Three family members diagnosed with hereditary transthyretin amyloidosis (hATTR) have been identified as carriers of an autosomal dominant His90Asp variant, according to a study recently published in the Canadian Journal of Neurological Sciences.
The study authors reported on a woman aged 74 years who presented with early satiety, postural hypotension, episodes of intractable vomiting, fluctuating diarrhea, and constipation accompanied by 50-pound unintentional weight loss. The patient, also referred to as proband, reported experiencing severe distal weakness and progressive sensory symptoms for longer than 6 months.
According to the patient’s family history, her father died at 70 years of age due to neuropathy and significant gait impairment. His autopsy revealed the cause of death to be the presence of amyloids.
The proband’s physical examination showed cachexia, hypotension, weakness in the distal lower extremities, absent proprioception up to and including the ankles, and symmetric absence of pinprick. She also reported numbness and tingling in the thumb and index finger of both hands approximately 1 year prior to presentation, while electrodiagnostic studies revealed severe sensorimotor axonal polyneuropathy.
Read more about hATTR etiology
A commercially available targeted genetic sequence analysis with deletion and duplication testing identified 2 heterozygous variants including TTR, c.328C>G (ATTRv His90Asp, p. His110Asp) and INF2 c.3725_3728del (p. Thr1242Argfs*5).
The patient died 9 months after the initial presentation, approximately 4.5 years from symptom onset. Postmortem examination demonstrated extensive deposition of amyloid within the myocardium, arteries and arterioles of most organs, peripheral somatic and autonomic nerves, and choroid plexus vessels, as well as variable deposition in fibroadipose tissues throughout the body.
In addition, the patient’s son presented at 53 years old with numbness and paresthesia in the feet. His medical history indicated carpal tunnel release of both hands, while electrodiagnostic studies demonstrated bilateral median neuropathies at the wrist. There was no evidence of sensorimotor axonal polyneuropathy.
His bone-marrow biopsy demonstrated 2 foci of Congo red positive amorphous deposits and vessels with amorphous, Congo red positive eosinophilic deposits. Moreover, the gallbladder pathology sample obtained from cholecystectomy was Congo red positive with 1–2 foci of amorphous eosinophilic material within small vessel walls, consistent with focal amyloid deposition. Commercially available targeted genetic sequence analysis of TTR revealed the same His90Asp variant as the proband.
“This family demonstrates autosomal dominant inheritance across three generations with clinical features of hATTR,” Pierce and colleagues wrote. “Both the proband and her father developed clinically significant symptoms in their late 60s and early 70s. For this reason, we suspect the proband’s son is early in his course.”
Although more than 130 pathogenic mutations have been identified in the TTR gene, the His90Asp variant is not currently classified as pathogenic.
Pierce J, Han K, Vinters HV, Zuckerman JE, Halabi A. Severe polyneuropathy in hereditary transthyretin amyloidosis caused by H90D variant. Can J Neurol Sci. Published online January 10, 2023. doi:10.1017/cjn.2023.4