From the Guidelines
The workup for a patient suspected of having Congenital Myasthenic Syndrome (CMS) due to DOK7 mutations should include a comprehensive clinical evaluation, specialized testing, and genetic analysis, with a focus on electromyography (EMG) with repetitive nerve stimulation and genetic testing for DOK7 gene mutations 1. The diagnostic approach begins with a detailed medical history, focusing on the age of symptom onset, pattern of weakness, exercise intolerance, and family history.
- Key aspects of the medical history include:
- Age of symptom onset
- Pattern of weakness (typically limb-girdle distribution with proximal muscle involvement)
- Exercise intolerance
- Family history Physical examination should assess for characteristic findings, including:
- Ptosis
- Facial weakness
- Proximal limb weakness that worsens with activity Diagnostic testing should include:
- Electromyography (EMG) with repetitive nerve stimulation, which typically shows decremental response at low frequencies (2-3 Hz) and may show incremental response at high frequencies
- Serum testing for acetylcholine receptor antibodies and MuSK antibodies to rule out autoimmune myasthenia gravis
- Single-fiber EMG may demonstrate increased jitter
- Muscle biopsy may show myopathic changes but is not specific for DOK7-related CMS Genetic testing, specifically sequencing of the DOK7 gene to identify pathogenic mutations, is essential for a definitive diagnosis. While awaiting genetic confirmation, a therapeutic trial with ephedrine or salbutamol may be initiated, as these medications typically improve symptoms in DOK7-CMS, whereas acetylcholinesterase inhibitors like pyridostigmine should be avoided as they often worsen symptoms in DOK7-CMS 1.
From the Research
Workup for Congenital Myasthenic Syndrome due to DOK7 Mutations
To work up a patient suspected of having Congenital Myasthenic Syndrome (CMS) due to DOK7 mutations, the following steps can be taken:
- Clinical evaluation: Assess for symptoms such as limb-girdle weakness, fluctuating symptoms, ptosis, bifacial weakness, reduced extraocular movement, bulbar symptoms, and dyspnea 2.
- Neurophysiological studies: Perform 3-Hz repetitive nerve stimulation (RNS) to assess for decremental responses, which were seen in 5 out of 6 patients in one study 2.
- Genetic testing: Use Whole Exome Sequencing to confirm the diagnosis of DOK7 CMS, as mutations in the DOK7 gene are a common cause of CMS 2, 3.
- Treatment trials: Consider prescribing salbutamol as the first-choice treatment option for DOK7 patients, as it was found to be effective in one study 2. Alternatively, ephedrine may be considered, as it has been shown to improve muscle strength in patients with DOK7 CMS 4, 5.
Special Considerations
- Neonatal symptoms: Be aware that some patients with DOK7 CMS may present with congenital stridor, feeding difficulty, and bilateral vocal cord palsy, which can precede other symptoms 6.
- Treatment monitoring: Use clinical symptoms and muscle strength assessments, such as the MRC scale, to monitor treatment response, as vital capacity measurements and repetitive stimulation tests may not improve in the same way 5.
- Genetic counseling: Inform patients and families about the genetic basis of DOK7 CMS and the potential for other family members to be affected, as mutations in the DOK7 gene are inherited in an autosomal recessive pattern 3.