Diagnosis and treatment of multisystem amyloidosis associated with SGPL1 mutation: A case report and review of the literature.

1. Introduction

Systemic amyloidosis is a group of conditions caused by the accumulation of extracellular deposits of insoluble amyloid fibers in multiple tissues and organs. Systemic amyloidosis has a complex and heterogenous presentation, which often leads to a delayed diagnosis. The most common types of amyloidosis are immunoglobulin light-chain amyloidosis (AL), systemic light-chain amyloidosis, and immunoglobulin heavy-chain amyloidosis (AH). [ 1 , 2 ] The AL type is more common than the AH type, with an incidence of 8 to 10 cases per million person-years. [ 3 ] Clinically, the various types of immunoglobulins and their light chains can be identified using immunofixation electrophoresis, which is helpful for diagnosis and treatment. These immunoglobulins mainly appear as monoclonal forms, and exist in a partially folded state as their primary structure; they are then further folded and curled to form their secondary structure of β-lamellae, and after binding with aminoglycans and serum amyloid P substance, they transform into an extremely difficult to dissolve and stable amyloid fiber sheath structure, which is deposited in multiple organs, causing organ damage. [ 4 ]

The relationship between amyloidosis and gene mutation is also a hot topic of research. Significant differences exist in the genetic basis of different amyloidosis subtypes. The AL type is mainly caused by the monoclonal proliferation of plasma cell clones producing monoclonal immunoglobulin light chains, while the AH type originates from heavy-chain abnormalities. Transthyretin amyloid polyneuropathy is an autosomal dominant disease caused by mutation of the transthyretin (TTR) gene, and is mainly characterized by peripheral nerve damage. [ 5 ] The pathological mechanism of Alzheimer disease is also related to amyloid, and amyloid deposition is a key step in the progression of Alzheimer disease. [ 6 , 7 ] Caloric restriction and regulation of mammalian target of rapamycin proteins may affect amyloid metabolism and clearance. [ 8 ] Although some progress has been made, the relationship between amyloidosis and gene mutations is insufficiently understood, and further discussion and research are needed.

Multisystem amyloidosis associated with sphingosine-1-phosphate lyase 1 ( SGPL1 ) mutation is a rare and genetically complex disease, supported by emerging evidence linking SGPL1 dysfunction to aberrant sphingolipid metabolism and amyloidogenesis. [ 9 , 10 ] Epidemiologically, this condition exhibits an extremely low incidence rate (no precise statistics are available due to its rarity, with only sporadic case reports documented globally), and affects patients across a wide age spectrum, ranging from adolescents to elderly individuals. The SGPL1 gene plays a key role in sphingolipid metabolism, and its mutation can affect the related metabolic pathways, leading to the production and accumulation of abnormal proteins, which then induce amyloid deposition. Serum and urine immunofixation electrophoresis provide a sensitive diagnostic method, while other laboratory abnormalities, including blood routine, liver function, kidney function, and proteinuria tests, can serve as supplementary diagnostic tests. [ 9 , 10 ] The goal of treatment is to reduce the level of monoclonal immunoglobulin light chains in the body, prevent the further deposition of amyloid protein, and reduce or reverse the organ dysfunction caused by amyloid protein deposition. [ 11 ] In a recent study, AL patients were treated with autologous peripheral blood stem-cell transplantation and immunotherapy in combination with chemotherapy. [ 12 ] The results of the study suggested that although high-dose melphalan combined with stem-cell transplantation is still considered a high-risk treatment for AL, the advent of new agents like bortezomib could potentially transform this treatment paradigm and enhance patient outcomes. Due to its rarity and complexity, the treatment of SGPL1 gene mutation-associated multisystem amyloidosis remains challenging. Current treatments are mainly aimed at relieving symptoms, delaying disease progression, and improving the quality of life of patients. In the future, with the in-depth study of the pathogenesis of this disease, more effective treatment strategies are expected to be developed.

Here, we report a case of monoclonal IgA-κ amyloidosis caused by an SGPL1 gene mutation, and review the literature on the potential effects of SGPL1 gene mutations on various organs, the underlying mechanism of SGPLI -related amyloidosis, and the prognosis of patients with this rare disorder.

2. Case presentation

2.1. Chief complaints

A 53-year-old man was admitted to the Affiliated Hospital of Zunyi Medical University with a 5-month history of abnormal renal function and abdominal distension, which had worsened in the past 2 days.

2.2. History of present illness

The patient had been found to have abnormal renal function 5 months ago in Zunyi Medical College Hospital, and had been diagnosed with nephrotic syndrome associated with abnormal liver function. He had been treated with prednisolone tablets, dipyridamole, and hydroxychloroquine sulfate for the nephrotic syndrome, and ursodeoxycholic acid to protect liver function. After comprehensive treatment, his symptoms improved, and he was discharged from the hospital. Then, 2 days ago, he began experiencing abdominal distension that was not related to eating, acid reflux, heartburn, fatigue, or loss of appetite. Consequently, he returned to the Affiliated Hospital of Zunyi Medical University for further treatment.

2.3. History of past illnesses

Over 10 years ago, the patient developed severe hydronephrosis secondary to a left renal stone, resulting in the complete loss of left renal function, and consequently, he underwent left nephrectomy at a local hospital. Six months prior, he presented to our institution with bilateral lower extremity edema; diagnostic evaluation by our team confirmed nephrotic syndrome. He completed a course of corticosteroid therapy combined with acid suppression and gastroprotective therapy (such as proton pump inhibitors) and renal supportive care, achieving clinical improvement prior to discharge. Two months earlier, he was diagnosed with essential hypertension (stage 2, very high-risk group) at Southwest Hospital. Although he was prescribed antihypertensive medications, his treatment adherence was suboptimal. Despite this, his blood pressure remained generally well-controlled. There was no history of diabetes mellitus, coronary artery disease, cerebrovascular accident, tuberculosis, viral hepatitis, typhoid fever, drug or food allergies, blood product transfusion, or renal/adrenal-related disorders.

2.4. Personal and family history

The patient has been a smoker since 20 years, and smokes 20 cigarettes per day. He denied having an alcohol addiction. He did not have any relevant family history. His immunization status is unknown.

2.5. Physical examination

A physical examination at admission revealed a body temperature of 36.5°C, a pulse rate of 86 beats/min, a respiratory rate of 20 breaths/min, a blood pressure of 115/68 mm Hg, and clear consciousness. The patient had good skin elasticity and yellow skin; he did not have liver palms or spider nevi. He had a purple periumbilical bruise measuring 1 × 3 cm (Fig. 1 ). Cardiopulmonary examination revealed no obvious positive signs. The abdominal area of the patient was flat, exhibiting tenderness in the left upper abdomen and below the xiphoid process, while showing no rebound tenderness or muscular tension. The patient’s liver was located 5 fingerbreadths below the xiphoid process and 3 fingerbreadths below the left clavicular midline. It was firm in texture, and had sharp edges. There were no palpable nodules or masses. There was slight pain on percussion in the liver area. The test for shifting dullness is negative in this patient. There was no edema in the lower limbs.

2.6. Laboratory examinations

Liver-function tests revealed elevated levels of alanine transaminase, aspartate transaminase, alkaline phosphatase, and gamma-glutamyl transferase. The serum albumin level was within the reference range. Kidney-function tests showed increases in the serum levels of urea, uric acid, creatinine, and a decrease in the creatinine clearance rate. Routine blood tests showed an increased white blood cell count and a decreased red blood cell count, platelet count, and hemoglobin level. The dynamic changes in the results of liver-function, renal-function, blood routine, 24-urinary protein, and plasma N-terminal pre-B-type brain natriuretic peptide tests were observed throughout the course of the disease (Tables 1 – 3 ). Serum immunoglobulin measurements suggested IgA-κ M proteinemia (Table 4 ).

A bone marrow biopsy was performed owing to a suspicion of multiple myeloma, but the results were normal. Immunofixation electrophoresis of serum and urine samples (Table 5 , Fig. 2 ) showed increased levels of monoclonal IgA-κ protein.

Whole exome sequencing for the detection of genetic disorders was performed, and the results revealed a heterozygous, autosomal recessive mutation in the SGPL1 gene on chromosome 10: c.1514G > A (p. Arg505Gln) (Fig. 3 ).

2.7. Imaging examinations

Abdominal color Doppler ultrasonography (Fig. 4 A) revealed the following: the liver was enlarged; the gallbladder wall was slightly thickened; the right renal parenchyma was slightly hyperechoic and slightly enlarged; and the left kidney was not detected. Echocardiography (Fig. 4 B) showed left ventricular wall thickening and a small amount of pericardial effusion, which are consistent with the ultrasonographic changes of myocardial amyloidosis. Lower extremity venous color Doppler ultrasonography (Fig. 4 C) showed no obvious abnormality. A chest computed tomography scan (Fig. 5 A) showed bilateral small focal fibrosis in the lungs, mild enlargement of the left ventricle, and enlargement of the spleen and liver with reduced density. Because abdominal color Doppler ultrasonography and chest computed tomography showed liver enlargement, a liver biopsy was performed. The results showed significant edema and punctate necrosis of liver cells, fibrous tissue proliferation in the portal area, and infiltration of acute and chronic inflammatory cells. On Congo red staining (+) of the liver tissue sample, most of the liver cells and interstitial amyloid changes in the examined tissues were observed to be accompanied by the interstitial infiltration of acute and chronic inflammatory cells (Fig. 6 ). Cardiac magnetic resonance imaging (MRI) was performed to further evaluate the cardiac changes (Fig. 5 B), and it revealed the following: uniform thickening of each segment of the left ventricular wall, recent subendocardial changes in the left ventricle, and linear enhancement around the right atrium and right ventricular inflow tract, which are consistent with the MRI findings of cardiac amyloidosis; a small amount of pericardial effusion, and mild mitral and tricuspid valve reflux; decreased left ventricular myocardial compliance, with slightly diminished diastolic function; and slight bilateral pleural effusion.

2.8. Final diagnosis

Considering the above findings, we established a final diagnosis of SGPL1 gene mutation-related multisystem AL with liver, heart, and kidney involvement after left nephrectomy.

2.9. Treatment

During the present hospitalization, the patient was diagnosed with nephrotic syndrome, hepatic insufficiency, and status post nephrectomy. Therefore, a series of treatment regimens were administered as follows: 1st, for nephrotic syndrome, dipyridamole tablets were given as anticoagulant therapy at a dose of 25 mg, po, tid, until the nephrotic syndrome stabilized. To delay the progression of kidney disease, methylprednisolone tablets combined with hydroxychloroquine sulfate were used. The initial dose of methylprednisolone was 40 mg, po, qd, which was gradually reduced based on the patient’s condition, with a total treatment course of 6 months. Hydroxychloroquine sulfate was administered continuously at a dose of 200 mg, po, bid, to delay the progression of kidney disease, until the patient’s kidney-function indicators and related symptoms improved. Second, for hepatic insufficiency, ursodeoxycholic acid was given at a dose of 250 mg, po, tid, for liver protection, until the patient’s liver-function indicators and related symptoms improved. During the hospitalization, bone marrow smear and flow cytometry tests showed no abnormal changes. However, echocardiography suggested myocardial amyloidosis. Serum immunofixation electrophoresis revealed an M protein band, which formed a specific precipitation band with anti-IgA and anti-κ. Urine immunofixation electrophoresis showed no M protein, and no specific reaction precipitation band was formed with anti-GAM, anti-κ, anti-λ, anti-free κ, or anti-free λ. Based on the combined results of serum and urine immunofixation electrophoresis, the diagnosis was IgA-κ type M proteinemia. The liver biopsy results indicated significant hepatocyte edema with spotty necrosis, fibrous tissue hyperplasia in the portal area with acute and chronic inflammatory cell infiltration, which is consistent with chronic hepatitis. Congo red staining was positive. Based on the patient’s relevant examinations and clinical symptoms, the diagnosis was confirmed as primary amyloidosis with multisystem involvement (liver, heart, and kidneys). Further chemotherapy was planned, but due to the patient’s poor physical condition, it was postponed until recovery. Therefore, a follow-up was scheduled 1 week after discharge.

2.10. Outcome and follow-up

After a definite diagnosis of primary amyloidosis with multisystem involvement (liver, heart, and kidney), the patient was re-admitted for chemotherapy. Based on the patient’s relevant examinations and clinical symptoms, the initial chemotherapy regimen was the BD regimen (January 15, 2022): bortezomib (2 mg, iv, d1, d4, d8, d11) and dexamethasone sodium phosphate injection (20 mg, iv, d1, d2, d4, d5, d8, d9, d12) in combination, with a treatment cycle of 21 days. [ 13 , 14 ] Adjustments were made based on the results of follow-up visits. During the 2nd cycle of the initial chemotherapy regimen, the patient developed symptoms of acute left heart failure. Cardiac MRI confirmed cardiac amyloidosis with decreased ventricular function and poor renal function. Thus, the chemotherapy regimen was changed to the MTP regimen (February 16, 2022): melphalan (2 mg, po, d1, d2, d3, d4, d5, d6, d7), thalidomide capsules (100 mg, po, d1–d30), and prednisone acetate tablets (40 mg, po, d1, d2, d3, d4, d5, d6, d7) in combination, with a treatment cycle of 28 days. [ 15 ] Follow-up tests, including blood routine, liver-function, renal-function, 24-hour urinary protein, and cardiac examinations (such as echocardiography), were conducted every 2 to 4 weeks. After 4 cycles of treatment, the patient experienced nausea, vomiting, and discomfort, with decreased renal function and poor treatment response. Hence, the chemotherapy regimen was changed once again, to the VBD regimen (June 27, 2022): bortezomib (1.9 mg, po, d1, d4, d8, d11), lenalidomide capsules (10 mg, po, d1–21), and dexamethasone sodium phosphate injection (20 mg, iv, d1, d2, d4, d5, d8, d9, d11, d12), with a treatment cycle of 28 days. [ 16 ] However, after 4 cycles, the patient showed a poor treatment response and severe chemotherapy reactions, leading to the discontinuation of this regimen. A 3rd adjustment was made, and the treatment was changed to the VRD regimen (March 6, 2023): bortezomib (1.9 mg, po, once a week), lenalidomide capsules (25 mg, po, d1–14), and dexamethasone tablets (20 mg, po, twice a week). [ 16 ] The patient continued to undergo treatment with the VRD regimen at the outpatient clinic. After the 3rd adjustment to the chemotherapy regimen, the patient developed numbness and pain in his hands and feet during follow-up, and the results of relevant reexaminations were worsened compared to before. Therefore, a fourth adjustment was made: the regimen was changed to the PCD regimen (July 15, 2023): bortezomib injection (1.8 mg, sc, once a week), cyclophosphamide (0.4 g, po, once a week), and dexamethasone (20 mg, po, twice a week). During follow-up, considering the patient’s condition and underlying disease, we had initially planned to treat him with an anti-CD38 monoclonal antibody. [ 17 , 18 ] However, the patient declined due to financial reasons. On April 8, 2025, a 5th adjustment was made, switching to the VRD regimen: bortezomib injection (2 mg, sc, on days 1, 4, 8, and 11), lenalidomide (5 mg, po, on days 1–21), and dexamethasone (10 mg, po, on days 1, 4, 8, and 11). On July 3, 2025, during administration of the VRD regimen, the patient developed skin allergies, prompting a sixth adjustment: the regimen was modified to a weekly schedule consisting of bortezomib injection (2 mg, sc, once weekly), lenalidomide (5 mg, po, on days 1–21), and dexamethasone (10 mg, po, once weekly). On July 29, 2025, the VRD regimen was scheduled again; however, due to prominent injection-site rash following subcutaneous bortezomib administration as well as chest tightness, palpitations, and epigastric distension and pain after lenalidomide intake, the regimen was changed to BD. On August 16, 2025, due to significant gastrointestinal symptoms associated with bortezomib, the treatment was ultimately adjusted to lenalidomide (5 mg, po, on days 1–21) and dexamethasone (20 mg, po, on days 1–21). A repeat test for serum M protein showed that this parameter remained within the normal range (September 24, 2025).

3. Discussion

This article reports a case of amyloidosis associated with SGPL1 gene mutation. The main manifestations of the patient were abnormal liver and kidney function and hepatomegaly. Monoclonal IgA-κ amyloidosis was diagnosed. Immunomodulatory therapy improved and stabilized the patient’s condition. Based on the clinical characteristics of the patient and a literature review, we speculate that this patient had multisystem amyloidosis due to the increased production of monoclonal IgA-κ protein by plasma cells as a result of a mutation in the SGPL1 gene. This case highlights the importance of genetic screening and an improved understanding of SGPL1 gene mutations in this disease.

Immunoglobulin light chains can be divided into 2 types: kappa (κ) chains and lambda (λ) chains. The κ and λ chains differ in amino acid sequence and disulfide position. [ 19 ] The gene encoding κ chains is composed of the Vκ, Jκ, and Cκ gene clusters. [ 20 ] Under physiological conditions, the ratio of κ and λ free light chains in the serum equals 0.26 to 1.65. [ 21 ] The κ:λ ratio is altered in conditions associated with the monoclonal proliferation of plasma cells, such as plasmacytoma, and can be used for diagnosis and prognostication. For example, [ 22 ] multiple myeloma patients with predominantly λ light chains have a worse prognosis than those with predominantly κ light chains. Moreover, the clinical manifestations of the AL-κ and AL-λ types of amyloidosis are different. In clinical practice, the AL-λ type is more common, and mainly involves the kidneys, whereas the AL-κ type typically involves the gastrointestinal tract and liver. [ 23 ] Furthermore, the severity of renal damage differs between the 2 types of amyloidosis: AL-λ type patients with nephrotic syndrome tend to have more severe proteinuria than AL-κ patients, whereas AL-κ patients show higher serum creatinine levels, less amyloid deposition, and a higher degree of renal tubular atrophy and interstitial fibrosis than AL-λ patients, though the specific mechanisms underlying these differences are unknown. [ 24 – 27 ] In the case reported here, the patient was diagnosed with monoclonal IgA-κ amyloidosis by means of serum and urine immunofixation electrophoresis.

The detection of monoclonal κ or λ immunoglobulin light chain deposition in extracellular tissues [ 28 , 29 ] should alert clinicians to neoplastic diseases, such as multiple myeloma. [ 30 ] In multiple myeloma, amyloidosis due to λ light chains is more common than that due to κ light chains. [ 4 ] Both primary and secondary AL are associated with multiple myeloma, yet they exhibit significant differences in clinical prognosis. [ 31 ] Early methods of immunoelectrophoresis and immunofixation were not sensitive enough to detect M protein. At present, the pathogenesis of multiple myeloma complicated with AL is unclear. About 10% of multiple myeloma patients have AL at the time of diagnosis, and another 10% to 15% may go on to develop AL. [ 32 ] Compared with the light chains generated in multiple myeloma, the light chains generated in amyloidosis show great stability and are less susceptible to degradation. [ 33 ] In clinical practice, the monoclonal IgG-κ type of amyloidosis has the highest incidence, followed by the IgA-κ type, IgM-κ type, and IgD-κ type; biclonal types are relatively rare. [ 34 ] Multiple myeloma and AL show similar protein electrophoresis results, but different clinical manifestations: multiple myeloma is clinically characterized by osteodynia, anemia, hypercalcemia, and renal abnormalities, and on diagnostic work-up, abnormalities are often revealed on bone marrow aspiration and flow cytometry, whereas AL primarily affects the viscera. In our patient, a liver biopsy confirmed the presence of hepatic amyloidosis, and a bone marrow biopsy revealed no obvious abnormality in the bone marrow and blood cells, ruling out multiple myeloma. After receiving immunotherapy, this patient exhibited significant clinical improvement. During subsequent regular follow-up periods, the serum M protein level consistently remained within the normal range, with detailed follow-up data presented in Tables 1 to 3. Comprehensive analysis of all follow-up indicators and test results indicates that following treatment with a systemic chemotherapy regimen, the patient’s condition has been effectively controlled and is currently in a stable state.

Although multiple myeloma was definitively ruled out in this patient, the specific cause of his disease remained unknown. Therefore, to further explore the cause and potentially improve the patient’s prognosis, we performed whole exome sequencing for the detection of genetic disorders. The results revealed an SGPL1 gene mutation. We then reviewed the literature on SGPL1 gene mutation-related diseases. The SGPL1 gene encodes the enzyme sphingosine-1-lyase phosphate, which is mainly located in the endoplasmic reticulum of glomerular cells, especially podocytes, mesangial cells, and endothelial cells. [ 35 ] Research indicates that homozygous mutations in SGPL1 may lead to a severe, specific type of steroid-resistant nephrotic syndrome. [ 36 ] This discovery underscores the central role of SGPL1 in maintaining the glomerular ultrafiltration barrier, which is a critical renal structure primarily constructed by glomerular podocytes that ensures proper filtration of the blood, while preventing the loss of proteins and other important molecules. [ 37 ]

The sphingosine-1-lyase phosphate enzyme breaks down sphingosine-1-phosphate (S1P). [ 38 ] S1P serves as a ligand for a family of 5 G-protein-coupled receptors (S1P receptors 1–5) [ 39 ] ; the S1P-mediated activation of different combinations of these receptors activates downstream signaling pathways. [ 40 ] The biological effects of the S1P signaling pathway may vary depending on differences between cell types. [ 41 ] S1P has important regulatory functions in a variety of normal physiological processes as well as disease processes, and mediates a wide range of biological functions. [ 42 , 43 ] By regulating the flow of sphingolipid metabolism, S1P plays a profound role in cellular metabolism and determining cell fate. [ 44 ] In endothelial cells, S1P has been demonstrated to enhance endothelial barrier function in a dose-dependent manner, as indicated by measuring transepithelial electrical resistance mediated through S1P receptor-1 and S1P receptor-3. [ 45 ] S1P also rapidly promotes the phosphorylation of myosin light chains. [ 46 ] The specific Src inhibitor PP2 was found to block S1P-induced FAK phosphorylation and reduce S1P-induced focal adhesion protein translocation to the cell periphery, indicating that S1P modulates FAK phosphorylation via Src activity. [ 47 ] Furthermore, research has found that S1P can increase the expression of E-cadherin in intestinal epithelial cells, promote the distribution of E-cadherin and β-catenin in the plasma membrane, and reduce paracellular permeability, thereby enhancing the barrier function of intestinal epithelial cells. [ 48 ] Thus, the SGPL1 gene via its encoded enzyme SGPL1 modulates S1P signaling pathways, and plays an important role in cell and tissue homeostasis.

In this case, we focused on the role of the SGPL1 gene and its related metabolite S1P in amyloidosis, which is still unclear. By reviewing the literature, we found that SGPL1 deficiency may result in a decreased ability to degrade S1P, [ 49 ] thus allowing S1P deposition in the liver, [ 50 ] thymus, [ 51 ] and other organs. These deposits could eventually lead to visceral involvement in amyloidosis. Therefore, we hypothesized that SGPL1 gene mutation can lead to the visceral deposition of S1P and subsequent amyloid deposits, leading to viscera-related amyloidosis.

The systemic multi-organ amyloidosis caused by SGPL1 gene mutation may also be associated with the activation of nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) in inflammasomes. [ 52 ] The NLRP3 inflammasome complex is a multiprotein complex composed of cytoplasmic NLRP3 sensor molecules, the bridging protein apoptosis-associated speck-like protein, and caspase-1. [ 53 ] As an important part of the innate immune system, the assembly and activation of the NLRP3 inflammasome can trigger the release of proinflammatory cytokines. [ 54 ] Serum amyloid A is a potent activator of the NLRP3 inflammasome, and activates the NLRP3 inflammasome through cathepsin B, triggering an inflammatory cascade that further activates caspase-1 and leading to the maturation of interleukin-1β, leading to the formation of amyloid fragments. [ 55 ] Activation of the NLRP3 inflammasome has been associated with Alzheimer disease. [ 56 ] Specifically, SGPL1 mutations stimulate the astrocyte purinergic receptor P2Y1R through the S1P/S1PR2/4 signaling axis, mediating the activation of the NLRP3 inflammasome, which after assembly, further activates caspase-1 to form amyloid fragments. [ 57 ] Therefore, we hypothesized that SGPL1 mutation could activate the NLRP3 inflammasome and trigger an inflammatory cascade to promote the development of amyloidosis. As discussed above, SGPL1 -related amyloidosis may represent a rare “inflammation-driven” subtype of amyloidosis, characterized by predominant renal involvement and multisystem manifestations. Its prognosis might be more favorable than that of conventional hereditary subtypes (such as ATTR), [ 58 , 59 ] yet it is crucial to differentiate it from acquired AL-type amyloidosis to prevent misdiagnosis. [ 60 ]

The SGPL1 gene has been associated with a variety of diseases, such as steroid-resistant nephrotic syndrome and adrenal insufficiency. [ 36 ] Inactivation of the SGPL1 gene via mutation is associated with sphingosine phosphate lyase insufficiency syndrome, which can lead to congenital nephrotic syndrome, adrenocortical insufficiency, ichthyosis, immune deficiency, and a variety of neurological pathologies. [ 61 ] Another SGPL1 gene mutation has been associated with low calcium levels, primary adrenocortical hypofunction, nephrotic syndrome, subclinical hypothyroidism, lymphopenia, ptosis, and pathological neuroimaging findings. [ 62 ] Current research reveals that diverse genetic mutations predispose individuals to multisystem amyloidosis. Pathogenic variants in the TTR gene frequently underlie familial amyloidotic polyneuropathy, driven by the aberrant folding and neural deposition of unstable TTR protein. [ 63 – 65 ] Mutations in the apolipoprotein A1 gene correlate with cerebral amyloid angiopathy, compromising cerebrovascular smooth muscle integrity. [ 66 ] Gelsolin gene mutations manifest as cranial neuropathy accompanied by corneal opacification, [ 67 ] while fibrinogen alpha chain gene alterations precipitate hereditary renal amyloidosis through glomerular damage. [ 68 , 69 ] These mechanisms universally involve misfolded proteins adopting amyloid conformations, ultimately impairing organ function. [ 70 ] Notably, our study identified SGPL1 mutations (distinct from classical amyloid precursors) that induce plasma extravasation and trigger inflammatory cascades, secondarily promoting amyloid deposition. This discovery expands the pathogenic framework of amyloidosis, offering a novel paradigm for precision diagnosis and therapeutic targeting. The above reports emphasize the key role of the SGPL1 gene in maintaining human health, and show that its mutations can lead to complex pathological changes. A recent study found a significant interplay between sphingosine, S1P lyase, and insulin signaling. [ 71 ] These findings of the above study underscore the significance of the close relationship between sphingolipid metabolism and insulin signaling in C2C12 myotubes (known as mouse myoblast cell line), highlighting its potential therapeutic relevance to diabetes mellitus. In addition, SGPL1 gene mutation has been correlated with the incidence of lung cancer, [ 72 ] providing a potential therapeutic target for lung cancer treatment. However, no specific treatment is currently available for SGPL1 gene mutation-related diseases, and further studies are required to develop effective treatments.

In summary, in this case report, SGPL1 gene mutation was considered to cause multisystem amyloidosis, based on the results of liver biopsy, serum and urine immunofixation electrophoresis, whole exome sequencing, imaging examination of affected organs, and a literature review. Immunomodulatory therapy stabilized the patients’ condition. Although this article has made a preliminary discussion on the mechanism of SGPL1 gene mutation-related amyloidosis, further animal model verification and in-depth research on the underlying mechanisms are needed.

4. Conclusion

SGPL1 gene mutation may be associated with multisystem amyloidosis. The underlying mechanism may be that SGPL1 gene mutation increases S1P production, activates plasma cells, and results in the continuous proliferation of plasma cells and increased secretion of monoclonal IgA-κ protein, which is deposited in various organs, leading to the occurrence of amyloidosis.

Acknowledgments

We thank Medjaden Inc. for the scientific editing of this manuscript.

Author contributions

Conceptualization: Yunfen Chen, Yue Lia, Yinghua Chen, Xiuying Fan, Yihuai He, Yawen Luo.

Data curation: Yunfen Chen, Yue Liao, Yinghua Chen, Bangneng Yu, Yihuai He.

Formal analysis: Yunfen Chen, Yue Liao, Ya Chen, Xiuying Fan, Xuedong Yi.

Funding acquisition: Yihuai He.

Investigation: Yunfen Chen, Yue Liao, Mingxia Ding, Ya Chen, Xiuying Fan, Xuedong Yi, Yihuai He, Yawen Luo.

Methodology: Yunfen Chen, Yue Liao, Ya Chen, Bangneng Yu, Xiuying Fan, Xuedong Yi, Yihuai He.

Project administration: Yihuai He, Yawen Luo.

Resources: Yawen Luo.

Supervision: Yihuai He, Yawen Luo.

Validation: Yunfen Chen, Yawen Luo.

Writing – original draft: Yunfen Chen, Yue Liao, Bangneng Yu.

Writing – review & editing: Yunfen Chen, Mingxia Ding, Yinghua Chen, Ya Chen, Xiuying Fan, Xuedong Yi, Yihuai He, Yawen Luo.

Abbreviations: AH immunoglobulin heavy-chain amyloidosis AL immunoglobulin light-chain amyloidosis MRI magnetic resonance imaging NLRP3 nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 S1P sphingosine-1-phosphate SGPL1 sphingosine-1-phosphate lyase 1 TTR transthyretin

This study was supported by the Science and Technology Planning Projects of Guizhou Province, and Zunyi City (No. QKHJC-MS (2025) 384, No. gzwkj2023-121, No. gzwkj2024-103, No. QZYY-2023-021, and No. ZSKH-HZ(2024)361), and WBE Liver Fibrosis Foundation (No. CFHPC2025028).

Written informed consent was obtained from the individual for the publication of any potentially identifiable images or data included in this article.

Ethics approval was not required because this is a case report. This study was conducted in compliance with the Declaration of Helsinki. Written informed consent was obtained from the individual participant included in the study.

The authors have no conflicts of interest to disclose.

All data generated or analyzed during this study are included in this published article [and its supplementary information files].

How to cite this article: Chen Y, Liao Y, Ding M, Chen Y, Chen Y, Yu B, Fan X, Yi X, He Y, Luo Y. Diagnosis and treatment of multisystem amyloidosis associated with SGPL1 mutation: A case report and review of the literature. Medicine 2026;105:1(e46653).

YC and YL contributed to this article equally.

Contributor Information

Yunfen Chen, Email: cy19921011@126.com.

Yue Liao, Email: 2595704213@qq.com.

Mingxia Ding, Email: 807893686@qq.com.

Yinghua Chen, Email: cy19921011@126.com.

Ya Chen, Email: cy19921011@126.com.

Bangneng Yu, Email: 54464572@qq.com.

Xiuying Fan, Email: 1473275295@qq.com.

Xuedong Yi, Email: yixuedong506@126.com.

Yihuai He, Email: 993565989@qq.com.

References

[1] Wechalekar AD, Gillmore JD, Hawkins PN. Systemic amyloidosis. Lancet. 2016;387:2641–54.

[2] Gertz MA. Immunoglobulin light chain amyloidosis: 2016 update on diagnosis, prognosis, and treatment. Am J Hematol. 2016;91:947–56.

[3] Chen W, Xie H, Wang H, et al. Prognostic significance of KIT mutations in core-binding factor acute myeloid leukemia: a systematic review and meta-analysis. PLoS One. 2016;11:e0146614.

[4] Gibier JB, Gnemmi V, Glowacki F, et al. Intratubular amyloid in light chain cast nephropathy is a risk factor for systemic light chain amyloidosis. Mod Pathol. 2018;31:452–62.

[5] Plante-Bordeneuve V, Lalu T, Misrahi M, et al. Genotypic–phenotypic variations in a series of 65 patients with familial amyloid polyneuropathy. Neurology. 1998;51:708–14.

[6] Frisoni GB, Altomare D, Thal DR, et al. The probabilistic model of Alzheimer disease: the amyloid hypothesis revised. Nat Rev Neurosci. 2022;23:53–66.

[7] Murrell JR, Hake AM, Quaid KA, Farlow MR, Ghetti B. Early-onset Alzheimer disease caused by a new mutation (V717L) in the amyloid precursor protein gene. Arch Neurol. 2000;57:885–7.

[8] Thellung S, Scoti B, Corsaro A, et al. Pharmacological activation of autophagy favors the clearing of intracellular aggregates of misfolded prion protein peptide to prevent neuronal death. Cell Death Dis. 2018;9:166.

[9] Priyanka, Raymandal B, Mondal S. Native state stabilization of amyloidogenic proteins by kinetic stabilizers: inhibition of protein aggregation and clinical relevance. ChemMedChem. 2024;19:e202400244.

[10] Diao X, Li J, Ouyang J, et al. Flow cytometry-based immunophenotypic analysis of primary systemic light chain amyloidosis. Oncol Lett. 2017;13:2691–7.

[11] Sanchorawala V. High-dose melphalan and autologous peripheral blood stem cell transplantation in AL amyloidosis. Acta Haematol. 2020;143:381–7.

[12] Huang X, Wang Q, Chen W, et al. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014;12:2.

[13] Kastritis E, Wechalekar AD, Dimopoulos MA, et al. Bortezomib with or without dexamethasone in primary systemic (light chain) amyloidosis. J Clin Oncol. 2010;28:1031–7.

[14] Huang B, Li J, Xu X, Zheng D, Zhou Z, Liu J. Successful treatment of renal light chain (AL) amyloidosis with bortezomib and dexamethasone (VD). Pathol Biol (Paris). 2015;63:17–20.

[15] Kastritis E, Leleu X, Arnulf B, et al. Bortezomib, melphalan, and dexamethasone for light-chain amyloidosis. J Clin Oncol. 2020;38:3252–60.

[16] Kastritis E, Dialoupi I, Gavriatopoulou M, et al. Primary treatment of light-chain amyloidosis with bortezomib, lenalidomide, and dexamethasone. Blood Adv. 2019;3:3002–9.

[17] Palladini G, Kastritis E, Maurer MS, et al. Daratumumab plus CyBorD for patients with newly diagnosed AL amyloidosis: safety run-in results of ANDROMEDA. Blood. 2020;136:71–80.

[18] Roussel M, Merlini G, Chevret S, et al. A prospective phase 2 trial of daratumumab in patients with previously treated systemic light-chain amyloidosis. Blood. 2020;135:1531–40.

[19] Wu H, L’Imperio V, Rossi M, Kapp ME, Paueksakon P. Differences between kappa and lambda light chain amyloidosis analyzed by a pathologic scoring system. Am J Clin Pathol. 2023;160:144–9.

[20] van der Kant R, Bauer J, Karow-Zwick AR, et al. Adaption of human antibody lambda and kappa light chain architectures to CDR repertoires. Protein Eng Des Sel. 2019;32:109–27.

[21] Gudowska-Sawczuk M, Mroczko B. Free light chains kappa and lambda as new biomarkers of selected diseases. Int J Mol Sci. 2023;24:9531.

[22] Jiang AS, Wu Z, Wei EX, et al. Plasma cell myeloma with dual expression of kappa and lambda light chains. Int J Clin Exp Pathol. 2018;11:4718–23.

[23] Rosenzweig M, Landau H. Light chain (AL) amyloidosis: update on diagnosis and management. J Hematol Oncol. 2011;4:47.

[24] Ahn YH, Rhee YY, Choi SC, Seo GS. Localized gastric amyloidosis with kappa and lambda light chain co-expression. Clin Endosc. 2018;51:285–8.

[25] Ling VYH, Reddivari S, Joseph AM, Cox R. Oligosecretory myeloma with gastrointestinal tract involvement: an unusual presentation and literature review. BMJ Case Rep. 2022;15:e247742.

[26] Said SM, Sethi S, Valeri AM, et al. Renal amyloidosis: origin and clinicopathologic correlations of 474 recent cases. Clin J Am Soc Nephrol. 2013;8:1515–23.

[27] Kumar S, Dispenzieri A, Katzmann JA, et al. Serum immunoglobulin free light-chain measurement in primary amyloidosis: prognostic value and correlations with clinical features. Blood. 2010;116:5126–9.

[28] Thimm A, Carpinteiro A, Oubari S, et al. Prevalence and predictors of neurological manifestations in systemic AL amyloidosis. J Neurol Sci. 2022;440:120341.

[29] Cardoso BA, Leal R, Sa H, Campos M. Acute liver failure due to primary amyloidosis in a nephrotic syndrome: a swiftly progressive course. BMJ Case Rep. 2016;2016:bcr2016214392.

[30] Asiri MMH, Engelsman S, Eijkelkamp N, Hoppener JWM. Amyloid proteins and peripheral neuropathy. Cells. 2020;9:1553.

[31] Leung N, Barnidge DR, Hutchison CA. Laboratory testing in monoclonal gammopathy of renal significance (MGRS). Clin Chem Lab Med. 2016;54:929–37.

[32] Perrone L, Gervaso L, Bosco E, Serra F, Quaquarini E. Non-traumatic splenic rupture in amyloidosis as a rare evolution of multiple myeloma. Clin Pract. 2019;9:1146.

[33] Blancas-Mejia LM, Horn TJ, Marin-Argany M, Auton M, Tischer A, Ramirez-Alvarado M. Thermodynamic and fibril formation studies of full length immunoglobulin light chain AL-09 and its germline protein using scan rate dependent thermal unfolding. Biophys Chem. 2015;207:13–20.

[34] Wang H, Gao C, Xu L, Yang Z, Zhao W, Kong X. Laboratory characterizations on 2007 cases of monoclonal gammopathies in East China. Cell Mol Immunol. 2008;5:293–8.

[35] Lovric S, Goncalves S, Gee HY, et al. Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency. J Clin Invest. 2017;127:912–28.

[36] Tastemel Ozturk T, Canpolat N, Saygili S, et al. A rare cause of nephrotic syndrome-sphingosine-1-phosphate lyase (SGPL1) deficiency: 6 cases and a review of the literature. Pediatr Nephrol. 2023;38:711–9.

[37] Imeri F, Stepanovska Tanturovska B, Manaila R, Pavenstadt H, Pfeilschifter J, Huwiler A. Loss of S1P lyase expression in human podocytes causes a reduction in nephrin expression that involves PKCdelta activation. Int J Mol Sci. 2023;24:3267.

[38] van Veldhoven PP, Mannaerts GP. Sphingosine-phosphate lyase. Adv Lipid Res. 1993;26:69–98.

[39] Gray N, Limberg MM, Brauer AU, Raap U. Novel functions of S1P in chronic itchy and inflammatory skin diseases. J Eur Acad Dermatol Venereol. 2022;36:365–72.

[40] Xiong Y, Piao W, Brinkman CC, et al. CD4 T cell sphingosine 1-phosphate receptor (S1PR)1 and S1PR4 and endothelial S1PR2 regulate afferent lymphatic migration. Sci Immunol. 2019;4:eaav1263.

[41] Masuda-Kuroki K, Di Nardo A. Sphingosine 1-phosphate signaling at the skin barrier interface. Biology (Basel). 2022;11:809.

[42] Hla T, Brinkmann V. Sphingosine 1-phosphate (S1P): physiology and the effects of S1P receptor modulation. Neurology. 2011;76:S3–8.

[43] Ito H, Yoshida K, Murakami M, et al. Heterogeneous sphingosine-1-phosphate lyase gene expression and its regulatory mechanism in human lung cancer cell lines. Biochim Biophys Acta. 2011;1811:119–28.

[44] Prasad R, Hadjidemetriou I, Maharaj A, et al. Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome. J Clin Invest. 2017;127:942–53.

[45] Garcia JG, Liu F, Verin AD, et al. Sphingosine 1-phosphate promotes endothelial cell barrier integrity by Edg-dependent cytoskeletal rearrangement. J Clin Invest. 2001;108:689–701.

[46] Camp SM, Chiang ET, Sun C, et al. Pulmonary endothelial cell barrier enhancement by novel FTY720 analogs: methoxy-FTY720, fluoro-FTY720, and beta-glucuronide-FTY720. Chem Phys Lipids. 2016;194:85–93.

[47] Wang L, Chiang ET, Simmons JT, Garcia JG, Dudek SM. FTY720-induced human pulmonary endothelial barrier enhancement is mediated by c-Abl. Eur Respir J. 2011;38:78–88.

[48] Greenspon J, Li R, Xiao L, et al. Sphingosine-1-phosphate regulates the expression of adherens junction protein E-cadherin and enhances intestinal epithelial cell barrier function. Dig Dis Sci. 2011;56:1342–53.

[49] Yuan F, Wang Z, Sun Y, et al. Sgpl1 deletion elevates S1P levels, contributing to NPR2 inactivity and p21 expression that block germ cell development. Cell Death Dis. 2021;12:574.

[50] Bektas M, Allende ML, Lee BG, et al. Sphingosine 1-phosphate lyase deficiency disrupts lipid homeostasis in liver. J Biol Chem. 2010;285:10880–9.

[51] Weber C, Krueger A, Munk A, Bode C, Van Veldhoven PP, Graler MH. Discontinued postnatal thymocyte development in sphingosine 1-phosphate-lyase-deficient mice. J Immunol. 2009;183:4292–301.

[52] Fu J, Wu H. Structural mechanisms of NLRP3 inflammasome assembly and activation. Annu Rev Immunol. 2023;41:301–16.

[53] Xu J, Nunez G. The NLRP3 inflammasome: activation and regulation. Trends Biochem Sci. 2023;48:331–44.

[54] Zhan X, Li Q, Xu G, Xiao X, Bai Z. The mechanism of NLRP3 inflammasome activation and its pharmacological inhibitors. Front Immunol. 2022;13:1109938.

[55] Niemi K, Teirila L, Lappalainen J, et al. Serum amyloid A activates the NLRP3 inflammasome via P2X7 receptor and a cathepsin B-sensitive pathway. J Immunol. 2011;186:6119–28.

[56] Saresella M, La Rosa F, Piancone F, et al. The NLRP3 and NLRP1 inflammasomes are activated in Alzheimer’s disease. Mol Neurodegener. 2016;11:23.

[57] Hirvonen TP, Aalto H, Pyykko I, Juhola M. Comparison of two head autorotation tests. J Vestib Res. 1999;9:119–25.

[58] Ruberg FL, Teruya S, Helmke S, et al. Transthyretin cardiac amyloidosis in older black and hispanic individuals with heart failure. JAMA Cardiol. 2025;10:1034–43.

[59] Yamane M, Umeda H, Toyobe M, et al. Catalytic photooxygenation demonstrates therapeutic efficacy in transthyretin amyloidosis. J Am Chem Soc. 2025;147:28860–74.

[60] Guaraldi P, Allegri I, Ariatti A, et al. Monitoring patients and asymptomatic carriers with hereditary transthyretin amyloidosis: regional protocol of Emilia-Romagna ATTR working group. Front Neurol. 2025;16:1666318.

[61] Ron HA, Scobell R, Strong A, Salazar EG, Ganetzky R. Congenital adrenal calcifications as the first clinical indication of sphingosine lyase insufficiency syndrome: a case report and review of the literature. Am J Med Genet A. 2022;188:3312–7.

[62] Buyukyilmaz G, Adiguzel KT, Aksoy OY, et al. Novel sphingosine-1-phosphate lyase mutation causes multisystemic diseases: case report. Turk J Pediatr. 2023;65:1025–32.

[63] Fontana M, Berk JL, Gillmore JD, et al. Vutrisiran in patients with transthyretin amyloidosis with cardiomyopathy. N Engl J Med. 2025;392:33–44.

[64] Gillmore JD, Judge DP, Cappelli F, et al. Efficacy and safety of acoramidis in transthyretin amyloid cardiomyopathy. N Engl J Med. 2024;390:132–42.

[65] Maurer MS, Kale P, Fontana M, et al. Patisiran treatment in patients with transthyretin cardiac amyloidosis. N Engl J Med. 2023;389:1553–65.

[66] Prokaeva T, Jayaraman S, Klimtchuk E, et al. An unusual phenotype of hereditary AApoAI amyloidosis caused by a novel Asp20Tyr substitution is linked to pH-dependent aggregation of apolipoprotein A-I. Biochim Biophys Acta Mol Basis Dis. 2025;1871:167820.

[67] Naiki H, Johnson M, Walters K, et al. Global patterns of amyloid typing: results of a survey by the International Society of Amyloidosis (ISA). Amyloid. 2025;32:139–44.

[68] Pande M, Kundu D, Srivastava R. Selective vitamins as potential options for dietary therapeutic interventions: in silico and in vitro insights from mutant C terminal fragment of FGA. J Steroid Biochem Mol Biol. 2023;230:106290.

[69] Meyer L, Ulrich M, Ducloux D, et al. Organ transplantation in hereditary fibrinogen A alpha-chain amyloidosis: a case series of French patients. Am J Kidney Dis. 2020;76:384–91.

[70] Sipe JD, Benson MD, Buxbaum JN, et al. Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines. Amyloid. 2016;23:209–13.

[71] Rustamov J, Roh YS, Hong JT, Yoo HS. GT-11 impairs insulin signaling through modulation of sphingolipid metabolism in C2C12 myotubes. Life Sci. 2024;342:122534.

[72] Nema R, Pandey R, Kumar A. A crosstalk between the receptor tyrosine kinase-like orphan receptors ROR1/2 and S1P signaling pathways in lung cancer. Asian Pac J Cancer Prev. 2024;25:725–33.