Alternative titles; symbols
SNOMEDCT: 838441009; ORPHA: 2466, 275543; DO: 0060246;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq28 | MASA syndrome | 303350 | X-linked recessive | 3 | L1CAM | 308840 |
A number sign (#) is used with this entry because MASA syndrome, also known as spastic paraplegia-1 (SPG1), is caused by mutation in the gene encoding the L1 cell adhesion molecule (L1CAM; 308840).
X-linked congenital hydrocephalus (HCYX; 307000) is an allelic disorder.
The hereditary spastic paraplegias (SPG) are a group of clinically and genetically diverse disorders characterized by progressive, usually severe, lower extremity spasticity; see reviews of Fink et al. (1996) and Fink (1997). Some forms of SPG are considered 'uncomplicated,' i.e., progressive spasticity occurs in isolation; others are considered 'complicated,' i.e., progressive spasticity occurs with other neurologic features. X-linked, autosomal dominant (see 182600), and autosomal recessive (see 270800) forms of SPG have been described.
Spastic paraplegia-1 is usually called MASA syndrome, the designation originally suggested by Bianchine and Lewis (1974), because the main clinical features are summarized by the acronym MASA (mental retardation, aphasia, shuffling gait, and adducted thumbs). The shuffling gait is probably caused by spasticity of the lower limbs, and all affected males have been reported to have increased reflexes. The adducted thumbs are thought to be caused by hypoplastic or absent extensor pollicis longus or brevis muscles. In affected males, the onset of speech is delayed (Winter et al., 1989).
See 314100 for isolated X-linked congenital clasped thumb and 201550 for an autosomal adducted thumbs syndrome.
Genetic Heterogeneity of Spastic Paraplegia
Other forms of X-linked spastic paraplegia include SPG2 (312920), caused by mutation in the myelin proteolipid protein gene (PLP1; 300401); SPG16 (300266), mapped to Xq11.2-q23; and SPG34 (300750), mapped to Xq24-q25.
See SPG3A (182600) and SPG5A (270800) for discussion of genetic heterogeneity of autosomal dominant and autosomal recessive forms of SPG, respectively. See SPGM (500018) for a mitochondrial form of SPG.
Bianchine and Lewis (1974) described a Mexican-American kindred in which 6 males in 4 sibships of 3 generations plus a female in one of them had mental retardation, aphasia, shuffling gait, and adducted thumbs (MASA). In addition to the features covered by the acronym, the patients showed small body size, microcephaly, exaggerated lumbar lordosis, and hyperactive deep tendon reflexes in the lower limbs. Bianchine and Lewis (1974) distinguished the MASA syndrome from X-linked aqueductal stenosis, which is characterized by congenital hydrocephalus, by the absence of this feature in their patients.
Gareis and Mason (1984) described a kindred in which 6 males in 3 generations had bilateral clasped thumbs, apparently due to absence of extensor pollicis brevis tendons, and mild mental retardation. CT scans of the brain in 2 affected patients were normal. Gareis and Mason (1984) suggested that the 2 mentally impaired brothers in a family reported by Edwards (1961) as having X-linked aqueductal stenosis with 'borderline' hydrocephalus may have had this disorder. Validation of the MASA syndrome was provided by Yeatman (1984) who described a kindred with at least 20 affected males in 3 generations. Features included mild mental retardation, flexion-adduction of the thumbs and, in some cases, of the index fingers, speech difficulties, lordosis, and spasticity of the lower limbs.
Under the rubric of X-linked 'complicated' spastic paraplegia type 1, Kenwrick et al. (1986) reported 6 patients with spastic paraparesis of the legs, hyperreflexia, and extensor plantar responses. In addition, all 6 patients had mental retardation and 4 had absent extensor pollicus longus. Mapping showed linkage to Xq28. Winter et al. (1989) reported a MASA family with 3 affected males in 2 generations. Prominent features included mild mental retardation, delayed motor and speech development, adducted thumbs, spasticity and hyperreflexia of the lower limbs, abnormal shuffling gait, and scoliosis in 1 patient. Close linkage to markers at Xq28 was demonstrated, similar to the disorder in the family described by Kenwrick et al. (1986) (see MAPPING). Winter et al. (1989) reviewed the similarities of the syndromes reported by Bianchine and Lewis (1974), Gareis and Mason (1984), Yeatman (1984), and Kenwrick et al. (1986) and suggested that they were all compatible with the MASA syndrome.
Schrander-Stumpel et al. (1990) studied a family in which an uncle and nephew had MASA syndrome and a maternal first cousin of the uncle died at the age of 15 years from congenital hydrocephalus. The uncle and nephew had macrocephaly, flexed and adducted thumbs, and spastic paraplegia of the legs. CT scan of the brain showed extensive widening of the lateral ventricles and moderate enlargement of the third ventricle. The lateral ventricles were irregularly shaped. Rietschel et al. (1991) emphasized clinical variability of the MASA syndrome and X-linked complicated and pure hereditary spastic paraplegias and noted the overlap of the syndromes. One of their patients had spastic paraplegia and psychomotor retardation but no adducted thumbs. Straussberg et al. (1991) described affected brothers who showed similar clinical features to the cases reported by Gareis and Mason (1984) and Yeatman (1984). However, they suggested that the MASA syndrome is separate from X-linked mental retardation with bilateral clasped thumbs.
Fryns et al. (1991) reported a family in which 5 males over 3 generations had neurologic abnormalities with mental retardation which varied greatly in severity and clinical expression. Two sibs apparently had HSAS, 1 had MASA, and 2 had spastic paraplegia with borderline intelligence. Within the family, Fryns et al. (1991) noted that more severe spastic paresis was present in patients with more severe mental impairment. Fryns et al. (1992) reported cases of 2 brothers and their borderline affected mother. Observations of these prepubertal cases suggested that the clinical diagnosis before age 4 years is difficult because of the progressively appearing manifestations and neurologic signs.
Kaepernick et al. (1994) described a family with expressing females. Adducted thumbs were present in 2 obligate carriers, learning problems or mild mental retardation in 3 females, 2 of whom were obligate carriers, and hydrocephalus with neonatal death in 3 females born to obligate carriers. X-inactivation analysis in lymphocytes from 2 women with adducted thumbs demonstrated preferential inactivation of one X chromosome, suggesting that nonrandom X-inactivation may be responsible for clinical expression in females. A photograph of adducted thumbs in 1 patient demonstrated the difference between clasped thumb and adducted thumb. Kaepernick et al. (1994) also illustrated the typical position in an adult with hyperlordosis, rounded shoulders, and internally rotated arms.
Schrander-Stumpel et al. (1994), who referred to 'the spectrum of complicated spastic paraplegia, MASA syndrome, and X-linked hydrocephalus,' described the use of DNA linkage analysis in 6 families, illustrating the problem of studying small families and the fact that genetic heterogeneity cannot be excluded. The clinical spectrum in these 6 families was delineated by Schrander-Stumpel et al. (1995). Variability appeared to be great, even within families. They suggested that since adducted thumbs and spastic paraplegia are found in 90% of the patients, the condition may present in males as nonspecific mental retardation.
The family reported by Kenwrick et al. (1986) with X-linked recessive spastic paraplegia and mental retardation demonstrated close linkage to DXS15 and DXS52 at Xq28. The family with MASA syndrome reported by Winter et al. (1989) showed linkage to the same markers, leading Winter et al. (1989) to conclude that the disorder reported by Kenwrick et al. (1986) is the same as the MASA syndrome.
Linkage studies performed by Schrander-Stumpel et al. (1990) also showed localization to Xq28. One crossover with F8C (300841), but none with DXS52 and DXS305, located the gene on the same side of the hemophilia A locus as DXS52 and DXS305, which are distal to F8C. Because of the same linkage relationships on Xq28 in their patients with MASA syndrome and because of the cerebral abnormalities reported in these patients and the occurrence of congenital hydrocephalus in a cousin, Schrander-Stumpel et al. (1990) suggested that X-linked aqueductal stenosis (HSAS; 307000) and the MASA syndrome are allelic disorders.
By linkage studies in a 5-generation Hispanic family in which 13 males and 1 female were affected, Macias et al. (1992) confirmed linkage to the Xq28 region with a maximum lod score of 3.01. In a large MASA family, Legius et al. (1994) found a maximum lod score of 6.37 at zero recombination for DXS52 and 5.99 at zero recombination for DXS305. Crossovers were demonstrated between the disorder and DXS455. Legius et al. (1994) noted that although the linkage data support the possibility that mutations in the same gene can cause HSAS and MASA in this and some other families, the data do not exclude the possibility of a second gene in Xq28 responsible for one or the other syndrome in other families.
The demonstration by Rosenthal et al. (1992) of mutation in the L1CAM gene in X-linked hydrocephalus suggested that a mutation in the same gene may be responsible for the MASA syndrome. That this is indeed the case was proved by the demonstration of mutations in the L1CAM gene in patients with MASA syndrome by Jouet et al. (1994) and Vits et al. (1994) (308840.0004; 308840.0005).
In affected members of 2 families, one reported by Fryns et al. (1991) and the other by Kaepernick et al. (1994), in which various members displayed features characteristic of spastic paraplegia type 1, MASA syndrome, or X-linked hydrocephalus due to aqueductal stenosis (307000), Ruiz et al. (1995) found mutations (308840.0010 and 308840.0011, respectively) in the L1CAM gene. Ruiz et al. (1995) commented that the 3 different phenotypes observed in different generations within the same family are variable expressions of the same mutation.
Fransen et al. (1995) pointed out that the inter- and intrafamilial variability in families with an L1CAM mutation is very wide, such that patients with hydrocephalus, MASA, SPG1, and ACC (agenesis of corpus callosum; see 217990) can be present within the same family.
Since phenotypic variability in families with an L1CAM mutation is very wide, Fransen et al. (1995) proposed to refer to this clinical syndrome occurring in the same family with the acronym CRASH, for corpus callosum hypoplasia, retardation, adducted thumbs, spastic paraplegia, and hydrocephalus. The spastic paraplegia component is almost always complicated by other features and has been referred to as spastic paraplegia type 1 (SPG1). The hydrocephalus component (HYCX; 307000) is almost always complicated by other features, but is not always a feature of the MASA syndrome.
Dahme et al. (1997) created an animal model of CRASH by targeting the L1cam gene in mice. Mutant mice were smaller and less sensitive to touch and pain than wildtype mice, and their hind legs appeared weak and uncoordinated. The size of the corticospinal tract was reduced and, depending on genetic background, the lateral ventricles were often enlarged. Nonmyelinating Schwann cells formed processes not associated with axons and showed reduced association with axons.
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