Tyr78Phe Transthyretin Mutation with Predominant Motor Neuropathy as the Initial Presentation

Abstract

Transthyretin (TTR) amyloidosis, the most frequent form of hereditary amyloidosis, is caused by dominant mutations in the TTR gene. More than 100 mutations have been identified. Clinical manifestations of TTR amyloidosis are usually induced by extracellular amyloid deposition in several organs. The major neurological manifestation is motor-sensory neuropathy associated with dysautonomic impairment. Here, we describe a63-year-old man who came to our institution due to a suspected motor neuron disease. During a 4-year follow-up period, he underwent extensive clinical examination, electromyographic studies, sural nerve biopsy and TTR gene analysis by direct sequencing. Despite the predominant motor involvement, the detailed clinical examination also showed some mild sensory and dysautonomic signs. In addition, his clinical and family history included multiorgan disorders, such as carpal tunnel syndrome, as well as conditions with cardiac, renal, eye, and hepatic involvement. The sural nerve biopsy disclosed amyloid deposition, and the sequence analysis of the TTR gene detected a heterozygous Tyr78Phe substitution. The TTR gene variant found in our patient had only been described once so far, in a French man of Italian origin presenting with late-onset peripheral neuropathy and bilateral carpal tunnel syndrome. The predominant motor involvement presented by our patient is an uncommon occurrence and demonstrates the clinical heterogeneity of TTR amyloidosis.

Evolving landscape in the management of transthyretin amyloidosis

“…Hand involvement, including weakness, sensory impairment, and reduction in fine motor skills, was also observed in the vast majority of patients with h-ATTR amyloidosis with polyneuropathy in a recent study ( 15 ). Disease characteristics can vary according to the specific mutation involved; for example patients with Tyr78Phe tend to present with predominant motor neuropathy ( 48 ). Age at onset and gender also influence disease characteristics ( 49 , 50 ).…”

Amyotrophic lateral sclerosis mimics

“…67,68 It is important for the clinician to be aware that non-motor features may not be apparent initially as patients may have subclinical or minimal sensory and autonomic symptoms, or rather sensory abnormalities may lag behind the motor abnormalities. 68…”

Transthyretin-Related Familial Amyloid Polyneuropathy: In the Light of New Developments

“…Hoarseness due to vocal cord involvement, spinal stenosis, and hypothermia are other rare involvements of the disease (10). Different mutation types cause different clinical features: dominant motor involvement with Tyr78Phe mutations, initiation of the disease from the upper extremities with Leu58His mutations, and initiation of the disease with Carpal Tunnel syndrome with Glu89Gln mutation are some examples (6,11). Presentation with isolated cardiac involvement but very mild neurologic involvement with Val122Ile mutations, and leptomeningeal amyloidosis with Asp18Gly, Ala25Thr, and Gly53Glu mutations have also been reported (6,12,13,14).…”