Familial amyloid polyneuropathy (FAP) patients carrying the Val30Met mutation are more frequently misdiagnosed and tend to have neurologic and cardiac complications more commonly if they have the late-onset form of the disease, according to a study of Brazilian patients.
The Val30Met mutation — an amino acid change from valine to methionine at position 30 of the TTR gene — is the most frequent gene variant in FAP patients. While patients with the classical form typically have the first symptoms in the third or fourth decade of life, those with the late-onset form have the first manifestations in their 60s or later.
Compared to the earlier-onset form, late-onset FAP with the Val30Met mutation is characterized by greater severity of motor and cardiac complications, and affects both large and small sensory nerve fibers.
Brazilian patients with classical FAP have a similar mean age at symptom onset compared to those in endemic regions in Japan and Portugal, as well as comparable frequency of patients with the Val30Met mutation and with positive family history.
The team’s prior work revealed that only 9% of Brazilian FAP patients have the late-onset form. However, unlike other parts of the world, this FAP variant is still scarcely characterized in Brazil.
Aiming to address this gap, the scientists studied demographic and clinical manifestations of patients from the Brazilian National Amyloid Referral Center (CEPARM). The data were collected from the ongoing, multinational THAOS survey, with an analysis cutoff date of Jan. 30, 2017.
The results revealed that 148 of 162 patients had the Val30Met mutation, 96 of whom were symptomatic and were included in the analysis. Twenty-five of these patients (26%) had the late-onset form of Val30Met FAP — defined as symptom onset at age 50 or later — while 71 (74%) had the earlier-onset variant.
Among the patients with later-onset disease, 63.4% were men, a similar percentage to that in the classical form (60%). The overall mean age at symptom onset was 38.7 years — 62.1 years in the late-onset group and 30.5 years in earlier-onset patients.
Significantly, more late-onset patients had been misdiagnosed compared to those with the classical form — 68% vs. 26.8%. The most common misdiagnosis in the late-onset group was chronic inflammatory demyelinating polyneuropathy (41%), followed by idiopathic peripheral neuropathy (23.5%). Patients with late-onset FAP showed a trend toward longer time for diagnosis — 5.1 vs. 2.8 years — but less frequent family history of FAP (40% vs. 95.8%) compared to earlier-onset disease.
As for clinical features, all late-onset patients experienced sensory neuropathy (nerve damage), 92% had motor neuropathy, 80% showed autonomic nerve damage, 92% imbalance, 80% insensitivity to pain or temperature, 84% gastrointestinal disorders, and 40% cardiac complications. Comparing the two groups, the patients with late-onset disease had significantly more imbalance and less autonomic neuropathy, as well as a trend toward more common muscle weakness.
Also, all late-onset patients had superficial and deep sensory loss, while most (88%) had distal lower limb weakness. These patients experienced deep sensory loss, distal lower and upper limb weakness, and diffuse loss of deep tendon reflexes — which determine muscle contraction upon tapping — more frequently than the earlier-onset group. A trend for more severe neurologic impairment was also seen in the late-onset group.
Abnormal electrocardiogram findings were more frequent in late-onset patients (88.9% versus 59.4%). Interventricular septum hypertrophy — enlargement of the wall separating the heart’s ventricles — was found only in this group (69.2%). Also, two of the nine patients with cardiomyopathy (heart muscle disease) had symptomatic heart failure. This group also showed greater interventricular septum thickness, posterior wall thickness and left atrium (one of the heart’s upper chambers) thickness than the patients with the classical FAP form.
Overall, late-onset FAP with the Val30Met mutation “is not unusual in Brazil, tending to be more difficult to diagnose and present with a more severe phenotype, with more large nerve fibers and cardiac involvement than [earlier-onset disease],” the scientists stated.