The findings of the study, “Ala97Ser mutation is common among ethnic Chinese Malaysians with transthyretin familial amyloid polyneuropathy,” were published in Amyloid The Journal of Protein Folding Disorders.
FAP, also known as hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN), is a rare progressive disease caused by genetic mutations in the TTR gene, which provides instructions for making a protein called transthyretin.
So far, more than 120 different mutations have been associated with FAP. When mutations occur, the structure of transthyretin changes, preventing it from binding to other transthyretin proteins, a process necessary for its normal transport function. The abnormal TTR protein then starts to form amyloid deposits that accumulate in tissues — including nerves, the heart, kidneys, and eyes — slowly causing damage, and eventually giving rise to symptoms associated with FAP.
To learn more about FAP in Chinese-Malaysian patients, a group of researchers from the University of Malaya in Malaysia set out to characterize the genetic mutations, demographics, and clinical features of this population. The researchers noted that most Chinese-Malaysians originated from Southern China, mainly from the provinces of Fujian and Guangdong, and share a similar ancestry to the Taiwanese.
The study involved a total of 11 people with FAP — six men and five women — who were followed at the University of Malaya Medical Centre between 2008 and 2017. Demographic and clinical data were gathered for all participants.
The patients underwent nerve conduction studies (NCS) that measured their nerves’ ability to send electrical signals. Electromyography (EMG) tests were used to assess their muscles’ ability to send electrical signals. All participants also had echocardiography to examine their heart function, and genetic testing. Sural nerve biopsy — a standard diagnostic procedure for peripheral neuropathies in which a nerve of the calf is examined — also was performed.
Among the 11 study participants, nine (82%) complained of numbness (loss of sensation) and weakness in their limbs, while the remaining two reported postural dizziness. More than half of the individuals (64%) had a family history of FAP.
The NCS/EMG studies performed on 10 of the 11 patients initially enrolled in the study revealed that eight (73%) showed signs of axonal neuropathy. In this form of Guillain-Barre syndrome (GBS), people lose their reflexes and become immobile while their nerve sensory function remains unaffected.
Sural nerve biopsy findings showed the majority of participants (82%) had amyloid deposits in their nerves. Moreover, a smaller but still significant percentage (64%) also had amyloid deposits in their hearts, which were visible in the echocardiogram.
Genetic analysis revealed that nine participants (82%) carried the Ala97Ser mutation. In that mutation, one amino acid — the building blocks of proteins — called alanine (ALA) is replaced by another called serine (Ser) in position 97 of the TTR gene sequence.
Among the two remaining patients, one had been diagnosed with familial amyloid cardiomyopathy (FAC), and carried the Asp39Val mutation. The other was found to have leptomeningeal amyloidosis and the Ala25Thr mutation.
“Ala97Ser is the commonest hATTR mutation among Chinese-Malaysians. This is also the reported ‘hotspot’ mutation for FAP in Taiwan but not in China. Similar to Taiwanese patients, our FAP patients with Ala97Ser mutation present in late middle age with progressive sensorimotor polyneuropathy, autonomic dysfunction and subclinical or mild cardiac involvement,” the researchers said.