Indian Pediatr 2015;52: 243-244
Limb Girdle Weakness Responding to Salbutamol:
An Indian Family with DOK7 Mutation
S Khadilkar, A Bhutada, *B Nallamilli and *M Hegde
From Department of Neurology, Grant Government
Medical College and JJ Hospital, Mumbai, India and *Department of Human
Genetics, Emory University School of Medicine, 615 Michael Street,
Atlanta, Georgia, 30322, USA
Correspondence to: Prof Satish Khadilkar, 110, New
Wing, First Floor, Bombay Hospital, 12,
New Marine Lines, Mumbai 400 020, India.
Received: September 01, 2014;
Initial review: September 15, 2014;
Accepted: December 24, 2014
Background: Congenital Myasthenic Syndromes (CMS) are heterogeneous
genetic diseases. Case characteristics: Two siblings presented
with progressive limb girdle weakness without significant fluctuations
or ocular muscle weakness. Repetitive nerve stimulation showed a
decremental response and there was no response to pyridostigmine
therapy. Outcome: A trial of salbutamol produced a remarkable,
consistent improvement. Mutation in exon 5 of the DOK7 gene was
found in both siblings. Message: Patients with congenital
myasthenic syndrome with DOK 7 mutation benefit remarkably with
Keywords: Congenital myasthenic syndrome,
Mutational analysis, Treatment.
Congenital Myasthenic Syndromes  are disorders
of neuromuscular transmission presenting in early life. They pose a
diagnostic challenge, as features characteristically associated with
neuromuscular transmission disorders like fatigability and fluctuations
may be subtle. Pathology can be pre or post-synaptic, and few show
remarkable improvement on therapy. Response to salbutamol is seen in a
set of CMS patients having genetic abnormalities in DOK7; a
protein important for neuromuscular synaptogenesis . We herein report
two siblings with congenital myasthenic syndrome, who had DOK7
mutations and responded satisfactorily to salbutamol.
A 10-year-old girl presented with steadily
progressive proximal and distal weakness of limbs, neck and trunk
muscles since 8 years. She did not have significant circadian
fluctuations in muscle strength. There was no ptosis, and extra-ocular
movements were normal. Mild bifacial weakness was present and tongue and
pharyngeal examination showed normal results. Neck flexor and extensors
were weak and she could barely lift her neck off the bed. She had
significant truncal and limb weakness but no clinical fatigability could
be demonstrated. Deep tendon reflexes, sensory system and coordination
were also normal and her gait was lordotic.
Her 6-year-old younger brother was evaluated and the
examination showed a similar phenotype, but with a milder presentation.
Both the siblings showed a delay in achieving all motor milestones and
continued to lag in sporting activities. Parents were not consanguineous
and no other family members were known to be affected.
Thus, both the children had very early onset,
gradually progressive, pure motor, generalized disease. Possibility of
congenital muscular dystrophies and congenital myopathies were
considered. In the index case, serum creatine kinase was 93 IU/L and
sensory and motor conductions were normal. Repetitive CMAPs were absent
and on slow rate repetitive nerve stimulation, both trapezius muscles
showed significant decremental response (Right 23%, Left 18%). Acetyl
choline receptor and anti-MuSK antibodies were negative.
With demonstration of significant decrementing
response, diagnosis of Congenital myasthenic syndrome was considered.
The index case was given pyridostigmine up to 180 mg per day; however,
she did not improve and treatment was stopped. Left quadriceps biopsy
showed fiber-size variation. There were no inflammatory cells, nuclei
were peripheral in location, and there were no de or regenerating fibers.
Index case was subsequently given trial of salbutamol 1 mg thrice daily
after consent from the parents, and the treatment was increased over 10
days to 2 mg thrice daily with blood pressure and pulse monitoring. She
showed remarkable improvement in her muscle power and functional
status.Younger sibling also showed good improvement. No adverse effects
were encountered. On re-examination on day 14 and after two months,
further clinical improvement was noted. Whole exon sequence was
performed in both patients. Genetic analysis confirmed the presence of
one copy of pathogenic mutation c.601C>T (p.R201X) in the exon 5 of
DOK7 gene in both patients. One copy of variant of unknown
significance c.887A>G (p.Q296R) was also identified in exon 7 of DOK7
gene in both siblings in the subsequent sanger sequence analysis. These
results confirm the most possible diagnosis of Congenital myasthenic
syndrome due to DOK7 mutations.
Our patients were found to have familial congenital
myesthenic syndrome, which responded to salbutamol and not to
pyridostigmine. Among congenital myesthenic syndrome those that respond
to salbutamol, DOK7 and COLQ mutations are common (20
to30%), while others like AGRN, MuSK, LAMB2 gene mutations are
much rare [1,3], Repetitive CMAPs can differentiate between these two
common types. In the present case, absence of repetitive CMAP on
electrophysiology suggested the possibility of DOK7 mutation. We
also successfully identified one copy of nonsense pathogenic mutation in
the DOK7 gene by using whole exome sequencing analysis in both
DOK7 congenital myasthenic syndrome was first
discovered in 2006  and is believed to account for 10 to 15% of all
Congenital myasthenic syndrome cases [1,3].
It can have prenatal, neonatal or early childhood onset.
Neonates can develop difficulty in breathing, feeding and occasionally
stridor. Most patients are affected with limb girdle pattern of weakness
with or without ptosis, facial weakness, head drop or respiratory
weakness. The natural history is usually progressive and patient may
eventually require a wheelchair [4,5]. Sometimes, lack of circadian
variability of symptoms and subtle electrophysiological changes may lead
to mis-diagnosis as congenital muscular dystrophy .
DOK7 (through activation of MuSK) is essential
for neuromuscular synaptogenesis and maintenance [2,7]. Mutations of
DOK7 have been shown to produce mild myopathic changes , which
explains EMG and muscle biopsy findings in our case. Interestingly the
nonsense mutation (c.601C>T (p.R201X)) identified in these siblings has
also been reported in German patient as pathogenic mutation [2, 8] for
congenital myasthenic syndrome.
Salbutamol is currently the first line of therapy for
DOK7 Congenital myasthenic syndrome patients of all ages.
Stimulation of beta 2 receptor on pre synaptic and post synaptic
terminals activates c-AMP-protein kinase A which directly feeds into
MuSK signaling pathway, thus partially supplementing DOK7 protein
activation through MuSK [8,9]. Salbutamol (0.1-0.3 mg/kg/d in children
up to 6 years and 6-18 mg/d in adults) is effective for patients of all
ages and causes significant improvements even if therapy is started late
in the course of disease, as was observed in the present case .
Patients continue to improve progressively over 6 to 8 months with this
Patients of congenital myasthenia with DOK7
mutation remarkably improve with salbutamol, which is easily available,
inexpensive and safe.
Contributors: KS, BA: Acquisition,
analysis, interpretation of clinical data, drafting of Manuscript,
patient management; NB and HM: Genetic Analysis and interpretation of
genetic results, drafting the genetic part of the manuscript.
Funding: None; Competing interest:
1. Engel AG. Current status of the congenital
myasthenic syndromes. Neuromuscul Disord. 2012;22:99-111.
2. Beeson D, Higuchi O, Palace J, Cossins J, Spearman
H, Maxwell S, et al. Dok-7 mutations underlie a neuromuscular
junction synaptopathy. Science 2006;313:1975-8.
3. Abicht A, Müller JS, Lochmüller H. Congenital
Myasthenic Syndromes. 2003 May 9 [Updated 2012 Jun 28]. In: Pagon
RA, Adam MP, Ardinger HH, et al., editors. GeneReviews®
[Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.
Available from: http://www.ncbi.nlm.nih.gov/books/NBK1168/
4. Müller JS, Herczegfalvi A, Vilchez JJ, Colomer J,
Bachinski LL, Mihaylova V, et al. Phenotypical spectrum of
DOK7 mutations in congenital myasthenic syndromes. Brain.
5. Palace J, Lashley D, Newsom-Davis J, Cossins J,
Maxwell S, Kennett R, et al. Clinical features of the DOK7
neuromuscular Junction synaptopathy. Brain. 2007;130:1507-15.
6. Mahjneh I, Lochmüller H, Muntoni F, Abicht A.
DOK7 limb-girdle myasthenic syndrome mimicking congenital muscular
dystrophy. Neuromuscul Disord. 2013;23:36-42.
7. Selcen D, Milone M, Shen XM, Harper CM, Stans AA,
Wieben ED, et al. Dok-7 myasthenia: phenotypic and molecular
genetic studies in 16 patients. Ann Neurol 2008; 64:71– 87.
8. Hamuro J, Higuchi O, Okada K, Ueno M, Iemura S,
Natsume T, et al. Mutations causing DOK7 congenital myasthenia
ablate functional motifs in Dok-7. J Biol Chem. 2008;283:5518 -24.
9. Yamanashi Y, Higuchi O, Beeson D. Dok7/MuSK
signaling and a congenital myasthenic syndrome. Acta Myologica.
10. Witting N, Vissing J. Pharmacologic treatment of
downstream of tyrosine kinase 7 congenital myasthenic syndrome. JAMA