CNS Affected at Early Stages in FAP Patients With Val30Met Mutation

CNS involvement follows three-part 'hierarchical sequence,' study also suggests

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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Familial amyloid polyneuropathy (FAP) patients who carry the Val30Met mutation may experience central nervous system involvement early in the disease course, likely before symptoms are noticeable, according to a small study.

Involvement of the central nervous system (CNS, the brain and spinal cord) follows a three-stage progression, its researchers suggested. Defining these stages may prove “useful to better understand pathogenic [disease] mechanisms leading to symptoms and to interpret neuroimaging biomarkers,” they wrote.

The study, “Neuropathology of central nervous system involvement in TTR amyloidosis,” was published in the journal Acta Neuropathologica.

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Progressive nature of CNS involvement with FAP mutation poorly understood

Also known as hereditary transthyretin amyloidosis, FAP is caused by mutations in the TTR gene, which has the instructions for making the transthyretin (TTR) protein. The mutations change the protein’s typical structure, causing it to clump and form deposits of amyloid fibrils inside different tissues, particularly those of the heart and nerves.

Over time, these deposits can affect the function of peripheral nerves — those that control movement and sensation in the arms and legs — leading to peripheral neuropathy.

However, the CNS also can be affected, particularly in patients carrying the Val30Met mutation, the most common one associated with FAP.

Yet the progressive nature of transthyretin accumulation in the CNS is not well understood.

A team led by researchers in Portugal, where the TTR gene mutation is particularly frequent, evaluated TTR accumulation and distribution in the CNS over time.

They analyzed post-mortem brain tissue from 16 FAP patients (ages at death ranging from 28 to 69, 56% women), who had a mean disease duration of 10.9 years. All except one carried a Val30Met mutation; the exception was a man with a mutation called Ser52Pro (case No. 5). Neuropathy, or nerve damage, was the earliest and most prevalent manifestation in all these people.

The three older patients with the longest disease duration developed cognitive impairments, one after experiencing a brain hemorrhage. Impairments of cranial nerves — which help in taste, smell, hear and feel sensations — were seen in six patients, including some with shorter disease duration. Hemorrhagic stroke, the result of bleeding into the brain by the rupture of a blood vessel, affected two patients.

Brain tissue analysis of the most serious cases linked severe blood vessel damage to cerebral amyloid angiopathy (CAA), a condition caused by abnormal buildup of amyloid deposits in the brain blood vessels.

In the cortical region, the outer layer of the brain, amyloid deposition was exclusively found in blood vessels of the cortex and the meninges, the membranes that surround and protect the CNS.

Further analysis showed a strong correlation between amyloid deposits and disease duration, regardless of age at death.

According to the location of amyloid deposits, the researchers were able to define three stages of disease. In stage one, deposition was restricted to vessels surrounding the brain (including the innermost layers of tissue that cover the CNS), but could be already present in the brainstem — the bottom portion of the brain — and spinal cord. In stage two, amyloid deposition extended to cortical regions and superficial cortical vessels; in stage three, deposition extended to the cells under the thin membrane that lines fluid-filled spaces in the brain and spinal cord, as well as blood vessels of the basal ganglia, which is responsible for motor control.

“Despite the small number of cases [available], the validity of these TTR stages was confirmed by demonstrating that the number of affected TTR areas increased with the proposed stage of TTR,” the scientists wrote.

“We show that the extension of CNS TTR amyloidosis increases with disease duration and that this deposition appears to affect different brain areas in a distinct hierarchical sequence that can be described in 3 stages,” they added.

No differences were seen in the frequency and severity of amyloid deposits in the brain’s different lobes. But few of the tissue samples available came from people with advanced disease, the study noted.

Amyloid deposition on olfactory bulbs — involved in the sense of smell  — was present in all six patients with this tissue available, suggesting that olfactory impairment could be a symptom of FAP patients carrying the Val30Met mutation.

Overall, these findings suggest early CNS involvement in FAP patients with the Val30Met mutation, likely before symptoms appear, and progression following “a hierarchical sequence, with [the] brainstem severely affected in earlier stages,” the researchers wrote.

“Future studies with more patients from different populations and TTR mutations will be important to confirm these findings,” they added.

“Defining stages of TTR pathology helps to identify pre-clinical or early stage cases for the better understanding of early pathogenic events and can be informative to understand neuroimaging biomarkers,” the study concluded.