A 28-year-old woman from Mumbai presents with a 6-week history of progressive weakness of the eyelids, facial muscles, and proximal limbs. She denies diplopia or bulbar symptoms. On examination, she has bilateral ptosis without ophthalmoplegia, facial weakness, and 4/5 strength in shoulder abductors and hip flexors. Repetitive nerve stimulation shows a decremental response. Serum anti-AChR and anti-MuSK antibodies are both negative. What is the most likely diagnosis?

Explanation

## Diagnostic Analysis **Key Point:** This patient has seronegative myasthenia gravis (MG), defined as MG with negative anti-AChR and anti-MuSK antibodies but characteristic clinical and electrophysiological features. ### Clinical Features Supporting Seronegative MG | Feature | This Patient | Seronegative MG | LEMS | Congenital MG | |---------|--------------|-----------------|------|---------------| | **Ptosis (without ophthalmoplegia)** | Present | Common | Rare | Variable | | **Facial weakness** | Present | Common | Rare | Possible | | **Proximal limb weakness** | Present | Common | Common | Possible | | **Bulbar symptoms** | Absent | Variable | Rare | Variable | | **Antibodies** | Negative | Negative (10–15% of MG) | Negative | Negative | | **RNS decremental response** | Present | Present | Absent/Incremental | Variable | | **Age of onset** | 28 years | Any age | Typically >40 years | Infancy/childhood | **High-Yield:** Seronegative MG accounts for 10–15% of MG cases and has a more benign course than seropositive disease, with lower rates of thymoma (5–10% vs. 10–15%). ### Why Seronegative MG is the Answer 1. **Clinical Phenotype**: Ptosis, facial weakness, and proximal limb weakness in a young woman are classic for MG. 2. **Electrophysiology**: Decremental response on repetitive nerve stimulation is diagnostic for neuromuscular junction disorder. 3. **Seronegative Status**: Negative anti-AChR and anti-MuSK antibodies do NOT exclude MG; ~10–15% of MG patients are seronegative. 4. **Absence of Bulbar Involvement**: While not required for diagnosis, the absence of ocular ophthalmoplegia and bulbar symptoms is consistent with seronegative MG, which often presents with ocular or generalized weakness without severe bulbar involvement. **Clinical Pearl:** Anti-MuSK-positive MG (muscle-specific kinase antibodies) is a distinct subset with different clinical features (often more bulbar and facial involvement, fewer ocular symptoms) and worse prognosis; this patient is negative for both, favoring seronegative MG. ### Pathophysiology of Seronegative MG ```mermaid flowchart TD A[Neuromuscular Junction Disorder]:::outcome --> B{Antibody Status?}:::decision B -->|Anti-AChR Positive| C[Seropositive MG]:::outcome B -->|Anti-MuSK Positive| D[MuSK-Associated MG]:::outcome B -->|Both Negative| E[Seronegative MG]:::outcome E --> F[~10-15% of MG cases]:::outcome E --> G[Likely other NMJ proteins involved]:::outcome G --> H[LRP4, agrin, or unknown antigens]:::outcome ``` **Key Point:** Seronegative MG likely involves antibodies against other neuromuscular junction proteins (e.g., LRP4, agrin) or T-cell-mediated autoimmunity not detected by standard serology. ### Why Other Diagnoses Are Incorrect **Lambert-Eaton Myasthenic Syndrome (LEMS)**: - Presents with proximal weakness, autonomic symptoms (dry mouth, constipation, erectile dysfunction), and **incremental response** (not decremental) on high-frequency RNS. - Ptosis and facial weakness are rare in LEMS. - Associated with small-cell lung cancer in 50–60% of cases (older patients). **Congenital Myasthenia**: - Presents in infancy or early childhood with feeding difficulties, ptosis, and hypotonia. - This patient is 28 years old with adult-onset disease, making congenital MG unlikely. - RNS findings vary depending on the specific genetic defect. **Inflammatory Myopathy (Polymyositis/Dermatomyositis)**: - Presents with proximal muscle weakness but typically WITH elevated CK, myositis-specific antibodies (anti-Jo-1, anti-Mi-2), and characteristic rash (dermatomyositis). - RNS shows normal or myopathic pattern, NOT decremental response. - Facial weakness and ptosis are not prominent features. **Mnemonic: SERONEG-MG** — **S**erum **E**negative, **R**epetitive **O**scillations **N**egative for **E**mbodies, **G**eneralized **M**yasthenia **G**ravis.