TTR gene mutation, unique to China, tied to eye condition, neuropathy
Gly103Arg mutation found exclusively in the country, blurred vision common
Gly103Arg, a mutation in the TTR gene that has been exclusively reported in Chinese people, is associated with a familial amyloid polyneuropathy-like profile marked by eye and neurological involvement, according to a case report and literature review study.
All three patients from a single family carrying the mutation had eye involvement primarily characterized by vitreous opacity, a condition due to the vitreous, the gel-like substance that fills most of the eye, shrinking and forming strands that appear in the visual field as floaters.
Data from these and 41 other cases with the Gly103Arg mutation reported in the literature showed that their first symptom was generally blurred vision. Nearly half also had peripheral neuropathy, the main FAP symptom. Peripheral neuropathy refers to damage of peripheral nerves, or those outside the brain and spinal cord.
“The peripheral neurologic presentations may be easily misdiagnosed as CIDP [chronic inflammatory demyelinating polyneuropathy]. It is therefore crucial to inquire about family history and ocular diseases to minimize the risk of misdiagnosis,” the researchers wrote.
More than 140 disease-causing TTR mutations are known worldwide
CIDP is an autoimmune condition that affects the protective sheath, called myelin, around peripheral nerves. People carrying the Gly103Arg mutation are often misdiagnosed with CIDP before reaching a diagnosis of hereditary transthyretin amyloidosis (hATTR), a group of conditions that includes FAP.
The study, “The Gly103Arg variant in hereditary transthyretin amyloidosis,” was published in Frontiers in Neurology.
hATTR, also known as ATTRv, is a group of conditions caused by mutations in the TTR gene that lead to the formation of toxic clumps of transthyretin (TTR) in different tissues.
In FAP, TTR clumps are mainly found in peripheral nerves, but they can also affect the eyes and heart. When the toxic clumps mainly accumulate in heart tissue, the condition is called ATTRv cardiomyopathy. When patients present both neurological and heart involvement, it is considered a mixed profile.
More than 140 disease-causing TTR mutations have been reported worldwide, including the Gly103Arg variant, which has only been identified in people of Chinese ethnicity. People carrying Gly103Arg typically begin with vision problems, particularly vitreous opacity, while other symptoms are usually mild and may occur several years after the onset of eye symptoms.
A team of researchers in China first reported the case of a 48-year-old man with Gly103Arg-associated FAP. He was admitted to a research hospital in Shenzhen due to numbness and weakness in both hands and below the knee over the past three years, which gradually led to typing and walking difficulties.
Six years earlier, he underwent a surgical procedure to replace the vitreous with another solution.
Man misdiagnosed with CIPD later found to have FAP
One month prior to his admission, he had been at a local hospital due to worsening limb weakness and shortness of breath, and diagnosed there with CIPD. Treatment with methylprednisolone, an anti-inflammatory medication, however, did not significantly ease his symptoms.
In the most recent admission, physical examination indicated low muscle volume in muscles of both hands and legs, a slight reduction in muscle strength. He also had impaired sensation in his wrists and ankles, absent deep tendon reflexes, as well as vision difficulties and vitreous opacities.
Further testing showed TTR clumps in abdominal fat tissue, and the presence of the Gly103Arg mutation.
His mother, maternal uncle, and eldest brother had a history of vitreous opacity and lower extremity weakness, while his maternal aunt and five cousins had vision loss. The man’s oldest brother, cousin, and a niece who had no symptoms also underwent genetic testing and were found to carry the same mutation.
Based on his signs and family history, the man was diagnosed with FAP and treated with tafamidis meglumine (20 mg/day), a therapy approved for FAP in several countries, but not the U.S. Over a three-year follow-up, the man’s symptoms remained stable.
Vitreous opacity affected all 44 patients in China with Gly103Arg mutation
Researchers then identified 41 other patients across 18 families, all Chinese, who were reported to carry the Gly103Arg mutation. When looking at data from all 44 patients, they found that a little over half were women (52.3%), and that mean age at disease onset was 39.1 years.
In general, all had blurred vision and vitreous opacity, with the initial symptom being eye problems, except for one patient whose first symptom was numbness in the arms. Of the 32 patients with available neurologic data, more than half (53.1%) had peripheral neuropathy, most commonly carpal tunnel syndrome, a condition that affects nerves in the wrist, and motor and sensory abnormalities.
Six patients had autonomic symptoms, or those affecting involuntary body functions, including heart rate, digestion, and sexual function. Heart abnormalities were detected in about 1 in every 10 patients who underwent such examinations.
“For Chinese especially in southern area with a family history of vitreous opacities, [severe nerve fiber] damage and ineffective … therapy of methylprednisolone, this mutation-associated ATTRv should be considered,” the researchers wrote.
“Timely … biopsy and genetic testing can assist in the early diagnosis of this condition,” the team wrote, adding that “abdominal [fat] tissue biopsy is a convenient, inexpensive, and minimally invasive means of confirming the diagnosis, with multiple sampling sites increasing the positive rate.”
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