Immunoglobulin light chain amyloidosis diagnosis and treatment algorithm 2021

Immunoglobulin light chain amyloidosis (AL) commonly presents with nephrotic range proteinuria, heart failure with preserved ejection fraction, nondiabetic peripheral neuropathy, unexplained hepatomegaly or diarrhea, and should be considered in patients presenting with these symptoms. More importantly, patients being monitored for smoldering multiple myeloma and a monoclonal gammopathy of undetermined significance (MGUS) are at risk for developing AL amyloidosis. MGUS and myeloma patients that have atypical features, including unexplained weight loss; lower extremity edema, early satiety, and dyspnea on exertion should be considered at risk for light chain amyloidosis. Overlooking the diagnosis of light chain amyloidosis leading to therapy delay is common, and it represents an error of diagnostic consideration. Herein we provide a review of established and investigational treatments for patients with AL amyloidosis and provide algorithms for workup and management of these patients.Subject terms: Myeloma, Chemotherapy     

A new transthyretin variant (Ser 24) associated with familial amyloid polyneuropathy.

An American kindred with systemic amyloidosis presenting with carpal tunnel syndrome, peripheral neuropathy, and cardiomyopathy is reported. The transthyretin gene of a patient was analysed by direct DNA sequencing and both cytosine and thymine were present at the first base of codon 24. This new point mutation in exon 2 results in the amino acid substitution of serine for proline in the A-B loop of the transthyretin molecule. DNA testing for this mutant allele by restriction fragment length polymorphism analysis based on the polymerase chain reaction is described.     

Androgen receptor YAC transgenic mice carrying CAG 45 alleles show trinucleotide repeat instability

X-linked spinal and bulbar muscular atrophy (SBMA) is caused by a CAG repeat expansion in the first exon of the androgen receptor (AR) gene. Disease-associated alleles (37-66 CAGs) change in length when transmitted from parents to offspring, with a significantly greater tendency to shift size when inherited paternally. As transgenic mice carrying human AR cDNAs with 45 and 66 CAG repeats do not display repeat instability, we attempted to model trinucleotide repeat instability by generating transgenic mice with yeast artificial chromosomes (YACs) carrying AR CAG repeat expansions in their genomic context. Studies of independent lines of AR YAC transgenic mice with CAG 45 alleles reveal intergenerational instability at an overall rate of approximately 10%. We also find that the 45 CAG repeat tracts are significantly more unstable with maternal transmission and as the transmitting mother ages. Of all the CAG/CTG repeat transgenic mice produced to date the AR YAC CAG 45 mice are unstable with the smallest trinucleotide repeat mutations, suggesting that the length threshold for repeat instability in the mouse may be lowered by including the appropriate flanking human DNA sequences. By sequence-tagged site content analysis and long range mapping we determined that one unstable transgenic line has integrated an approximately 70 kb segment of the AR locus due to fragmentation of the AR YAC. Identification of the cis - acting elements that permit CAG tract instability and the trans -acting factors that modulate repeat instability in the AR YAC CAG 45 mice may provide insights into the molecular basis of trinucleotide repeat instability in humans.      

Identification of two groups of smoldering multiple myeloma patients who are either high or low producers of interleukin-1.

Interleukin-1beta (IL-1beta) is abnormally expressed by the plasma cells obtained from myeloma patients, and it is a potent inducer of the important myeloma growth factor, IL-6. We investigated whether levels of IL-1beta biologic activity might distinguish different groups of patients with smoldering multiple myeloma (SMM). We measured the ability of IL-6 production by bone marrow stromal cells to serve as a surrogate marker for IL-1beta biologic activity. Using this IL-1beta bioassay, we found that it is sensitive at < 1 pg/ml of recombinant IL-1beta and that IL-1beta biologic activity is detectable with either mature or pro-IL-1beta-transduced myeloma cell lines. Patients with active myeloma induced quantitatively higher levels of stromal cell IL-6 production when compared with those with monoclonal gammopathy of undetermined significance (MGUS). The bioassay distinguished two groups of SMM patients, those who were high producers, similar to patients with active MM, and those who were low producers, comparable to MGUS patients. IL-1 antagonists inhibited the paracrine IL-6 production by > or = 90% in the majority of patients with an elevated IL-6 level. Based on such studies, it may be possible to predict patients that will progress to active MM and to delay or prevent this progression with IL-1 antagonists.     

Pulmonary marginal zone lymphoma of MALT type as a cause of localised pulmonary amyloidosis

AIM: To describe six patients with pulmonary marginal zone lymphoma in whom amyloid deposition was identified. Marginal zone lymphoma is a recently recognised type of low grade non-Hodgkin's lymphoma. METHODS: A computerised search was performed of all patients seen at the Mayo Clinic with a diagnosis of pulmonary amyloidosis. Six patients with pulmonary amyloidosis who had biopsy confirmed extranodal marginal zone lymphoma of mucosa associated lymphoid tissue type were identified. All were women, ranging in age from 45 to 85 years. RESULTS: Five patients had amyloid deposition in conjunction with pulmonary marginal zone lymphoma at the time of the original diagnosis. One patient was referred for evaluation of localised pulmonary amyloidosis and was found to have coexisting pulmonary marginal zone lymphoma. Clinical presentation was limited to pulmonary symptoms (two of the six) or constitutional symptoms (two), or was asymptomatic (two). In all six cases, initial findings of nodular densities on screening chest roentgenograms led to further evaluation and eventual lobectomy; these findings included multiple pulmonary nodules (four), single nodule (one), and single nodule with diffuse bilateral interstitial infiltrates (one). Bone marrow was examined in five patients and was normal in all. Protein studies performed in four patients revealed no monoclonal protein. No patients had manifestations of systemic amyloidosis, such as renal, neurological, or cardiac involvement, at a median follow up of 50 months. Four of the six patients remain alive at a median of five years. CONCLUSIONS: Pulmonary marginal zone lymphoma may be found in association with localised amyloid deposition and should be considered in the differential diagnosis of localised pulmonary amyloidosis.