• Amiodarone
• Cationic amphiphilic drug
• Drug-induced phospholipidosis
• Enzyme replacement therapy
• Fabry disease
• Glycosphingolipid
• Hydroxychloroquine
• α-Galactosidase A

• amiodarone
• drug-induced-phospholipidosis
• hydroxychloroquine
• monoclonal gammopathy of renal significance
• zebra bodies

• Humans
• Acute Kidney Injury/chemically induced
• Amiodarone/adverse effects
• Hydroxychloroquine/adverse effects
• Hydroxychloroquine/therapeutic use
• Lipidoses/chemically induced
• Paraproteinemias/chemically induced
• Phospholipids
• Female
• Aged

• Hydroxychloroquine
• phospholipidosis
• proteinuria

• Development
• Disease modeling
• Human pluripotent stem cell
• Kidney
• Organoids
• Vascular system

• Children
• Genetic
• Monogenic
• Noonan syndrome
• RAS/MAPK
• SHOC2
• Systemic lupus erythematosus
• Zebra bodies

• Adolescent
• Humans
• Male
• Loose Anagen Hair Syndrome
• Lupus Erythematosus, Systemic/complications
• Lupus Erythematosus, Systemic/diagnosis
• Lupus Erythematosus, Systemic/genetics
• Lupus Nephritis/diagnosis
• Lupus Nephritis/genetics
• Lupus Nephritis/complications
• Noonan Syndrome/complications
• Noonan Syndrome/diagnosis
• Noonan Syndrome/genetics

• Case report
• Fabry disease
• Hydroxychloroquine
• Renal phospholipidosis

• Cardiovascular medicine
• Cardiovascular system
• Heart failure
• Rheumatoid arthritis

• Classical phenotype
• Evolution
• Fabry disease
• Initial manifestation
• Renal involvement

• Calcineurin inhibitor
• Chronic kidney disease
• Drug-induced phospholipidosis
• Fabry disease
• Lung transplantation
• Zebra body

Niemann-Pick type C (NPC) is an autosomal recessive lysosomal storage disease (LSD) caused by mutations in NPC1 or NPC2 genes. Mutations result in abnormal cholesterol trafficking, which is manifested by abnormal cholesterol and glycosphingolipid accumulation in lysosomes of various cells.

The patient had a history of hyperlipidemia, hypertension, depression, and elevated alkaline phosphatase and initially presented for a workup regarding chronic kidney disease stage G3b/A3 with proteinuria of 1.9 g/day.

Kidney biopsy revealed numerous lamellar bodies (LB) in podocytes with differential diagnoses of Fabry disease (FD), nail-patella syndrome (which is associated with LMX1B gene mutations), and drug-induced phospholipidosis per pathology report. Her workup was negative for a galactosidase-alpha (GLA) mutation with normal serum and leukocyte alpha-galactosidase A activity. She was serendipitously discovered to have compound heterozygous mutations in NPC1 genes (one pathogenic and the other a variant of uncertain significance) from the comprehensive lysosomal storage gene panel as part of her genetic workup for FD. Further studies were done to determine the significance of the NPC1 mutation and revealed elevated oxysterols. (The profile was consistent with NPC, with elevated cholestane-3beta,5alpha,6beta-triol and 7-ketocholesterol and normal lyso-sphingomyelin.) Sonogram revealed hepatosplenomegaly (liver measuring 20 cm and spleen 15.8 cm). These findings in conjunction with lysosomal lipid accumulation on kidney biopsy were consistent with NPC.

She was on 2 cationic amphiphilic agents (CAAs), fluoxetine and atorvastatin, both of which were stopped. There was no significant difference in proteinuria 2 months off CAAs. The treatment of NPC remained supportive care and avoiding medications that can induce seizures or excessive salivary secretion.

The presence of LB is classically described as a feature of FD which is an LSD. Niemann-Pick type C is another example of an LSD and is typically manifested by neurovisceral symptoms and varies by the age of onset. Renal diseases are typically not described as one of the manifestations of NPC. To our knowledge, there is only one report each for Niemann-Pick disease type A/B and NPC with LB on kidney biopsy. The finding reaffirms that the presence of LB indicates lysosomal lipid accumulation from a variety of etiologies and is not a pathognomonic finding of FD. Niemann-Pick type C should be included as one of the diseases capable of causing renal LB.

• Fabry disease
• Niemann-Pick type C
• lamellar bodies
• oxysterols
• renal phospholipidosis

• Chronic kidney disease
• Fatty acid oxidation
• Metabolism
• Mitochondria
• Nephrology

• Animals
• Diabetic Nephropathies/metabolism
• Fatty Acids/metabolism
• Female
• Homozygote
• Male
• Mice
• Mitochondria/metabolism
• Sequence Deletion

• P30 DK072476 NIDDK NIH HHS
• R01 DK103860 NIDDK NIH HHS
• P20 GM135002 NIGMS NIH HHS
• R01 HL148114 NHLBI NIH HHS
• P20 GM103528 NIGMS NIH HHS
• R01 DK115749 NIDDK NIH HHS

• Cationic amphiphilic drugs
• Fabry disease
• drug-induced phospholipidosis
• lamellar bodies
• myelin-like bodies
• myeloid bodies
• phospholipidosis
• zebra bodies

•

Fabry is an X-linked lysosomal storage disease with deficiency in α-galactosidase.

Lipidomics analysis or lipid profiling is a system-based analysis of all lipids in a sample to provide a comprehensive understanding of lipids within a biological system. In the last few years, lipidomics has made it possible to better understand the metabolic processes associated with several rare disorders and proved to be a powerful tool for their clinical investigation. Fabry disease is a rare X-linked lysosomal storage disorder (LSD) caused by a deficiency in α-galactosidase A (α-GAL A). This deficiency results in the progressive accumulation of glycosphingolipids, mostly globotriaosylceramide (Gb₃), globotriaosylsphingosine (lyso-Gb₃), as well as galabiosylceramide (Ga₂) and their isoforms/analogs in the vascular endothelium, nerves, cardiomyocytes, renal glomerular podocytes, and biological fluids.

The primary objective of this study was to evaluate lipidomic signatures in renal biopsies to help understand variations in Fabry disease markers that could be used in future diagnostic tests.

Lipidomic analysis was performed by ultra-high pressure liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS) on kidney biopsies that were left over after clinical pathology analysis to diagnose Fabry disease.

We employed UHPLC-HRMS lipidomics analysis on the renal biopsy of a patient suspicious for Fabry disease. Our result confirmed α-GAL A enzyme activity declined in this patient since a Ga2-related lipid biomarker was substantially higher in the patient's renal tissue biopsy compared with two controls. This suggests this patient has a type of LSD that could be non-classical Fabry disease.

This study shows that lipidomics analysis is a valuable tool for rare disorder diagnosis, which can be conducted on leftover tissue samples without disrupting normal patient care.

• induced pluripotent stem cells
• stem-cell differentiation

Drug-induced lysosomal storage disease (DILSD) caused by cationic amphiphilic drugs (CADs), which exhibits toxic manifestations and pathological findings mimicking Fabry disease (α-galactosidase A deficiency), has attracted the interests of clinicians and pathologists. Although the affected region is lysosomes in both the diseases, DILSD is characterized by intralysosomal accumulation of phospholipids and Fabry disease that of globotriaosylceramide (Gb3) and globotriaosylsphingosine (Lyso-Gb3). However, it is unknown whether administration of CADs affects the catabolism of Gb3 and Lyso-Gb3 in Fabry disease. In this study, we independently administered hydroxychloroquine/amiodarone to wild-type and Fabry mice and examined the effects of the drugs on the enzyme activity and substrates accumulated in organs and tissues. The results revealed that the administration of the drugs induced accumulation of phosphatidylcholine in both the wild-type and Fabry mice. However, reduction of α-galactosidase A activity in the organs and tissues of the wild-type mice was not found, and the storage of Gb3 and Lyso-Gb3 was not accelerated by these drugs in the Fabry mice. This suggests that hydroxychloroquine/amiodarone do not have any significant impact on the catabolism of Gb3 and Lyso-Gb3 in organs and tissues of both wild-type and Fabry mice.

•

Effects of cationic amphiphilic drugs on the catabolism of Gb3/Lyso-Gb3 were examined.

• Amiodarone
• CAD, cationic amphiphilic drug
• DILSD, drug-induced lysosomal storage disease
• Drug-induced lysosomal storage disease
• Fabry disease
• Gb3, globotriaosylceramide
• Globotriaosylceramide
• Globotriaosylsphingosine
• Hydroxychloroquine
• ILV, intralysosomal luminal vesicle
• LC, liquid chromatography
• Lyso-Gb3, globotriaosylsphingosine
• MRM, multiple reaction monitoring
• MS/MS, tandem mass spectrometry
• PhC, phosphatidylcholine
• Phospholipid
• α-Gal, α-galactosidase A
• α-Galactosidase A

There are more than 150 different rare genetic kidney diseases. They can be classified according to diagnostic findings as (i) disorders of growth and structure, (ii) glomerular diseases, (iii) tubular, and (iv) metabolic diseases. In recent years, there has been a shift of paradigm in this field. Molecular testing has become more accessible, our understanding of the underlying pathophysiologic mechanisms of these diseases has evolved, and new therapeutic strategies have become more available. Therefore, the role of nephrologists has progressively shifted from a mere spectator to an active player, part of a multidisciplinary team in the diagnosis and treatment of these disorders. This article provides an overview of the recent advances in rare hereditary kidney disorders by discussing the genetic aspects, clinical manifestations, diagnostic, and therapeutic approaches of some of these disorders, named familial focal and segmental glomerulosclerosis, tuberous sclerosis complex, Fabry nephropathy, and MYH-9 related disorder.

• fabry disease
• neuropathy
• pain
• nerve
• drg
• human
• preclinical
• animal models
• nociceptors

• Fabry Disease/complications
• Humans
• Neuralgia/etiology
• Neurons
• Quality of Life
• alpha-Galactosidase/genetics
• alpha-Galactosidase/therapeutic use

• R01 NS040538 NINDS NIH HHS
• R01 NS070711 NINDS NIH HHS
• R37 NS108278 NINDS NIH HHS

Chloroquine (CQ) and its hydroxylated analog, hydroxychloroquine (HCQ), are 4-aminoquinoline initially used as an antimalarial treatment. CQ and HCQ (4-aminoquinoline, 4-AQ) are today used in rheumatology, especially to treat rheumatoid arthritis and systemic lupus erythematosus. Their mechanism of action revolves around a singular triptych: 4-AQ acts as alkalizing agents, ionized amphiphilic molecules, and by binding to numerous targets. 4-AQ have so pleiotropic and original mechanisms of action, providing them an effect at the heart of the regulation of several physiological functions. However, this broad spectrum of action is also at the origin of various and original side effects, notably a remarkable chronic systemic toxicity. We describe here the 4-AQ-induced lesions on the eye, the heart, muscle, the nerves, the inner ear, and the kidney. We also describe their prevalence, their pathophysiological mechanisms, their risk factors, their potential severity, and the means to detect them early. Most of these side effects are reversible if treatment is stopped promptly. This 4-AQ-induced toxicity must be known to prescribing physicians, to closely monitor its appearance and stop treatment in time if necessary.

• Hydroxychloroquine
• Iatrogenesis

• diseases
• medical research

• Adult
• Aged
• Creatine Kinase/metabolism
• Fructose-Bisphosphate Aldolase/metabolism
• Humans
• Hydroxychloroquine/administration & dosage
• Hydroxychloroquine/adverse effects
• Hydroxychloroquine/toxicity
• L-Lactate Dehydrogenase/metabolism
• Middle Aged
• Muscle Weakness/epidemiology
• Muscle Weakness/etiology
• Muscle, Skeletal/drug effects
• Muscle, Skeletal/metabolism
• Muscle, Skeletal/pathology
• Observational Studies as Topic

• R01 NS105621 NINDS NIH HHS
• R01 AG060341 NIA NIH HHS
• P01 AG039355 NIA NIH HHS
• R01 DK119066 NIDDK NIH HHS
• R01 AG056504 NIA NIH HHS
• George W. and Hazel M. Jay and Evanston Research Endowments
• FAPESP
• National Institutes of Aging
• National Institutes of Neurological Disorders and Stroke
• National Institutes of Diabetes, Digestive, and Kidney Diseases Kidney

Zebra bodies in kidney biopsy specimens are widely accepted as a specific feature of Fabry disease but they can also be present in a drug-induced mimic of Fabry disease, phospholipidosis. Chloroquine and hydroxychloroquine may both induce zebra body formation and kidney phospholipidosis. However, the frequency and clinical significance of such changes remain unknown. We report 5 serial kidney biopsy cases diagnosed as lupus nephritis during hydroxychloroquine administration. All 5 patients exhibited a few, but varying amounts, of zebra bodies in glomerular intrinsic cells, that is, podocytes, parietal epithelial cells, mesangial cells, and endothelial cells. Most of the zebra bodies detected were subtle, though certainly recognizable; these zebra bodies were much smaller than those observed in Fabry disease. Zebra bodies were not observed in patients with lupus nephritis in the absence of chloroquine or hydroxychloroquine administration. All patients with lupus nephritis who received hydroxychloroquine achieved complete remission during continuous use of hydroxychloroquine, though kidney toxicity of drug-induced phospholipidosis might be masked by immunosuppression. Based on this small series of cases, we speculate that the hydroxychloroquine-associated manifestation of zebra bodies and phospholipidosis in the kidney may be frequent phenomena and may have only a subclinical influence on kidney function, at least in the short term.

• Chloroquine
• Fabry disease
• hydroxychloroquine
• lupus nephritis
• phospholipidosis
• zebra body

• Fabry
• chronic kidney disease
• end-stage renal disease
• kidney disease
• renal failure

• Fabry disease
• Systemic lupus erythematosus
• hydroxychloroquine
• proteinuria
• renal biopsy

• Covid-19
• Pandemic
• acute kidney injury
• acute tubular injury
• hydroxychloroquine
• zebra bodies

• HLA-C antibody-mediated renal transplant rejection
• zebra bodies in renal transplant

Fabry disease is a kind of lysosomal storage disease resulting from deficient activity of the lysosomal hydrolase alpha-galactosidase A (GLA). A mutation in the GLA gene leads to a loss of activity of alpha-galactosidase A. Some drugs, such as hydroxychloroquine, can cause pathological changes similar to those usually seen in Fabry disease.

We report the case of a 41-year-old female patient who was diagnosed with undifferentiated connective tissue disease in 2008. Hydroxychloroquine treatment started 2 years ago, and proteinuria and hematuria increased. Renal biopsy demonstrated renal phospholipidosis. Zebra bodies and myelin figures were found by renal electron microscopy and were initially thought to be indicators of Fabry disease. A genetic analysis of the patient and her family members did not reveal mutations in the GLA gene, supporting a diagnosis of hydroxychloroquine-induced renal phospholipidosis.

This report reveals one of the adverse effects of hydroxychloroquine. We should pay more attention to hydroxychloroquine-induced renal phospholipidosis.

• Fabry disease
• Undifferentiated connective tissue disease
• Hydroxychloroquine
• Renal phospholipidosis
• Case report

• pathology
• proteinurea
• renal system
• unwanted effects/adverse reactions