# 254300

MYASTHENIC SYNDROME, CONGENITAL, 10; CMS10


Alternative titles; symbols

MYASTHENIA, LIMB-GIRDLE, FAMILIAL, FORMERLY; LGM, FORMERLY
CONGENITAL MYASTHENIC SYNDROME TYPE Ib, FORMERLY; CMS1B, FORMERLY
CMS Ib, FORMERLY
MYASTHENIC MYOPATHY, FORMERLY


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
4p16.3 Myasthenic syndrome, congenital, 10 254300 AR 3 DOK7 610285
Clinical Synopsis
 
Phenotypic Series
 

INHERITANCE
- Autosomal recessive
HEAD & NECK
Face
- Facial weakness
- Myopathic facies
Eyes
- Ptosis
RESPIRATORY
- Respiratory muscle weakness (in some patients)
SKELETAL
Spine
- Scoliosis (in some patients)
- Lordosis (in some patients)
Limbs
- Joint contractures (later in life)
MUSCLE, SOFT TISSUES
- Hypotonia, neonatal (in some patients)
- Limb-girdle muscle weakness
- Limb-girdle muscle atrophy
- Proximal muscle weakness due to defect at the neuromuscular junction
- Easy fatigability
- Bulbar muscle weakness
- Muscle biopsy shows degenerating endplates and junctional folds
- Denuded postsynaptic regions
- Decreased acetylcholine receptors (AChR) at endplate junctional folds (less common)
- Degenerating nerve terminals
- Decreased postsynaptic length
- Electromyographic decrements in some muscles
- Decreased endplate potential and amplitudes
- Disorganization of the neuromuscular junction
IMMUNOLOGY
- Absence of acetylcholine receptor (AChR) autoantibodies
PRENATAL MANIFESTATIONS
Movement
- Decreased fetal movements (in some patients)
LABORATORY ABNORMALITIES
- Normal or mildly increased serum creatine kinase
MISCELLANEOUS
- Onset in first decade (birth to age 10 years)
- Variable severity
- Intermittent exacerbations
- Most patients remain ambulatory in adulthood
- Slowly progressive
- Static disease course (in some patients)
- Poor response to acetylcholinesterase inhibitors or cholinergic agents
- Favorable response to ephedrine treatment
MOLECULAR BASIS
- Caused by mutation in the downstream of tyrosine kinase 7 gene (DOK7, 610285.0001)
Myasthenic syndrome, congenital - PS601462 - 32 Entries
Location Phenotype Inheritance Phenotype
mapping key
Phenotype
MIM number
Gene/Locus Gene/Locus
MIM number
1p36.33 Myasthenic syndrome, congenital, 8, with pre- and postsynaptic defects AR 3 615120 AGRN 103320
1p21.3 ?Myasthenic syndrome, congenital, 15, without tubular aggregates AR 3 616227 ALG14 612866
1q32.1 Myasthenic syndrome, congenital, 7A, presynaptic, and distal motor neuropathy, autosomal dominant AD 3 616040 SYT2 600104
1q32.1 Myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive AR 3 619461 SYT2 600104
2p21 Myasthenic syndrome, congenital, 22 AR 3 616224 PREPL 609557
2p13.3 Myasthenia, congenital, 12, with tubular aggregates AR 3 610542 GFPT1 138292
2q12.3 Myasthenic syndrome, congenital, 20, presynaptic AR 3 617143 SLC5A7 608761
2q31.1 Myasthenic syndrome, congenital, 1A, slow-channel AD 3 601462 CHRNA1 100690
2q31.1 Myasthenic syndrome, congenital, 1B, fast-channel AD, AR 3 608930 CHRNA1 100690
2q37.1 ?Myasthenic syndrome, congenital, 3A, slow-channel AD 3 616321 CHRND 100720
2q37.1 ?Myasthenic syndrome, congenital, 3C, associated with acetylcholine receptor deficiency AR 3 616323 CHRND 100720
2q37.1 Myasthenic syndrome, congenital, 3B, fast-channel AR 3 616322 CHRND 100720
3p25.1 Myasthenic syndrome, congenital, 5 AR 3 603034 COLQ 603033
4p16.3 Myasthenic syndrome, congenital, 10 AR 3 254300 DOK7 610285
9q22.33 Myasthenic syndrome, congenital, 14, with tubular aggregates AR 3 616228 ALG2 607905
9q31.3 Myasthenic syndrome, congenital, 9, associated with acetylcholine receptor deficiency AR 3 616325 MUSK 601296
10q11.23 Myasthenic syndrome, congenital, 6, presynaptic AR 3 254210 CHAT 118490
10q11.23 Myasthenic syndrome, congenital, 21, presynaptic AR 3 617239 SLC18A3 600336
10q22.1 Myasthenic syndrome, congenital, 19 AR 3 616720 COL13A1 120350
11p11.2 ?Myasthenic syndrome, congenital, 17 AR 3 616304 LRP4 604270
11p11.2 Myasthenic syndrome, congenital, 11, associated with acetylcholine receptor deficiency AR 3 616326 RAPSN 601592
11q23.3 Myasthenic syndrome, congenital, 13, with tubular aggregates AR 3 614750 DPAGT1 191350
12p13.31 Myasthenic syndrome, congenital, 25 AR 3 618323 VAMP1 185880
15q23 Myasthenic syndrome, congenital, 24, presynaptic AR 3 618198 MYO9A 604875
17p13.2 Myasthenic syndrome, congenital, 4B, fast-channel AR 3 616324 CHRNE 100725
17p13.2 Myasthenic syndrome, congenital, 4C, associated with acetylcholine receptor deficiency AR 3 608931 CHRNE 100725
17p13.2 Myasthenic syndrome, congenital, 4A, slow-channel AD, AR 3 605809 CHRNE 100725
17p13.1 ?Myasthenic syndrome, congenital, 2C, associated with acetylcholine receptor deficiency AR 3 616314 CHRNB1 100710
17p13.1 Myasthenic syndrome, congenital, 2A, slow-channel AD 3 616313 CHRNB1 100710
17q23.3 Myasthenic syndrome, congenital, 16 AR 3 614198 SCN4A 603967
20p12.2 ?Myasthenic syndrome, congenital, 18 AD 3 616330 SNAP25 600322
22q11.21 Myasthenic syndrome, congenital, 23, presynaptic AR 3 618197 SLC25A1 190315

TEXT

A number sign (#) is used with this entry because of evidence that congenital myasthenic syndrome-10 (CMS10) is caused by homozygous or compound heterozygous mutation in the DOK7 gene (610285) on chromosome 4p16.


Description

Congenital myasthenic syndromes (CMS) are a group of inherited disorders affecting the neuromuscular junction (NMJ). Patients present clinically with onset of variable muscle weakness between infancy and adulthood. These disorders have been classified according to the location of the defect: presynaptic, synaptic, and postsynaptic. CMS10 is an autosomal recessive CMS resulting from a postsynaptic defect affecting endplate maintenance of the NMJ. Patients present with limb-girdle weakness in the first decade. Treatment with ephedrine or salbutamol may be beneficial; cholinesterase inhibitors should be avoided (summary by Engel et al., 2015).

For a discussion of genetic heterogeneity of CMS, see CMS1A (601462).


Clinical Features

Azulay et al. (1994) reported a woman with proximal muscle weakness of the myasthenic type. Family history was not reported.

Shankar et al. (2002) reported 2 Indian sisters with classic features of limb-girdle myasthenia.

Beeson et al. (2006) summarized the clinical features of 19 of 21 index patients with limb-girdle myasthenia and the affected brother of case 11, all of whom had mutations in DOK7. All patients displayed electromyographic (EMG) evidence of a defect in neuromuscular transmission and all but 3 patients developed weakness within the first 5 years of life. The clinical onset of disease was generally characterized by difficulty in walking after initially achieving normal walking milestones. Features typically seen in patients with mutations in rapsyn (RAPSN; 601592), such as congenital joint deformity and squint, were not present. In adulthood, a proximal weakness of the affected patients' upper and lower extremities was evident, and most had weakness in the trunk and neck regions. All of the patients had weak facial muscles, and all but 2 patients had ptosis. Eye movements were generally unaffected. Anticholinesterase medication either had no effect or made the weakness worse, although a short-lived initial response was occasionally seen. Beeson et al. (2006) also undertook an analysis of motorpoint muscle biopsies, which showed that many features of the NMJ were normal, including the quantal release per unit area of synaptic content and the size and kinetics of the miniature endplate currents. However, 2 major abnormalities were identified: reduced size of the NMJs and reduced postsynaptic folding.

Selcen et al. (2008) reported 16 patients with DOK7-related congenital myasthenia. The age at onset ranged from the first day of life to age 5 years, and there was great variability in disease severity and rate of progression. Some patients had mild static weakness limited to limb-girdle muscles, whereas others had severe generalized disease with marked muscle atrophy. Ten patients had intermittent worsenings lasting from days to weeks. All patients reported fatigue on exertion and proximal muscle weakness. Other common features included ptosis (14 patients), facial weakness (13), bulbar symptoms (11), and respiratory difficulties (13). Oculoparesis was less common (6), and only 3 showed decreased fetal movements. In general, there was a poor response to cholinesterase inhibitors and cholinergic agents. The authors found no consistent correlation between the clinical severity and expression of DOK7 at the endplate; in fact, some patients with severe disease showed almost normal expression. Electron microscopy of endplates showed variable changes, including degeneration of junctional folds, reduced nerve terminals, or degeneration of subsynaptic organelles, but some endplates appeared normal. In vitro microelectrode studies showed decreased numbers of released quanta and decreased synaptic response to acetylcholine. Acetylcholine receptors (AChR) were decreased in areas of degenerating junctional folds, but AChR kinetics were normal. Selcen et al. (2008) noted that the studies did not reveal a clear correlation between histologic or electrophysiologic findings and disease severity in individual patients, but indicated that changes in the structural integrity of the endplate likely contributed to the decreased safety margin of neuromuscular transmission.

Mahjneh et al. (2013) reported a large highly consanguineous Palestinian family in which 6 individuals, ranging from 38 to 53 years of age, had CMS10 associated with a homozygous frameshift mutation in the DOK7 gene (c.957delC; 610285.0011). The family had originally been reported by Mahjneh et al. (1992) as having 'congenital muscular dystrophy.' Mahjneh et al. (2013) reviewed the phenotype in the 6 patients, noting that generalized muscle weakness and hypotonia were present at birth and that subsequent motor development and walking was delayed (walking between 14 and 76 months). With growth, the pattern of muscle weakness clearly affected the proximal muscles of the upper and lower limbs, was slowly progressive, and showed variable severity; some patients had a more stable disease course. Episodic crises without clear precipitating factors were reported, and many had breathing problems during these episodes or during exercise. One patient required nocturnal ventilation. Physical examination showed myopathic facies, ptosis, waddling gait, and muscle weakness and wasting in the proximal upper limbs. Four patients had rigid spine, 2 had several scoliosis, 2 had mild scoliosis, 4 had joint contractures, and 3 had a positive Gowers sign. Treatment with salbutamol resulted in dramatic improvement of muscle weakness and respiratory and bulbar function. Mahjneh et al. (1999) and Sellick et al. (2005) had also studied this family. They stated that there were 10 family members who presented with neonatal hypotonia and absent antigravity movements; reduced fetal movements were noted in all affected pregnancies. There were no feeding or respiratory issues, and none had contractures. Four of these patients died between 7 months and 36 years, although their mutation status was not known at the time. Interestingly, 9 additional family members had adult-onset limb-girdle muscular dystrophy type 2B (253601) caused by mutation in the gene encoding dysferlin (DYSF; 603009.0006); the patients with congenital muscular dystrophy did not have the DYSF mutation (Bashir et al., 1998). The pattern of muscle weakness and wasting in the patients diagnosed with the congenital disorder was more marked in the proximal upper limb-girdle and trunk muscles. Lower limb muscles were mildly involved. Muscle biopsy showed a dystrophic pattern with normal staining for dystrophin (300377), laminin alpha-2 of merosin (156225), and the sarcoglycans (see, e.g., SGCA; 600119).

Aharoni et al. (2017) reported a patient (45), born of consanguineous parents in Israel (family 35), with CMS10 due to a homozygous frameshift mutation in the DOK7 gene (610285.0011). Clinical details were limited, but he had onset of limb weakness and ptosis around 10 years of age.


Clinical Management

Selcen et al. (2008) reported 16 patients with DOK7-related congenital myasthenia, noting that there was a poor response to cholinesterase inhibitors and cholinergic agents.

Lashley et al. (2010) reported that ephedrine therapy was a favorable and effective treatment for congenital myasthenic syndrome due to DOK7 mutations. A prospective trial of 12 patients showed that 10 tolerated ephedrine well. Over a 6 to 8 month treatment period, these 10 patients showed significant improvements in quantitative myasthenia gravis and mobility scores. Ephedrine was administered orally between 15 and 90 mg/day. Lashley et al. (2010) noted that these patients do not usually respond to acetylcholinesterase inhibitors, and postulated that the beneficial effect of ephedrine may be related to its action as a beta-2-adrenergic receptor (109690) agonist.

Beeson et al. (2006) noted that another genetic congenital myasthenic syndrome with a limb girdle-like pattern of muscle weakness is associated with tubular aggregates in muscle biopsies (see CMSTA1, 610542). Tubular aggregates were present in the 1 patient from the study by Slater et al. (2006) in whom no DOK7 mutation was found, but were not present in patients with DOK7 mutations. The patient with tubular aggregates was later found by Belaya et al. (2012) to carry compound heterozygous mutations in the DPAGT1 gene (191350.0002 and 191350.0003; see CMSTA2, 614750). In contrast with patients harboring DOK7 mutations, patients with tubular aggregates tend to respond well to anticholinesterase medication, suggesting that the phenotypes constitute separate disorders.

Mahjneh et al. (2013) reported a family with CMD10 in which salbutamol resulted in dramatic improvement of muscle weakness and respiratory and bulbar function.


Inheritance

The transmission pattern of CMS10 in the family reported by Mahjneh et al. (2013) was consistent with autosomal recessive inheritance.


Mapping

By genomewide analysis of a large consanguineous Palestinian family diagnosed with merosin-positive congenital muscular dystrophy, Sellick et al. (2005) identified a candidate disease locus on chromosome 4p16.3. Combined data from both a high-density SNP array and microsatellite markers delineated a 4.14-Mb interval flanked centromerically by marker D4S432 (multipoint lod score of 3.4). Mutations in the SPON2 (605918) and MYL5 (160782) genes were excluded.


Molecular Genetics

Beeson et al. (2006) identified frameshift mutations in the DOK7 gene (610285) in 16 unrelated patients with limb-girdle type congenital myasthenic syndrome. In 3 additional patients, a frameshift mutation was identified in combination with a nonsense mutation, a splice site mutation, and a missense change of a conserved residue. These mutations were found in homozygosity or compound heterozygosity, consistent with recessive inheritance seen in this phenotype. Beeson et al. (2006) also identified C-terminal domain frameshift mutations in DOK7 in DNA available from 6 of 7 patients included in the study by Slater et al. (2006). The seventh patient reported by Slater et al. (2006) was found by Belaya et al. (2012) to carry compound heterozygous mutations in the DPAGT1 gene (191350.0002 and 191350.0003; see 614750).

Among 16 patients with limb-girdle congenital myasthenic syndrome, Selcen et al. (2008) identified 17 different mutations in the DOK7 gene, including 10 novel mutations (see, e.g., 610285.0009; 610285.0010). All of the mutations resulted in a termination codon or a frameshift, except for 3 that resulted in the in-frame deletion of 1 or more exons. In vitro functional expression studies in murine myotubes showed that many of the mutations resulted in decreased axial length and density of AChR clusters at the endplate. Selcen et al. (2008) concluded that the pathogenesis of the disorder results from destruction and simplification of synaptic structures with resultant decrease in neuromuscular transmission.

In 6 affected members of a large highly consanguineous Palestinian family with CMS10, Mahjneh et al. (2013) identified a homozygous frameshift mutation in the DOK7 gene (c.957delC; 610285.0011). The family had originally been reported by Mahjneh et al. (1992) as having 'congenital muscular dystrophy.' Functional studies of the mutation and studies of patient cells were not performed.

Aharoni et al. (2017) identified a homozygous c.957delC mutation in the DOK7 gene in 1 of 55 Israeli individuals with a clinical diagnosis of congenital myasthenic syndrome.


Animal Model

Okada et al. (2006) generated mice lacking Dok7 and observed that all homozygous Dok7-deficient mice were immobile at birth and died shortly thereafter. Alveoli of these mice were not expanded at birth, indicating a failure to breathe and suggesting a severe defect in neuromuscular transmission in skeletal muscles. Heterozygous-deficient littermates were normal. Okada et al. (2006) found that Dok7 homozygous mutants formed neither AChR clusters nor neuromuscular synapses. They concluded that neuromuscular synaptogenesis requires DOK7 within skeletal muscle.

Muller et al. (2010) reported that Dok7 deficiency led to motility defects in zebrafish embryos and larvae. The relative importance of Dok7 at different stages of neuromuscular junction development varied; it was crucial for the earliest step, the formation of acetylcholine receptor (AChR) clusters in the middle of the muscle fiber prior to motor neuron contact. At later stages, presence of Dok7 was not absolutely essential, as focal and nonfocal synapses did form when Dok7 expression was downregulated. However, these contacts were smaller than in the wildtype zebrafish, reminiscent of the neuromuscular endplate pathology seen in patients with DOK7 mutations. Changes in slow muscle fiber arrangement were also observed. The authors suggested an additional role for Dok7 in muscle that is independent of the muscle-specific tyrosine kinase MuSK (601296), the binding partner of Dok7 at the neuromuscular junction.

In a mouse model of DOK7 myasthenia, Arimura et al. (2014) showed that therapeutic administration of an adeno-associated virus (AAV) vector encoding human DOK7 resulted in an enlargement of neuromuscular junctions (NMJs) and substantial increases in muscle strength and life span. When applied to model mice of another neuromuscular disorder, autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD2; 181350), DOK7 gene therapy likewise resulted in enlargement of NMJs as well as positive effects on motor activity and life span. Arimura et al. (2014) concluded that these results suggested that therapies aimed at enlarging the NMJ may be useful for a range of neuromuscular disorders.


REFERENCES

  1. Aharoni, S., Sadeh, M., Shapira, Y., Edvardson, S., Daana, M., Dor-Wollman, T., Mimouni-Bloch, A., Halevy, A., Cohen, R., Sagie, L., Argov, Z., Rabie, M., Spiegel, R., Chervinsky, I., Orenstein, N., Engel, A. G., Nevo, Y. Congenital myasthenic syndrome in Israel: genetic and clinical characterization. Neuromusc. Disord. 27: 136-140, 2017. [PubMed: 28024842, related citations] [Full Text]

  2. Arimura, S., Okada, T., Tezuka, T., Chiyo, T., Kasahara, Y., Yoshimura, T., Motomura, M., Yoshida, N., Beeson, D., Takeda, S., Yamanashi, Y. DOK7 gene therapy benefits mouse models of diseases characterized by defects in the neuromuscular junction. Science 345: 1505-1508, 2014. [PubMed: 25237101, related citations] [Full Text]

  3. Azulay, J.-P., Pouget, J., Figarella-Branger, D., Colamarino, R., Pellissier, J.-F., Serratrice, G. Faiblesse musculaire proximale isolee revelatrice d'un syndrome myasthenique. Rev. Neurol. 150: 377-381, 1994. [PubMed: 7878325, related citations]

  4. Bashir, R., Britton, S., Strachan, T., Keers, S., Vafiadaki, E., Lako, M., Richard, I., Marchand, S., Bourg, N., Argov, Z., Sadeh, M., Mahjneh, I., Marconi, G., Passos-Bueno, M. R., Moreira, E. S., Zatz, M., Beckmann, J. S., Bushby, K. A gene related to Caenorhabditis elegans spermatogenesis factor fer-1 is mutated in limb-girdle muscular dystrophy type 2B. Nature Genet. 20: 37-42, 1998. [PubMed: 9731527, related citations] [Full Text]

  5. Beeson, D., Higuchi, O., Palace, J., Cossins, J., Spearman, H., Maxwell, S., Newsom-Davis, J., Burke, G., Fawcett, P., Motomura, M., Muller, J. S., Lochmuller, H., Slater, C., Vincent, A., Yamanashi, Y. Dok-7 mutations underlie a neuromuscular junction synaptopathy. Science 313: 1975-1978, 2006. [PubMed: 16917026, related citations] [Full Text]

  6. Belaya, K., Finlayson, S., Slater, C. R., Cossins, J., Liu, W. W., Maxwell, S., McGowan, S. J., Maslau, S., Twigg, S. R. F., Walls, T. J., Pascual Pascual, S. I., Palace, J., Beeson, D. Mutations in DPAGT1 cause a limb-girdle congenital myasthenic syndrome with tubular aggregates. Am. J. Hum. Genet. 91: 193-201, 2012. [PubMed: 22742743, images, related citations] [Full Text]

  7. Engel, A. G., Shen, X.-M., Selcen, D., Sine, S. M. Congenital myasthenic syndromes: pathogenesis, diagnosis, and treatment. Lancet Neurol. 14: 420-434, 2015. Note: Erratum: Lancet Neurol. 14: 461 only, 2015. [PubMed: 25792100, images, related citations] [Full Text]

  8. Lashley, D., Palace, J., Jayawant, S., Robb, S., Beeson, D. Ephedrine treatment in congenital myasthenic syndrome due to mutations in DOK7. Neurology 74: 1517-1523, 2010. [PubMed: 20458068, images, related citations] [Full Text]

  9. Mahjneh, I., Bushby, K., Anderson, L., Muntoni, F., Tolvanen-Mahjneh, H., Bashir, R., Pizzi, A., Brockington, M., Marconi, G. Merosin-positive congenital muscular dystrophy: a large inbred family. Neuropediatrics 30: 22-28, 1999. [PubMed: 10222457, related citations] [Full Text]

  10. Mahjneh, I., Lochmuller, H., Muntoni, F., Abicht, A. DOK7 limb-girdle myasthenic syndrome mimicking congenital muscular dystrophy. Neuromusc. Disord. 23: 36-42, 2013. [PubMed: 22884442, related citations] [Full Text]

  11. Mahjneh, I., Vannelli, G., Bushby, K., Marconi, G. P. A large inbred Palestinian family with two forms of muscular dystrophy. Neuromusc. Disord. 2: 277-283, 1992. [PubMed: 1483054, related citations] [Full Text]

  12. Muller, J. S., Jepson, C. D., Laval, S. H., Bushby, K., Straub, V., Lochmuller, H. Dok-7 promotes slow muscle integrity as well as neuromuscular junction formation in a zebrafish model of congenital myasthenic syndromes. Hum. Molec. Genet. 19: 1726-1740, 2010. [PubMed: 20147321, related citations] [Full Text]

  13. Okada, K., Inoue, A., Okada, M., Murata, Y., Kakuta, S., Jigami, T., Kubo, S., Shiraishi, H., Eguchi, K., Motomura, M., Akiyama, T., Iwakura, Y., Higuchi, O., Yamanashi, Y. The muscle protein Dok-7 is essential for neuromuscular synaptogenesis. Science 312: 1802-1805, 2006. [PubMed: 16794080, related citations] [Full Text]

  14. Selcen, D., Milone, M., Shen, X.-M., Harper, C. M., Stans, A. A., Wieben, E. D., Engel, A. G. Dok-7 myasthenia: phenotypic and molecular genetic studies in 16 patients. Ann. Neurol. 64: 71-87, 2008. [PubMed: 18626973, images, related citations] [Full Text]

  15. Sellick, G. S., Longman, C., Brockington, M., Mahjneh, I., Sagi, L., Bushby, K., Topaloglu, H., Muntoni, F., Houlston, R. S. Localisation of merosin-positive congenital muscular dystrophy to chromosome 4p16.3. Hum. Genet. 117: 207-212, 2005. [PubMed: 15886997, related citations] [Full Text]

  16. Shankar, A., Solomon, T., Joseph, T. P., Gnanamuthu, C. Autosomal recessive limb girdle myasthenia in two sisters. Neurol. India 50: 500-503, 2002. [PubMed: 12577107, related citations]

  17. Slater, C. R., Fawcett, P. R. W., Walls, T. J., Lyons, P. R., Bailey, S. J., Beeson, D., Young, C., Gardner-Medwin, D. Pre- and post-synaptic abnormalities associated with impaired neuromuscular transmission in a group of patients with 'limb-girdle myasthenia'. Brain 129: 2061-2076, 2006. [PubMed: 16870884, related citations] [Full Text]


Cassandra L. Kniffin - updated : 03/16/2023
Ada Hamosh - updated : 10/10/2014
George E. Tiller - updated : 12/1/2011
Cassandra L. Kniffin - updated : 6/25/2010
Cassandra L. Kniffin - updated : 10/9/2009
Cassandra L. Kniffin - updated : 10/16/2008
Ada Hamosh - updated : 10/25/2006
Cassandra L. Kniffin - updated : 9/29/2004
Creation Date:
Victor A. McKusick : 6/4/1986
alopez : 03/17/2023
ckniffin : 03/16/2023
carol : 10/14/2019
alopez : 08/12/2016
carol : 04/29/2015
carol : 4/27/2015
mcolton : 4/22/2015
ckniffin : 4/21/2015
carol : 2/20/2015
carol : 11/6/2014
alopez : 10/10/2014
alopez : 4/14/2014
ckniffin : 4/9/2014
terry : 8/6/2012
terry : 8/6/2012
carol : 8/2/2012
ckniffin : 8/1/2012
alopez : 12/5/2011
terry : 12/1/2011
wwang : 7/7/2010
ckniffin : 6/25/2010
wwang : 10/16/2009
wwang : 10/16/2009
ckniffin : 10/9/2009
wwang : 10/20/2008
ckniffin : 10/16/2008
ckniffin : 10/16/2008
terry : 9/17/2007
alopez : 11/2/2006
terry : 10/25/2006
joanna : 10/13/2004
carol : 10/7/2004
ckniffin : 9/29/2004
mimman : 2/8/1996
supermim : 3/17/1992
supermim : 3/20/1990
ddp : 10/26/1989
marie : 3/25/1988
reenie : 6/4/1986

# 254300

MYASTHENIC SYNDROME, CONGENITAL, 10; CMS10


Alternative titles; symbols

MYASTHENIA, LIMB-GIRDLE, FAMILIAL, FORMERLY; LGM, FORMERLY
CONGENITAL MYASTHENIC SYNDROME TYPE Ib, FORMERLY; CMS1B, FORMERLY
CMS Ib, FORMERLY
MYASTHENIC MYOPATHY, FORMERLY


ORPHA: 590, 98913;   DO: 0110668;  


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
4p16.3 Myasthenic syndrome, congenital, 10 254300 Autosomal recessive 3 DOK7 610285

TEXT

A number sign (#) is used with this entry because of evidence that congenital myasthenic syndrome-10 (CMS10) is caused by homozygous or compound heterozygous mutation in the DOK7 gene (610285) on chromosome 4p16.


Description

Congenital myasthenic syndromes (CMS) are a group of inherited disorders affecting the neuromuscular junction (NMJ). Patients present clinically with onset of variable muscle weakness between infancy and adulthood. These disorders have been classified according to the location of the defect: presynaptic, synaptic, and postsynaptic. CMS10 is an autosomal recessive CMS resulting from a postsynaptic defect affecting endplate maintenance of the NMJ. Patients present with limb-girdle weakness in the first decade. Treatment with ephedrine or salbutamol may be beneficial; cholinesterase inhibitors should be avoided (summary by Engel et al., 2015).

For a discussion of genetic heterogeneity of CMS, see CMS1A (601462).


Clinical Features

Azulay et al. (1994) reported a woman with proximal muscle weakness of the myasthenic type. Family history was not reported.

Shankar et al. (2002) reported 2 Indian sisters with classic features of limb-girdle myasthenia.

Beeson et al. (2006) summarized the clinical features of 19 of 21 index patients with limb-girdle myasthenia and the affected brother of case 11, all of whom had mutations in DOK7. All patients displayed electromyographic (EMG) evidence of a defect in neuromuscular transmission and all but 3 patients developed weakness within the first 5 years of life. The clinical onset of disease was generally characterized by difficulty in walking after initially achieving normal walking milestones. Features typically seen in patients with mutations in rapsyn (RAPSN; 601592), such as congenital joint deformity and squint, were not present. In adulthood, a proximal weakness of the affected patients' upper and lower extremities was evident, and most had weakness in the trunk and neck regions. All of the patients had weak facial muscles, and all but 2 patients had ptosis. Eye movements were generally unaffected. Anticholinesterase medication either had no effect or made the weakness worse, although a short-lived initial response was occasionally seen. Beeson et al. (2006) also undertook an analysis of motorpoint muscle biopsies, which showed that many features of the NMJ were normal, including the quantal release per unit area of synaptic content and the size and kinetics of the miniature endplate currents. However, 2 major abnormalities were identified: reduced size of the NMJs and reduced postsynaptic folding.

Selcen et al. (2008) reported 16 patients with DOK7-related congenital myasthenia. The age at onset ranged from the first day of life to age 5 years, and there was great variability in disease severity and rate of progression. Some patients had mild static weakness limited to limb-girdle muscles, whereas others had severe generalized disease with marked muscle atrophy. Ten patients had intermittent worsenings lasting from days to weeks. All patients reported fatigue on exertion and proximal muscle weakness. Other common features included ptosis (14 patients), facial weakness (13), bulbar symptoms (11), and respiratory difficulties (13). Oculoparesis was less common (6), and only 3 showed decreased fetal movements. In general, there was a poor response to cholinesterase inhibitors and cholinergic agents. The authors found no consistent correlation between the clinical severity and expression of DOK7 at the endplate; in fact, some patients with severe disease showed almost normal expression. Electron microscopy of endplates showed variable changes, including degeneration of junctional folds, reduced nerve terminals, or degeneration of subsynaptic organelles, but some endplates appeared normal. In vitro microelectrode studies showed decreased numbers of released quanta and decreased synaptic response to acetylcholine. Acetylcholine receptors (AChR) were decreased in areas of degenerating junctional folds, but AChR kinetics were normal. Selcen et al. (2008) noted that the studies did not reveal a clear correlation between histologic or electrophysiologic findings and disease severity in individual patients, but indicated that changes in the structural integrity of the endplate likely contributed to the decreased safety margin of neuromuscular transmission.

Mahjneh et al. (2013) reported a large highly consanguineous Palestinian family in which 6 individuals, ranging from 38 to 53 years of age, had CMS10 associated with a homozygous frameshift mutation in the DOK7 gene (c.957delC; 610285.0011). The family had originally been reported by Mahjneh et al. (1992) as having 'congenital muscular dystrophy.' Mahjneh et al. (2013) reviewed the phenotype in the 6 patients, noting that generalized muscle weakness and hypotonia were present at birth and that subsequent motor development and walking was delayed (walking between 14 and 76 months). With growth, the pattern of muscle weakness clearly affected the proximal muscles of the upper and lower limbs, was slowly progressive, and showed variable severity; some patients had a more stable disease course. Episodic crises without clear precipitating factors were reported, and many had breathing problems during these episodes or during exercise. One patient required nocturnal ventilation. Physical examination showed myopathic facies, ptosis, waddling gait, and muscle weakness and wasting in the proximal upper limbs. Four patients had rigid spine, 2 had several scoliosis, 2 had mild scoliosis, 4 had joint contractures, and 3 had a positive Gowers sign. Treatment with salbutamol resulted in dramatic improvement of muscle weakness and respiratory and bulbar function. Mahjneh et al. (1999) and Sellick et al. (2005) had also studied this family. They stated that there were 10 family members who presented with neonatal hypotonia and absent antigravity movements; reduced fetal movements were noted in all affected pregnancies. There were no feeding or respiratory issues, and none had contractures. Four of these patients died between 7 months and 36 years, although their mutation status was not known at the time. Interestingly, 9 additional family members had adult-onset limb-girdle muscular dystrophy type 2B (253601) caused by mutation in the gene encoding dysferlin (DYSF; 603009.0006); the patients with congenital muscular dystrophy did not have the DYSF mutation (Bashir et al., 1998). The pattern of muscle weakness and wasting in the patients diagnosed with the congenital disorder was more marked in the proximal upper limb-girdle and trunk muscles. Lower limb muscles were mildly involved. Muscle biopsy showed a dystrophic pattern with normal staining for dystrophin (300377), laminin alpha-2 of merosin (156225), and the sarcoglycans (see, e.g., SGCA; 600119).

Aharoni et al. (2017) reported a patient (45), born of consanguineous parents in Israel (family 35), with CMS10 due to a homozygous frameshift mutation in the DOK7 gene (610285.0011). Clinical details were limited, but he had onset of limb weakness and ptosis around 10 years of age.


Clinical Management

Selcen et al. (2008) reported 16 patients with DOK7-related congenital myasthenia, noting that there was a poor response to cholinesterase inhibitors and cholinergic agents.

Lashley et al. (2010) reported that ephedrine therapy was a favorable and effective treatment for congenital myasthenic syndrome due to DOK7 mutations. A prospective trial of 12 patients showed that 10 tolerated ephedrine well. Over a 6 to 8 month treatment period, these 10 patients showed significant improvements in quantitative myasthenia gravis and mobility scores. Ephedrine was administered orally between 15 and 90 mg/day. Lashley et al. (2010) noted that these patients do not usually respond to acetylcholinesterase inhibitors, and postulated that the beneficial effect of ephedrine may be related to its action as a beta-2-adrenergic receptor (109690) agonist.

Beeson et al. (2006) noted that another genetic congenital myasthenic syndrome with a limb girdle-like pattern of muscle weakness is associated with tubular aggregates in muscle biopsies (see CMSTA1, 610542). Tubular aggregates were present in the 1 patient from the study by Slater et al. (2006) in whom no DOK7 mutation was found, but were not present in patients with DOK7 mutations. The patient with tubular aggregates was later found by Belaya et al. (2012) to carry compound heterozygous mutations in the DPAGT1 gene (191350.0002 and 191350.0003; see CMSTA2, 614750). In contrast with patients harboring DOK7 mutations, patients with tubular aggregates tend to respond well to anticholinesterase medication, suggesting that the phenotypes constitute separate disorders.

Mahjneh et al. (2013) reported a family with CMD10 in which salbutamol resulted in dramatic improvement of muscle weakness and respiratory and bulbar function.


Inheritance

The transmission pattern of CMS10 in the family reported by Mahjneh et al. (2013) was consistent with autosomal recessive inheritance.


Mapping

By genomewide analysis of a large consanguineous Palestinian family diagnosed with merosin-positive congenital muscular dystrophy, Sellick et al. (2005) identified a candidate disease locus on chromosome 4p16.3. Combined data from both a high-density SNP array and microsatellite markers delineated a 4.14-Mb interval flanked centromerically by marker D4S432 (multipoint lod score of 3.4). Mutations in the SPON2 (605918) and MYL5 (160782) genes were excluded.


Molecular Genetics

Beeson et al. (2006) identified frameshift mutations in the DOK7 gene (610285) in 16 unrelated patients with limb-girdle type congenital myasthenic syndrome. In 3 additional patients, a frameshift mutation was identified in combination with a nonsense mutation, a splice site mutation, and a missense change of a conserved residue. These mutations were found in homozygosity or compound heterozygosity, consistent with recessive inheritance seen in this phenotype. Beeson et al. (2006) also identified C-terminal domain frameshift mutations in DOK7 in DNA available from 6 of 7 patients included in the study by Slater et al. (2006). The seventh patient reported by Slater et al. (2006) was found by Belaya et al. (2012) to carry compound heterozygous mutations in the DPAGT1 gene (191350.0002 and 191350.0003; see 614750).

Among 16 patients with limb-girdle congenital myasthenic syndrome, Selcen et al. (2008) identified 17 different mutations in the DOK7 gene, including 10 novel mutations (see, e.g., 610285.0009; 610285.0010). All of the mutations resulted in a termination codon or a frameshift, except for 3 that resulted in the in-frame deletion of 1 or more exons. In vitro functional expression studies in murine myotubes showed that many of the mutations resulted in decreased axial length and density of AChR clusters at the endplate. Selcen et al. (2008) concluded that the pathogenesis of the disorder results from destruction and simplification of synaptic structures with resultant decrease in neuromuscular transmission.

In 6 affected members of a large highly consanguineous Palestinian family with CMS10, Mahjneh et al. (2013) identified a homozygous frameshift mutation in the DOK7 gene (c.957delC; 610285.0011). The family had originally been reported by Mahjneh et al. (1992) as having 'congenital muscular dystrophy.' Functional studies of the mutation and studies of patient cells were not performed.

Aharoni et al. (2017) identified a homozygous c.957delC mutation in the DOK7 gene in 1 of 55 Israeli individuals with a clinical diagnosis of congenital myasthenic syndrome.


Animal Model

Okada et al. (2006) generated mice lacking Dok7 and observed that all homozygous Dok7-deficient mice were immobile at birth and died shortly thereafter. Alveoli of these mice were not expanded at birth, indicating a failure to breathe and suggesting a severe defect in neuromuscular transmission in skeletal muscles. Heterozygous-deficient littermates were normal. Okada et al. (2006) found that Dok7 homozygous mutants formed neither AChR clusters nor neuromuscular synapses. They concluded that neuromuscular synaptogenesis requires DOK7 within skeletal muscle.

Muller et al. (2010) reported that Dok7 deficiency led to motility defects in zebrafish embryos and larvae. The relative importance of Dok7 at different stages of neuromuscular junction development varied; it was crucial for the earliest step, the formation of acetylcholine receptor (AChR) clusters in the middle of the muscle fiber prior to motor neuron contact. At later stages, presence of Dok7 was not absolutely essential, as focal and nonfocal synapses did form when Dok7 expression was downregulated. However, these contacts were smaller than in the wildtype zebrafish, reminiscent of the neuromuscular endplate pathology seen in patients with DOK7 mutations. Changes in slow muscle fiber arrangement were also observed. The authors suggested an additional role for Dok7 in muscle that is independent of the muscle-specific tyrosine kinase MuSK (601296), the binding partner of Dok7 at the neuromuscular junction.

In a mouse model of DOK7 myasthenia, Arimura et al. (2014) showed that therapeutic administration of an adeno-associated virus (AAV) vector encoding human DOK7 resulted in an enlargement of neuromuscular junctions (NMJs) and substantial increases in muscle strength and life span. When applied to model mice of another neuromuscular disorder, autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD2; 181350), DOK7 gene therapy likewise resulted in enlargement of NMJs as well as positive effects on motor activity and life span. Arimura et al. (2014) concluded that these results suggested that therapies aimed at enlarging the NMJ may be useful for a range of neuromuscular disorders.


REFERENCES

  1. Aharoni, S., Sadeh, M., Shapira, Y., Edvardson, S., Daana, M., Dor-Wollman, T., Mimouni-Bloch, A., Halevy, A., Cohen, R., Sagie, L., Argov, Z., Rabie, M., Spiegel, R., Chervinsky, I., Orenstein, N., Engel, A. G., Nevo, Y. Congenital myasthenic syndrome in Israel: genetic and clinical characterization. Neuromusc. Disord. 27: 136-140, 2017. [PubMed: 28024842] [Full Text: https://doi.org/10.1016/j.nmd.2016.11.014]

  2. Arimura, S., Okada, T., Tezuka, T., Chiyo, T., Kasahara, Y., Yoshimura, T., Motomura, M., Yoshida, N., Beeson, D., Takeda, S., Yamanashi, Y. DOK7 gene therapy benefits mouse models of diseases characterized by defects in the neuromuscular junction. Science 345: 1505-1508, 2014. [PubMed: 25237101] [Full Text: https://doi.org/10.1126/science.1250744]

  3. Azulay, J.-P., Pouget, J., Figarella-Branger, D., Colamarino, R., Pellissier, J.-F., Serratrice, G. Faiblesse musculaire proximale isolee revelatrice d'un syndrome myasthenique. Rev. Neurol. 150: 377-381, 1994. [PubMed: 7878325]

  4. Bashir, R., Britton, S., Strachan, T., Keers, S., Vafiadaki, E., Lako, M., Richard, I., Marchand, S., Bourg, N., Argov, Z., Sadeh, M., Mahjneh, I., Marconi, G., Passos-Bueno, M. R., Moreira, E. S., Zatz, M., Beckmann, J. S., Bushby, K. A gene related to Caenorhabditis elegans spermatogenesis factor fer-1 is mutated in limb-girdle muscular dystrophy type 2B. Nature Genet. 20: 37-42, 1998. [PubMed: 9731527] [Full Text: https://doi.org/10.1038/1689]

  5. Beeson, D., Higuchi, O., Palace, J., Cossins, J., Spearman, H., Maxwell, S., Newsom-Davis, J., Burke, G., Fawcett, P., Motomura, M., Muller, J. S., Lochmuller, H., Slater, C., Vincent, A., Yamanashi, Y. Dok-7 mutations underlie a neuromuscular junction synaptopathy. Science 313: 1975-1978, 2006. [PubMed: 16917026] [Full Text: https://doi.org/10.1126/science.1130837]

  6. Belaya, K., Finlayson, S., Slater, C. R., Cossins, J., Liu, W. W., Maxwell, S., McGowan, S. J., Maslau, S., Twigg, S. R. F., Walls, T. J., Pascual Pascual, S. I., Palace, J., Beeson, D. Mutations in DPAGT1 cause a limb-girdle congenital myasthenic syndrome with tubular aggregates. Am. J. Hum. Genet. 91: 193-201, 2012. [PubMed: 22742743] [Full Text: https://doi.org/10.1016/j.ajhg.2012.05.022]

  7. Engel, A. G., Shen, X.-M., Selcen, D., Sine, S. M. Congenital myasthenic syndromes: pathogenesis, diagnosis, and treatment. Lancet Neurol. 14: 420-434, 2015. Note: Erratum: Lancet Neurol. 14: 461 only, 2015. [PubMed: 25792100] [Full Text: https://doi.org/10.1016/S1474-4422(14)70201-7]

  8. Lashley, D., Palace, J., Jayawant, S., Robb, S., Beeson, D. Ephedrine treatment in congenital myasthenic syndrome due to mutations in DOK7. Neurology 74: 1517-1523, 2010. [PubMed: 20458068] [Full Text: https://doi.org/10.1212/WNL.0b013e3181dd43bf]

  9. Mahjneh, I., Bushby, K., Anderson, L., Muntoni, F., Tolvanen-Mahjneh, H., Bashir, R., Pizzi, A., Brockington, M., Marconi, G. Merosin-positive congenital muscular dystrophy: a large inbred family. Neuropediatrics 30: 22-28, 1999. [PubMed: 10222457] [Full Text: https://doi.org/10.1055/s-2007-973452]

  10. Mahjneh, I., Lochmuller, H., Muntoni, F., Abicht, A. DOK7 limb-girdle myasthenic syndrome mimicking congenital muscular dystrophy. Neuromusc. Disord. 23: 36-42, 2013. [PubMed: 22884442] [Full Text: https://doi.org/10.1016/j.nmd.2012.06.355]

  11. Mahjneh, I., Vannelli, G., Bushby, K., Marconi, G. P. A large inbred Palestinian family with two forms of muscular dystrophy. Neuromusc. Disord. 2: 277-283, 1992. [PubMed: 1483054] [Full Text: https://doi.org/10.1016/0960-8966(92)90060-j]

  12. Muller, J. S., Jepson, C. D., Laval, S. H., Bushby, K., Straub, V., Lochmuller, H. Dok-7 promotes slow muscle integrity as well as neuromuscular junction formation in a zebrafish model of congenital myasthenic syndromes. Hum. Molec. Genet. 19: 1726-1740, 2010. [PubMed: 20147321] [Full Text: https://doi.org/10.1093/hmg/ddq049]

  13. Okada, K., Inoue, A., Okada, M., Murata, Y., Kakuta, S., Jigami, T., Kubo, S., Shiraishi, H., Eguchi, K., Motomura, M., Akiyama, T., Iwakura, Y., Higuchi, O., Yamanashi, Y. The muscle protein Dok-7 is essential for neuromuscular synaptogenesis. Science 312: 1802-1805, 2006. [PubMed: 16794080] [Full Text: https://doi.org/10.1126/science.1127142]

  14. Selcen, D., Milone, M., Shen, X.-M., Harper, C. M., Stans, A. A., Wieben, E. D., Engel, A. G. Dok-7 myasthenia: phenotypic and molecular genetic studies in 16 patients. Ann. Neurol. 64: 71-87, 2008. [PubMed: 18626973] [Full Text: https://doi.org/10.1002/ana.21408]

  15. Sellick, G. S., Longman, C., Brockington, M., Mahjneh, I., Sagi, L., Bushby, K., Topaloglu, H., Muntoni, F., Houlston, R. S. Localisation of merosin-positive congenital muscular dystrophy to chromosome 4p16.3. Hum. Genet. 117: 207-212, 2005. [PubMed: 15886997] [Full Text: https://doi.org/10.1007/s00439-005-1301-4]

  16. Shankar, A., Solomon, T., Joseph, T. P., Gnanamuthu, C. Autosomal recessive limb girdle myasthenia in two sisters. Neurol. India 50: 500-503, 2002. [PubMed: 12577107]

  17. Slater, C. R., Fawcett, P. R. W., Walls, T. J., Lyons, P. R., Bailey, S. J., Beeson, D., Young, C., Gardner-Medwin, D. Pre- and post-synaptic abnormalities associated with impaired neuromuscular transmission in a group of patients with 'limb-girdle myasthenia'. Brain 129: 2061-2076, 2006. [PubMed: 16870884] [Full Text: https://doi.org/10.1093/brain/awl200]


Contributors:
Cassandra L. Kniffin - updated : 03/16/2023
Ada Hamosh - updated : 10/10/2014
George E. Tiller - updated : 12/1/2011
Cassandra L. Kniffin - updated : 6/25/2010
Cassandra L. Kniffin - updated : 10/9/2009
Cassandra L. Kniffin - updated : 10/16/2008
Ada Hamosh - updated : 10/25/2006
Cassandra L. Kniffin - updated : 9/29/2004

Creation Date:
Victor A. McKusick : 6/4/1986

Edit History:
alopez : 03/17/2023
ckniffin : 03/16/2023
carol : 10/14/2019
alopez : 08/12/2016
carol : 04/29/2015
carol : 4/27/2015
mcolton : 4/22/2015
ckniffin : 4/21/2015
carol : 2/20/2015
carol : 11/6/2014
alopez : 10/10/2014
alopez : 4/14/2014
ckniffin : 4/9/2014
terry : 8/6/2012
terry : 8/6/2012
carol : 8/2/2012
ckniffin : 8/1/2012
alopez : 12/5/2011
terry : 12/1/2011
wwang : 7/7/2010
ckniffin : 6/25/2010
wwang : 10/16/2009
wwang : 10/16/2009
ckniffin : 10/9/2009
wwang : 10/20/2008
ckniffin : 10/16/2008
ckniffin : 10/16/2008
terry : 9/17/2007
alopez : 11/2/2006
terry : 10/25/2006
joanna : 10/13/2004
carol : 10/7/2004
ckniffin : 9/29/2004
mimman : 2/8/1996
supermim : 3/17/1992
supermim : 3/20/1990
ddp : 10/26/1989
marie : 3/25/1988
reenie : 6/4/1986