Alternative titles; symbolsSPINAL MUSCULAR ATROPHY, X-LINKED LETHAL INFANTILESPINAL MUSCULAR ATROPHY, INFANTILE X-LINKED; XLSMAARTHROGRYPOSIS MULTIPLEX CONGENITA...
Alternative titles; symbols
X-linked spinal muscular atrophy-2 (SMAX2) is characterized by neonatal onset of severe hypotonia, areflexia, and multiple congenital contractures, known as arthrogryposis, associated with loss of anterior horn cells and infantile death (summary by Ramser et al., 2008).
Historically, Hall et al. (1982) distinguished at least 3 clinical varieties of X-linked arthrogryposis. (1) One family had a severe lethal form with severe contractures, scoliosis, chest deformities, hypotonia, micrognathia, and death from respiratory insufficiency by age 3 months. Apparently progressive loss of anterior horn cells was the cause. (2) Two families had moderately severe AMC associated with ptosis, microphallus, cryptorchidism, inguinal hernias, and normal intelligence. Nonprogressive intrauterine myopathy appeared to be the 'cause'. (3) In 2 families and a sporadic case, the disorder took the form of a resolving AMC, with mild to moderate contractures improving dramatically with time, normal intelligence, and no other anomalies; tight connective tissues on misplaced tendons was postulated.
▼ Clinical Features
Greenberg et al. (1988) described under the label 'X-linked infantile spinal muscular atrophy' a disorder that appeared to be X-linked and was associated with contractures as in X-linked arthrogryposis. Kobayashi et al. (1995) studied the family originally reported by Greenberg et al. (1988). Affected individuals showed hypotonia, areflexia, chest deformities, facial dysmorphic features, and congenital joint contractures. The findings of electromyography and muscle biopsy were consistent with loss of anterior horn cells as in autosomal recessive infantile spinal muscular atrophy (253300). At the time of the linkage study by Kobayashi et al. (1995), 1 affected male was living at age 13 years, whereas the other affected males died within the first 2 years of life.
Baumbach et al. (1994) described an X-linked form of proximal spinal muscular atrophy in 2 unrelated multigeneration families with similar clinical presentations of severe hypotonia, muscle weakness, and a disease course similar to that of Werdnig-Hoffmann disease (253300) except for the additional finding of congenital or early-onset contractures. Muscle biopsy and/or autopsy indicated anterior horn cell loss in affected males. The pedigree pattern in this and 2 additional families was that of an X-linked recessive disorder. Several sporadic male cases were also identified.
By linkage studies in 2 families with an X-linked form of proximal spinal muscular atrophy, Baumbach et al. (1994) identified two 16-cM regions on Xp with complete concordance to the SMAX2 disease phenotype. One of these regions surrounded the Kallmann gene (KAL1; 300836). The remainder of the X chromosome was excluded, including the locus for the Kennedy type of spinal and bulbar muscular atrophy (SMAX1; 313200).
Kobayashi et al. (1995) demonstrated linkage of the disorder in the family reported by Greenberg et al. (1988) to markers in the region of the centromere of the X chromosome: Xp11.3-q11.2.
Dressman et al. (2007) studied 7 new families with new markers and narrowed the gene interval for the XLSMA locus on Xp11.3-q11.1.
▼ Molecular Genetics
To identify the XLSMA disease gene, Ramser et al. (2008) performed large-scale mutation analysis in genes located between markers DXS8080 and DXS7132 on Xp11.3-q11.1. This resulted in detection of 3 rare novel variants in exon 15 of the gene encoding ubiquitin-activating enzyme-1 (UBE1; 314370) that segregated with the disease. Two of the mutations were missense mutations (314370.0001, 314370.0002), and the third was a synonymous C-to-T substitution (314370.0003) that led to significant reduction of UBE1 expression with alteration in the methylation pattern of exon 15, implying a plausible role of this DNA element in developmental UBE1 expression in humans. Thus, XLSMA is one of several neurodegenerative disorders associated with defects in the ubiquitin-proteasome pathway; these disorders include Parkinson disease with mutations in PARK2 (602544) and UCHL1 (191342), and a distinctive X-linked form of mental retardation (300354) caused by mutations in CUL4B (300304). The experience of the authors indicated that synonymous C-to-T transitions have the potential to affect gene expression.
The symbol SMAX2 is used for this disorder, since Kennedy disease (SMAX1; 313200) represents the first recognized form of X-linked spinal muscular atrophy.