Val30Met FAP Patients’ Loss of Sensation Occurs in Both Upper and Lower Limbs, Study Reports

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by Joana Carvalho |

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loss of sensation

Familial amyloid polyneuropathy (FAP) patients who carry the Val30Met mutation experience loss of sensation (numbness), especially sense of touch pressure, rather than heat pain or thermal sensibility, in both their arms and legs, a study has found.

The study, “Kind and distribution of cutaneous sensation loss in hereditary transthyretin amyloidosis with polyneuropathy,” were published in Journal of the Neurological Sciences.

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.

More than 120 different mutations have been associated with hATTR-PN. However, the most frequent mutation causes one amino acid (the building blocks of proteins) called valine (Val) to be replaced by another called methionine (Met) in position 30 of the TTR gene sequence. This mutation is known as Val30Met.

Degeneration of sensory nerve fibers throughout the body causing loss of sensation is considered one of the hallmarks of hATTR-PN. Its distribution and severity are relevant indicators of disease progression and severity that can be used to monitor the health status of a patient or the effect of a treatment during clinical trials.

However, methods to assess sensation loss in a clinical setting have been far from ideal.

“Standard quantitative and graded stimuli are not used, algorithms of testing are not standard, defined or validated, and reference values for somatotopic [correspondence of a region of the body to a specific region of the central nervous system] sites studied are not available,” the researchers wrote.

“Even quantitative sensation testing at a standard site, e.g., of the foot or hand, provides only limited information because it is restricted to a single site which is not representative of the body surface distribution of sensation loss,” they added.

The team of investigators tested the utility of an automated, highly reproducible method to determine the distribution, severity, and kind — associated with large (TP) or small nerve fibers (HP) — of sensation loss on the body’s surface, called Smart Somatotopic Quantitative Sensation Testing (S ST QSTing), using a Computer Assisted Sensation Evaluator IVc (CASE IVc) system.

The study involved 169 untreated hATTR-PN patients — 40 with Val30Met at an early stage of disease, 47 with Val30Met at a later stage of disease, and 82 without Val30Met — who had been enrolled in the Phase 2/3 Ionis NEURO-TTR trial (NCT01737398).

Of these participants, 97% experienced loss of sensation, both TP and HP simultaneously (75%), or TP (23%) and HP (2%) alone. Numbness affected both legs in 90% of the patients and the arms in 82%. In general, TP loss was greater than HP loss, except for Val30Met patients who were still at the early stages of disease.

“We found that HP sensation loss was slightly greater than for TP in the early-onset Val30Met mutation group, with approximately 88% of these patients evaluated in centers in Portugal and Brazil (endemic hATTR-PN regions). Therefore, we conclude that typically in this polyneuropathy, in a multinational large cohort mostly from non-endemic areas, cutaneous sensation loss involves both large and small sensory fibers but slightly more small fibers in early-onset Val30Met patients,” the researchers said.

These findings support the use of S ST QSTing, a highly reliable and useful method, to monitor the distribution and severity of sensation loss in hATTR-PN patients.

“The introduction of S ST QSTing provides a novel, accurate, and reproducible way of evaluation of sensation loss in mild-to-severe stages of hATTR-PN. Furthermore, the S ST QSTing approaches used here make its results useful in the conduct of therapeutic trials,” the investigators concluded.