Alternative titles; symbols
SNOMEDCT: 702356009; ORPHA: 3077; DO: 0060827;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq28 | Intellectual developmental disorder, X-linked syndromic 13 | 300055 | X-linked recessive | 3 | MECP2 | 300005 |
A number sign (#) is used with this entry because of evidence that X-linked syndromic intellectual developmental disorder-13 (MRXS13) is caused by mutation in the methyl-CpG-binding protein-2 gene (MECP2; 300005) on chromosome Xq28.
The MECP2 gene is mutated in Rett syndrome (RTT; 312750), a severe neurodevelopmental disorder that almost always occurs in females. Males with non-RTT mutations in the MECP2 gene can demonstrate a wide variety of phenotypes, including X-linked syndromic intellectual developmental disorder-13, described here, and Lubs-type X-linked syndromic intellectual developmental disorder (MRXSL; 300260). Males with RTT-associated MECP2 mutations have neonatal severe encephalopathy that is usually lethal (300673) (Moog et al., 2003; Villard, 2007).
Lindsay et al. (1996) described an X-linked mental retardation syndrome linked to Xq28. This syndrome was identified in a 3-generation family in which 4 of 6 moderately retarded males also had episodes of manic-depressive psychosis. The phenotype also included pyramidal signs, parkinsonism, and macroorchidism, leading the authors to the designation PPMX (psychosis, pyramidal signs, and macroorchidism). Lindsay et al. (1996) contended that despite the known high psychiatric morbidity in individuals with learning difficulties and the specific association between mental retardation and atypical manic-depressive illness, the frequency and severity of the psychiatric illness in this family suggested a syndromic basis for the disorder. The authors noted, however, that it was difficult to be sure that the neurologic features were not secondary to treatment with neuroleptic drugs.
Claes et al. (1997) reported a family in which affected males had X-linked mental retardation with progressive spasticity. Affected males showed delayed development (first steps at 2 to 5.5 years) and were never able to speak. They showed facial hypotonia and sialorrhea and a habitus suggesting complicated spastic paraplegia; their head circumferences were at the 75th to 90th percentile. One of them had choreoathetotic movements in the right arm, and global bradyarrhythmia as indicated by electroencephalogram, and bilateral juvenile cataract; he was confined to a wheelchair and died from pneumonia at age 39 years. Meloni et al. (2000) studied the same family and compared the phenotypic findings with those of Rett syndrome. Similarities included absence of language, ataxic gait, seizures, grinding of teeth, and sialorrhea. Moreover, spastic paraparesis is a frequent end-stage finding in Rett syndrome. Salient differences included absence of growth retardation, of loss of acquired purposeful hand skills, and of acquired microcephaly. Microcephaly is one of the major diagnostic criteria of Rett syndrome, in contrast with the macrocephaly in the family studied by Meloni et al. (2000).
Gendrot et al. (1999) reported a large 4-generation family in which 11 males had a nonspecific form of X-linked mental retardation, termed MRX16. All affected males had a moderate delay in all milestones. The degree of retardation ranged from mild to profound, and all had speech handicap. Three had large ears and 3 had scoliosis or kyphosis. Obligate female carriers were unaffected. Gomot et al. (2003) provided follow-up of the family reported by Gendrot et al. (1999). Mood and behavior in affected males was variable, ranging from friendly personality to autistic-like behavior. Patients had severe verbal impairment with difficulties in speech articulation and verbal stereotypies. Most patients also had brisk tendon reflexes and were slow, clumsy, and with poor coordination. Gomot et al. (2003) concluded that some affected male patients in this family had features seen in classic Rett syndrome, including regression of written and oral language, verbal and motor stereotypies, clumsiness, and spasticity. Female carriers of the mutation were unaffected but did not show remarkable X-inactivation patterns.
Orrico et al. (2000) reported a 63-year-old mildly retarded female with microcephaly, asthenic habitus, speech difficulties, genu valgum, and gait disturbance. Of 5 living children, 4 sons presented with severe mental retardation and movement disorders. The single daughter was a 41-year-old woman who presented with a mild mental handicap with clinical features similar to those of her mother. The 4 affected sons, aged 27 to 40 years, had normal head size, severe mental retardation with friendly personalities, impaired expressive language development, resting tremors, and slowness of movement. They did not show regression of higher brain functions after initial normal development. In particular, there was no deterioration in language skills, which always appeared very poor. The males put only some words together and communicated in short and simple sentences. None of the affected members of the family had autistic-like behavior. An apparently unaffected son died accidentally when he was 4 years old. Dotti et al. (2002) reviewed the clinical findings of the family reported by Orrico et al. (2000) and noted that although the mental retardation and neurologic signs were more pronounced in the men than in the women, the women did demonstrate abnormalities, in contrast to other reported families with asymptomatic female carriers. Features present in all 6 family members included slowly progressive spastic paraparesis/pyramidal signs, distal atrophy of the legs, and mild dysmorphic features.
Winnepenninckx et al. (2002) reported a kindred in which 5 affected males from a large kindred had X-linked mental retardation. Variable clinical features included delayed psychomotor development, tremor, mood instability, autistic features, and hyperkinetic behavior. Four carrier females in the family appeared to be unaffected.
Moog et al. (2003) reported a 21-year-old man with severe mental retardation, spastic tetraplegia, dystonia, apraxia, and neurogenic scoliosis. He was noted to have developmental delay and axial hypotonia with head lag at 3.5 months of age. He never learned to sit alone or walk. From 2 years of age, he showed motor restlessness and developed extrapyramidal symptoms. There was no speech development. At age 16 years, he lost purposeful hand use and developed wrist contractures. Other features included seizures, small head, small hands, joint contractures, and apneic periods. Moog et al. (2003) noted that some of the features were reminiscent of Rett syndrome.
The highest lod score observed in the family described by Lindsay et al. (1996) was 3.311 at theta = 0 with marker DXS1123. The marker DXS1691 defined the proximal boundary of the approximately 8-Mb region that contains the putative disease gene. On cytogenetic analysis no fragile sites were detected, and no CGG repeat expansions were detected at the FRAXA (309550), FRAXE (309548,) or FRAXF (300031) loci.
In a large family designated MRX16, Gendrot et al. (1999) found significant linkage to the Xq28 region with loci DXS52, DXS15, BGN, and DXS1108, with maximum lod scores of 4.86, 4.01, 4.83, and 5.43, respectively. Recombination was observed at the locus DXS1113, thus mapping the gene in an 8-Mb interval between this marker and the Xq telomere.
In a family in which 5 males had X-linked mental retardation, Winnepenninckx et al. (2002) found linkage to a locus on Xq27.3-q28, designated MRX79.
By SSCP followed by direct sequencing of PCR products that showed abnormal migration, Meloni et al. (2000) found a mutation of the MECP2 gene (E406X; 300005.0009) in the affected males in the family reported by Claes et al. (1997).
In the family with MRX16 reported by Gendrot et al. (1999), Couvert et al. (2001) identified a mutation in the MECP2 gene (300005.0017).
In a family with X-linked mental retardation and spasticity, Orrico et al. (2000) identified a point mutation in the MECP2 gene (A140V; 300005.0015). Klauck et al. (2002) identified the A140V mutation in affected members of the family with PPMX originally reported by Lindsay et al. (1996).
Winnepenninckx et al. (2002) identified the A140V mutation in 5 affected males from a large kindred with X-linked mental retardation associated with delayed psychomotor development, tremor, mood instability, autistic features, and hyperkinetic behavior. Winnepenninckx et al. (2002) referred to several other reports of the A140V mutation and estimated that this mutation occurs in approximately 1% of all X-linked mental retardation families.
In a 21-year-old man with severe mental retardation and spasticity, Moog et al. (2003) identified a mutation in the MECP2 gene (P225L; 300005.0033).
Yntema et al. (2002) reported a family in which 3 males in 2 generations had mild nonspecific mental retardation without any morphologic or neurologic anomalies and no history of mental regression. Affected individuals had a 240-bp in-frame deletion in the C terminus of the MECP2 gene (300005.0022). One unaffected carrier female showed extremely skewed X inactivation. Gomot et al. (2003) provided follow-up of the family reported by Yntema et al. (2002). Affected males had various mood or behavioral problems, including emotional disturbance and aggression. Two had verbal stereotypies. Motor abilities were relatively preserved. Gomot et al. (2003) suggested that the pure mental retardation phenotype without severe motor manifestations in this family may be explained by the distal localization of the in-frame deletion.
Claes, S., Devriendt, K., D'Adamo, P., Meireleire, J., Raeymaekers, P., Toniolo, D., Cassiman, J.-J., Fryns, J.-P. X-linked severe mental retardation and a progressive neurological disorder in a Belgian family: clinical and genetic studies. Clin. Genet. 52: 155-161, 1997. [PubMed: 9377804] [Full Text: https://doi.org/10.1111/j.1399-0004.1997.tb02536.x]
Couvert, P., Bienvenu, T., Aquaviva, C., Poirier, K., Moraine, C., Gendrot, C., Verloes, A., Andres, C., Le Fevre, A. C., Souville, I., Steffann, J., des Portes, V., Ropers, H.-H., Yntema, H. G., Fryns, J.-P., Briault, S., Chelly, J., Cherif, B. MECP2 is highly mutated in X-linked mental retardation. Hum. Molec. Genet. 10: 941-946, 2001. [PubMed: 11309367] [Full Text: https://doi.org/10.1093/hmg/10.9.941]
Dotti, M. T., Orrico, A., De Stefano, N., Battisti, C., Sicurelli, F., Severi, S., Lam, C. W., Galli, L., Sorrentino, V., Federico, A. A Rett syndrome MECP2 mutation that causes mental retardation in men. Neurology 58: 226-230, 2002. [PubMed: 11805248] [Full Text: https://doi.org/10.1212/wnl.58.2.226]
Gendrot, C., Ronce, N., Raynaud, M., Ayrault, A.-D., Dourlens, J., Castelnau, P., Muh, J.-P., Chelly, J., Moraine, C. X-linked nonspecific mental retardation (MRX16) mapping to distal Xq28: linkage study and neuropsychological data in a large family. Am. J. Med. Genet. 83: 411-418, 1999. [PubMed: 10232754]
Gomot, M., Gendrot, C., Verloes, A., Raynaud, M., David, A., Yntema, H. G., Dessay, S., Kalscheuer, V., Frints, S., Couvert, P., Briault, S., Blesson, S., Toutain, A., Chelly, J., Desportes, V., Moraine, C. MECP2 gene mutations in non-syndromic X-linked mental retardation: phenotype-genotype correlation. Am. J. Med. Genet. 123A: 129-139, 2003. [PubMed: 14598336] [Full Text: https://doi.org/10.1002/ajmg.a.20247]
Klauck, S. M., Lindsay, S., Beyer, K. S., Splitt, M., Burn, J., Poustka, A. A mutation hot spot for nonspecific X-linked mental retardation in the MECP2 gene causes the PPM-X syndrome. Am. J. Hum. Genet. 70: 1034-1037, 2002. [PubMed: 11885030] [Full Text: https://doi.org/10.1086/339553]
Lindsay, S., Splitt, M., Edney, S., Berney, T. P., Knight, S. J. L., Davies, K. E., O'Brien, O., Gale, M., Burn, J. PPM-X: A new X-linked mental retardation syndrome with psychosis, pyramidal signs, and macroorchidism maps to Xq28. Am. J. Hum. Genet. 58: 1120-1126, 1996. [PubMed: 8651288]
Meloni, I., Bruttini, M., Longo, I., Mari, F., Rizzolio, F., D'Adamo, P., Denvriendt, K., Fryns, J.-P., Toniolo, D., Renieri, A. A mutation in the Rett syndrome gene, MECP2, causes X-linked mental retardation and progressive spasticity in males. Am. J. Hum. Genet. 67: 982-985, 2000. [PubMed: 10986043] [Full Text: https://doi.org/10.1086/303078]
Moog, U., Smeets, E. E. J., van Roozendaal, K. E. P., Schoenmakers, S., Herbergs, J., Schoonbrood-Lenssen, A. M. J., Schrander-Stumpel, C. T. R. M. Neurodevelopmental disorders in males related to the gene causing Rett syndrome in females (MECP2). Europ. J. Paediat. Neurol. 7: 5-12, 2003. [PubMed: 12615169] [Full Text: https://doi.org/10.1016/s1090-3798(02)00134-4]
Orrico, A., Lam, C.-W., Galli, L., Dotti, M. T., Hayek, G., Tong, S.-F., Poon, P. M. K., Zappella, M., Federico, A., Sorrentino, V. MECP2 mutation in male patients with non-specific X-linked mental retardation. FEBS Lett. 481: 285-288, 2000. [PubMed: 11007980] [Full Text: https://doi.org/10.1016/s0014-5793(00)01994-3]
Villard, L. MECP2 mutations in males. J. Med. Genet. 44: 417-423, 2007. [PubMed: 17351020] [Full Text: https://doi.org/10.1136/jmg.2007.049452]
Winnepenninckx, B., Errijgers, V., Hayez-Delatte, F., Reyniers, E., Kooy, R. F. Identification of a family with nonspecific mental retardation (MRX79) with the A140V mutation in the MECP2 gene: is there a need for routine screening? Hum. Mutat. 20: 249-252, 2002. [PubMed: 12325019] [Full Text: https://doi.org/10.1002/humu.10130]
Yntema, H. G., Oudakker, A. R., Kleefstra, T., Hamel, B. C. J., van Bokhoven, H., Chelly, J., Kalscheuer, V. M., Fryns, J.-P., Raynaud, M., Moizard, M.-P., Moraine, C. In-frame deletion in MECP2 causes mild nonspecific mental retardation. (Letter) Am. J. Med. Genet. 107: 81-83, 2002. [PubMed: 11807877] [Full Text: https://doi.org/10.1002/ajmg.10085]