AL Lambda Amyloidosis Activates Acute Liver Failure in the Absence of Plasma Cell Dyscrasia.

A patient with systemic amyloidosis developed portal hypertension, acute liver failure and multiorgan dysfunction. Extensive testing was unrevealing for paraproteinemia, plasma cell dyscrasia, infectious, or inflammatory conditions. He was transferred to our institution for orthotopic liver transplant evaluation but was ultimately declined given clinical instability and dysautonomia. Post-mortem evaluation revealed extensive amyloid deposition in multiple organs determined to be AL-lambda amyloidosis.

Targeting transthyretin - Mechanism-based treatment approaches and future perspectives in hereditary amyloidosis.

The liver-derived, circulating transport protein transthyretin (TTR) is the cause of systemic hereditary (ATTRv) and wild-type (ATTRwt) amyloidosis. TTR stabilization and knockdown are approved therapies to mitigate the otherwise lethal disease course. To date, the variety in phenotypic penetrance is not fully understood. This systematic review summarizes the current literature on TTR pathophysiology with its therapeutic implications. Tetramer dissociation is the rate-limiting step of amyloidogenesis. Besides destabilizing TTR mutations, other genetic (RBP4, APCS, AR, ATX2, C1q, C3) and external (extracellular matrix, Schwann cell interaction) factors influence the type of onset and organ tropism. The approved small molecule tafamidis stabilizes the tetramer and significantly decelerates the clinical course. By sequence-specific mRNA knockdown, the approved small interfering RNA (siRNA) patisiran and antisense oligonucleotide (ASO) inotersen both significantly reduce plasma TTR levels and improve neuropathy and quality of life compared to placebo. With enhanced hepatic targeting capabilities, GalNac-conjugated siRNA and ASOs have recently entered phase III clinical trials. Bivalent TTR stabilizers occupy both binding groves in vitro, but have not been tested in trials so far. Tolcapone is another stabilizer with the potential to cross the blood-brain barrier, but its half-life is short and liver failure a potential side effect. Amyloid-directed antibodies and substances like doxycycline aim at reducing the amyloid load, however, none of the yet developed antibodies has successfully passed clinical trials. ATTR-amyloidosis has become a model disease for pathophysiology-based treatment. Further understanding of disease mechanisms will help to overcome the remaining limitations, including application burden, side effects, and blood-brain barrier permeability.

Presence of val30Met and val122ile mutations in a patient with hereditary amyloidosis.

Amyloidosis, caused by a mutation in the transthyretin (TTR) gene, is the most common hereditary type disease. More than 120 mutations have been described, with extensive phenotypic heterogeneity. Val30Met (p.Val50Met) is the most frequent mutation, and patients exhibit polyneuropathy, possibly including cardiac, renal, gastrointestinal, and/or ocular involvement. Val122Ile (p.Val142Ile) is the mutation associated with cardiomyopathy, and few cases have been reported in Brazil. Most individuals are heterozygous for one pathogenic mutation. Herein, we report a compound heterozygote with two pathogenic mutations (Val30Met/ Val122Ile), and a family history of a deceased brother with amyloidosis, who also carried the same TTR gene mutations. The patient presented with neuropathic, cardiac, and renal impairment and a faster disease progression. Cases of the double mutation have been linked to changes in disease presentation. The concomitance of two pathogenic mutations may have contributed to more exuberant manifestations and faster disease progression.

Efficacy of therapeutic soft contact lens in the management of gelatinous drop-like corneal dystrophy.

BACKGROUND/AIMS: To investigate the efficacy of therapeutic soft contact lenses (SCLs) in gelatinous drop-like corneal dystrophy (GDLD) management. METHODS: This was a retrospective, consecutive, observational case series, including 20 patients (40 eyes) with GDLD treated in Osaka University Hospital within the last 15 years. We tested the effects of therapeutic SCL on clinical features, visual acuity and surgical interventions. Examinations for clinical features and visual acuity were done on patients who had no surgical intervention for 3 years. Scoring and evaluation of changes in three main clinical GDLD features and visual acuity (logMAR units) were performed using Fisher's exact test and Mann-Whitney U test. Surgery-free survival time was compared by Kaplan-Meier analyses in all patients. RESULTS: We found a significantly lower rate of progression in GDLD nodular lesions in patients wearing SCLs compared with those who did not (p=0.0179). No suppressant effects were observed regarding opacity and neovascularisation, and no significant improvements were found in visual acuity (in logMAR values, SCL-on: mean=- 0.036, median=0; SCL-off: mean=0.149, median=+ 0.088; p=0.14). The surgery-free survival time for all 16 SCL-on eyes was 2770 ± 1918 days, significantly longer than that for 22 SCL-off eyes, 1342 ± 1323 days (Kaplan-Meier analysis, p=0.0007), suggesting that therapeutic SCL extends the period until surgical intervention and reduces their necessity in patients with GDLD. CONCLUSION: Wearing therapeutic SCLs in GDLD slows the progression of nodular lesions and decreases the need for surgical interventions.

Severe elastolysis in hereditary gelsolin (AGel) amyloidosis.

AGel amyloidosis is a dominantly inherited systemic amyloidosis caused by mutations p.D214N or p.D214Y resulting in gelsolin amyloid (AGel) formation. AGel accumulates extracellularly in many tissues and alongside elastic fibres. AGel deposition associates with elastic fibre degradation leading to severe clinical manifestations, such as cutis laxa and angiopathic complications. We analysed elastic fibre pathology in dermal and vascular tissue and plasma samples from 35 patients with AGel amyloidosis and 40 control subjects by transmission electron microscopy, immunohistochemistry and ELISA methods. To clarify the pathomechanism(s) of AGel-related elastolysis, we studied the roles of MMP-2, -7, -9, -12 and -14, TIMP-1 and TGFß. We found massive accumulation of amyloid fibrils along elastic fibres as well as fragmentation and loss of elastic fibres in all dermal and vascular samples of AGel patients. Fibrils of distinct types formed fibrous matrix. The degradation pattern of elastic fibres in AGel patients was different from the age-related degradation in controls. The elastin of elastic fibres in AGel patients was strongly decreased compared to controls. MMP-9 was expressed at lower and TGFß at higher levels in AGel patients than in controls. The accumulation of amyloid fibrils with severe elastolysis characterises both dermal and vascular derangement in AGel amyloidosis.

Sutureless Customized Lamellar Corneal Transplant in a Patient with Gelatinous Drop-Like Corneal Dystrophy.

Patients with gelatinous drop-like corneal dystrophy need to be effectively managed as the disease is severely debilitating in view of associated pho-tophobia and glare. Here, we report a rare case of gelatinous drop-like corneal dystrophy effectively managed by intraoperative anterior segment optical coherence tomography-guided manual deep anterior lamellar keratoplasty in 1 eye and sutureless fibrin glue-aided, microkeratome-assisted automated lamellar therapeutic keratoplasty in the other eye. The patient, a 22-year old man, presented with gradual diminution of vision associated with foreign body sensation, glare, photophobia, and watering due to corneal lesions, which were consistent with a diagnosis of gelatinous drop-like corneal dystrophy. Visual acuity at pre-sentation was 4/60 and 3/60 in the right and left eye, respectively. The patient received customized component lamellar keratoplasty in both eyes, and host tissue was sent for histopathologic examination. Treatment resulted in a best-corrected distance visual acuity of 6/9 and 6/12 in the right and left eye, respectively. The graft was clear and well apposed, with minimal interface haze bilaterally. The histopathologic report suggested intralamellar amyloid deposition in the form of homogenous, acellular eosinophilic deposits in the epithelium and anterior corneal stroma. This is a first report of the exclusive use of a fibrin-aprotinin tissue adhesive to stabilize a donor corneal lamellar graft as a treatment modality for a patient with gelatinous drop-like corneal dystrophy, suggesting that this treatment could supplant the need for sutures.

Apolipoprotein A-1-related amyloidosis 2 case reports and review of the literature.

RATIONALE: Apolipoprotein A-1 (ApoA-1)-related amyloidosis is characterized by the deposition of ApoA-1 in various organs and can be either hereditary or nonhereditary. It is rare and easily misdiagnosed. Renal involvement is common in hereditary ApoA-1 amyloidosis, but rare in the nonhereditary form. PATIENT CONCERNS: We reported two cases with ApoA-1 amyloidosis, a 64-year-old man suffering from nephrotic syndrome and a 40-year-old man with nephrotic syndrome and splenomegaly. Renal biopsies revealed glomerular, interstitial and vascular amyloid deposits and positive phospholipase A2 receptor staining in the glomerular capillary loop in case 1, and mesangial amyloid deposits in case 2. DIAGNOSES: After immunostaining failed to determine the specific amyloid protein, proteomic analysis of amyloid deposits by mass spectrometry was performed and demonstrated the ApoA-1 origin of the amyloid. Genetic testing revealed no mutation of the APOA1 gene in case 1 but a heterozygous mutation, Trp74Arg, in case 2. Case 1 was thus diagnosed as nonhereditary ApoA-1 associated renal amyloidosis with membranous nephropathy, and case 2 as hereditary ApoA-1 amyloidosis with multiorgan injuries (kidney and spleen) and a positive family history. INTERVENTIONS: Case 1 was treated with glucocorticoid combined with cyclosporine. Case 2 was treated with calcitriol and angiotensin converting enzyme inhibitors. OUTCOMES: Two cases were followed up for 5 months and 2 years, respectively; and case 1 was found to have attenuated proteinuria while case 2 had an elevation of cholestasis indices along with renal insufficiency. LESSONS: Proteomic analysis by mass spectrometry of the amyloid deposits combined with genetic analysis can provide accurate diagnosis of ApoA-1 amyloidosis. Besides, these 2 cases expand our knowledge of ApoA-1-related renal amyloidosis.

Gelatinous drop-like corneal dystrophy: a review.

Gelatinous drop-like corneal dystrophy (GDLD) is a rare autosomal recessive form of corneal dystrophy characterised by subepithelial and stromal amyloid deposits. It is relatively common in Japan. It usually presents in the first two decades of life with subepithelial nodular lesions that later coalesce to form mulberry-like opacities. Although various surgical modalities have been attempted, recurrence remains a major challenge.

El volumen extracelular detecta la amiloidosis cardiaca y está correlacionado con el deterioro neurológico en la amiloidosis familiar relacionada con la transtiretina / Extracellular volume detects amyloidotic cardiomyopathy and correlates with neurological impairment in transthyretin-familial amyloidosis

INTRODUCCIÓN Y OBJETIVOS: La afección cardiaca determina el pronóstico y las opciones de tratamiento en la amiloidosis familiar relacionada con la transtiretina. Las técnicas de mapeo T1 de resonancia magnética cardiaca son útiles para determinar el volumen extracelular miocárdico. En este estudio se planteó la hipótesis de que el volumen extracelular miocárdico permite la identificación de la amiloidosis cardiaca y está correlacionado con el grado de deterioro neurológico en la amiloidosis familiar relacionada con la transtiretina. MÉTODOS: A un total de 31 pacientes con amiloidosis familiar relacionada con la transtiretina (19 varones; media de edad, 49 ± 12 años; 26 pacientes con la mutación Val30Met), se les realizaron estudios de mapeo T1 con resonancia magnética cardiaca y una evaluación neurológica con la Neuropathy Impairment Score of the Lower Limb, el cuestionario Norfolk Quality of Life y el índice de Karnofsky. RESULTADOS: Cinco pacientes tenían amiloidosis cardiaca (en todos los casos, confirmada mediante gammagrafía con 99mTc-DPD). El valor medio del volumen extracelular estaba aumentado en los pacientes con amiloidosis cardiaca (0,490 ± 0,131 frente a 0,289 ± 0,035; p = 0,026). El volumen extracelular mostró correlación con la edad (R = 0,467; p = 0,008), fracción aminoterminal del propéptido natriurético tipo B (Rs = 0,846; p < 0,001), el grosor máximo de la pared (R = 0,621; p < 0,001), el índice de masa ventricular izquierda (R = 0,685; p < 0,001), la fracción de eyección del ventrículo izquierdo (R = -0,378; p = 0,036), la puntuación de la Neuropathy Impairment Score of the Lower Limb (Rs = 0,604; p < 0,001), el cuestionario Norfolk Quality of Life (Rs = 0,529; p = 0,003) y el índice de Karnofsky (Rs = -0,517; p = 0,004). Se consideró que un valor de corte del volumen extracelular de 0,357 es diagnóstico de amiloidosis cardiaca con sensibilidad y especificidad del 100% (p < 0,001). El volumen extracelular y la fracción aminoterninal del propéptido natriurético tipo B son los únicos parámetros cardiacos que mostraron correlación significativa con las puntuaciones neurológicas. CONCLUSIONES: La cuantificación del volumen extracelular permite la identificación de la amiloidosis cardiaca y está correlacionada con el grado de deterioro neurológico en la amiloidosis familiar relacionada con la transtiretina. Esta técnica no invasiva puede ser un instrumento útil para el diagnóstico precoz de amiloidosis cardiaca y el seguimiento de la afección cardiaca y extracardiaca

INTRODUCTION AND OBJECTIVES: Cardiac involvement determines prognosis and treatment options in transthyretin-familial amyloidosis. Cardiac magnetic resonance T1 mapping techniques are useful to assess myocardial extracellular volume. This study hypothesized that myocardial extracellular volume allows identification of amyloidotic cardiomyopathy and correlates with the degree of neurological impairment in transthyretin-familial amyloidosis. METHODS: A total of 31 transthyretin-familial amyloidosis patients (19 mean age, 49 ± 12 years; 26 with the Val30Met mutation) underwent a T1 mapping cardiac magnetic resonance study and a neurological evaluation with Neuropathy Impairment Score of the Lower Limb score, Norfolk Quality of Life questionnaire, and Karnofsky index. RESULTS: Five patients had cardiac amyloidosis (all confirmed by 99mTc-DPD scintigraphy). Mean extracellular volume was increased in patients with cardiac amyloidosis (0.490 ± 0.131 vs 0.289 ± 0.035; P = .026). Extracellular volume correlated with age (R = 0.467; P = .008), N-terminal pro-B-type natriuretic peptide (RS = 0.846; P < .001), maximum wall thickness (R = 0.621; P < .001), left ventricular mass index (R = 0.685; P < .001), left ventricular ejection fraction (R = -0.378; P = .036), Neuropathy Impairment Score of the Lower Limb (RS = 0.604;P = .001), Norfolk Quality of Life questionnaire (RS = 0.529; P = .003) and Karnofsky index (RS= -0.517; P = .004). A cutoff value of extracellular volume of 0.357 was diagnostic of cardiac amyloidosis with 100% sensitivity and specificity (P < .001). Extracellular volume and N-terminal pro-B-type natriuretic peptide were the only cardiac parameters that significantly correlated with neurologic scores. CONCLUSIONS: Extracellular volume quantification allows identification of cardiac amyloidosis and correlates with the degree of neurological impairment in transthyretin-familial amyloidosis. This noninvasive technique could be a useful tool for early diagnosis of cardiac amyloidosis and to track cardiac and extracardiac amyloid disease

Boston Type 1 Keratoprosthesis for Gelatinous Drop-Like Corneal Dystrophy.

PURPOSE: To report the outcomes of Boston type 1 keratoprosthesis in the management of advanced gelatinous drop-like corneal dystrophy (GDLD). METHODS: A retrospective, noncomparative, interventional case series was conducted at Ramathibodi Hospital, Bangkok, Thailand. Four eyes of three siblings with molecularly and histologically confirmed GDLD from a Thai family underwent an uneventful Boston type 1 keratoprosthesis implantation for visual rehabilitation. Clinical data were obtained from a review of the medical records. Visual acuity, device retention, and postoperative complications were the main outcome measures. The follow-up ranged from 8 to 96 months. RESULTS: One eye received keratoprosthesis surgery as a primary penetrating procedure. The other three eyes had the surgery as a secondary procedure after graft failure. Best-corrected visual acuity was favorably improved from counting fingers to 20/25 in two eyes, from hand movement to 20/20 in one eye, and from hand movement to counting fingers at 2 feet in one eye caused by severe amblyopia. The improved vision was maintained for 8 months to 6.2 years after surgery. Postoperative complications included disease recurrence in the donor graft (N = 3), manageable retroprosthetic membrane (N = 3), intraocular pressure elevation responded to antiglaucoma drugs (N = 2), and Pseudomonas keratitis with severe corneal melting requiring device removal (N = 1). All of our patients failed to have a comfortably well-fitting contact lens after surgery. CONCLUSIONS: Boston type 1 keratoprosthesis could be considered as a reasonable option in the management of advanced GDLD. However, patients remain at risk for sight-threatening postoperative complications as long as the keratoprosthesis is retained. The use of Boston keratoprosthesis implantation needed to be individualized on a case-by-case basis.

Combined Excimer Laser Photoablation and Amniotic Membrane Overlay for Relief of Symptomatic Discomfort in Gelatinous Drop-like Corneal Dystrophy.

PURPOSE: To describe the efficacy of combined excimer laser photoablation and amniotic overlay membrane in the relief of symptomatic discomfort in a 17-year-old patient who had gelatinous drop-like corneal dystrophy. METHODS: The best-corrected visual acuity (BCVA) was measured with Snellen letters. Slit-lamp examination of the ocular surface and anterior chamber was performed at baseline. Results were photodocumented. Excimer laser photoablation was performed and subsequently 2 amniotic membranes were transconjunctivally fixated with 10.0 nylon sutures. Investigations and documentation were performed at baseline, every 2 months in the first year, and then every 6 months. The duration of follow-up was 22 months. RESULTS: At baseline, the BCVA was 20/70 in the right eye and 20/200 in the left eye. The patient reported distinct photophobia. Slit-lamp examination was difficult because of blepharospasm. Although gelatinous drops developed again and the BCVA decreased to 2/200, the patient reported significant relief after both microsurgical treatments and remained comfortable at 20 and 22 months. CONCLUSIONS: Excimer laser photocoagulation combined with amniotic membrane overlay does not stop the development of gelatinous drop-like corneal dystrophy but may improve subjective comfort. Such treatment does not hinder subsequent lamellar or penetrating grafts and is helpful in providing the necessary time for preparation of matched keratoplasties.

An ER-directed gelsolin nanobody targets the first step in amyloid formation in a gelsolin amyloidosis mouse model.

Hereditary gelsolin amyloidosis is an autosomal dominantly inherited amyloid disorder. A point mutation in the GSN gene (G654A being the most common one) results in disturbed calcium binding by the second gelsolin domain (G2). As a result, the folding of G2 is hampered, rendering the mutant plasma gelsolin susceptible to a proteolytic cascade. Consecutive cleavage by furin and MT1-MMP-like proteases generates 8 and 5 kDa amyloidogenic peptides that cause neurological, ophthalmological and dermatological findings. To this day, no specific treatment is available to counter the pathogenesis. Using GSN nanobody 11 as a molecular chaperone, we aimed to protect mutant plasma gelsolin from furin proteolysis in the trans-Golgi network. We report a transgenic, GSN nanobody 11 secreting mouse that was used for crossbreeding with gelsolin amyloidosis mice. Insertion of the therapeutic nanobody gene into the gelsolin amyloidosis mouse genome resulted in improved muscle contractility. X-ray crystal structure determination of the gelsolin G2:Nb11 complex revealed that Nb11 does not directly block the furin cleavage site. We conclude that nanobodies can be used to shield substrates from aberrant proteolysis and this approach might establish a novel therapeutic strategy in amyloid diseases.

Boston type I keratoprosthesis for treatment of gelatinous drop-like corneal dystrophy after repeated graft failure.

PURPOSE: To describe the use of a Boston type I keratoprosthesis as a secondary penetrating procedure to treat gelatinous drop-like corneal dystrophy (GDLD), with presentation of pathologic findings, genetic analysis, and discussion of other surgical options. METHODS: A 43-year-old woman with GDLD in both eyes, best corrected visual acuity (BCVA) of counting fingers in both eyes, and recurrent corneal opacification following two penetrating keratoplasties presented for visual rehabilitation. A Boston type I keratoprosthesis was implanted in her left eye after extracapsular clear lens extraction. RESULTS: The surgery was uneventful and one month after surgery, best corrected vision improved to 20/30, which has been maintained for a period of more than nine months. At the 12-month visit, her vision was noted to be diminished to 20/200 due to a retroprosthetic membrane and improved to 20/25 two weeks after a Yag capsulotomy. Histopathologic examination of the corneal specimen disclosed predominantly subepithelial amyloid deposition. Genetic analysis is presented. CONCLUSIONS: GDLD is a rare disorder of primary corneal amyloidosis. Recurrence of this condition following surgery is very common. Boston type I keratoprosthesis as a secondary procedure can be successful in restoring vision in affected patients.

A new family with hereditary lysozyme amyloidosis with gastritis and inflammatory bowel disease as prevailing symptoms.

BACKGROUND: Systemic amyloidoses is a heterogeneous group of diseases either acquired or hereditary. Amyloidoses can involve the gastrointestinal tract and the nature of the precursor protein that forms the fibrils deposits should be identified to adjust the treatment and evaluate the prognosis. Lysozyme amyloidosis (ALys) is a rare, systemic non neuropathic hereditary amyloidosis with a heterogenous phenotype including gastrointestinal, renal and hepatic symptoms. CASE PRESENTATION: We report and describe symptoms and gastrointestinal tract involvement in a new family with hereditary lysozyme amyloidosis. Clinical manifestations and organ involvement of nine affected members of a new family with the p.Trp82Arg ALys variant were recorded. All affected individuals suffered with prevailing gastrointestinal symptoms leading to the diagnosis of ALys. 8/9 had non specific upper gastrointestinal symptoms and 3/9 had rectocolic inflammation evoking inflammatory bowel disease. No other organ involvement by amyloidosis was found. Histological examination revealed amyloid deposits in all cases and all carried the p.Trp82Arg ALys variant at a heterozygous state. CONCLUSION: Hereditary amyloidosis associated with the p.Trp82Arg lysozyme variant in this new family is predominantly associated with mild upper gastrointestinal tract involvement and in some cases with inflammatory bowel disease. Amyloidosis should be considered in atypical or treatment resistant, upper or lower chronic gastrointestinal symptoms. When associated with a familial history a lysozyme gene mutation must be searched.

Boston type I keratoprosthesis for visual rehabilitation in a patient with gelatinous drop-like corneal dystrophy.

PURPOSE: To report the use of a Boston type I keratoprosthesis as a primary penetrating procedure to treat gelatinous drop-like corneal dystrophy (GDLD), with presentation of pathologic findings and discussion of other surgical options. CASE REPORT: A 49-year-old woman with GDLD in both eyes and history of recurrent corneal opacification following multiple superficial keratectomies is presented. Best corrected visual acuity (BCVA) was counting fingers in both eyes. A Boston type I keratoprosthesis was implanted in her left eye after optical iridectomy, extracapsular cataract extraction, and anterior vitrectomy. RESULTS: The surgery was uneventful and one month after surgery, best corrected vision improved to 20/20 and has been maintained for a period of more than 14 months. No post-operative complications were observed. Histopathology of the corneal specimen is presented. CONCLUSIONS: GDLD is a rare disorder of amyloid deposition. Recurrence of this condition following surgery is extremely common. Boston type I keratoprosthesis is an effective procedure for restoring vision in affected patients.

Comparison of quantitative sensory testing and heart rate variability in Swedish Val30Met ATTR.

Patients with transthyretin amyloidosis (ATTR) polyneuropathy, a hereditary fatal disease, often report defects in both thermal perception and autonomic nervous system function as their first clinical symptoms. While elevated thermal perception thresholds (TPT) for cold and warmth only recently have been shown as an early marker of small nerve fiber dysfunction in these patients, heart rate variability (HRV) has frequently been used to quantify autonomic neuropathy. The main purpose with this report was to elucidate a possible relationship between estimates of HRV and TPT in a selected group of early and late-onset Swedish Val30Met ATTR patients. The results show significantly more pronounced elevation of TPT in early compared to late-onset patients. Significant correlations between HRV and TPT were found among late-onset cases, indicating a possible relationship between loss of thin nerve fibers in somatic and autonomic nerves, while generally no such relationships were found among early-onset cases. This observation emphasizes the importance of testing both HRV and TPT to ensure optimal early detection of neuropathic changes in an as wide as possible range of small nerve fibers in suspected ATTR patients. This is of particular importance as the phenotype of the ATTR disease varies between groups with different age of onset.