Lynda Lam

Bio: Lynda Lam is an academic researcher from Kaiser Permanente. The author has contributed to research in topics: Transthyretin & Polyneuropathy. The author has an hindex of 1, co-authored 1 publications receiving 13 citations.

Amyloid polyneuropathy caused by wild‐type transthyretin

Abstract: Introduction Amyloidosis derived from transthyretin (TTR) molecules is typically caused by mutations of the TTR gene. Methods We describe an elderly patient with a severe length-dependent polyneuropathy that unexpectedly proved to be caused by wild-type transthyretin amyloidosis. Results The diagnosis was made by muscle biopsy, because no amyloid deposits were found in the biopsied nerve segment. Most cases of wild-type transthyretin amyloidosis occur in elderly patients with cardiomyopathy, but a few cases of polyneuropathy have been reported. Conclusions This entity is especially noteworthy in light of emerging treatment options for hereditary transthyretin amyloidosis, which are likely to also be beneficial in wild-type disease. Muscle Nerve 52: 146–149, 2015

Current and future treatment of amyloid diseases.

Abstract: There are more than 30 human proteins whose aggregation appears to cause degenerative maladies referred to as amyloid diseases or amyloidoses. These disorders are named after the characteristic cross-β-sheet amyloid fibrils that accumulate systemically or are localized to specific organs. In most cases, current treatment is limited to symptomatic approaches and thus disease-modifying therapies are needed. Alzheimer's disease is a neurodegenerative disorder with extracellular amyloid β-peptide (Aβ) fibrils and intracellular tau neurofibrillary tangles as pathological hallmarks. Numerous clinical trials have been conducted with passive and active immunotherapy, and small molecules to inhibit Aβ formation and aggregation or to enhance Aβ clearance; so far such clinical trials have been unsuccessful. Novel strategies are therefore required and here we will discuss the possibility of utilizing the chaperone BRICHOS to prevent Aβ aggregation and toxicity. Type 2 diabetes mellitus is symptomatically treated with insulin. However, the underlying pathology is linked to the aggregation and progressive accumulation of islet amyloid polypeptide as fibrils and oligomers, which are cytotoxic. Several compounds have been shown to inhibit islet amyloid aggregation and cytotoxicity in vitro. Future animal studies and clinical trials have to be conducted to determine their efficacy in vivo. The transthyretin (TTR) amyloidoses are a group of systemic degenerative diseases compromising multiple organ systems, caused by TTR aggregation. Liver transplantation decreases the generation of misfolded TTR and improves the quality of life for a subgroup of this patient population. Compounds that stabilize the natively folded, nonamyloidogenic, tetrameric conformation of TTR have been developed and the drug tafamidis is available as a promising treatment.

Neuropathy Associated with Systemic Amyloidosis.

Abstract: Peripheral neuropathy occurs in the setting of both hereditary and acquired amyloidosis. The most common form of hereditary amyloidosis is caused by 1 of 140 mutations in the transthyretin (TTR) gene, which can lead to neuropathic hereditary transthyretin amyloidosis (hATTR; previously referred to as transthyretin familial amyloid polyneuropathy), whereas acquired immunoglobulin light chain (AL) amyloidosis is the most common acquired form. Patients typically present with a sensorimotor polyneuropathy, focal neuropathy such as carpal tunnel syndrome, or autonomic neuropathy. When neuropathy is the sole or dominant presenting symptom, the diagnosis is commonly delayed. With the advent of new drug therapies for AL amyloidosis and hATTR amyloidosis, including proteasome inhibitors, TTR silencers, and TTR protein stabilizers, the neurologist is uniquely positioned to diagnose neurologic manifestations of systemic amyloidosis, leading to earlier disease identification and treatment. This article reviews the epidemiology, clinical presentations, pathophysiology, diagnostic workup, and treatment of neuropathy in the setting of amyloidosis.

Rare Variants in MME, Encoding Metalloprotease Neprilysin, Are Linked to Late-Onset Autosomal-Dominant Axonal Polyneuropathies

Abstract: Axonal polyneuropathies are a frequent cause of progressive disability in the elderly. Common etiologies comprise diabetes mellitus, paraproteinaemia, and inflammatory disorders, but often the underlying causes remain elusive. Late-onset axonal Charcot-Marie-Tooth neuropathy (CMT2) is an autosomal-dominantly inherited condition that manifests in the second half of life and is genetically largely unexplained. We assumed age-dependent penetrance of mutations in a so far unknown gene causing late-onset CMT2. We screened 51 index case subjects with late-onset CMT2 for mutations by whole-exome (WES) and Sanger sequencing and subsequently queried WES repositories for further case subjects carrying mutations in the identified candidate gene. We studied nerve pathology and tissue levels and function of the abnormal protein in order to explore consequences of the mutations. Altogether, we observed heterozygous rare loss-of-function and missense mutations in MME encoding the metalloprotease neprilysin in 19 index case subjects diagnosed with axonal polyneuropathies or neurodegenerative conditions involving the peripheral nervous system. MME mutations segregated in an autosomal-dominant fashion with age-related incomplete penetrance and some affected individuals were isolated case subjects. We also found that MME mutations resulted in strongly decreased tissue availability of neprilysin and impaired enzymatic activity. Although neprilysin is known to degrade β-amyloid, we observed no increased amyloid deposition or increased incidence of dementia in individuals with MME mutations. Detection of MME mutations is expected to increase the diagnostic yield in late-onset polyneuropathies, and it will be tempting to explore whether substances that can elevate neprilysin activity could be a rational option for treatment.

Familial transthyretin amyloidosis

Abstract: A case of familial transthyretin amyloidosis with TTR Cys 114 gene polymorphism is described (first in Russia and third in the world). The clinical picture of the proband was dominated by symptoms of autonomous polyneuropathy (orthostatic hypotension, erectile dysfunction, diarrhea, tachycardia, foot dyshydrosis) and of somatic nerve lesions (dumbness, impaired surface and deep sensitivity in the limbs). The patient presented with vitreous body opacity, disturbed eye movements, lateralized sensory symptoms, and difficulty of speech (baryphonia). Electromyographic quantitative autonomous testing and measurement of evoked sympathetic skin potentials confirmed affection of peripheral nerves. Heart ultrasound revealed restrictive amyloid cardiopathy. Histological analysis showed amyloid deposition in the intestines and sural nerve. The proband, his daughter, brother (monozygous twin), and brother's daughter had mutant TTR Cys 114 gene. The brother also had amyloid deposits in the absence of clinical signs of the disease. Analysis of familial medical history demonstrated autosomal dominant inheritance of this mutation in 4 generations. Its possible origin and clinical features of the disease are discussed.

How your ears can tell what is hidden in your heart: wild-type transthyretin amyloidosis as potential cause of sensorineural hearing loss inelderly-AmyloDEAFNESS pilot study.

Abstract: Background: Wild-type transthyretin amyloidosis (ATTRwt) is an age-related life-threatening condition. Prognosis is mainly dependent on cardiac involvement. Other organs and tissues may be affected...