SNOMEDCT: 771303004; ORPHA: 209370; DO: 0111932;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq28 | Encephalopathy, neonatal severe | 300673 | X-linked recessive | 3 | MECP2 | 300005 |
A number sign (#) is used with this entry because this form of neonatal severe encephalopathy is caused by mutations in the MECP2 gene (300005).
The MECP2 gene is mutated in Rett syndrome (RTT; 312750), a severe neurodevelopmental disorder that almost always occurs in females. Although it was first thought that MECP2 mutations causing Rett syndrome were lethal in males, later reports identified a severe neonatal encephalopathy in surviving male sibs of patients with Rett syndrome. Since then, additional reports have confirmed a severe phenotype in males with RTT-associated MECP2 mutations (Moog et al., 2003; Villard, 2007).
Males with non-RTT mutations in the MECP2 gene can demonstrate a wide variety of phenotypes: see also X-linked syndromic intellectual developmental disorder-13 (300055), Lubs-type X-linked syndromic intellectual developmental disorder (300260), and neonatal severe encephalopathy (300673).
Schanen et al. (1998) reported 2 males with severe encephalopathy born to putative mutant gene carriers in families with recurrent RTT. One of them was the son of the obligate carrier in a family reported by Schanen et al. (1997). The infant was judged to be normal at birth, was sent home, and suffered an apneic event at 5 days of age. He had phenotypic features that were associated with Rett syndrome, including acquired microcephaly, profound developmental delay, hypotonia, seizures, respiratory irregularities, constipation, and growth retardation.
Hoffbuhr et al. (2001) reported 2 brothers with severe neonatal encephalopathy, significant developmental delay, and microcephaly associated with a hemizygous deletion in the MECP2 gene (300005.0034). They died at ages 21 and 18 months, respectively. The unaffected mother was a carrier with skewed X inactivation.
Geerdink et al. (2002) reported a male infant, the brother of a girl with Rett syndrome, who had severe neonatal encephalopathy, respiratory insufficiency with apnea, central hypoventilation, and poor feeding. He had axial hypotonia with hyperextension and rigidity of the limbs. At age 3 months, he developed seizures and stereotypic rubbing of his hand over his face. He also had gastroesophageal reflux. He died at age 13 months of respiratory failure. Postmortem examination showed bilateral polymicrogyria.
Zeev et al. (2002) reported an Israeli family in which a girl had classic Rett syndrome and her brother had severe neonatal encephalopathy.
Leuzzi et al. (2004) reported a 28-month-old boy with neonatal encephalopathy. After a normal pregnancy and cesarean section, the patient was markedly hypotonic with weak suction and vomiting. He showed chaotic ocular movements, masticatory automatisms, and brief seizure-like episodes. Brain MRI was normal. Examination at age 10 months showed microcephaly, severe developmental delay, axial hypotonia, limb rigidity, hyperreflexia, lack of purposeful hand movements, and poor eye contact. In addition, he had paroxysmal myoclonic movements of the upper limbs that were unresponsive to conventional antiepileptic drugs. Neurophysiologic investigations showed arrhythmic multifocal myoclonus that was of cortical origin, although not associated with cortical hyperexcitability. The findings were similar to those observed in patients with Rett syndrome and believed to result from reduced dendritic branching and circuitry derangement (Guerrini et al., 1998). Molecular analysis identified an MECP2 mutation (300005.0003). The patient's mother did not carry the mutation, suggesting germline mosaicism or a de novo mutation.
Kankirawatana et al. (2006) reported 4 unrelated boys with neonatal encephalopathy due to hemizygous MECP2 mutations. All had progressive microcephaly and respiratory insufficiency. Variable features included limb rigidity, axial hypotonia, and movement disorders. Three died by 27 months of age; 1 was alive at age 25 months. Two of the patients' mothers had had previous spontaneous abortions. The authors reviewed the clinical features of 11 similarly affected boys reported in the literature. Seven had sisters or female relatives with Rett syndrome. All the boys had a similar phenotype with neonatal encephalopathy, severe developmental delay, respiratory insufficiency, intractable seizures, abnormal muscle tone and movements, and usually early death.
Schule et al. (2008) reported a male infant with congenital encephalopathy due to a frameshift mutation in the MECP2 gene. He died at age 15 months from central respiratory failure. Neuropathologic examination showed a small brain with disproportionate reduction of the frontal and temporal lobes. Synaptophysin (SYP; 313475) staining of synaptic vesicles was greatly decreased in the cerebellum and spinal cord. Pyramidal neurons from the frontal and temporal lobes showed significantly decreased dendritic arborization compared to controls, as determined by Sholl analysis.
In a boy who died of congenital encephalopathy, Wan et al. (1999) identified a hemizygous 1-bp deletion in the MECP2 gene (806delG; 300005.0003). His sister and aunt, who both carried the mutation, had Rett syndrome. His carrier mother had motor coordination problems, mild learning disability, and skewed X inactivation.
Villard et al. (2000) reported a family in which a daughter had classic Rett syndrome and her 2 brothers died in infancy from severe encephalopathy. The affected girl and 1 brother tested had a mutation in the MECP2 gene (T158M; 300005.0007). The unaffected carrier mother had a completely biased pattern of X-chromosome inactivation that favored expression of the normal allele. One of the affected boys showed severe mental retardation and hypotonia soon after birth and died at age 11 months.
In a girl with Rett syndrome and her brother with lethal neonatal encephalopathy, Geerdink et al. (2002) identified a mutation in the MECP2 gene (300005.0032).
Geerdink, N., Rotteveel, J. J., Lammens, M., Sistermans, E. A., Heikens, G. T., Gabreels, F. J. M., Mullaart, R. A., Hamel, B. C. J. MECP2 mutation in a boy with severe neonatal encephalopathy: clinical, neuropathological and molecular findings. Neuropediatrics 33: 33-36, 2002. [PubMed: 11930274] [Full Text: https://doi.org/10.1055/s-2002-23598]
Guerrini, R., Bonanni, P., Parmeggiani, L., Santucci, M., Parmeggiani, A., Sartucci, F. Cortical reflex myoclonus in Rett syndrome. Ann. Neurol. 43: 472-479, 1998. [PubMed: 9546328] [Full Text: https://doi.org/10.1002/ana.410430410]
Hoffbuhr, K., Devaney, J. M., LaFleur, B., Sirianni, N., Scacheri, C., Giron, J., Schuette, J., Innis, J., Marino, M., Philippart, M., Narayanan, V., Umansky, R., Kronn, D., Hoffman, E. P., Naidu, S. MeCP2 mutations in children with and without the phenotype of Rett syndrome. Neurology 56: 1486-1495, 2001. [PubMed: 11402105] [Full Text: https://doi.org/10.1212/wnl.56.11.1486]
Kankirawatana, P., Leonard, H., Ellaway, C., Scurlock, J., Mansour, A., Makris, C. M., Dure, L. S., IV, Friez, M., Lane, J., Kiraly-Borri, C., Fabian, V., Davis, M., Jackson, J., Christodoulou, J., Kaufmann, W. E., Ravine, D., Percy, A. K. Early progressive encephalopathy in boys and MECP2 mutations. Neurology 67: 164-166, 2006. [PubMed: 16832102] [Full Text: https://doi.org/10.1212/01.wnl.0000223318.28938.45]
Leuzzi, V., Di Sabato, M. L., Zollino, M., Montanaro, M. L., Seri, S. Early-onset encephalopathy and cortical myoclonus in a boy with MECP2 gene mutation. Neurology 63: 1968-1970, 2004. [PubMed: 15557528] [Full Text: https://doi.org/10.1212/01.wnl.0000144350.97844.94]
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]
Schanen, N. C., Dahle, E. J. R., Capozzoli, F., Holm, V. A., Zoghbi, H. Y., Francke, U. A new Rett syndrome family consistent with X-linked inheritance expands the X chromosome exclusion map. Am. J. Hum. Genet. 61: 634-641, 1997. [PubMed: 9326329] [Full Text: https://doi.org/10.1086/515525]
Schanen, N. C., Kurczynski, T. W., Brunnelle, D., Woodcock, M. M., Dure, L. S., IV, Percy, A. K. Neonatal encephalopathy in two boys in families with recurrent Rett syndrome. J. Child Neurol. 13: 229-231, 1998. [PubMed: 9620015] [Full Text: https://doi.org/10.1177/088307389801300507]
Schule, B., Armstrong, D. D., Vogel, H., Oviedo, A., Francke, U. Severe congenital encephalopathy caused by MECP2 null mutations in males: central hypoxia and reduced neuronal dendritic structure. Clin. Genet. 74: 116-126, 2008. [PubMed: 18477000] [Full Text: https://doi.org/10.1111/j.1399-0004.2008.01005.x]
Villard, L., Kpebe, A., Cardoso, C., Chelly, J., Tardieu, M., Fontes, M. Two affected boys in a Rett syndrome family: clinical and molecular findings. Neurology 55: 1188-1193, 2000. [PubMed: 11071498] [Full Text: https://doi.org/10.1212/wnl.55.8.1188]
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]
Wan, M., Lee, S. S. J., Zhang, X., Houwink-Manville, I., Song, H.-R., Amir, R. E., Budden, S., Naidu, S., Pereira, J. L. P., Lo, I. F. M., Zoghbi, H. Y., Schanen, N. C., Francke, U. Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots. Am. J. Hum. Genet. 65: 1520-1529, 1999. [PubMed: 10577905] [Full Text: https://doi.org/10.1086/302690]
Zeev, B. B., Yaron, Y., Schanen, N. C., Wolf, H., Brandt, N., Ginot, N., Shomrat, R., Orr-Urtreger, A. Rett syndrome: clinical manifestations in males with MECP2 mutations. J. Child Neurol. 17: 20-24, 2002. [PubMed: 11913564] [Full Text: https://doi.org/10.1177/088307380201700105]