A recent study published in BMC Neurology extends the spectrum of known amyloidogenic transthyretin (TTR) mutations by reporting on a case of a patient with late-onset hereditary transthyretin amyloidosis (hATTR) who was initially misdiagnosed with cardiac wild-type form of the disease (wtATTR).

The study authors reported on a 73-year-old male patient with mixed neuropathic and cardiac phenotype hATTR who first presented to the outpatient clinic with progressive impairment of gait, persisting neuropathic pain in his legs, dizziness due to postural changes, and unexplained 20 kg weight loss during the last 2 to 3 years.

After being diagnosed with lumbar spinal stenosis, the patient had decompression surgery and was about to undergo another surgical procedure when the preoperative diagnostic echocardiography revealed left ventricular hypertrophy. The researchers then performed an endomyocardial biopsy which showed extensive amyloid deposition and initiated treatment with tafamidis that resulted in no obvious improvement after approximately 1 year of regular use.

The patient’s family history included frequent deaths due to cardiac events in first-degree relatives.

Read more about hATTR diagnosis

Next, the researchers used molecular genetic analysis to identify a heterozygous sequence variant in exon 2 of the TTR gene classified as likely pathogenic (class 4) under the American College of Medical Genetics (ACMG) classification system.

Presuming this genotype to be amyloidogenic, the patient’s brother also underwent the targeted genetic testing by Sanger sequencing and was found to be the carrier of the same heterozygous sequence variant.

“As the patient exhibits a progressive disease course despite treatment with tafamidis, the detection of his TTR mutation and evaluation of his severe neuropathy enables a change of the treatment strategy considering patisiran and inotersen as potential new options,” Thimm and colleagues wrote.

According to the diagnosis protocol, it is mandatory to perform the whole TTR gene sequencing even in bioptically confirmed cases in order to distinguish between the hATTR and wtATTR because of different treatment approaches.


Thimm A, Oubari S, Hoffmann J, et al. A novel TTR mutation (p.Ala65Val) underlying late-onset hereditary transthyretin (ATTRv) amyloidosis with mixed cardiac and neuropathic phenotype: a case report. BMC Neurol. Published online on December 9, 2022. doi:10.1186/s12883-022-02952-3