Rare FAP

Nov 23, 2023

Report may be first Gly67Glu mutation in mainland China, researchers said

by Margarida Maia, PhD | August 28, 2023

A rare mutation in the TTR gene was identified as the cause of familial amyloid polyneuropathy (FAP) in a family in China whose first symptom was diarrhea, according to a case report.

All the affected family members eventually developed muscle weakness and some had numbness and/or deficient control of their blood pressure, according to “FAP due to a rare Gly67Glu mutation in the TTR gene,” which was published as a letter in Acta Neurologica Belgica.

FAP is an inherited condition that occurs when a mutation in the TTR gene causes a faulty transthyretin protein to be produced that forms toxic clumps, or amyloids. These aggregates build up mostly in the peripheral nerves, those outside the brain and spinal cord, leading to damage in many nerves, called polyneuropathy. They can also accumulate in the heart muscle, however.

Symptoms can range from numbness and muscle weakness to bowel issues and orthostatic hypotension, a condition wherein blood pressure suddenly drops when standing up, causing lightheadedness or dizziness.

Researchers in China described the case of a family of Han Chinese origin affected by FAP that initially caused diarrhea and was associated with a rare TTR mutation.

The first member to bring her case to the doctors’ attention was a 50-year-old woman who went to the hospital because she’d been having diarrhea for about four years, with watery stools three to six times a day, especially after eating.

In the past two years, she started feeling numbness, tingling, and weakness in both feet, and could walk only short distances. She had a poor appetite and was gradually losing weight.

The woman had previously been diagnosed with irritable bowel syndrome, motor neuropathy, and even psychosis. Motor neuropathy refers to damage to motor nerves, or those that control voluntary movement.

She showed a clear, normal mental state on examination, but was very thin, weighing 33.6 kgs (about 74 pounds) and having a body mass index (BMI) of 15.1, indicating severe underweight. BMI is a ratio of height and weight.

The woman’s muscles appeared to have wasted away in her hands and feet. She lost some sensation below the elbows and couldn’t feel touch below the knees. She had no reflexes in her knees and ankles.

The woman’s muscles didn’t respond to nerve signals as expected and she had polyneuropathy and carpal tunnel syndrome, a common FAP symptom that causes tingling and pain in the hand.

She showed damage to her autonomic nerves, those that control involuntary bodily functions such as bowel and bladder control, blood pressure, and heart rate. Besides diarrhea, she had orthostatic hypotension and abnormalities in her heart’s electrical wiring system, despite having no heart symptoms.

Her mother, older brother, and younger brother also had diarrhea and limb weakness. Disease onset in the woman’s mother occurred in her 50s, but her children’s began in their 40s. Her mother died five years after the onset of symptoms and her older brother died at age 48 due to an unknown cause.

Her younger brother, aged 48 and confined to a wheelchair two years after the onset of symptoms, also had a poor appetite and orthostatic hypotension.

Another brother died in a traffic accident when he was 38 and was therefore uncertain about whether he would have developed the disease in his 40s like his brothers and sister.

“The initial symptom was diarrhea in this family. With disease progression, the motor, sensory and autonomic nerves were also involved,” the researchers wrote.

Based on the woman’s symptoms and family history, the researchers suspected FAP and genetic testing identified a rare TTR mutation, called Gly67Glu. The same mutation was found in her younger brother as well as her son, who didn’t show symptoms at the time. “The other family members refused genetic testing,” the researchers wrote.

Gly67Glu, which results in a change in one amino acid (protein building block) of the transthyretin protein, has been described in two FAP-affected families in Macau, a collection of coastal islands administered by China.

“This may be the first report of the Gly67Glu mutation in mainland China,” the researchers wrote, adding that “compared to other mutations of TTR, patients with the Gly67Glu mutation have prominent bowel symptoms, autonomic disorder, and polyneuropathy.”

One of the previously reported families had serious heart damage, highlighting that “even the same mutation may have different manifestations,” they wrote. “We hope that this report will help to improve the knowledge of this disease.”