| #611588 | ||||||||||||||||||
| MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (LIMB-GIRDLE), TYPE C, 4; MDDGC4 | ||||||||||||||||||
| Alternative titles; symbols | ||||||||||||||||||
| MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 2M; LGMD2M | ||||||||||||||||||
| Phenotype Gene Relationships | ||||||||||||||||||
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| Phenotypic Series | ||||||||||||||||||
| Clinical Synopsis | ||||||||||||||||||
| TEXT | ||||||||||||||||||
| A number sign (#) is used with this entry because this form of limb-girdle muscular dystrophy-dystroglycanopathy (type C4; MDDGC4), previously designated limb-girdle muscular dystrophy type 2M (LGMD2M), is caused by mutation in the FKTN gene (607440) on chromosome 9q31. Mutation in the FKTN gene can also cause a severe muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A4; MDDGA4; 253800) and a form of congenital muscular dystrophy-dystroglycanopathy without mental retardation (type B4; MDDGB4; 613152). For a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type C, see MDDGC1 (609308). | ||||||||||||||||||
| Description | ||||||||||||||||||
| MDDGC4 is an autosomal recessive muscular dystrophy with onset in infancy or early childhood. Cognition and brain structure are usually normal (Godfrey et al., 2006). It is part of a group of similar disorders resulting from defective glycosylation of DAG1 (128239), collectively known as 'dystroglycanopathies' (Mercuri et al., 2009). | ||||||||||||||||||
| Clinical Features | ||||||||||||||||||
| Godfrey et al. (2006) reported 3 children from 2 unrelated families with autosomal recessive limb-girdle muscular dystrophy. All developed hypotonia and muscle weakness in infancy between ages 4 and 10 months. Two patients presented with severe acute motor deterioration after febrile viral illnesses; the third patient already had motor symptoms but also showed deterioration after a febrile illness at age 3 years. The patients showed mainly proximal muscle weakness with delayed motor development, decreased endurance, frequent falls, proximal muscle weakness, hypertrophy of lower limb muscles, and increased serum creatine kinase. All 3 patients eventually achieved independent ambulation. Skeletal muscle biopsies showed virtually absent glycosylation of alpha-dystroglycan (DAG1; 128239) and dystrophic features with mild macrophage infiltration. All patients had normal intellectual development, normal brain structure, and responded favorably to steroid treatment. Godfrey et al. (2007) identified 5 patients with FKTN-related limb-girdle muscular dystrophy, including 2 pairs of sibs, among 92 probands with muscular dystrophy and evidence of a dystroglycanopathy. Age at onset ranged from 4 months to 4 years, and all had normal cognition. Motor achievement varied: 3 walking, and 2 running. Two patients had contractures, and most had muscle hypertrophy. Brain MRI was essentially normal, but 1 patient had mild hydrocephalus. Some of the patients had been reported by Godfrey et al. (2006). Puckett et al. (2009) reported 2 brothers of Japanese and Caucasian ancestry with limb-girdle muscular dystrophy. The younger brother showed poor growth in infancy and muscle weakness at 21 months. Physical examination showed pectus excavatum, modified Gowers maneuver, and decreased deep tendon reflexes. There was no evidence of calf hypertrophy or cardiac involvement, and cognitive and motor development were normal. Although calf hypertrophy was evident within the next year, the physical examination was unchanged at age 5 years. His older brother was referred at age 4 years. He had normal motor development and subtle muscle abnormalities, including mild hypotonia, decreased muscle strength, calf hypertrophy, partial Gowers maneuver, and decreased deep tendon reflexes. He later developed lumbar lordosis, pectus excavatum, and waddling gait. Both patients had increased serum creatine kinase. Both remained ambulant at ages 4 and 6 years. Skeletal muscle biopsy of 1 patient showed mild dystrophic changes, with small numbers of necrotic and regenerating myofibers and hypoglycosylated alpha-dystroglycan. Vuillaumier-Barrot et al. (2009) reported a girl, born of consanguineous Turkish parents, with a moderately severe form of muscular dystrophy. She had delayed motor development, pes equinovarus, increased serum creatine kinase, generalized proximal muscle weakness, and diffuse muscle wasting of the calves. The disorder was progressive, and she lost ambulation at 11 years and developed contractures. Intelligence and brain MRI were normal. Muscle biopsy showed dystrophic changes and decreased glycosylated alpha-dystroglycan. Genetic analysis revealed a homozygous R307Q mutation in the FKTN gene (607440.0009). They also reported an unrelated French boy with FKTN-related muscular dystrophy who began to walk at 15 months and had increased serum creatine kinase. At age 7 years, he had calf hypertrophy, normal gait, and complained of episodic myalgia after effort. He was able to run, swim, and ride a bicycle without difficulty. Both patients had normal brain MRI and intelligence, and neither had signs of cardiac involvement. | ||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||
| In 3 patients with limb-girdle muscular dystrophy, Godfrey et al. (2006) identified compound heterozygosity for 2 mutations in the FKTN gene (607440.0005; 607440.0008; 607440.0009). The authors noted that the phenotype was much less severe than that observed in the allelic disorder Fukuyama congenital muscular dystrophy (FCMD; 253800). In 2 brothers of Japanese and Caucasian ancestry with limb-girdle muscular dystrophy, Puckett et al. (2009) identified compound heterozygosity for 2 mutations in the FKTN gene (A114T, 607440.0014 and F176S, 607440.0015). One of the mutations (A114T) had been reported in 2 sibs with limb-girdle muscular dystrophy (Godfrey et al., 2007). Mercuri et al. (2009) identified compound heterozygosity for 2 mutations in the FKTN gene (R307Q; 607440.0009 and 42delG; 607440.0019) in 1 of 81 Italian patients with congenital muscular dystrophy associated with defective glycosylation of alpha-dystroglycan. The patient did not have mental retardation and had no structural brain abnormalities. | ||||||||||||||||||
| Nomenclature | ||||||||||||||||||
| Godfrey et al. (2006) originally referred to this disorder as LGMD2L. However, since an LGMD locus on chromosome 11p13-p12 had already been designated LGMD2L (see Jarry et al., 2007; 611307), LGMD due to mutation in the FKTN gene was referred to as 'LGMD2M.' The disorder is now designated MDDGC4. | ||||||||||||||||||
| REFERENCES | ||||||||||||||||||
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