Genetic testing reveals young woman’s porphyria after years of misdiagnosis
Muscle weakness, breathing problems long mistaken for myasthenia gravis
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A young woman whose recurrent muscle weakness and breathing problems were long mistaken for myasthenia gravis, a neuromuscular disorder, was ultimately diagnosed with variegate porphyria (VP) after advanced genetic testing uncovered a disease-causing mutation, a case report shows.
“In the described case, the patient’s atypical clinical manifestations led to a prolonged and complex diagnostic workup,” researchers wrote, adding that “this case highlights the importance of comprehensive evaluation of the clinical presentation in patients with unexplained neuromuscular symptoms.”
The case, “A Rare Clinical Presentation of Variegate Porphyria,” was published in Molecular Genetics & Genomic Medicine.
Variegate porphyria caused by mutations in key gene
A type of porphyria, VP is caused by mutations in the PPOX gene that reduce the activity of an enzyme needed to make heme, a molecule that helps red blood cells carry oxygen. As a result, porphyrins and related compounds involved in heme production build up to harmful levels, causing symptoms that can include severe abdominal pain, skin sensitivity to sunlight, and fatigue.
Doctors usually diagnose VP based on a person’s symptoms; laboratory tests showing elevated porphyrin levels in the blood, urine, or stool; and genetic testing to confirm disease-causing mutations in the PPOX gene. As genetic testing has become more widely available, doctors have increasingly identified people whose symptoms are influenced by more than one inherited disorder, making diagnosis more challenging.
In these situations, carefully interpreting a person’s symptoms alongside genetic findings is essential for making the correct diagnosis and guiding treatment.
Woman had litany of medical issues
In their report, researchers at the Research Center for Medical Genetics in Russia described the case of a 26-year-old woman whose VP was initially mistaken for myasthenia gravis, an autoimmune disease affecting communication between nerves and muscle that causes muscle weakness and fatigue.
The young woman was referred to the researchers’ center because of fatigue and recurrent episodes of respiratory failure. Her symptoms began in infancy with breathing difficulties that persisted throughout childhood, accompanied by frequent respiratory infections and reduced facial expression.
As a teenager, she developed recurrent respiratory failure accompanied by weakness affecting her arms, legs, neck, and trunk, as well as urinary retention and difficulty speaking and swallowing. At age 17, one attack became severe enough to require a breathing machine. The following year, she had surgery to help her breathe. She was diagnosed with myasthenia gravis and treated with standard medications.
However, during adolescence, she also experienced recurrent episodes of severe abdominal pain that led to four hospitalizations, although exploratory surgery found no underlying cause. By age 25, she had experienced two episodes of a sun-induced skin rash — a feature typical of porphyria.
Genetic analysis identified change in gene
When she was evaluated at the researchers’ center, blood tests for the disease-causing antibodies typically found in people with myasthenia gravis were negative. Although specialized nerve testing still suggested impaired communication between nerves and muscles, the combination of unexplained abdominal pain, skin symptoms, and negative antibody tests prompted further genetic investigation.
Advanced genetic analysis identified a change in the PPOX gene, called c.338G>C, that had previously been reported in people with VP but remained classified as a variant of uncertain significance, meaning there was not enough evidence to determine whether it caused disease. The test also detected a second uncertain variant in the MYMK gene, which is associated with a rare neuromuscular disorder called Carey-Fineman-Ziter syndrome.
Computer analyses predicted that the variant would disrupt how cells process the gene’s instructions before making the PPOX protein. To test this, the researchers analyzed RNA, the molecule that carries the genetic instructions cells use to build proteins. They found that the mutation caused an important section of the gene’s instructions to be skipped, producing an incomplete PPOX protein that would likely not function normally.
These findings allowed the researchers to reclassify the PPOX variant as disease-causing, confirming a VP diagnosis.
The MYMK variant remains of uncertain significance. However, the researchers said it could explain some of the woman’s unusual facial features and long-standing respiratory problems, raising the possibility that she “likely presented with both mild PPOX-related variegate porphyria and mild Carey-Fineman-Ziter syndrome,” the researchers wrote.
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