Alternative titles; symbols
ORPHA: 370959, 370968, 370980, 52428; DO: 0110635;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 19q13.32 | Muscular dystrophy-dystroglycanopathy (congenital with or without impaired intellectual development), type B, 5 | 606612 | Autosomal recessive | 3 | FKRP | 606596 |
A number sign (#) is used with this entry because this form of congenital muscular dystrophy-dystroglycanopathy with or without impaired intellectual development (type B5; MDDGB5), previously designated MDC1C, is caused by homozygous or compound heterozygous mutation in the gene encoding fukutin-related protein (FKRP; 606596) on chromosome 19q13.3.
Mutation in the FKRP gene can also cause a more severe congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A5; MDDGA5; 613153) and a less severe limb-girdle muscular dystrophy-dystroglycanopathy (type C5; MDDGC5; 607155).
MDDGB5 is an autosomal recessive congenital muscular dystrophy with impaired intellectual development and structural brain abnormalities (Brockington et al., 2001). It is part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239), collectively known as 'dystroglycanopathies' (Mercuri et al., 2006).
For a discussion of genetic heterogeneity of congenital muscular dystrophy-dystroglycanopathy type B, see MDDGB1 (613155).
Brockington et al. (2001) reported 7 families with a unique form of congenital muscular dystrophy, which they called MDC1C. Two families were consanguineous. Patients presented soon after birth with hypotonia and feeding difficulties. There was hypertrophy of the leg muscles, wasting and weakness of the shoulder girdle muscles, and elevated serum creatine kinase. Cognition and brain MRI were normal.
Mercuri et al. (2003) described in detail the clinical phenotypes of 4 patients with MDC1C who had previously been reported by Brockington et al. (2001). All patients had onset at birth and none acquired independent ambulation. Other features included significant facial weakness, hypertrophy of the lower limb muscles, wasting of the shoulder girdle with pronation of the forearm, contractures of the Achilles tendon, and elevated creatine kinase. Muscle biopsies showed a severe decrease in alpha-dystroglycan and a mild secondary reduction in the laminin alpha-2 chain (LAMA2; 156225). In addition, the molecular mass of alpha-dystroglycan was reduced in muscle. Together these findings suggested that the DAG1 protein is abnormally glycosylated in MDC1C and is central to the pathogenesis of the disorder.
In 2 unrelated patients with MDC1C, 1 of whom had previously been reported by Talim et al. (2000), Topaloglu et al. (2003) identified 2 different homozygous mutations in the FKRP gene (606596.0007 and 606596.0008). In addition to the classic features of MDC1C, such as weakness, inability to achieve ambulation, and dystrophic findings on muscle biopsy, both patients had mildly impaired intellectual development and cerebellar cysts on brain imaging. Topaloglu et al. (2003) noted that although the latter findings are unusual in patients with FKRP mutations, the features may expand the phenotypic spectrum of MDC1C. Louhichi et al. (2004) reported 7 unrelated patients with MDC1C and central nervous system (CNS) abnormalities, including impaired intellectual development and cerebellar cysts on MRI.
Mercuri et al. (2006) found that 10 of 13 patients with FKRP mutations had a clinical phenotype compatible with congenital muscular dystrophy with leg hypertrophy, upper limb wasting, and high levels of creatine kinase. Among the other 3, 1 had a phenotype compatible with Walker-Warburg syndrome (WWS, see 236670) and 2 had a phenotype compatible with muscle-eye-brain disease (MEB). Of the 10 with congenital muscular dystrophy, 5 had had normal brain MRIs with no evidence of cortical, subcortical, or white matter involvement. All attended mainstream schools and had normal cognitive abilities (4 of the 5 patients had been reported by Brockington et al., 2001 and Mercuri et al., 2003). Three patients (2 of whom were reported by Topaloglu et al., 2003) had isolated cerebellar cysts without any cortical involvement, and varying degrees of mental retardation; 1 had microcephaly. Another patient had cerebellar cysts associated with unilateral left frontotemporal nodular heterotopia and bilateral frontal pachygyria: this child had a normal IQ and no microcephaly. The last patient had pontine hypoplasia, marked dysplasia of cerebellar hemispheres and vermis, ventricular dilatation with loss of white matter and increased extracerebellar space, and absent septum pellucidum. The child had microcephaly and was able to speak, read, and attend school. Overall, there was no correlation with severity of the neurologic involvement and FKRP mutation. Mercuri et al. (2006) postulated that the variability may be related to the severity of disruption of alpha-dystroglycan glycosylation.
The transmission pattern of MDDGB5 in the families reported by Brockington et al. (2001) was consistent with autosomal recessive inheritance.
In 7 families with MDC1C, Brockington et al. (2001) identified 11 mutations in the FKRP gene (see, e.g., 606596.0001). Nine of the mutations were missense mutations and 2 were nonsense mutations. In 4 families, the affected individuals were compound heterozygotes; in the other 3, the patients were homozygous for the particular mutation.
In 6 unrelated Tunisian patients with MDC1C associated with mental retardation and white matter changes and/or cerebellar structural abnormalities on MRI, Louhichi et al. (2004) identified a homozygous mutation in the FKRP gene (A455D; 606596.0009). Microsatellite marker analysis suggested a founder effect. An unrelated Algerian patient with the same phenotype had a different homozygous mutation in the FKRP gene (V405L; 606596.0010). Louhichi et al. (2004) noted the similarities to the patients reported by Topaloglu et al. (2003).
In 2 unrelated girls of Mexican descent with MDC1C, MacLeod et al. (2007) identified a homozygous mutation in the FKRP gene (N463D; 606596.0018). Both girls had onset of muscle weakness from birth without neurologic or cardiac abnormalities. Skeletal muscle biopsies showed chronic myopathic changes with decreased immunoreactivity for alpha- and beta-dystroglycan, as well as several sarcoglycans (see, e.g., SGCA; 600119), suggesting that multiple members of the membrane glycoprotein complex were affected.
Brockington, M., Blake, D. J., Prandini, P., Brown, S. C., Torelli, S., Benson, M. A., Ponting, C. P., Estournet, B., Romero, N. B., Mercuri, E., Voit, T., Sewry, C. A., Guicheney, P., Muntoni, F. Mutations in the fukutin-related protein gene (FKRP) cause a form of congenital muscular dystrophy with secondary laminin alpha-2 deficiency and abnormal glycosylation of alpha-dystroglycan. Am. J. Hum. Genet. 69: 1198-1209, 2001. [PubMed: 11592034] [Full Text: https://doi.org/10.1086/324412]
Louhichi, N., Triki, C., Quijano-Roy, S., Richard, P., Makri, S., Meziou, M., Estournet, B., Mrad, S., Romero, N. B., Ayadi, H., Guicheney, P., Fakhfakh, F. New FKRP mutations causing congenital muscular dystrophy associated with mental retardation and central nervous system abnormalities: identification of a founder mutation in Tunisian families. Neurogenetics 5: 27-34, 2004. [PubMed: 14652796] [Full Text: https://doi.org/10.1007/s10048-003-0165-9]
MacLeod, H., Pytel, P., Wollmann, R., Chelmicka-Schorr, E., Silver, K., Anderson, R. B., Waggoner, D., McNally, E. M. A novel FKRP mutation in congenital muscular dystrophy disrupts the dystrophin glycoprotein complex. Neuromusc. Disord. 17: 285-289, 2007. [PubMed: 17336067] [Full Text: https://doi.org/10.1016/j.nmd.2007.01.005]
Mercuri, E., Brockington, M., Straub, V., Quijano-Roy, S., Yuva, Y., Herrmann, R., Brown, S. C., Torelli, S., Dubowitz, V., Blake, D. J., Romero, N. B., Estournet, B., Sewry, C. A., Guicheney, P., Voit, T., Muntoni, F. Phenotypic spectrum associated with mutations in the fukutin-related protein gene. Ann. Neurol. 53: 537-542, 2003. [PubMed: 12666124] [Full Text: https://doi.org/10.1002/ana.10559]
Mercuri, E., Topaloglu, H., Brockington, M., Berardinelli, A., Pichiecchio, A., Santorelli, F., Rutherford, M., Talim, B., Ricci, E., Voit, T., Muntoni, F. Spectrum of brain changes in patients with congenital muscular dystrophy and FKRP gene mutations. Arch. Neurol. 63: 251-257, 2006. [PubMed: 16476814] [Full Text: https://doi.org/10.1001/archneur.63.2.251]
Talim, B., Ferreiro, A., Cormand, B., Vignier, N., Oto, A., Gogus, S., Cila, A., Lehesjoki, A.-E., Pihko, H., Guicheney, P., Topaloglu, H. Merosin-deficient congenital muscular dystrophy with mental retardation and cerebellar cysts unlinked to the LAMA2, FCMD and MEB loci. Neuromusc. Disord. 10: 548-552, 2000. [PubMed: 11053680] [Full Text: https://doi.org/10.1016/s0960-8966(00)00140-1]
Topaloglu, H., Brockington, M., Yuva, Y., Talim, B., Haliloglu, G., Blake, D., Torelli, S., Brown, S. C., Muntoni, F. FKRP gene mutations cause congenital muscular dystrophy, mental retardation, and cerebellar cysts. Neurology 60: 988-992, 2003. Note: Erratum: Neurology 60: 1875 only, 2003. [PubMed: 12654965] [Full Text: https://doi.org/10.1212/01.wnl.0000052996.14099.dc]