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Underdiagnosed amyloidosis: Amyloidosis of lysozyme variant

2005; Elsevier BV; Volume: 118; Issue: 3 Linguagem: Inglês

10.1016/j.amjmed.2004.10.022

1555-7162

B. Granel, Jacques Serratrice, P. Disdier, Pierre‐Jean Weiller, Sophie Valleix, Gilles Grateau, D Droz,

Porphyrin Metabolism and Disorders

Lysozyme amyloidosis is rare, and only five families with the disorder previously have been described.1Pepys M.B. Hawkins P.N. Booth D.R. et al.Human lysozyme gene mutations cause hereditary systemic amyloidosis.Nature. 1993; 362: 553-557Crossref PubMed Scopus (554) Google Scholar, 2Valleix S. Drunat S. Philip J.B. et al.Hereditary renal amyloidosis caused by a new variant lysozyme W64R in a French family.Kidney Int. 2002; 61: 907-912Crossref PubMed Scopus (106) Google Scholar, 3Gillmore J.D. Booth D.R. Madhoo S. et al.Hereditary renal amyloidosis associated with variant lysozyme in a large English family.Nephrol Dial Transplant. 1999; 14: 2639-2644Crossref PubMed Scopus (65) Google Scholar, 4Harrison R.F. Hawkins P.N. Roche W.R. et al.Fragile liver and massive hepatic haemorrhage due to hereditary amyloidosis.Gut. 1996; 38: 151-152Crossref PubMed Scopus (58) Google Scholar, 5Granel B. Serratrice J. Valleix S. et al.A family with gastrointestinal amyloidosis associated with variant lysozyme.Gastroenterol. 2002; 123: 1346-1349Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar We report a new case in a 62-year-old woman born in Piedmont, Italy, who presented in 2000 with chronic abdominal pain and moderate weight loss.The patient’s physical examination on presentation was unrevealing. Biological evaluation revealed monoclonal immunoglobulin G λ (9.5 g/L; reference range, 7 g/L to 14 g/L) without Bence Jones proteinuria. Amyloidosis characterized by positive Congo red stain was observed in her bone marrow, labial salivary glands, and deep colic mucosa. No medullar plasmocytosis was noted. Results of electrocardiography, echocardiography, abdominal ultrasonography, electromyography, and ophthalmological examination were normal.The patient was diagnosed as having systemic digestive and medullar amyloidosis. AL amyloidosis was initially suggested, but the results of immunohistochemical staining were negative for κ/λ light chains. Using data on systemic amyloidosis located in the digestive system,6Friedman S. Janowitz H.D. Systemic amyloidosis and the gastrointestinal tract.Gastroenterol Clin North Am. 1998; 27: 595-614Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar such as we described in lysozyme amyloidosis,5Granel B. Serratrice J. Valleix S. et al.A family with gastrointestinal amyloidosis associated with variant lysozyme.Gastroenterol. 2002; 123: 1346-1349Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar we found that results of a complementary search for lysozyme amyloidosis were positive in colic mucosa. The patient gave informed consent, and analysis of the lysozyme gene revealed a heterozygous change for a single base substitution of thymidine by adenine in codon 64. This nucleotide substitution changes the amino acid from tryptophane to arginine (Trp64Arg).We therefore concluded that the patient had lysozyme amyloidosis associated with monoclonal gammopathy of undetermined significance. Symptomatic treatment was prescribed. On clinical follow-up in 2004, the patient remained healthy. No other cases of amyloidosis were noted in the patient’s family.Lysozyme amyloidosis is a rare variant that can affect the viscera, with severe involvement when located in the kidneys and liver. Renal dysfunction of varying levels of severity can be the predominant manifestation.2Valleix S. Drunat S. Philip J.B. et al.Hereditary renal amyloidosis caused by a new variant lysozyme W64R in a French family.Kidney Int. 2002; 61: 907-912Crossref PubMed Scopus (106) Google Scholar, 3Gillmore J.D. Booth D.R. Madhoo S. et al.Hereditary renal amyloidosis associated with variant lysozyme in a large English family.Nephrol Dial Transplant. 1999; 14: 2639-2644Crossref PubMed Scopus (65) Google Scholar Massive hepatic hemorrhage constitutes the other severe visceral involvement.4Harrison R.F. Hawkins P.N. Roche W.R. et al.Fragile liver and massive hepatic haemorrhage due to hereditary amyloidosis.Gut. 1996; 38: 151-152Crossref PubMed Scopus (58) Google Scholar Dermatological manifestations are rare (e.g., sicca syndrome,2Valleix S. Drunat S. Philip J.B. et al.Hereditary renal amyloidosis caused by a new variant lysozyme W64R in a French family.Kidney Int. 2002; 61: 907-912Crossref PubMed Scopus (106) Google Scholar petechiae, purpura7Zalin A.M. Jones S. Fitch N.J.S. Ramsden D.B. Familial nephropathic non-neuropathic amyloidosis clinical features, immunohistochemistry and chemistry.Q J Med. 1991; 81: 945-956PubMed Google Scholar). Digestive involvement can induce malabsorption or bleeding lesions,3Gillmore J.D. Booth D.R. Madhoo S. et al.Hereditary renal amyloidosis associated with variant lysozyme in a large English family.Nephrol Dial Transplant. 1999; 14: 2639-2644Crossref PubMed Scopus (65) Google Scholar, 4Harrison R.F. Hawkins P.N. Roche W.R. et al.Fragile liver and massive hepatic haemorrhage due to hereditary amyloidosis.Gut. 1996; 38: 151-152Crossref PubMed Scopus (58) Google Scholar, 5Granel B. Serratrice J. Valleix S. et al.A family with gastrointestinal amyloidosis associated with variant lysozyme.Gastroenterol. 2002; 123: 1346-1349Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar but can also be feebly symptomatic, as previously observed.5Granel B. Serratrice J. Valleix S. et al.A family with gastrointestinal amyloidosis associated with variant lysozyme.Gastroenterol. 2002; 123: 1346-1349Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar We believe that this variant is probably underdiagnosed, as Congo red staining is not systematically performed.Previously studied families with lysozyme amyloidosis were of English,3Gillmore J.D. Booth D.R. Madhoo S. et al.Hereditary renal amyloidosis associated with variant lysozyme in a large English family.Nephrol Dial Transplant. 1999; 14: 2639-2644Crossref PubMed Scopus (65) Google Scholar, 4Harrison R.F. Hawkins P.N. Roche W.R. et al.Fragile liver and massive hepatic haemorrhage due to hereditary amyloidosis.Gut. 1996; 38: 151-152Crossref PubMed Scopus (58) Google Scholar Scandinavian1Pepys M.B. Hawkins P.N. Booth D.R. et al.Human lysozyme gene mutations cause hereditary systemic amyloidosis.Nature. 1993; 362: 553-557Crossref PubMed Scopus (554) Google Scholar and French descent.2Valleix S. Drunat S. Philip J.B. et al.Hereditary renal amyloidosis caused by a new variant lysozyme W64R in a French family.Kidney Int. 2002; 61: 907-912Crossref PubMed Scopus (106) Google Scholar, 5Granel B. Serratrice J. Valleix S. et al.A family with gastrointestinal amyloidosis associated with variant lysozyme.Gastroenterol. 2002; 123: 1346-1349Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar Interestingly, our last reported family with digestive lysozyme amyloidosis was also of Piedmont origin without consanguinity.5Granel B. Serratrice J. Valleix S. et al.A family with gastrointestinal amyloidosis associated with variant lysozyme.Gastroenterol. 2002; 123: 1346-1349Abstract Full Text Full Text PDF PubMed Scopus (25) Google ScholarFrom a genetic point of view, only three mutations have been described in the lysozyme gene: Trp64Arg,2Valleix S. Drunat S. Philip J.B. et al.Hereditary renal amyloidosis caused by a new variant lysozyme W64R in a French family.Kidney Int. 2002; 61: 907-912Crossref PubMed Scopus (106) Google Scholar, 5Granel B. Serratrice J. Valleix S. et al.A family with gastrointestinal amyloidosis associated with variant lysozyme.Gastroenterol. 2002; 123: 1346-1349Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar Asp67His3Gillmore J.D. Booth D.R. Madhoo S. et al.Hereditary renal amyloidosis associated with variant lysozyme in a large English family.Nephrol Dial Transplant. 1999; 14: 2639-2644Crossref PubMed Scopus (65) Google Scholar, 8Lachmann H.J. Booth D.R. Booth S.E. et al.Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis.N Engl J Med. 2002; 346: 1786-1791Crossref PubMed Scopus (530) Google Scholar and Ile56Thr.1Pepys M.B. Hawkins P.N. Booth D.R. et al.Human lysozyme gene mutations cause hereditary systemic amyloidosis.Nature. 1993; 362: 553-557Crossref PubMed Scopus (554) Google Scholar The Trp64Arg mutation reported here has been associated with renal2Valleix S. Drunat S. Philip J.B. et al.Hereditary renal amyloidosis caused by a new variant lysozyme W64R in a French family.Kidney Int. 2002; 61: 907-912Crossref PubMed Scopus (106) Google Scholar and digestive involvement.5Granel B. Serratrice J. Valleix S. et al.A family with gastrointestinal amyloidosis associated with variant lysozyme.Gastroenterol. 2002; 123: 1346-1349Abstract Full Text Full Text PDF PubMed Scopus (25) Google ScholarIn the case of this patient, an incorrect diagnosis of systemic AL amyloidosis could have been made if complete analysis of the amyloid deposits had not been performed. In the study by Lachmann et al,8Lachmann H.J. Booth D.R. Booth S.E. et al.Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis.N Engl J Med. 2002; 346: 1786-1791Crossref PubMed Scopus (530) Google Scholar a misdiagnosis of hereditary amyloidosis as AL amyloidosis was observed in 34 of 350 patients, with one case of misdiagnosis as lysozyme amyloidosis. Lysozyme amyloidosis belongs to the group of hereditary systemic autosomal dominant amyloidoses, but sporadic cases, such as those observed by Lachmann et al and in the present case, could occur due to low penetrance of the mutation.8Lachmann H.J. Booth D.R. Booth S.E. et al.Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis.N Engl J Med. 2002; 346: 1786-1791Crossref PubMed Scopus (530) Google Scholar, 9Hachulla E. Grateau G. Diagnostic tools for amyloidosis.Joint Bone Spine. 2002; 69: 538-545Crossref PubMed Scopus (56) Google ScholarThis observation reveals the need to precisely determine the nature of amyloid fibrils. Amyloidosis of different types (i.e., AA, AL, transthyretin, lysozyme, fibrinogen) can produce similar visceral involvement but prognosis and treatment are completely different.8Lachmann H.J. Booth D.R. Booth S.E. et al.Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis.N Engl J Med. 2002; 346: 1786-1791Crossref PubMed Scopus (530) Google Scholar, 9Hachulla E. Grateau G. Diagnostic tools for amyloidosis.Joint Bone Spine. 2002; 69: 538-545Crossref PubMed Scopus (56) Google Scholar Lysozyme amyloidosis is rare, and only five families with the disorder previously have been described.1Pepys M.B. Hawkins P.N. Booth D.R. et al.Human lysozyme gene mutations cause hereditary systemic amyloidosis.Nature. 1993; 362: 553-557Crossref PubMed Scopus (554) Google Scholar, 2Valleix S. Drunat S. Philip J.B. et al.Hereditary renal amyloidosis caused by a new variant lysozyme W64R in a French family.Kidney Int. 2002; 61: 907-912Crossref PubMed Scopus (106) Google Scholar, 3Gillmore J.D. Booth D.R. Madhoo S. et al.Hereditary renal amyloidosis associated with variant lysozyme in a large English family.Nephrol Dial Transplant. 1999; 14: 2639-2644Crossref PubMed Scopus (65) Google Scholar, 4Harrison R.F. Hawkins P.N. Roche W.R. et al.Fragile liver and massive hepatic haemorrhage due to hereditary amyloidosis.Gut. 1996; 38: 151-152Crossref PubMed Scopus (58) Google Scholar, 5Granel B. Serratrice J. Valleix S. et al.A family with gastrointestinal amyloidosis associated with variant lysozyme.Gastroenterol. 2002; 123: 1346-1349Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar We report a new case in a 62-year-old woman born in Piedmont, Italy, who presented in 2000 with chronic abdominal pain and moderate weight loss. The patient’s physical examination on presentation was unrevealing. Biological evaluation revealed monoclonal immunoglobulin G λ (9.5 g/L; reference range, 7 g/L to 14 g/L) without Bence Jones proteinuria. Amyloidosis characterized by positive Congo red stain was observed in her bone marrow, labial salivary glands, and deep colic mucosa. No medullar plasmocytosis was noted. Results of electrocardiography, echocardiography, abdominal ultrasonography, electromyography, and ophthalmological examination were normal. The patient was diagnosed as having systemic digestive and medullar amyloidosis. AL amyloidosis was initially suggested, but the results of immunohistochemical staining were negative for κ/λ light chains. Using data on systemic amyloidosis located in the digestive system,6Friedman S. Janowitz H.D. Systemic amyloidosis and the gastrointestinal tract.Gastroenterol Clin North Am. 1998; 27: 595-614Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar such as we described in lysozyme amyloidosis,5Granel B. Serratrice J. Valleix S. et al.A family with gastrointestinal amyloidosis associated with variant lysozyme.Gastroenterol. 2002; 123: 1346-1349Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar we found that results of a complementary search for lysozyme amyloidosis were positive in colic mucosa. The patient gave informed consent, and analysis of the lysozyme gene revealed a heterozygous change for a single base substitution of thymidine by adenine in codon 64. This nucleotide substitution changes the amino acid from tryptophane to arginine (Trp64Arg). We therefore concluded that the patient had lysozyme amyloidosis associated with monoclonal gammopathy of undetermined significance. Symptomatic treatment was prescribed. On clinical follow-up in 2004, the patient remained healthy. No other cases of amyloidosis were noted in the patient’s family. Lysozyme amyloidosis is a rare variant that can affect the viscera, with severe involvement when located in the kidneys and liver. Renal dysfunction of varying levels of severity can be the predominant manifestation.2Valleix S. Drunat S. Philip J.B. et al.Hereditary renal amyloidosis caused by a new variant lysozyme W64R in a French family.Kidney Int. 2002; 61: 907-912Crossref PubMed Scopus (106) Google Scholar, 3Gillmore J.D. Booth D.R. Madhoo S. et al.Hereditary renal amyloidosis associated with variant lysozyme in a large English family.Nephrol Dial Transplant. 1999; 14: 2639-2644Crossref PubMed Scopus (65) Google Scholar Massive hepatic hemorrhage constitutes the other severe visceral involvement.4Harrison R.F. Hawkins P.N. Roche W.R. et al.Fragile liver and massive hepatic haemorrhage due to hereditary amyloidosis.Gut. 1996; 38: 151-152Crossref PubMed Scopus (58) Google Scholar Dermatological manifestations are rare (e.g., sicca syndrome,2Valleix S. Drunat S. Philip J.B. et al.Hereditary renal amyloidosis caused by a new variant lysozyme W64R in a French family.Kidney Int. 2002; 61: 907-912Crossref PubMed Scopus (106) Google Scholar petechiae, purpura7Zalin A.M. Jones S. Fitch N.J.S. Ramsden D.B. Familial nephropathic non-neuropathic amyloidosis clinical features, immunohistochemistry and chemistry.Q J Med. 1991; 81: 945-956PubMed Google Scholar). Digestive involvement can induce malabsorption or bleeding lesions,3Gillmore J.D. Booth D.R. Madhoo S. et al.Hereditary renal amyloidosis associated with variant lysozyme in a large English family.Nephrol Dial Transplant. 1999; 14: 2639-2644Crossref PubMed Scopus (65) Google Scholar, 4Harrison R.F. Hawkins P.N. Roche W.R. et al.Fragile liver and massive hepatic haemorrhage due to hereditary amyloidosis.Gut. 1996; 38: 151-152Crossref PubMed Scopus (58) Google Scholar, 5Granel B. Serratrice J. Valleix S. et al.A family with gastrointestinal amyloidosis associated with variant lysozyme.Gastroenterol. 2002; 123: 1346-1349Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar but can also be feebly symptomatic, as previously observed.5Granel B. Serratrice J. Valleix S. et al.A family with gastrointestinal amyloidosis associated with variant lysozyme.Gastroenterol. 2002; 123: 1346-1349Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar We believe that this variant is probably underdiagnosed, as Congo red staining is not systematically performed. Previously studied families with lysozyme amyloidosis were of English,3Gillmore J.D. Booth D.R. Madhoo S. et al.Hereditary renal amyloidosis associated with variant lysozyme in a large English family.Nephrol Dial Transplant. 1999; 14: 2639-2644Crossref PubMed Scopus (65) Google Scholar, 4Harrison R.F. Hawkins P.N. Roche W.R. et al.Fragile liver and massive hepatic haemorrhage due to hereditary amyloidosis.Gut. 1996; 38: 151-152Crossref PubMed Scopus (58) Google Scholar Scandinavian1Pepys M.B. Hawkins P.N. Booth D.R. et al.Human lysozyme gene mutations cause hereditary systemic amyloidosis.Nature. 1993; 362: 553-557Crossref PubMed Scopus (554) Google Scholar and French descent.2Valleix S. Drunat S. Philip J.B. et al.Hereditary renal amyloidosis caused by a new variant lysozyme W64R in a French family.Kidney Int. 2002; 61: 907-912Crossref PubMed Scopus (106) Google Scholar, 5Granel B. Serratrice J. Valleix S. et al.A family with gastrointestinal amyloidosis associated with variant lysozyme.Gastroenterol. 2002; 123: 1346-1349Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar Interestingly, our last reported family with digestive lysozyme amyloidosis was also of Piedmont origin without consanguinity.5Granel B. Serratrice J. Valleix S. et al.A family with gastrointestinal amyloidosis associated with variant lysozyme.Gastroenterol. 2002; 123: 1346-1349Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar From a genetic point of view, only three mutations have been described in the lysozyme gene: Trp64Arg,2Valleix S. Drunat S. Philip J.B. et al.Hereditary renal amyloidosis caused by a new variant lysozyme W64R in a French family.Kidney Int. 2002; 61: 907-912Crossref PubMed Scopus (106) Google Scholar, 5Granel B. Serratrice J. Valleix S. et al.A family with gastrointestinal amyloidosis associated with variant lysozyme.Gastroenterol. 2002; 123: 1346-1349Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar Asp67His3Gillmore J.D. Booth D.R. Madhoo S. et al.Hereditary renal amyloidosis associated with variant lysozyme in a large English family.Nephrol Dial Transplant. 1999; 14: 2639-2644Crossref PubMed Scopus (65) Google Scholar, 8Lachmann H.J. Booth D.R. Booth S.E. et al.Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis.N Engl J Med. 2002; 346: 1786-1791Crossref PubMed Scopus (530) Google Scholar and Ile56Thr.1Pepys M.B. Hawkins P.N. Booth D.R. et al.Human lysozyme gene mutations cause hereditary systemic amyloidosis.Nature. 1993; 362: 553-557Crossref PubMed Scopus (554) Google Scholar The Trp64Arg mutation reported here has been associated with renal2Valleix S. Drunat S. Philip J.B. et al.Hereditary renal amyloidosis caused by a new variant lysozyme W64R in a French family.Kidney Int. 2002; 61: 907-912Crossref PubMed Scopus (106) Google Scholar and digestive involvement.5Granel B. Serratrice J. Valleix S. et al.A family with gastrointestinal amyloidosis associated with variant lysozyme.Gastroenterol. 2002; 123: 1346-1349Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar In the case of this patient, an incorrect diagnosis of systemic AL amyloidosis could have been made if complete analysis of the amyloid deposits had not been performed. In the study by Lachmann et al,8Lachmann H.J. Booth D.R. Booth S.E. et al.Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis.N Engl J Med. 2002; 346: 1786-1791Crossref PubMed Scopus (530) Google Scholar a misdiagnosis of hereditary amyloidosis as AL amyloidosis was observed in 34 of 350 patients, with one case of misdiagnosis as lysozyme amyloidosis. Lysozyme amyloidosis belongs to the group of hereditary systemic autosomal dominant amyloidoses, but sporadic cases, such as those observed by Lachmann et al and in the present case, could occur due to low penetrance of the mutation.8Lachmann H.J. Booth D.R. Booth S.E. et al.Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis.N Engl J Med. 2002; 346: 1786-1791Crossref PubMed Scopus (530) Google Scholar, 9Hachulla E. Grateau G. Diagnostic tools for amyloidosis.Joint Bone Spine. 2002; 69: 538-545Crossref PubMed Scopus (56) Google Scholar This observation reveals the need to precisely determine the nature of amyloid fibrils. Amyloidosis of different types (i.e., AA, AL, transthyretin, lysozyme, fibrinogen) can produce similar visceral involvement but prognosis and treatment are completely different.8Lachmann H.J. Booth D.R. Booth S.E. et al.Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis.N Engl J Med. 2002; 346: 1786-1791Crossref PubMed Scopus (530) Google Scholar, 9Hachulla E. Grateau G. Diagnostic tools for amyloidosis.Joint Bone Spine. 2002; 69: 538-545Crossref PubMed Scopus (56) Google Scholar