recombinant events identified D9S1831 and D9S164 as flanking markers, defining an interval of approximately 5 cM that harbors the ALS4 gene on chromosome 9q34. Thus, the gene for this disorder, designated ALS4, is genetically distinct from previously mapped familial ALS syndromes. Blair et al. (2000) refined the position of the ALS4 locus to a critical interval of less than 3 cM on 9q34.
In 3 families with a clinical syndrome with similarities to both ALS4 and dHMN, De Jonghe et al. (2002) found positive linkage (lod scores greater than 3) with markers located within the ALS4 locus region on 9q34. They narrowed the locus to a 5-cM region between markers D9S64 and D9S164.
The transmission pattern of ALS4 in the families reported by Chen et al. (2004) was consistent with autosomal dominant inheritance.
To identify the molecular basis of ALS4, Chen et al. (2004) tested 19 genes within the critical region for ALS4 identified by linkage studies and detected 3 different heterozygous missense mutations in the senataxin gene (SETX; 608465).
De Jonghe et al. (2002) commented on potential nomenclature and classification confusion of the disorders designated distal HMN, distal spinal muscular atrophy, spinal CMT, and ALS that show linkage to the ALS4 locus.
Blair, I. P., Bennett, C. L., Abel, A., Rabin, B. A., Griffin, J. W., Fischbeck, K. H., Cornblath, D. R., Chance, P. F. A gene for autosomal dominant juvenile amyotrophic lateral sclerosis (ALS4) localizes to a 500-kb interval on chromosome 9q34. Neurogenetics 3: 1-6, 2000. [PubMed: 11085590] [Full Text: https://doi.org/10.1007/pl00022976]
Chance, P. F., Rabin, B. A., Ryan, S. G., Ding, Y., Scavina, M., Crain, B., Griffin, J. W., Cornblath, D. R. Linkage of the gene for an autosomal dominant form of juvenile amyotrophic lateral sclerosis to chromosome 9q34. Am. J. Hum. Genet. 62: 633-640, 1998. [PubMed: 9497266] [Full Text: https://doi.org/10.1086/301769]
Chen, Y.-Z., Bennett, C. L., Huynh, H. M., Blair, I. P., Puls, I., Irobi, J., Dierick, I., Abel, A., Kennerson, M. L., Rabin, B. A., Nicholson, G. A., Auer-Grumbach, M., Wagner, K., De Jonghe, P., Griffin, J. W., Fischbeck, K. H., Timmerman, V., Cornblath, D. R., Chance, P. F. DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am. J. Hum. Genet. 74: 1128-1135, 2004. [PubMed: 15106121] [Full Text: https://doi.org/10.1086/421054]
De Jonghe, P., Auer-Grumbach, M., Irobi, J., Wagner, K., Plecko, B., Kennerson, M., Zhu, D., De Vriendt, E., van Gerwen, V., Nicholson, G., Hartung, H.-P., Timmerman, V. Autosomal dominant juvenile amyotrophic lateral sclerosis and distal hereditary motor neuronopathy with pyramidal tract signs: synonyms for the same disorder? Brain 125: 1320-1325, 2002. [PubMed: 12023320] [Full Text: https://doi.org/10.1093/brain/awf127]
Myrianthopoulos, N. C., Lane, M. H., Silberberg, D. H., Vincent, B. L. Nerve conduction and other studies in families with Charcot-Marie-Tooth disease. Brain 87: 589-610, 1964. [PubMed: 14236005] [Full Text: https://doi.org/10.1093/brain/87.4.589]
Rabin, B. A., Griffin, J. W., Crain, B. J., Scavina, M., Chance, P. F., Cornblath, D. R. Autosomal dominant juvenile amyotrophic lateral sclerosis. Brain 122: 1539-1550, 1999. [PubMed: 10430837] [Full Text: https://doi.org/10.1093/brain/122.8.1539]