Sphingosine Phosphate Lyase Insufficiency Syndrome

Genetic MONDO:0033203 Pathograph 41 Show in embeddings browser MONDO:0044765 MONDO:0018117

Sphingosine phosphate lyase insufficiency syndrome (SPLIS; nephrotic syndrome type 14, OMIM #617575) is an autosomal recessive, non-lysosomal inborn error of sphingolipid metabolism first described in 2017, caused by biallelic inactivating variants in SGPL1. SGPL1 encodes sphingosine-1-phosphate (S1P) lyase, a pyridoxal 5'-phosphate-dependent endoplasmic reticulum enzyme that irreversibly cleaves S1P at the only exit point of sphingolipid catabolism. Loss of the enzyme causes accumulation of S1P, sphingosine and ceramide species in blood and tissues, with cell-type-specific consequences: podocyte cytoskeletal disorganization and loss (steroid-resistant nephrotic syndrome, most often with focal segmental glomerulosclerosis, progressing to kidney failure), disrupted adrenocortical zonation and steroidogenesis (primary adrenal insufficiency, often with adrenal calcification), impaired lymphocyte egress (T-cell lymphopenia and immunodeficiency), keratinocyte hyperdifferentiation (ichthyosis), and a progressive neurological disorder with deep grey nuclei involvement, cranial nerve palsies, sensorineural hearing loss and peripheral neuropathy. Additional endocrinopathies include primary hypothyroidism and, in boys, primary gonadal insufficiency. The phenotype is highly variable, from nonimmune fetal hydrops and neonatal death to adolescent-onset isolated adrenal insufficiency or nephropathy. Roughly half of reported patients have died, most in infancy from kidney failure or sepsis; diagnosis of nephropathy in the first year of life and prenatal presentation mark the highest-risk groups, while the common p.Arg222Gln (R222Q) allele is associated with milder disease. Pyridoxine (vitamin B6) cofactor supplementation benefits a subset of patients with responsive missense alleles, kidney transplantation extends survival, and AAV-mediated SGPL1 gene replacement and ROCK inhibition are in preclinical development.

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1
Inheritance
9
Pathophys.
25
Phenotypes
2
Gaps
41
Pathograph
1
Genes
3
Variants
8
Medical Actions
2
Differentials
2
Trials
4
Models
1
References
1
Deep Research
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Classifications

Harrison's Part
KIDNEY URINARY TRACT ENDOCRINOLOGY METABOLISM GENETICS ENVIRONMENT DISEASE
ICIMD (Inherited Metabolic Disorders)
sphingolipid synthesis and recycling
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Inheritance

1
Autosomal recessive HP:0000007
SPLIS is inherited in an autosomal recessive manner; parental consanguinity is reported in about 70% of patients. Expressivity is highly variable, including within kindreds, and there is no clear overall genotype-phenotype correlation apart from the milder R222Q-associated course.
Autosomal recessive inheritance Penetrance: COMPLETE Expressivity: VARIABLE
Show evidence (2 references)
PMID:33074640 SUPPORT Human Clinical
"SPLIS is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an SGPL1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being..."
GeneReviews statement of the inheritance pattern and recurrence risk.
PMID:35904228 SUPPORT Human Clinical
"There is no clear genotype-phenotype correlation overall in the syndrome, with variable disease penetrance within individual kindreds."
Documents the variable expressivity, including intrafamilial variability.
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Discussions and Knowledge Gaps

2
Which S1P-receptor-dependent and receptor-independent pathways link sphingolipid accumulation to adrenocortical and neuronal injury in SPLIS, and why are these tissues vulnerable while others are spared?
KNOWLEDGE GAP OPEN splis_organ_specific_mechanism_gap
Attached to
pathophysiology#Adrenocortical Zonation and Steroidogenesis Failure pathophysiology#Neuronal and Myelin Sphingolipid Dysregulation
The lymphopenia is mechanistically explained by loss of the S1P egress gradient and the podocyte lesion by Rho/ROCK hyperactivation, but the adrenal and neurological pathogenesis remains unknown; recent data showing that S1P does not invariably accumulate in SPL-deficient cells make the tissue-specific trigger an open question.
Show evidence (1 reference)
PMID:34133011 SUPPORT Human Clinical
"Other manifestations of SPLIS include nephrotic syndrome, neuronal defects, and adrenal insufficiency, but their pathogenesis remains unknown."
Authors' explicit statement of the mechanistic gap.
Does the constitutive Sgpl1 knockout mouse, which dies within weeks of birth, model the later-onset, R222Q-associated and isolated-adrenal presentations of human SPLIS?
HUMAN MODEL MISMATCH OPEN splis_knockout_lethality_model_mismatch
Attached to
pathophysiology#Biallelic SGPL1 Loss of Function
The null mouse models the severe infantile end of the spectrum but cannot reproduce the milder hypomorphic disease; the pyridoxine-dependent R222Q knock-in, which is phenotypically silent on B6-enriched chow, is the first model of a hypomorphic allele and shows that diet can gate the phenotype, so extrapolation from the null to the common human genotype needs care.
Show evidence (1 reference)
PMID:42182331 SUPPORT Model Organism
"SPLR222Q mice fed pyridoxine-enriched chow lacked obvious phenotypes."
Shows the hypomorphic model's phenotype is conditional on cofactor availability.
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Pathophysiology

9
Biallelic SGPL1 Loss of Function
Biallelic SGPL1 variants abolish or severely reduce sphingosine-1-phosphate lyase, the pyridoxal 5'-phosphate-dependent endoplasmic reticulum enzyme that irreversibly cleaves S1P into hexadecenal and phosphoethanolamine. Missense alleles reduce activity and can mislocalise the protein; truncating alleles abolish it. Because the lyase guards the only exit from sphingolipid metabolism, its loss blocks the entire degradative pathway.
sphingosine-1-phosphate lyase activity GO:0008117 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased sphingosine-1-phosphate lyase activity, annotated with sphinganine-1-phosphate aldolase activity (GO:0008117). GO:0008117 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Sphingoid Base Phosphate and Sphingolipid Accumulation
Show evidence (2 references)
PMID:28165339 SUPPORT In Vitro
"All mutations resulted in reduced or absent SGPL1 protein and/or enzyme activity. Overexpression of cDNA representing SGPL1 mutations resulted in subcellular mislocalization of SGPL1."
Functional characterisation of the disease alleles as loss of function.
PMID:30274713 SUPPORT Other
"Sphingosine-1-phosphate lyase (SPL) is an intracellular enzyme that controls the final step in the sphingolipid degradative pathway, the only biochemical pathway for removal of sphingolipids."
Review establishing why loss of this single enzyme blocks all sphingolipid removal.
Sphingoid Base Phosphate and Sphingolipid Accumulation
Without the lyase, S1P, sphingosine, ceramides and sphingomyelin accumulate in plasma, urine and cells. S1P is a bioactive signalling lipid acting through five G-protein-coupled S1P receptors and intracellular targets, so the accumulation is not inert storage but excessive signalling. Metabolic labelling shows that cells partly buffer S1P by feedback-inhibiting de novo synthesis and diverting ceramide into glycosphingolipids; pathological intracellular S1P accumulation emerges when these compensations are overwhelmed, and Sgpl1-null kidneys show pronounced S1P enrichment and urinary excretion.
sphingolipid catabolic process GO:0030149 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased sphingolipid catabolic process (GO:0030149). GO:0030149 is a biological process from the Gene Ontology. ↓ DECREASED sphingosine-1-phosphate receptor signaling pathway GO:0003376 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased sphingosine-1-phosphate receptor signaling pathway (GO:0003376). GO:0003376 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Podocyte Cytoskeletal Disorganization and Loss
Adrenocortical Zonation and Steroidogenesis Failure
Impaired Lymphocyte Egress and T-Cell Lymphopenia
Keratinocyte Hyperdifferentiation and Epidermal Barrier Disruption
Mitochondrial Dysfunction
Neuronal and Myelin Sphingolipid Dysregulation
Show evidence (2 references)
PMID:32682944 SUPPORT In Vitro
"Mass spectrometric analysis of patient dermal fibroblasts revealed significantly elevated levels of sphingosine-1-phosphate, sphingosine, ceramide species and sphingomyelin when compared to control."
Quantifies the breadth of sphingolipid accumulation in patient cells.
PMID:42024444 SUPPORT In Vitro
"Metabolic stable isotope labeling revealed that SPL deficiency does not invariably result in S1P accumulation. Instead, SPL-deficient cells maintain near-normal S1P levels through (a) feedback regulation of de novo sphingolipid synthesis via the ORMDL-ceramide axis and (b) increased diversion of..."
Qualifies the accumulation model: compensatory rerouting buffers S1P until the sphingolipid load exceeds it.
Podocyte Cytoskeletal Disorganization and Loss
SGPL1 is expressed in podocytes and mesangial cells. Excess S1P drives Rho/ROCK hyperactivation, disorganising the podocyte actin cytoskeleton; ultrastructure in the R222Q mouse shows foot process effacement and podocyte loss, and knockdown in mesangial cells impairs migration in an S1P-receptor-dependent manner. This is the disorder-specific initiating podocyte insult of the conserved nephrotic podocytopathy chain.
podocyte CL:0000653 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves podocyte (CL:0000653). CL:0000653 is a cell type from the Cell Ontology. glomerular mesangial cell CL:1000742 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves glomerular mesangial cell (CL:1000742). CL:1000742 is a cell type from the Cell Ontology.
actin cytoskeleton organization GO:0030036 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal actin cytoskeleton organization (GO:0030036). GO:0030036 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Animal models
Sgpl1 knockout mouse Mouse recapitulates Renal S1P enrichment with cytoskeletal disorganisation and impaired epithelial morphogenesis, rescued by ROCK inhibition.
SGPL1 R222Q knock-in mouse Mouse recapitulates Reproduces the human allele, its pyridoxine dependence and the podocyte lesion.
Drosophila Sply mutant Drosophila melanogaster partially recapitulates Nephrocyte filtration defect used to test the functional consequence of patient alleles.
Downstream
Glomerular Filtration Barrier Failure and Glomerulosclerosis
Show evidence (2 references)
PMID:28165339 SUPPORT In Vitro
"Immunofluorescence revealed SGPL1 expression in mouse podocytes and mesangial cells. Knockdown of Sgpl1 in rat mesangial cells inhibited cell migration, which was partially rescued by VPC23109, an S1P receptor antagonist."
Localises the enzyme to the glomerular cells and shows an S1P-receptor-dependent cellular defect.
PMID:42024444 SUPPORT Model Organism
"Pharmacological ROCK inhibition with fasudil mitigated renal cytoskeletal defects in Sgpl1-/- and Sgpl1rosa+fl/fl mice and partially restored epithelial architecture."
Pharmacological rescue confirms Rho/ROCK as the mediator of the cytoskeletal lesion.
Glomerular Filtration Barrier Failure and Glomerulosclerosis
Podocyte injury breaks the size- and charge-selective filtration barrier, producing steroid-resistant nephrotic-range proteinuria. Kidney biopsies show focal segmental glomerulosclerosis (including the collapsing variant) or diffuse mesangial sclerosis, and Sgpl1-knockout kidneys show STAT3 activation with proinflammatory and profibrogenic cytokine elevation. Progression to end-stage kidney disease ranges from under a month to five years after onset of proteinuria.
glomerular filtration GO:0003094 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal glomerular filtration (GO:0003094). GO:0003094 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Animal models
Sgpl1 knockout mouse Mouse recapitulates Nephrosis with glomerular pathology and profibrotic cytokine signalling, prevented by AAV-SGPL1 gene transfer.
Downstream
Steroid-resistant nephrotic syndrome
Focal segmental glomerulosclerosis
Stage 5 chronic kidney disease
Show evidence (2 references)
PMID:33755599 SUPPORT Model Organism
"STAT3 pathway activation and elevated proinflammatory and profibrogenic cytokines observed in KO kidneys were attenuated by treatment."
Identifies the inflammatory and profibrotic signalling in the knockout kidney that underlies glomerulosclerosis.
PMID:35748945 SUPPORT Human Clinical
"Kidney biopsy showed focal segmental glomerulosclerosis in 2 patients and diffuse mesangial sclerosis in one patient. Steroids were given to 3 patients, but they did not respond. All 6 patients progressed to chronic kidney disease"
Histology and steroid resistance in a clinical series.
Adrenocortical Zonation and Steroidogenesis Failure
Sgpl1-null mice show disrupted adrenocortical zonation and defective expression of steroidogenic enzymes, and patient fibroblasts show reduced cortisol output after progesterone stimulation. In patients this manifests as glucocorticoid deficiency in early childhood, with mineralocorticoid deficiency in about a third, and prenatally detectable adrenal calcification in some. The intermediate steps by which sphingolipid accumulation disrupts adrenal development and steroidogenesis are not established.
adrenocortical cell CL:0002097 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves adrenocortical cell, annotated with cortical cell of adrenal gland (CL:0002097). CL:0002097 is a cell type from the Cell Ontology.
glucocorticoid biosynthetic process GO:0006704 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased glucocorticoid biosynthetic process (GO:0006704). GO:0006704 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Sgpl1 knockout mouse Mouse recapitulates Adrenal histology in the null mouse shows disrupted zonation and reduced steroidogenic enzyme expression.
Downstream
Primary adrenal insufficiency
Adrenal calcification
Show evidence (2 references)
PMID:28165343 SUPPORT Model Organism
"Sgpl1-/- mice displayed disrupted adrenocortical zonation and defective expression of steroidogenic enzymes as well as renal histology in keeping with a glomerular phenotype."
Knockout adrenal histology establishing the tissue-level lesion.
PMID:32682944 SUPPORT In Vitro
"Reduced cortisol output in response to progesterone stimulation was observed in two patient dermal fibroblast cell lines."
Patient-cell steroidogenic defect corroborating the adrenal phenotype.
Impaired Lymphocyte Egress and T-Cell Lymphopenia
Lymphocyte egress from thymus and lymph nodes follows an S1P gradient sensed by S1P receptor 1; loss of the lyase abolishes the gradient, trapping lymphocytes in lymphoid organs. T-cell lymphopenia is a near-universal feature, and although some T-cell function persists, patients have recurrent viral, fungal and bacterial infections and sepsis is a leading cause of death.
T cell CL:0000084 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T cell (CL:0000084). CL:0000084 is a cell type from the Cell Ontology.
T cell migration GO:0072678 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased T cell migration (GO:0072678). GO:0072678 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Decreased total lymphocyte count
Recurrent infections
Show evidence (2 references)
PMID:34133011 SUPPORT Human Clinical
"buildup of sphingolipid intermediates, including its bioactive substrate, sphingosine-1-phosphate (S1P), the latter causing lymphopenia, a hallmark of the disease"
Attributes the lymphopenia to S1P accumulation.
PMID:28181337 SUPPORT Other
"S1P is an intracellular and extracellular signaling molecule involved in angiogenesis, vascular maturation, and immunity."
Background for the immune role of S1P signalling disrupted in the disease.
Keratinocyte Hyperdifferentiation and Epidermal Barrier Disruption
In SGPL1-knockout keratinocytes and organotypic skin equivalents, accumulated S1P, sphingosine and ceramide drive premature differentiation, a thickened retained stratum corneum, altered calcium-signalling gene expression and loss of E-cadherin junctions, reproducing the ichthyosis, acanthosis and hyperpigmentation seen in most patients with a reported skin phenotype.
keratinocyte CL:0000312 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves keratinocyte (CL:0000312). CL:0000312 is a cell type from the Cell Ontology.
Experimental models
SGPL1-knockout keratinocyte organotypic skin equivalent CELL LINE Reproduces sphingolipid accumulation, advanced differentiation and a thickened retained stratum corneum.
Downstream
Ichthyosis
Show evidence (1 reference)
PMID:36868360 SUPPORT In Vitro
"SGPL1_KO upregulated differentiation markers, while SGPL1_OE upregulated basal and proliferative markers. The advanced differentiation of SGPL1_KO was confirmed by 3D organotypic models that also presented with a thickened and retained stratum corneum and a breakdown of E-cadherin junctions."
Direct demonstration of the keratinocyte differentiation and barrier defect in a human skin model.
Mitochondrial Dysfunction
Patient fibroblasts and SGPL1-knockout HeLa cells show reduced total mitochondrial volume and altered mitochondrial dynamics and oxidative phosphorylation parameters, consistent with sphingolipid-induced mitochondrial dysregulation. Its contribution to organ pathology and to phenotype severity is proposed but not yet established.
mitochondrion organization GO:0007005 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal mitochondrion organization (GO:0007005). GO:0007005 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Show evidence (1 reference)
PMID:32682944 SUPPORT In Vitro
"Total mitochondrial volume was reduced in both S1P lyase deficient patient and HeLa cell lines. Mitochondrial dynamics and parameters of oxidative phosphorylation were altered when compared to matched controls, though differentially across the cell lines."
Primary measurement of the mitochondrial phenotype in patient-derived and engineered cells.
Neuronal and Myelin Sphingolipid Dysregulation
Accumulated sphingolipids perturb membrane rafts and myelin, and loss of the lyase's products impairs autophagic flux important for axonal integrity. Clinically this produces a spectrum from callosal dysgenesis and microcephaly to progressive involvement of the globus pallidus, thalamus and dentate nucleus with atrophy, cranial nerve deficits, sensorineural hearing loss, peripheral motor and sensory neuropathy, seizures and developmental regression.
myelination GO:0042552 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal myelination (GO:0042552). GO:0042552 is a biological process from the Gene Ontology. ⚠ ABNORMAL autophagy GO:0006914 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated autophagy (GO:0006914). GO:0006914 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Downstream
Developmental regression
Peripheral neuropathy
Sensorineural hearing impairment
Cranial nerve paralysis
Seizure
Microcephaly
Aplasia/Hypoplasia of the corpus callosum
Show evidence (2 references)
PMID:36187293 SUPPORT Other
"In addition, the products of the SPL reaction have biological functions including regulation of autophagic flux, which is important in axonal and neuronal integrity."
Review of the proposed neuronal mechanisms, including the autophagy role of the lyase products.
PMID:32855188 SUPPORT Human Clinical
"Analysis reveals recurring patterns of features in affected patients, including isolated callosal dysgenesis and prominent involvement of the globus pallidus, thalamus, and dentate nucleus, with progressive atrophy and worsening of brain lesions."
Imaging evidence for the progressive deep grey nuclei and callosal lesions.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Sphingosine Phosphate Lyase Insufficiency Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

25
Blood 2
Decreased total lymphocyte count VERY_FREQUENT HP:0001888 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lymphopenia, annotated with Decreased total lymphocyte count (HP:0001888). HP:0001888 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:34133011 SUPPORT Human Clinical
"the latter causing lymphopenia, a hallmark of the disease"
Identifies lymphopenia as a hallmark feature.
PMID:32233035 SUPPORT Human Clinical
"Patients with SPLIS exhibit lymphopenia, nephrosis, adrenal insufficiency, and/or neurological defects."
Lists lymphopenia among the core manifestations.
Anemia HP:0001903 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anemia (HP:0001903). HP:0001903 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30090628 SUPPORT Other
"Immunodeficienies include lymphopenia, deficiency of cellular immunity, multiple bacterial infection, hypogammaglobulinemia, thrombocytopenia and anemia."
Review listing anaemia among the reported findings.
Cardiovascular 1
Abnormality of the cardiovascular system HP:0001626 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cardiac manifestations, annotated with Abnormality of the cardiovascular system (HP:0001626). HP:0001626 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33074640 SUPPORT Other
"Cardiac manifestations are reported in some individuals."
GeneReviews statement of cardiac involvement without a frequency.
PMID:28181337 SUPPORT Human Clinical
"One male patient had non-palpable testes and micropenis, and another patient had pericardial and pleural effusions, generalized hydrops, and a cleft palate."
Pericardial effusion in a hydropic patient.
Ear 1
Sensorineural hearing impairment OCCASIONAL HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorineural hearing loss, annotated with Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36187293 SUPPORT Human Clinical
"The latter can include sensorineural hearing loss, cranial nerve defects, peripheral neuropathy, abnormal brain development, seizures and/or neurodegeneration."
Review listing sensorineural hearing loss among the neurological manifestations.
Endocrine 4
Primary adrenal insufficiency FREQUENT HP:0008207 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Primary adrenal insufficiency (HP:0008207). HP:0008207 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:36371483 SUPPORT Human Clinical
"The most prevalent clinical feature was endocrinopathies, including primary adrenal insufficiency (PAI) (71.2%) and hypothyroidism (32.7%)."
Systematic review frequency of PAI.
PMID:35904228 SUPPORT Human Clinical
"Glucocorticoid insufficiency in early childhood is the most common endocrine manifestation affecting 64% of the 50 patients reported with SPLIS, and a third of these individuals have additional mineralocorticoid deficiency."
Endocrine case series quantifying glucocorticoid and mineralocorticoid deficiency.
PMID:30517686 SUPPORT Human Clinical
"The patient presented with hypoglycemia and seizures at age 2 years and was ultimately diagnosed with PAI (isolated glucocorticoid deficiency)."
Isolated glucocorticoid deficiency as the presenting feature in an R222Q homozygote.
Decreased circulating aldosterone concentration OCCASIONAL HP:0004319 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mineralocorticoid deficiency, annotated with Decreased circulating aldosterone concentration (HP:0004319). HP:0004319 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35904228 SUPPORT Human Clinical
"a third of these individuals have additional mineralocorticoid deficiency"
Quantifies mineralocorticoid deficiency among patients with adrenal disease.
Adrenal calcification OCCASIONAL HP:0010512 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Adrenal calcification (HP:0010512). HP:0010512 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28181337 SUPPORT Human Clinical
"We identified two unrelated consanguineous families with three children affected by the rare association of congenital nephrotic syndrome (CNS) diagnosed in the first days of life, of hypogonadism, and of prenatally detected adrenal calcifications, associated with congenital adrenal..."
Original description of prenatal adrenal calcification in SGPL1 deficiency.
Hypothyroidism FREQUENT HP:0000821 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Primary hypothyroidism, annotated with Hypothyroidism (HP:0000821). HP:0000821 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35904228 SUPPORT Human Clinical
"Mild primary hypothyroidism affects approximately a third of patients."
Endocrine series frequency of hypothyroidism.
Genitourinary 5
Steroid-resistant nephrotic syndrome VERY_FREQUENT HP:0012588 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Steroid-resistant nephrotic syndrome (HP:0012588). HP:0012588 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36371483 SUPPORT Human Clinical
"Kidney disorders (42, 80.8%) were mainly in the form of steroid-resistant nephrotic syndrome (SRNS)"
Systematic review frequency of kidney involvement, predominantly SRNS.
PMID:33074640 SUPPORT Human Clinical
"Sphingosine phosphate lyase insufficiency syndrome (SPLIS) is characterized by varying combinations of steroid-resistant nephrotic syndrome (ranging from nonimmune fetal hydrops to adolescent onset)"
GeneReviews summary of the renal phenotype and its onset range.
Focal segmental glomerulosclerosis FREQUENT HP:0000097 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Focal segmental glomerulosclerosis (HP:0000097). HP:0000097 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35748945 SUPPORT Human Clinical
"Kidney biopsy showed focal segmental glomerulosclerosis in 2 patients and diffuse mesangial sclerosis in one patient."
Biopsy findings in a clinical series.
Stage 5 chronic kidney disease FREQUENT HP:0003774 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is End-stage kidney disease, annotated with Stage 5 chronic kidney disease (HP:0003774). HP:0003774 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36371483 SUPPORT Human Clinical
"progressed to end-stage kidney disease (ESKD) in 19 (36.5%) patients at a median (IQR) age of 6 (1.4-42.6) months"
Quantifies ESKD frequency and timing.
Cryptorchidism OCCASIONAL HP:0000028 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cryptorchidism (HP:0000028). HP:0000028 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35904228 SUPPORT Human Clinical
"Primary gonadal insufficiency, manifesting with microphallus and cryptorchidism, is reported in less than one-third of affected boys, all with concomitant adrenal disease."
Quantifies gonadal involvement in boys.
Micropenis OCCASIONAL HP:0000054 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Micropenis (HP:0000054). HP:0000054 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28165343 SUPPORT Human Clinical
"Undervirilization was reported in patient 6, who had micropenis, right cryptorchidism, and bilateral microorchidism, associated with low serum anti-Müllerian hormone, suggesting that partial gonadal dysfunction may be part of the clinical picture."
Micropenis as part of gonadal dysfunction in a reported patient.
PMID:28181337 SUPPORT Human Clinical
"A micropenis and cryptorchidism with a small inguinal testis at the right side and no testis at the left side were noted."
Second independent report.
Head and Neck 1
Microcephaly OCCASIONAL HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32855188 SUPPORT Human Clinical
"MR imaging findings of abnormal deep gray nuclei, microcephaly, or callosal dysgenesis in an infant or young child exhibiting other typical clinical features of sphingosine-1-phosphate lyase insufficiency syndrome should trigger prompt genetic testing for SGPL1 mutations."
Neuroradiological series naming microcephaly among the recurring findings.
Immune 1
Recurrent infections FREQUENT HP:0002719 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent infections (HP:0002719). HP:0002719 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35748945 SUPPORT Human Clinical
"Three patients had hypothyroidism, 2 had ichthyosis, 4 had immunodeficiency, 5 had neurological findings, and 2 had genitourinary system anomalies."
Frequency of immunodeficiency and other extrarenal features in a clinical series.
PMID:36371483 SUPPORT Human Clinical
"Twenty-six (49.1%) patients with available outcome were deceased at a median (IQR) age of 5 (1.5-30.5) months, mostly following ESKD (23%) or sepsis/septic shock (23%)."
Sepsis as a leading cause of death reflects the clinical impact of the immunodeficiency.
Integument 2
Ichthyosis VERY_FREQUENT HP:0008064 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ichthyosis (HP:0008064). HP:0008064 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36868360 SUPPORT Human Clinical
"Where a skin phenotype is reported, 94% had abnormalities such as ichthyosis, acanthosis, and hyperpigmentation."
Frequency of skin abnormalities among patients with a reported skin phenotype.
PMID:28165339 SUPPORT Human Clinical
"In 7 families with SRNS and facultative ichthyosis, adrenal insufficiency, immunodeficiency, and neurological defects, we identified 9 different recessive mutations in SGPL1"
Ichthyosis as a facultative feature in the discovery cohort.
Hyperpigmentation of the skin OCCASIONAL HP:0000953 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperpigmentation of the skin (HP:0000953). HP:0000953 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30090628 SUPPORT Human Clinical
"Her brother died previously with the same phenotype and hyperpigmentation of the skin."
Case report documenting hyperpigmentation with adrenal insufficiency.
Metabolism 2
Nonimmune hydrops fetalis OCCASIONAL HP:0001790 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nonimmune hydrops fetalis (HP:0001790). HP:0001790 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33074640 SUPPORT Human Clinical
"steroid-resistant nephrotic syndrome (ranging from nonimmune fetal hydrops to adolescent onset)"
GeneReviews places nonimmune hydrops at the severe end of the renal spectrum.
Hypoglycemia OCCASIONAL HP:0001943 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoglycemia (HP:0001943). HP:0001943 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30517686 SUPPORT Human Clinical
"The patient presented with hypoglycemia and seizures at age 2 years and was ultimately diagnosed with PAI (isolated glucocorticoid deficiency)."
Hypoglycaemia as the presenting feature of adrenal insufficiency.
Nervous System 5
Developmental regression FREQUENT HP:0002376 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Developmental regression (HP:0002376). HP:0002376 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33074640 SUPPORT Human Clinical
"neurologic abnormalities (cranial nerve deficits, developmental delay, regression/progression, and peripheral motor and sensory neuropathy)"
GeneReviews enumeration of the neurological features.
PMID:32855188 SUPPORT Human Clinical
"prominent involvement of the globus pallidus, thalamus, and dentate nucleus, with progressive atrophy and worsening of brain lesions"
Progressive imaging changes underlying regression.
Cranial nerve paralysis OCCASIONAL HP:0006824 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cranial nerve deficits, annotated with Cranial nerve paralysis (HP:0006824). HP:0006824 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36187293 SUPPORT Human Clinical
"The latter can include sensorineural hearing loss, cranial nerve defects, peripheral neuropathy, abnormal brain development, seizures and/or neurodegeneration."
Review listing cranial nerve defects among the neurological manifestations.
Peripheral neuropathy OCCASIONAL HP:0009830 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Peripheral motor and sensory neuropathy, annotated with Peripheral neuropathy (HP:0009830). HP:0009830 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33074640 SUPPORT Human Clinical
"neurologic abnormalities (cranial nerve deficits, developmental delay, regression/progression, and peripheral motor and sensory neuropathy)"
GeneReviews lists peripheral motor and sensory neuropathy.
Seizure OCCASIONAL HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizures, annotated with Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36187293 SUPPORT Human Clinical
"The latter can include sensorineural hearing loss, cranial nerve defects, peripheral neuropathy, abnormal brain development, seizures and/or neurodegeneration."
Review listing seizures among the neurological manifestations.
Aplasia/Hypoplasia of the corpus callosum OCCASIONAL HP:0007370 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Callosal dysgenesis, annotated with Aplasia/Hypoplasia of the corpus callosum (HP:0007370). HP:0007370 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32855188 SUPPORT Human Clinical
"Analysis reveals recurring patterns of features in affected patients, including isolated callosal dysgenesis"
Neuroradiological series identifying callosal dysgenesis as a recurring pattern.
Growth 1
Failure to thrive HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33074640 SUPPORT Other
"Supportive care: Multidisciplinary management of steroid-resistant nephrotic syndrome, endocrine involvement, immunodeficiency, neurologic involvement, developmental delay / intellectual disability, hearing loss, ichthyosis, poor weight gain / feeding issues, and cardiac manifestations."
GeneReviews lists poor weight gain and feeding issues among the features needing supportive management.
🧬

Genetic Associations

1
SGPL1
Gene: SGPL1 hgnc:10817 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SGPL1 (hgnc:10817). hgnc:10817 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:28165339 SUPPORT Human Clinical
"In 7 families with SRNS and facultative ichthyosis, adrenal insufficiency, immunodeficiency, and neurological defects, we identified 9 different recessive mutations in SGPL1, which encodes sphingosine-1-phosphate (S1P) lyase. All mutations resulted in reduced or absent SGPL1 protein and/or..."
One of the three simultaneous 2017 gene-discovery reports establishing SGPL1 as causative.
PMID:28165343 SUPPORT Human Clinical
"In this work, we have identified 4 different homozygous mutations, c.665G>A (p.R222Q), c.1633_1635delTTC (p.F545del), c.261+1G>A (p.S65Rfs*6), and c.7dupA (p.S3Kfs*11), in 5 families with the condition."
Independent simultaneous gene-discovery report in the adrenal-insufficiency cohort.
Variants (3)
c.665G>A (p.Arg222Gln) Pathogenic
missense
The most common SPLIS allele, present in roughly 20-30% of reported patients. Molecular modelling suggests it distorts the dimer interface; the residual enzyme is stabilised by pyridoxal 5'-phosphate cofactor supplementation, and homozygotes show longer survival and a preponderance of isolated glucocorticoid deficiency.
Show evidence (2 references)
PMID:32233035 SUPPORT Human Clinical
"One responsive patient is homozygous for an SPL R222Q variant present in almost 30% of SPLIS patients. Molecular modeling suggests the variant distorts the dimer interface which could be overcome by cofactor supplementation."
Establishes the allele frequency and the structural basis for B6 responsiveness.
PMID:36371483 SUPPORT Human Clinical
"Among 30 different mutations in SGPL1, the most common was c.665G > A (p.Arg222Gln) in 11 (20%) patients."
Systematic review quantifying the share of patients carrying this allele.
c.1513C>T (p.Arg505*) and c.934delC (p.Leu312Phefs*30) Pathogenic
nonsense
Homozygous truncating variants identified in two consanguineous families with congenital nephrotic syndrome, hypogonadism and prenatally detected adrenal calcifications; associated with markedly elevated blood and fibroblast S1P.
Show evidence (1 reference)
PMID:28181337 SUPPORT Human Clinical
"Using exome sequencing and targeted Sanger sequencing, two homozygous truncating mutations, c.1513C>T (p.Arg505*) and c.934delC (p.Leu312Phefs*30), were identified in SGPL1-encoding sphingosine-1-phosphate (S1P) lyase 1."
Original report of these truncating alleles in the congenital nephrotic presentation.
p.Tyr416Cys, p.Arg340Trp, p.Ser346Ile and p.Arg222Trp (recurrent severe alleles) Pathogenic
missense
Together with p.Arg222Gln these four recurrent missense alleles account for three quarters of reported cases. They carry a genotype-severity signal: no patient homozygous for p.Ser346Ile (a Moroccan founder allele) or p.Arg222Trp (Turkish ancestry) survived, with median age at last report under six months, whereas p.Arg222Gln homozygotes survive into later childhood.
Show evidence (3 references)
PMID:39334450 SUPPORT Human Clinical
"Five missense variants (R222Q, Y416C, R340W, S346I, and R222W) accounted for 75% of all reported SPLIS cases"
Quantifies the share of cases explained by the recurrent alleles.
PMID:39334450 SUPPORT Human Clinical
"In contrast to the generally more favorable outcome of SPLIS patients homozygous for the R222Q variant, no patients homozygous for R222W variant survived"
Genotype-survival relationship for the Arg222Trp allele.
PMID:39334450 SUPPORT Human Clinical
"The S346I variant representing 11% of variants and 7% of SPLIS cases was found in homozygous state in one Moroccan family, and no case survived"
Genotype-survival relationship for the Ser346Ile allele.
💊

Medical Actions

8
Pyridoxine (vitamin B6) cofactor supplementation
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: pyridoxine CHEBI:16709 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses pyridoxine (CHEBI:16709). CHEBI:16709 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Targeted therapy for patients with pyridoxine-responsive alleles, notably R222Q: pyridoxal 5'-phosphate stabilises and augments the residual mutant enzyme, lowering sphingolipid biomarkers and improving neurological status in responders. It is recommended by GeneReviews and is limited to patients with a susceptible allele.
Mechanism Target:
Biallelic SGPL1 Loss of Function — Cofactor supplementation partially restores activity of destabilised missense SGPL1 variants.
Show evidence (3 references)
PMID:32233035 SUPPORT Human Clinical
"We demonstrate the first potential targeted therapy for SPLIS and suggest that 30% of SPLIS patients might respond to cofactor supplementation."
First report of clinical and biochemical response to B6.
PMID:42182331 SUPPORT Human Clinical
"Neurological improvement, plasma S1P normalization, and increased SPL activity in patient-derived fibroblasts were observed after pyridoxine supplementation in a patient with R222Q-variant SPLIS."
Clinical response in an R222Q patient, corroborated by the R222Q mouse model.
PMID:33074640 SUPPORT Human Clinical
"Targeted therapy: Vitamin B6 supplementation."
GeneReviews management recommendation.
Glucocorticoid and mineralocorticoid replacement
Action: Hormone replacement therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Hormone replacement therapy (NCIT:C15599). NCIT:C15599 is a clinical intervention from the NCI Thesaurus. Ontology label: Hormone Replacement Therapy NCIT:C15599
Agent: hydrocortisone CHEBI:17650 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses hydrocortisone, annotated with cortisol (CHEBI:17650). CHEBI:17650 is a therapeutic agent from Chemical Entities of Biological Interest. fludrocortisone CHEBI:50885 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses fludrocortisone (CHEBI:50885). CHEBI:50885 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Standard hormone replacement for primary adrenal insufficiency, with stress dosing; adrenal function should be reassessed every 6-12 months and before major procedures because adrenal insufficiency can emerge late.
Target Phenotypes: Primary adrenal insufficiency HP:0008207 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Primary adrenal insufficiency (HP:0008207). HP:0008207 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33074640 SUPPORT Human Clinical
"assess primary adrenal function every six to 12 months and before any major procedure"
GeneReviews surveillance guidance underpinning replacement therapy.
PMID:35904228 SUPPORT Human Clinical
"While endocrinopathy in the syndrome generally presents in infancy, late-onset disease also occurs. Screening for these is therefore warranted both at diagnosis and through follow-up."
Rationale for ongoing endocrine screening and replacement.
Levothyroxine replacement
Action: Hormone replacement therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Hormone replacement therapy (NCIT:C15599). NCIT:C15599 is a clinical intervention from the NCI Thesaurus. Ontology label: Hormone Replacement Therapy NCIT:C15599
Agent: levothyroxine CHEBI:18332 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses levothyroxine, annotated with L-thyroxine (CHEBI:18332). CHEBI:18332 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Replacement for the primary hypothyroidism seen in about a third of patients; annual thyroid function testing is recommended.
Target Phenotypes: Hypothyroidism HP:0000821 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Hypothyroidism (HP:0000821). HP:0000821 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33074640 SUPPORT Human Clinical
"annual free thyroxine and thyroid-stimulating hormone"
GeneReviews surveillance recommendation for thyroid function.
Kidney replacement therapy and kidney transplantation
Action: Kidney transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Kidney transplantation (NCIT:C15265). NCIT:C15265 is a clinical intervention from the NCI Thesaurus. Ontology label: Kidney Transplantation NCIT:C15265
Platform: Surgery
Dialysis and kidney transplantation for end-stage kidney disease; transplantation significantly extends survival and the nephropathy does not recur in the graft, because the enzyme defect is systemic but the glomerular lesion is intrinsic to the native podocytes.
Target Phenotypes: End-stage kidney disease HP:0003774 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets End-stage kidney disease, annotated with Stage 5 chronic kidney disease (HP:0003774). HP:0003774 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39334450 SUPPORT Human Clinical
"Kidney transplantation significantly extended survival outcomes."
Natural history evidence for the survival benefit of transplantation.
PMID:35748945 SUPPORT Human Clinical
"All 6 patients progressed to chronic kidney disease; 5 required kidney replacement therapy (KRT) at a median age of 6 months. Deceased kidney transplantation was performed in one patient."
Clinical series documenting kidney replacement therapy and transplantation.
Infection prevention and immunodeficiency precautions
Action: Supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Because of T-cell lymphopenia, GeneReviews advises avoiding live vaccines, exposure to infectious agents and non-irradiated transfusion products, with immunological reassessment every 6-12 months; nephrotoxic drugs should also be avoided.
Target Phenotypes: Recurrent infections HP:0002719 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Recurrent infections (HP:0002719). HP:0002719 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33074640 SUPPORT Human Clinical
"Agents/circumstances to avoid: Nephrotoxic medications; medications that require renal excretion (for individuals with renal insufficiency); live vaccines; exposure to infectious agents; transfusion products that have not been irradiated."
GeneReviews list of agents and circumstances to avoid.
AAV9-mediated SGPL1 gene replacement (preclinical)
Action: Gene therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Gene therapy (NCIT:C15238). NCIT:C15238 is a clinical intervention from the NCI Thesaurus. Ontology label: Gene Therapy NCIT:C15238
Platform: Gene therapy
Systemic AAV9-SGPL1 given to newborn Sgpl1-knockout mice dramatically prolonged survival and prevented nephrosis, neurodevelopmental delay, anaemia and hypercholesterolaemia; a CAG-promoter version (AAV-SPL 2.0) performs at least as well but treated mice eventually develop glomerulosclerosis, indicating that improved kidney targeting is needed. Proposed as a universal, genotype-independent therapy.
Mechanism Target:
Biallelic SGPL1 Loss of Function — Restores enzyme expression and activity, correcting the metabolic block at its source.
Show evidence (2 references)
PMID:33755599 SUPPORT Model Organism
"Treatment dramatically prolonged survival and prevented nephrosis, neurodevelopmental delay, anemia, and hypercholesterolemia."
Proof-of-concept efficacy in the knockout mouse.
PMID:37958544 SUPPORT Model Organism
"Over time, treated mice developed nephrosis and glomerulosclerosis, which likely resulted in their demise. Our overall findings show that AAV-SPL 2.0 performs equal to or better than AAV-SPL. However, improved kidney targeting may be necessary to achieve maximally optimized gene therapy as a..."
Second-generation vector results and the remaining kidney-targeting limitation.
ROCK inhibition with fasudil (preclinical)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: fasudil CHEBI:43871 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses fasudil (CHEBI:43871). CHEBI:43871 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Pharmacological Rho-kinase inhibition mitigated renal cytoskeletal defects and partially restored epithelial architecture in Sgpl1-deficient mice, identifying S1P-driven Rho/ROCK hyperactivation as a tractable downstream target independent of genotype.
Mechanism Target:
Podocyte Cytoskeletal Disorganization and Loss — Blocks the Rho/ROCK signalling through which excess S1P disorganises the renal epithelial cytoskeleton.
Show evidence (1 reference)
PMID:42024444 SUPPORT Model Organism
"Pharmacological ROCK inhibition with fasudil mitigated renal cytoskeletal defects in Sgpl1-/- and Sgpl1rosa+fl/fl mice and partially restored epithelial architecture."
Preclinical efficacy of ROCK inhibition on the renal lesion.
Genetic counseling and testing of at-risk relatives
Action: Genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Autosomal recessive counselling with a 25% recurrence risk; GeneReviews recommends clarifying the genetic status of at-risk sibs so that treatment and precautions can begin before symptoms.
Show evidence (1 reference)
PMID:33074640 SUPPORT Human Clinical
"It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment and awareness of agents/circumstances to avoid."
GeneReviews recommendation on evaluation of relatives at risk.
🔬

Biochemical Markers

1
Elevated plasma sphingosine-1-phosphate and sphingosine (present)
Pathograph Readouts
Readout Of Sphingoid Base Phosphate and Sphingolipid Accumulation Positive Diagnostic
Elevated circulating sphingoid base phosphates report the metabolic block at the lyase step and fall when residual enzyme activity is restored.
Show evidence (2 references)
PMID:28181337 SUPPORT Human Clinical
"The levels of SGPL1 substrates, S1P, and sphingosine were markedly increased in the patients' blood and fibroblasts, as determined by liquid chromatography-tandem mass spectrometry."
Establishes the plasma biomarker.
PMID:32233035 SUPPORT Human Clinical
"In two patients, disease biomarkers responded to B6 supplementation. S1P abundance and activity levels increased and sphingolipids decreased in response to B6."
Shows the biomarker is treatment-responsive.
🔬

Diagnosis

4
Molecular genetic testing for biallelic SGPL1 variants
The diagnosis is established in a proband with at least one suggestive finding and biallelic pathogenic SGPL1 variants; SGPL1 should be included in steroid-resistant nephrotic syndrome and primary adrenal insufficiency gene panels, including for isolated adrenal insufficiency.
Show evidence (2 references)
PMID:33074640 SUPPORT Human Clinical
"The diagnosis of SPLIS is established in a proband with at least one suggestive finding and biallelic pathogenic variants in SGPL1 identified by molecular genetic testing."
GeneReviews diagnostic criterion.
PMID:30517686 SUPPORT Human Clinical
"We suggest that screening for SGPL1 mutations should not be reserved only for patients with nephrotic syndrome but may also include patients with PAI who lack other clinical manifestations of NPHS14 because, in certain cases, kidney disease and accompanying features might develop."
Supports testing in isolated adrenal insufficiency.
Plasma sphingolipid profiling
LC-MS/MS shows markedly elevated S1P and sphingosine in blood and fibroblasts, supporting the diagnosis and providing a biomarker for treatment response.
Show evidence (1 reference)
PMID:28181337 SUPPORT Human Clinical
"The levels of SGPL1 substrates, S1P, and sphingosine were markedly increased in the patients' blood and fibroblasts, as determined by liquid chromatography-tandem mass spectrometry."
Biochemical diagnostic finding.
Brain MRI
Recurring patterns include isolated callosal dysgenesis and progressive involvement of the globus pallidus, thalamus and dentate nucleus; these findings in an infant with nephrotic syndrome or adrenal insufficiency should prompt SGPL1 testing.
Show evidence (1 reference)
PMID:32855188 SUPPORT Human Clinical
"MR imaging findings of abnormal deep gray nuclei, microcephaly, or callosal dysgenesis in an infant or young child exhibiting other typical clinical features of sphingosine-1-phosphate lyase insufficiency syndrome should trigger prompt genetic testing for SGPL1 mutations."
Neuroradiological diagnostic guidance.
Endocrine, immunological and renal surveillance
Urine studies, adrenal function every 6-12 months, annual thyroid function, testicular function review, immunological assessment, neurological and audiological evaluation.
Show evidence (1 reference)
PMID:33074640 SUPPORT Human Clinical
"Surveillance: Urine studies per nephrologist in those with kidney disease or annually in those without known kidney disease; assess primary adrenal function every six to 12 months and before any major procedure; annual free thyroxine and thyroid-stimulating hormone; annual review of testicular function"
GeneReviews surveillance schedule.
📈

Progression

2
Prenatal and infantile-onset nephropathy (high-risk)
Prenatal presentation (nonimmune hydrops, adrenal calcifications) and nephropathy diagnosed before one year of age define the highest-risk subgroups; fewer than 30% of infants with nephropathy diagnosed before age one survive two years, and prenatally diagnosed patients died at a median age of 2 months.
Show evidence (2 references)
PMID:39334450 SUPPORT Human Clinical
"Of children diagnosed with SPLIS nephropathy before age one (n = 30), less than 30% were alive 2 years after diagnosis, and 17% were living at last report."
Natural history data defining the early-onset high-risk course.
PMID:36371483 SUPPORT Human Clinical
"all patients with a prenatal diagnosis of SPLIS (27.5%) died at a median"
Systematic review showing uniformly fatal outcome of prenatally diagnosed disease.
Later-onset and R222Q-associated milder course
Patients whose nephropathy is diagnosed at or after one year of age, and those homozygous for p.Arg222Gln, survive substantially longer; kidney transplantation extends survival. Time from onset of proteinuria to end-stage kidney disease ranges from under one month to five years.
Show evidence (1 reference)
PMID:39334450 SUPPORT Human Clinical
"Among those diagnosed at or after age one (n = 18), ~ 70% were alive 2 years after diagnosis, and 72% were living at time of last report. SPLIS patients homozygous for the SPL R222Q variant survived longer compared to patients with other genotypes. Kidney transplantation significantly extended..."
Defines the later-onset, better-prognosis subgroup and the genotype effect.
📊

Prevalence

2
Worldwide (gnomAD v2.1.1-derived estimate)
Point Prevalence 0.015 per 100,000 (0.01–0.021) <1 in 1,000,000
Genomic-database estimate from cumulative pathogenic allele frequencies, not an observed case count: 0.015 per 100,000 (95% CI 0.010-0.021) worldwide, with higher estimates in Turkish and Iranian populations (0.046-0.078 per 100,000).
Show evidence (1 reference)
PMID:39669624 SUPPORT Computational
"The SPLIS prevalence estimate based on the total number of samples included from gnomAD v.2.1.1 (n = 141,430) was 0.015/100,000 (95% CI: 0.010 to 0.021)."
Allele-frequency-based prevalence estimate; classified as computational because it is derived in silico from population genomic data rather than observed cases.
Worldwide
Cases In Literature Ultra Rare
Seventy-six molecularly confirmed patients were analysed in the 2024 natural history study; a 2023 systematic review found 55 patients across 19 articles.
Show evidence (1 reference)
PMID:39334450 SUPPORT Human Clinical
"We performed a retrospective analysis of 76 patients in whom the diagnosis of SPLIS was established in a proband with at least one suggestive finding and biallelic SGPL1 variants identified by molecular genetic testing."
Largest published patient series, giving the reported-case denominator.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Sphingosine Phosphate Lyase Insufficiency Syndrome:

Familial glucocorticoid deficiency
Overlapping Features Isolated glucocorticoid deficiency due to MC2R, MRAP or other genes; SGPL1 variants were found when patients with familial glucocorticoid deficiency or triple A syndrome lacking nephrotic syndrome were sequenced, so SPLIS belongs in that differential.
Distinguishing Features
  • Nephrotic syndrome, ichthyosis, lymphopenia or neurological findings favour SPLIS
  • Elevated plasma S1P and sphingosine
  • Biallelic SGPL1 variants
Show evidence (1 reference)
PMID:30517686 SUPPORT Human Clinical
"Sequencing of the SGPL1 gene in 21 patients with familial glucocorticoid disease or triple A syndrome"
SGPL1 variants identified within a familial glucocorticoid deficiency cohort.
Other monogenic steroid-resistant nephrotic syndromes
Overlapping Features NPHS1, NPHS2, LAMB2, WT1 and PLCE1 account for most congenital and early-onset SRNS; the syndromic combination with adrenal insufficiency, ichthyosis, immunodeficiency and neurological disease distinguishes SPLIS.
Distinguishing Features
  • Primary adrenal insufficiency or adrenal calcification
  • Ichthyosis, lymphopenia, neurological involvement
  • Elevated plasma sphingoid base phosphates
Show evidence (1 reference)
PMID:28165339 SUPPORT Human Clinical
"A mutation in 1 of over 40 monogenic genes can be detected in approximately 30% of individuals with SRNS whose symptoms manifest before 25 years of age."
Context of the monogenic SRNS differential in which SGPL1 was discovered.
🔬

Clinical Trials

2
NCT04885179 NOT_APPLICABLE UNKNOWN
International observational study and patient registry for SPLIS collecting clinical, biochemical, genetic and biosample data; no intervention is administered.
Show evidence (1 reference)
clinicaltrials:NCT04885179 SUPPORT Other
"This protocol aims to gather information about sphingosine phosphate lyase insufficiency syndrome (SPLIS), also known as NPHS14, and to create a SPLIS patient registry."
Registry protocol summary.
NCT06669949 NOT_APPLICABLE UNKNOWN
Prospective longitudinal natural history study with a retrospective cross-sectional arm testing whether age of onset, disease features and biomarkers predict quality of life and survival.
Show evidence (1 reference)
clinicaltrials:NCT06669949 SUPPORT Other
"The central hypothesis is that age of onset, other disease features, and disease biomarkers will be predictive of quality of life (QOL) and survival in SPLIS patients."
Natural history study summary.
🧫

Experimental Models

1
SGPL1-knockout keratinocyte organotypic skin equivalent CELL_LINE
CRISPR-Cas9 SGPL1 knockout in immortalised human keratinocytes (N/TERT-1) grown as 3D organotypic skin equivalents, with lentiviral overexpression as the opposite pole.
keratinocyte CL:0000312 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses keratinocyte (CL:0000312). CL:0000312 is a cell type from the Cell Ontology.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Publication
PMID:36868360
Pathograph links
Keratinocyte Hyperdifferentiation and Epidermal Barrier Disruption recapitulates fidelity: moderate observes: tissue Reproduces sphingolipid accumulation, advanced differentiation and a thickened retained stratum corneum.
Limitations: Immortalised keratinocytes without immune or dermal components; no in vivo confirmation in patient skin biopsies.
Show evidence (1 reference)
PMID:36868360 SUPPORT In Vitro
"The advanced differentiation of SGPL1_KO was confirmed by 3D organotypic models that also presented with a thickened and retained stratum corneum and a breakdown of E-cadherin junctions."
Reports the organotypic epidermal phenotype.
🐁

Animal Models

3
Sgpl1 knockout mouse
Constitutive knockout that dies in the first weeks of life and recapitulates the main human features: glomerular nephrosis, disrupted adrenocortical zonation with defective steroidogenic enzyme expression, lymphopenia, anaemia, hypercholesterolaemia and neurodevelopmental delay; renal S1P enrichment with cytoskeletal disorganisation.
Species
Mouse
Genotype
Sgpl1-/- (constitutive null)
Publication
PMID:28165343
Pathograph links
Adrenocortical Zonation and Steroidogenesis Failure recapitulates fidelity: moderate observes: tissue Adrenal histology in the null mouse shows disrupted zonation and reduced steroidogenic enzyme expression.
Limitations: Early postnatal lethality precludes study of the childhood-onset, late-emerging adrenal insufficiency seen in patients.
Readouts
Adrenocortical zonation and steroidogenic enzyme expression
Direction: ALTERED
Interpretation: Histological correlate of the adrenal steroidogenic failure.
Show evidence (1 reference)
PMID:28165343 SUPPORT Model Organism
"Sgpl1-/- mice displayed disrupted adrenocortical zonation and defective expression of steroidogenic enzymes"
Reports the adrenal histological measurement.
Show evidence (1 reference)
PMID:28165343 SUPPORT Model Organism
"Sgpl1-/- mice recapitulated the main characteristics of the human disease with abnormal adrenal and renal morphology."
Authors' statement that the knockout recapitulates the human disease.
Glomerular Filtration Barrier Failure and Glomerulosclerosis recapitulates fidelity: high observes: tissue Nephrosis with glomerular pathology and profibrotic cytokine signalling, prevented by AAV-SGPL1 gene transfer.
Readouts
Nephrosis and renal STAT3/cytokine activation
Direction: INCREASED
Interpretation: Proteinuric glomerular disease with inflammatory signalling in the knockout kidney.
Show evidence (1 reference)
PMID:33755599 SUPPORT Model Organism
"STAT3 pathway activation and elevated proinflammatory and profibrogenic cytokines observed in KO kidneys were attenuated by treatment."
Reports the renal readout and its correction by gene therapy.
Show evidence (1 reference)
PMID:33755599 SUPPORT Model Organism
"As proof of concept, we evaluated the efficacy of adeno-associated virus 9-mediated transfer of human SGPL1 (AAV-SPL) given to newborn Sgpl1-KO mice that model SPLIS and die in the first weeks of life."
Establishes the knockout as the SPLIS model used for the renal readouts.
Podocyte Cytoskeletal Disorganization and Loss recapitulates fidelity: moderate observes: cellular Renal S1P enrichment with cytoskeletal disorganisation and impaired epithelial morphogenesis, rescued by ROCK inhibition.
Readouts
Renal epithelial cytoskeletal organisation
Direction: ALTERED
Interpretation: Cytoskeletal disorganisation driven by S1P/Rho/ROCK signalling.
Show evidence (1 reference)
PMID:42024444 SUPPORT Model Organism
"In vivo, Sgpl1-/- mice had pronounced urinary S1P excretion and renal S1P enrichment, accompanied by cytoskeletal disorganization and impaired epithelial morphogenesis."
Reports the renal cytoskeletal readout.
SGPL1 R222Q knock-in mouse
Gene-edited model of the most common human allele; phenotypically silent on pyridoxine-enriched chow but develops enzyme inactivation, S1P accumulation, wasting, anaemia, proteinuria, glomerulosclerosis, podocyte loss and foot process effacement on reduced-pyridoxine chow, demonstrating pyridoxine responsiveness in vivo.
Species
Mouse
Genotype
Sgpl1 R222Q homozygous knock-in
Publication
PMID:42182331
Pathograph links
Podocyte Cytoskeletal Disorganization and Loss recapitulates fidelity: high observes: cellular Reproduces the human allele, its pyridoxine dependence and the podocyte lesion.
Readouts
Podocyte number and foot process morphology
Direction: DECREASED
Interpretation: Podocyte loss and foot process effacement on pyridoxine-deficient diet.
Show evidence (1 reference)
PMID:42182331 SUPPORT Model Organism
"Ultrastructural analysis and super-resolution microscopy showed podocyte loss and foot process effacement."
Reports the ultrastructural podocyte readout.
Show evidence (1 reference)
PMID:42182331 SUPPORT Model Organism
"However, SPL inactivation, S1P accumulation, wasting, anemia, proteinuria, and glomerulosclerosis developed in SPLR222Q but not WT mice fed chow with reduced pyridoxine."
Establishes the diet-dependent disease phenotype of the knock-in model.
Drosophila Sply mutant
Flies lacking the S1P lyase orthologue show a nephrocyte phenotype reminiscent of nephrotic syndrome that is rescued by wild-type but not patient-variant Sply.
Species
Drosophila melanogaster
Genotype
Sply loss-of-function
Publication
PMID:28165339
Pathograph links
Podocyte Cytoskeletal Disorganization and Loss partially recapitulates fidelity: low observes: cellular Nephrocyte filtration defect used to test the functional consequence of patient alleles.
Limitations: Insect nephrocytes are a functional analogue of podocytes without a glomerulus; the model tests allele function rather than mammalian glomerular pathology.
Show evidence (1 reference)
PMID:28165339 SUPPORT Model Organism
"In Drosophila, Sply mutants, which lack SGPL1, displayed a phenotype reminiscent of nephrotic syndrome in nephrocytes. WT Sply, but not the disease-associated variants, rescued this phenotype."
Reports the nephrocyte phenotype and allele-specific rescue.
{ }

Source YAML

click to show 
name: Sphingosine Phosphate Lyase Insufficiency Syndrome
category: Genetic
creation_date: "2026-09-05T16:30:00Z"
synonyms:
- SPLIS
- Nephrotic syndrome type 14
- NPHS14
- SGPL1 deficiency
- Sphingosine-1-phosphate lyase deficiency
- RENI syndrome (renal, endocrine, neurologic, immune)
- Primary adrenal insufficiency and steroid-resistant nephrotic syndrome due to SGPL1 deficiency
description: >
  Sphingosine phosphate lyase insufficiency syndrome (SPLIS; nephrotic syndrome type 14,
  OMIM #617575) is an autosomal recessive, non-lysosomal inborn error of sphingolipid
  metabolism first described in 2017, caused by biallelic inactivating variants in SGPL1.
  SGPL1 encodes sphingosine-1-phosphate (S1P) lyase, a pyridoxal 5'-phosphate-dependent
  endoplasmic reticulum enzyme that irreversibly cleaves S1P at the only exit point of
  sphingolipid catabolism. Loss of the enzyme causes accumulation of S1P, sphingosine and
  ceramide species in blood and tissues, with cell-type-specific consequences: podocyte
  cytoskeletal disorganization and loss (steroid-resistant nephrotic syndrome, most often
  with focal segmental glomerulosclerosis, progressing to kidney failure), disrupted
  adrenocortical zonation and steroidogenesis (primary adrenal insufficiency, often with
  adrenal calcification), impaired lymphocyte egress (T-cell lymphopenia and
  immunodeficiency), keratinocyte hyperdifferentiation (ichthyosis), and a progressive
  neurological disorder with deep grey nuclei involvement, cranial nerve palsies,
  sensorineural hearing loss and peripheral neuropathy. Additional endocrinopathies include
  primary hypothyroidism and, in boys, primary gonadal insufficiency. The phenotype is
  highly variable, from nonimmune fetal hydrops and neonatal death to adolescent-onset
  isolated adrenal insufficiency or nephropathy. Roughly half of reported patients have
  died, most in infancy from kidney failure or sepsis; diagnosis of nephropathy in the
  first year of life and prenatal presentation mark the highest-risk groups, while the
  common p.Arg222Gln (R222Q) allele is associated with milder disease. Pyridoxine
  (vitamin B6) cofactor supplementation benefits a subset of patients with responsive
  missense alleles, kidney transplantation extends survival, and AAV-mediated SGPL1 gene
  replacement and ROCK inhibition are in preclinical development.
disease_term:
  preferred_term: Sphingosine phosphate lyase insufficiency syndrome
  term:
    id: MONDO:0033203
    label: nephrotic syndrome 14
parents:
- MONDO:0044765
- MONDO:0018117
classifications:
  icimd_category:
  - classification_value: sphingolipid_synthesis_and_recycling
    notes: >-
      SGPL1 deficiency is an inborn error of the final, irreversible step of sphingolipid
      degradation and is classified with the disorders of sphingolipid synthesis and
      recycling (ICIMD category 14, lipid metabolism), distinct from the lysosomal
      sphingolipidoses.
  harrisons_chapter:
  - classification_value: KIDNEY_URINARY_TRACT
  - classification_value: ENDOCRINOLOGY_METABOLISM
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
prevalence:
- population: Worldwide (gnomAD v2.1.1-derived estimate)
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  rate_per_100000: 0.015
  rate_low: 0.010
  rate_high: 0.021
  notes: >-
    Genomic-database estimate from cumulative pathogenic allele frequencies, not an
    observed case count: 0.015 per 100,000 (95% CI 0.010-0.021) worldwide, with higher
    estimates in Turkish and Iranian populations (0.046-0.078 per 100,000).
  evidence:
  - reference: PMID:39669624
    reference_title: "Prevalence estimate of sphingosine phosphate lyase insufficiency syndrome in worldwide and select populations."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "The SPLIS prevalence estimate based on the total number of samples included from gnomAD v.2.1.1 (n = 141,430) was 0.015/100,000 (95% CI: 0.010 to 0.021)."
    explanation: >-
      Allele-frequency-based prevalence estimate; classified as computational because it
      is derived in silico from population genomic data rather than observed cases.
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Seventy-six molecularly confirmed patients were analysed in the 2024 natural history
    study; a 2023 systematic review found 55 patients across 19 articles.
  evidence:
  - reference: PMID:39334450
    reference_title: "Factors influencing survival in sphingosine phosphate lyase insufficiency syndrome: a retrospective cross-sectional natural history study of 76 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We performed a retrospective analysis of 76 patients in whom the diagnosis of SPLIS was established in a proband with at least one suggestive finding and biallelic SGPL1 variants identified by molecular genetic testing."
    explanation: Largest published patient series, giving the reported-case denominator.
progression:
- phase: Prenatal and infantile-onset nephropathy (high-risk)
  notes: >-
    Prenatal presentation (nonimmune hydrops, adrenal calcifications) and nephropathy
    diagnosed before one year of age define the highest-risk subgroups; fewer than 30% of
    infants with nephropathy diagnosed before age one survive two years, and prenatally
    diagnosed patients died at a median age of 2 months.
  evidence:
  - reference: PMID:39334450
    reference_title: "Factors influencing survival in sphingosine phosphate lyase insufficiency syndrome: a retrospective cross-sectional natural history study of 76 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of children diagnosed with SPLIS nephropathy before age one (n = 30), less than 30% were alive 2 years after diagnosis, and 17% were living at last report."
    explanation: Natural history data defining the early-onset high-risk course.
  - reference: PMID:36371483
    reference_title: "Sphingosine phosphate lyase insufficiency syndrome: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "all patients with a prenatal diagnosis of SPLIS (27.5%) died at a median"
    explanation: Systematic review showing uniformly fatal outcome of prenatally diagnosed disease.
- phase: Later-onset and R222Q-associated milder course
  notes: >-
    Patients whose nephropathy is diagnosed at or after one year of age, and those
    homozygous for p.Arg222Gln, survive substantially longer; kidney transplantation
    extends survival. Time from onset of proteinuria to end-stage kidney disease ranges
    from under one month to five years.
  evidence:
  - reference: PMID:39334450
    reference_title: "Factors influencing survival in sphingosine phosphate lyase insufficiency syndrome: a retrospective cross-sectional natural history study of 76 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among those diagnosed at or after age one (n = 18), ~ 70% were alive 2 years after diagnosis, and 72% were living at time of last report. SPLIS patients homozygous for the SPL R222Q variant survived longer compared to patients with other genotypes. Kidney transplantation significantly extended survival outcomes."
    explanation: Defines the later-onset, better-prognosis subgroup and the genotype effect.
genetic:
- name: SGPL1
  gene_term:
    preferred_term: SGPL1
    term:
      id: hgnc:10817
      label: SGPL1
  relationship_type: CAUSATIVE
  notes: >
    Biallelic loss-of-function variants in SGPL1 (10q22.1; sphingosine-1-phosphate lyase 1)
    cause SPLIS. More than 45 disease-associated variants have been reported, including
    missense, nonsense, frameshift, splice-site and in-frame deletion alleles; all tested
    alleles reduce or abolish protein and/or enzyme activity, and several missense variants
    mislocalise the protein. The recurrent p.Arg222Gln (c.665G>A) allele accounts for
    roughly 20-30% of patients, is associated with isolated glucocorticoid deficiency and
    a milder course, and is pyridoxine-responsive in vitro and in some patients.
  variants:
  - name: c.665G>A (p.Arg222Gln)
    description: >
      The most common SPLIS allele, present in roughly 20-30% of reported patients.
      Molecular modelling suggests it distorts the dimer interface; the residual enzyme is
      stabilised by pyridoxal 5'-phosphate cofactor supplementation, and homozygotes show
      longer survival and a preponderance of isolated glucocorticoid deficiency.
    type: missense
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:32233035
      reference_title: "Responsiveness of sphingosine phosphate lyase insufficiency syndrome to vitamin B6 cofactor supplementation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "One responsive patient is homozygous for an SPL R222Q variant present in almost 30% of SPLIS patients. Molecular modeling suggests the variant distorts the dimer interface which could be overcome by cofactor supplementation."
      explanation: Establishes the allele frequency and the structural basis for B6 responsiveness.
    - reference: PMID:36371483
      reference_title: "Sphingosine phosphate lyase insufficiency syndrome: a systematic review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Among 30 different mutations in SGPL1, the most common was c.665G > A (p.Arg222Gln) in 11 (20%) patients."
      explanation: Systematic review quantifying the share of patients carrying this allele.
  - name: c.1513C>T (p.Arg505*) and c.934delC (p.Leu312Phefs*30)
    description: >
      Homozygous truncating variants identified in two consanguineous families with
      congenital nephrotic syndrome, hypogonadism and prenatally detected adrenal
      calcifications; associated with markedly elevated blood and fibroblast S1P.
    type: nonsense
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:28181337
      reference_title: "Deficiency of the sphingosine-1-phosphate lyase SGPL1 is associated with congenital nephrotic syndrome and congenital adrenal calcifications."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Using exome sequencing and targeted Sanger sequencing, two homozygous truncating mutations, c.1513C>T (p.Arg505*) and c.934delC (p.Leu312Phefs*30), were identified in SGPL1-encoding sphingosine-1-phosphate (S1P) lyase 1."
      explanation: Original report of these truncating alleles in the congenital nephrotic presentation.
  - name: p.Tyr416Cys, p.Arg340Trp, p.Ser346Ile and p.Arg222Trp (recurrent severe alleles)
    description: >
      Together with p.Arg222Gln these four recurrent missense alleles account for three
      quarters of reported cases. They carry a genotype-severity signal: no patient
      homozygous for p.Ser346Ile (a Moroccan founder allele) or p.Arg222Trp (Turkish
      ancestry) survived, with median age at last report under six months, whereas
      p.Arg222Gln homozygotes survive into later childhood.
    type: missense
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:39334450
      reference_title: "Factors influencing survival in sphingosine phosphate lyase insufficiency syndrome: a retrospective cross-sectional natural history study of 76 patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Five missense variants (R222Q, Y416C, R340W, S346I, and R222W) accounted for 75% of all reported SPLIS cases"
      explanation: Quantifies the share of cases explained by the recurrent alleles.
    - reference: PMID:39334450
      reference_title: "Factors influencing survival in sphingosine phosphate lyase insufficiency syndrome: a retrospective cross-sectional natural history study of 76 patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In contrast to the generally more favorable outcome of SPLIS patients homozygous for the R222Q variant, no patients homozygous for R222W variant survived"
      explanation: Genotype-survival relationship for the Arg222Trp allele.
    - reference: PMID:39334450
      reference_title: "Factors influencing survival in sphingosine phosphate lyase insufficiency syndrome: a retrospective cross-sectional natural history study of 76 patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The S346I variant representing 11% of variants and 7% of SPLIS cases was found in homozygous state in one Moroccan family, and no case survived"
      explanation: Genotype-survival relationship for the Ser346Ile allele.
  evidence:
  - reference: PMID:28165339
    reference_title: "Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 7 families with SRNS and facultative ichthyosis, adrenal insufficiency, immunodeficiency, and neurological defects, we identified 9 different recessive mutations in SGPL1, which encodes sphingosine-1-phosphate (S1P) lyase. All mutations resulted in reduced or absent SGPL1 protein and/or enzyme activity."
    explanation: One of the three simultaneous 2017 gene-discovery reports establishing SGPL1 as causative.
  - reference: PMID:28165343
    reference_title: "Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this work, we have identified 4 different homozygous mutations, c.665G>A (p.R222Q), c.1633_1635delTTC (p.F545del), c.261+1G>A (p.S65Rfs*6), and c.7dupA (p.S3Kfs*11), in 5 families with the condition."
    explanation: Independent simultaneous gene-discovery report in the adrenal-insufficiency cohort.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  penetrance: COMPLETE
  expressivity: VARIABLE
  description: >
    SPLIS is inherited in an autosomal recessive manner; parental consanguinity is reported
    in about 70% of patients. Expressivity is highly variable, including within kindreds,
    and there is no clear overall genotype-phenotype correlation apart from the milder
    R222Q-associated course.
  evidence:
  - reference: PMID:33074640
    reference_title: "Sphingosine Phosphate Lyase Insufficiency Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SPLIS is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an SGPL1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier"
    explanation: GeneReviews statement of the inheritance pattern and recurrence risk.
  - reference: PMID:35904228
    reference_title: "A retrospective analysis of endocrine disease in sphingosine-1-phosphate lyase insufficiency: case series and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There is no clear genotype-phenotype correlation overall in the syndrome, with variable disease penetrance within individual kindreds."
    explanation: Documents the variable expressivity, including intrafamilial variability.
pathophysiology:
- name: Biallelic SGPL1 Loss of Function
  description: >
    Biallelic SGPL1 variants abolish or severely reduce sphingosine-1-phosphate lyase, the
    pyridoxal 5'-phosphate-dependent endoplasmic reticulum enzyme that irreversibly cleaves
    S1P into hexadecenal and phosphoethanolamine. Missense alleles reduce activity and can
    mislocalise the protein; truncating alleles abolish it. Because the lyase guards the only
    exit from sphingolipid metabolism, its loss blocks the entire degradative pathway.
  biological_scale: MOLECULAR
  molecular_functions:
  - preferred_term: sphingosine-1-phosphate lyase activity
    term:
      id: GO:0008117
      label: sphinganine-1-phosphate aldolase activity
    modifier: DECREASED
  downstream:
  - target: Sphingoid Base Phosphate and Sphingolipid Accumulation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28181337
      reference_title: "Deficiency of the sphingosine-1-phosphate lyase SGPL1 is associated with congenital nephrotic syndrome and congenital adrenal calcifications."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The levels of SGPL1 substrates, S1P, and sphingosine were markedly increased in the patients' blood and fibroblasts, as determined by liquid chromatography-tandem mass spectrometry."
      explanation: Directly links loss of the enzyme to substrate accumulation in patients.
  evidence:
  - reference: PMID:28165339
    reference_title: "Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "All mutations resulted in reduced or absent SGPL1 protein and/or enzyme activity. Overexpression of cDNA representing SGPL1 mutations resulted in subcellular mislocalization of SGPL1."
    explanation: Functional characterisation of the disease alleles as loss of function.
  - reference: PMID:30274713
    reference_title: "Sphingosine phosphate lyase insufficiency syndrome (SPLIS): A novel inborn error of sphingolipid metabolism."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Sphingosine-1-phosphate lyase (SPL) is an intracellular enzyme that controls the final step in the sphingolipid degradative pathway, the only biochemical pathway for removal of sphingolipids."
    explanation: Review establishing why loss of this single enzyme blocks all sphingolipid removal.
- name: Sphingoid Base Phosphate and Sphingolipid Accumulation
  description: >
    Without the lyase, S1P, sphingosine, ceramides and sphingomyelin accumulate in plasma,
    urine and cells. S1P is a bioactive signalling lipid acting through five G-protein-coupled
    S1P receptors and intracellular targets, so the accumulation is not inert storage but
    excessive signalling. Metabolic labelling shows that cells partly buffer S1P by
    feedback-inhibiting de novo synthesis and diverting ceramide into glycosphingolipids;
    pathological intracellular S1P accumulation emerges when these compensations are
    overwhelmed, and Sgpl1-null kidneys show pronounced S1P enrichment and urinary excretion.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: sphingolipid catabolic process
    term:
      id: GO:0030149
      label: sphingolipid catabolic process
    modifier: DECREASED
  - preferred_term: sphingosine-1-phosphate receptor signaling pathway
    term:
      id: GO:0003376
      label: sphingosine-1-phosphate receptor signaling pathway
    modifier: INCREASED
  downstream:
  - target: Podocyte Cytoskeletal Disorganization and Loss
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:42024444
      reference_title: "Redirection of sphingolipid metabolism drives cytoskeletal defects in SPLIS and reveals ROCK inhibition as therapy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In vivo, Sgpl1-/- mice had pronounced urinary S1P excretion and renal S1P enrichment, accompanied by cytoskeletal disorganization and impaired epithelial morphogenesis. Mechanistically, we identify aberrant Rho/ROCK signaling as a key mediator of S1P-driven cytoskeletal dysregulation."
      explanation: Links renal S1P accumulation to the cytoskeletal lesion via Rho/ROCK signalling.
  - target: Adrenocortical Zonation and Steroidogenesis Failure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Impaired Lymphocyte Egress and T-Cell Lymphopenia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34133011
      reference_title: "Genotype/Phenotype Interactions and First Steps Toward Targeted Therapy for Sphingosine Phosphate Lyase Insufficiency Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Inactivating mutations of SGPL1-the gene encoding SPL-lead to a deficiency of its downstream products, and buildup of sphingolipid intermediates, including its bioactive substrate, sphingosine-1-phosphate (S1P), the latter causing lymphopenia, a hallmark of the disease."
      explanation: States that S1P buildup is the cause of the lymphopenia.
  - target: Keratinocyte Hyperdifferentiation and Epidermal Barrier Disruption
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36868360
      reference_title: "Ichthyosis linked to sphingosine 1-phosphate lyase insufficiency is due to aberrant sphingolipid and calcium regulation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Loss of SGPL1 caused an accumulation of S1P, sphingosine, and ceramides, while its overexpression caused a reduction of these species."
      explanation: Keratinocyte knockout reproduces the sphingolipid accumulation upstream of the differentiation phenotype.
  - target: Mitochondrial Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32682944
      reference_title: "Sphingosine-1-phosphate lyase (SGPL1) deficiency is associated with mitochondrial dysfunction."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Accumulation of sphingolipid intermediates, as seen with loss of function mutations in SGPL1, has been implicated in mitochondrial dysregulation, including alterations in mitochondrial membrane potentials and initiation of mitochondrial apoptosis."
      explanation: Frames sphingolipid accumulation as the trigger for the mitochondrial changes measured in the study.
  - target: Neuronal and Myelin Sphingolipid Dysregulation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36187293
      reference_title: "Neurological Consequences of Sphingosine Phosphate Lyase Insufficiency."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "SPL guards the only exit point for sphingolipid metabolism, and its inactivation leads to accumulation of various types of sphingolipids which have biophysical roles in plasma membrane rafts and myelin, and signaling roles in cell cycle progression, vesicular trafficking, cell migration, and programmed cell death."
      explanation: Review connecting sphingolipid accumulation to membrane, myelin and neuronal signalling roles.
  evidence:
  - reference: PMID:32682944
    reference_title: "Sphingosine-1-phosphate lyase (SGPL1) deficiency is associated with mitochondrial dysfunction."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Mass spectrometric analysis of patient dermal fibroblasts revealed significantly elevated levels of sphingosine-1-phosphate, sphingosine, ceramide species and sphingomyelin when compared to control."
    explanation: Quantifies the breadth of sphingolipid accumulation in patient cells.
  - reference: PMID:42024444
    reference_title: "Redirection of sphingolipid metabolism drives cytoskeletal defects in SPLIS and reveals ROCK inhibition as therapy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Metabolic stable isotope labeling revealed that SPL deficiency does not invariably result in S1P accumulation. Instead, SPL-deficient cells maintain near-normal S1P levels through (a) feedback regulation of de novo sphingolipid synthesis via the ORMDL-ceramide axis and (b) increased diversion of excess ceramides into glycosphingolipids."
    explanation: >-
      Qualifies the accumulation model: compensatory rerouting buffers S1P until the
      sphingolipid load exceeds it.
- name: Podocyte Cytoskeletal Disorganization and Loss
  description: >
    SGPL1 is expressed in podocytes and mesangial cells. Excess S1P drives Rho/ROCK
    hyperactivation, disorganising the podocyte actin cytoskeleton; ultrastructure in the
    R222Q mouse shows foot process effacement and podocyte loss, and knockdown in mesangial
    cells impairs migration in an S1P-receptor-dependent manner. This is the
    disorder-specific initiating podocyte insult of the conserved nephrotic podocytopathy
    chain.
  biological_scale: CELLULAR
  conforms_to: "nephrotic_podocyte_injury#Podocyte Injury"
  cell_types:
  - preferred_term: podocyte
    term:
      id: CL:0000653
      label: podocyte
  - preferred_term: glomerular mesangial cell
    term:
      id: CL:1000742
      label: glomerular mesangial cell
  biological_processes:
  - preferred_term: actin cytoskeleton organization
    term:
      id: GO:0030036
      label: actin cytoskeleton organization
    modifier: ABNORMAL
  downstream:
  - target: Glomerular Filtration Barrier Failure and Glomerulosclerosis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:42182331
      reference_title: "Pyridoxine supplementation confers protection against SGPL1 (R222Q) variant sphingosine phosphate lyase insufficiency syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Ultrastructural analysis and super-resolution microscopy showed podocyte loss and foot process effacement. Transcriptional profiling revealed a pattern of cytokine upregulation and extracellular matrix remodeling."
      explanation: Podocyte loss and effacement accompany proteinuria and glomerulosclerosis in the R222Q model.
  evidence:
  - reference: PMID:28165339
    reference_title: "Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Immunofluorescence revealed SGPL1 expression in mouse podocytes and mesangial cells. Knockdown of Sgpl1 in rat mesangial cells inhibited cell migration, which was partially rescued by VPC23109, an S1P receptor antagonist."
    explanation: Localises the enzyme to the glomerular cells and shows an S1P-receptor-dependent cellular defect.
  - reference: PMID:42024444
    reference_title: "Redirection of sphingolipid metabolism drives cytoskeletal defects in SPLIS and reveals ROCK inhibition as therapy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Pharmacological ROCK inhibition with fasudil mitigated renal cytoskeletal defects in Sgpl1-/- and Sgpl1rosa+fl/fl mice and partially restored epithelial architecture."
    explanation: Pharmacological rescue confirms Rho/ROCK as the mediator of the cytoskeletal lesion.
- name: Glomerular Filtration Barrier Failure and Glomerulosclerosis
  description: >
    Podocyte injury breaks the size- and charge-selective filtration barrier, producing
    steroid-resistant nephrotic-range proteinuria. Kidney biopsies show focal segmental
    glomerulosclerosis (including the collapsing variant) or diffuse mesangial sclerosis,
    and Sgpl1-knockout kidneys show STAT3 activation with proinflammatory and profibrogenic
    cytokine elevation. Progression to end-stage kidney disease ranges from under a month to
    five years after onset of proteinuria.
  biological_scale: TISSUE
  conforms_to: "nephrotic_podocyte_injury#Glomerular Filtration Barrier Breakdown"
  biological_processes:
  - preferred_term: glomerular filtration
    term:
      id: GO:0003094
      label: glomerular filtration
    modifier: ABNORMAL
  downstream:
  - target: Steroid-resistant nephrotic syndrome
    causal_link_type: DIRECT
  - target: Focal segmental glomerulosclerosis
    causal_link_type: DIRECT
  - target: Stage 5 chronic kidney disease
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36371483
      reference_title: "Sphingosine phosphate lyase insufficiency syndrome: a systematic review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Kidney disorders (42, 80.8%) were mainly in the form of steroid-resistant nephrotic syndrome (SRNS) and progressed to end-stage kidney disease (ESKD) in 19 (36.5%) patients at a median (IQR) age of 6 (1.4-42.6) months."
      explanation: Documents progression from SRNS to kidney failure in over a third of patients.
  evidence:
  - reference: PMID:33755599
    reference_title: "Efficacy of AAV9-mediated SGPL1 gene transfer in a mouse model of S1P lyase insufficiency syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "STAT3 pathway activation and elevated proinflammatory and profibrogenic cytokines observed in KO kidneys were attenuated by treatment."
    explanation: Identifies the inflammatory and profibrotic signalling in the knockout kidney that underlies glomerulosclerosis.
  - reference: PMID:35748945
    reference_title: "A rare cause of nephrotic syndrome-sphingosine-1-phosphate lyase (SGPL1) deficiency: 6 cases and a review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Kidney biopsy showed focal segmental glomerulosclerosis in 2 patients and diffuse mesangial sclerosis in one patient. Steroids were given to 3 patients, but they did not respond. All 6 patients progressed to chronic kidney disease"
    explanation: Histology and steroid resistance in a clinical series.
- name: Adrenocortical Zonation and Steroidogenesis Failure
  description: >
    Sgpl1-null mice show disrupted adrenocortical zonation and defective expression of
    steroidogenic enzymes, and patient fibroblasts show reduced cortisol output after
    progesterone stimulation. In patients this manifests as glucocorticoid deficiency in
    early childhood, with mineralocorticoid deficiency in about a third, and prenatally
    detectable adrenal calcification in some. The intermediate steps by which sphingolipid
    accumulation disrupts adrenal development and steroidogenesis are not established.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: adrenocortical cell
    term:
      id: CL:0002097
      label: cortical cell of adrenal gland
  biological_processes:
  - preferred_term: glucocorticoid biosynthetic process
    term:
      id: GO:0006704
      label: glucocorticoid biosynthetic process
    modifier: DECREASED
  downstream:
  - target: Primary adrenal insufficiency
    causal_link_type: DIRECT
  - target: Adrenal calcification
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:28165343
    reference_title: "Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Sgpl1-/- mice displayed disrupted adrenocortical zonation and defective expression of steroidogenic enzymes as well as renal histology in keeping with a glomerular phenotype."
    explanation: Knockout adrenal histology establishing the tissue-level lesion.
  - reference: PMID:32682944
    reference_title: "Sphingosine-1-phosphate lyase (SGPL1) deficiency is associated with mitochondrial dysfunction."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Reduced cortisol output in response to progesterone stimulation was observed in two patient dermal fibroblast cell lines."
    explanation: Patient-cell steroidogenic defect corroborating the adrenal phenotype.
- name: Impaired Lymphocyte Egress and T-Cell Lymphopenia
  description: >
    Lymphocyte egress from thymus and lymph nodes follows an S1P gradient sensed by S1P
    receptor 1; loss of the lyase abolishes the gradient, trapping lymphocytes in lymphoid
    organs. T-cell lymphopenia is a near-universal feature, and although some T-cell
    function persists, patients have recurrent viral, fungal and bacterial infections and
    sepsis is a leading cause of death.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  biological_processes:
  - preferred_term: T cell migration
    term:
      id: GO:0072678
      label: T cell migration
    modifier: DECREASED
  downstream:
  - target: Decreased total lymphocyte count
    causal_link_type: DIRECT
  - target: Recurrent infections
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:34133011
    reference_title: "Genotype/Phenotype Interactions and First Steps Toward Targeted Therapy for Sphingosine Phosphate Lyase Insufficiency Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "buildup of sphingolipid intermediates, including its bioactive substrate, sphingosine-1-phosphate (S1P), the latter causing lymphopenia, a hallmark of the disease"
    explanation: Attributes the lymphopenia to S1P accumulation.
  - reference: PMID:28181337
    reference_title: "Deficiency of the sphingosine-1-phosphate lyase SGPL1 is associated with congenital nephrotic syndrome and congenital adrenal calcifications."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "S1P is an intracellular and extracellular signaling molecule involved in angiogenesis, vascular maturation, and immunity."
    explanation: Background for the immune role of S1P signalling disrupted in the disease.
- name: Keratinocyte Hyperdifferentiation and Epidermal Barrier Disruption
  description: >
    In SGPL1-knockout keratinocytes and organotypic skin equivalents, accumulated S1P,
    sphingosine and ceramide drive premature differentiation, a thickened retained stratum
    corneum, altered calcium-signalling gene expression and loss of E-cadherin junctions,
    reproducing the ichthyosis, acanthosis and hyperpigmentation seen in most patients with
    a reported skin phenotype.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  downstream:
  - target: Ichthyosis
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:36868360
    reference_title: "Ichthyosis linked to sphingosine 1-phosphate lyase insufficiency is due to aberrant sphingolipid and calcium regulation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "SGPL1_KO upregulated differentiation markers, while SGPL1_OE upregulated basal and proliferative markers. The advanced differentiation of SGPL1_KO was confirmed by 3D organotypic models that also presented with a thickened and retained stratum corneum and a breakdown of E-cadherin junctions."
    explanation: Direct demonstration of the keratinocyte differentiation and barrier defect in a human skin model.
- name: Mitochondrial Dysfunction
  description: >
    Patient fibroblasts and SGPL1-knockout HeLa cells show reduced total mitochondrial
    volume and altered mitochondrial dynamics and oxidative phosphorylation parameters,
    consistent with sphingolipid-induced mitochondrial dysregulation. Its contribution to
    organ pathology and to phenotype severity is proposed but not yet established.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: mitochondrion organization
    term:
      id: GO:0007005
      label: mitochondrion organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:32682944
    reference_title: "Sphingosine-1-phosphate lyase (SGPL1) deficiency is associated with mitochondrial dysfunction."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Total mitochondrial volume was reduced in both S1P lyase deficient patient and HeLa cell lines. Mitochondrial dynamics and parameters of oxidative phosphorylation were altered when compared to matched controls, though differentially across the cell lines."
    explanation: Primary measurement of the mitochondrial phenotype in patient-derived and engineered cells.
- name: Neuronal and Myelin Sphingolipid Dysregulation
  description: >
    Accumulated sphingolipids perturb membrane rafts and myelin, and loss of the lyase's
    products impairs autophagic flux important for axonal integrity. Clinically this
    produces a spectrum from callosal dysgenesis and microcephaly to progressive
    involvement of the globus pallidus, thalamus and dentate nucleus with atrophy, cranial
    nerve deficits, sensorineural hearing loss, peripheral motor and sensory neuropathy,
    seizures and developmental regression.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: myelination
    term:
      id: GO:0042552
      label: myelination
    modifier: ABNORMAL
  - preferred_term: autophagy
    term:
      id: GO:0006914
      label: autophagy
    modifier: DYSREGULATED
  downstream:
  - target: Developmental regression
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Peripheral neuropathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Sensorineural hearing impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Cranial nerve paralysis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Seizure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Microcephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Aplasia/Hypoplasia of the corpus callosum
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:36187293
    reference_title: "Neurological Consequences of Sphingosine Phosphate Lyase Insufficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In addition, the products of the SPL reaction have biological functions including regulation of autophagic flux, which is important in axonal and neuronal integrity."
    explanation: Review of the proposed neuronal mechanisms, including the autophagy role of the lyase products.
  - reference: PMID:32855188
    reference_title: "MRI Spectrum of Brain Involvement in Sphingosine-1-Phosphate Lyase Insufficiency Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Analysis reveals recurring patterns of features in affected patients, including isolated callosal dysgenesis and prominent involvement of the globus pallidus, thalamus, and dentate nucleus, with progressive atrophy and worsening of brain lesions."
    explanation: Imaging evidence for the progressive deep grey nuclei and callosal lesions.
phenotypes:
- name: Steroid-resistant nephrotic syndrome
  category: Renal
  frequency: VERY_FREQUENT
  description: >
    The most common presentation; onset ranges from congenital (including in utero) to
    adolescence, does not respond to corticosteroids, and progresses to kidney failure in a
    large proportion of patients.
  phenotype_term:
    preferred_term: Steroid-resistant nephrotic syndrome
    term:
      id: HP:0012588
      label: Steroid-resistant nephrotic syndrome
  evidence:
  - reference: PMID:36371483
    reference_title: "Sphingosine phosphate lyase insufficiency syndrome: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Kidney disorders (42, 80.8%) were mainly in the form of steroid-resistant nephrotic syndrome (SRNS)"
    explanation: Systematic review frequency of kidney involvement, predominantly SRNS.
  - reference: PMID:33074640
    reference_title: "Sphingosine Phosphate Lyase Insufficiency Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sphingosine phosphate lyase insufficiency syndrome (SPLIS) is characterized by varying combinations of steroid-resistant nephrotic syndrome (ranging from nonimmune fetal hydrops to adolescent onset)"
    explanation: GeneReviews summary of the renal phenotype and its onset range.
- name: Focal segmental glomerulosclerosis
  category: Renal
  frequency: FREQUENT
  description: >
    The usual biopsy lesion, including the aggressive collapsing variant; diffuse
    mesangial sclerosis is also reported.
  phenotype_term:
    preferred_term: Focal segmental glomerulosclerosis
    term:
      id: HP:0000097
      label: Focal segmental glomerulosclerosis
  evidence:
  - reference: PMID:35748945
    reference_title: "A rare cause of nephrotic syndrome-sphingosine-1-phosphate lyase (SGPL1) deficiency: 6 cases and a review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Kidney biopsy showed focal segmental glomerulosclerosis in 2 patients and diffuse mesangial sclerosis in one patient."
    explanation: Biopsy findings in a clinical series.
- name: Stage 5 chronic kidney disease
  category: Renal
  frequency: FREQUENT
  description: >
    Progression to end-stage kidney disease occurs in over a third of patients, at a
    median age of 6 months, and is a leading cause of death.
  phenotype_term:
    preferred_term: End-stage kidney disease
    term:
      id: HP:0003774
      label: Stage 5 chronic kidney disease
  evidence:
  - reference: PMID:36371483
    reference_title: "Sphingosine phosphate lyase insufficiency syndrome: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "progressed to end-stage kidney disease (ESKD) in 19 (36.5%) patients at a median (IQR) age of 6 (1.4-42.6) months"
    explanation: Quantifies ESKD frequency and timing.
- name: Primary adrenal insufficiency
  category: Endocrine
  frequency: FREQUENT
  description: >
    Glucocorticoid insufficiency in early childhood is the most common endocrine
    manifestation; about a third of affected individuals also have mineralocorticoid
    deficiency. Adrenal insufficiency can be the sole presenting feature, particularly with
    the R222Q allele, and may present with hypoglycaemia and seizures.
  phenotype_term:
    preferred_term: Primary adrenal insufficiency
    term:
      id: HP:0008207
      label: Primary adrenal insufficiency
  evidence:
  - reference: PMID:36371483
    reference_title: "Sphingosine phosphate lyase insufficiency syndrome: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most prevalent clinical feature was endocrinopathies, including primary adrenal insufficiency (PAI) (71.2%) and hypothyroidism (32.7%)."
    explanation: Systematic review frequency of PAI.
  - reference: PMID:35904228
    reference_title: "A retrospective analysis of endocrine disease in sphingosine-1-phosphate lyase insufficiency: case series and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Glucocorticoid insufficiency in early childhood is the most common endocrine manifestation affecting 64% of the 50 patients reported with SPLIS, and a third of these individuals have additional mineralocorticoid deficiency."
    explanation: Endocrine case series quantifying glucocorticoid and mineralocorticoid deficiency.
  - reference: PMID:30517686
    reference_title: "SGPL1 Deficiency: A Rare Cause of Primary Adrenal Insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient presented with hypoglycemia and seizures at age 2 years and was ultimately diagnosed with PAI (isolated glucocorticoid deficiency)."
    explanation: Isolated glucocorticoid deficiency as the presenting feature in an R222Q homozygote.
- name: Decreased circulating aldosterone concentration
  category: Endocrine
  frequency: OCCASIONAL
  description: >
    Mineralocorticoid deficiency accompanies glucocorticoid deficiency in about a third of
    those with adrenal involvement.
  phenotype_term:
    preferred_term: Mineralocorticoid deficiency
    term:
      id: HP:0004319
      label: Decreased circulating aldosterone concentration
  evidence:
  - reference: PMID:35904228
    reference_title: "A retrospective analysis of endocrine disease in sphingosine-1-phosphate lyase insufficiency: case series and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a third of these individuals have additional mineralocorticoid deficiency"
    explanation: Quantifies mineralocorticoid deficiency among patients with adrenal disease.
- name: Adrenal calcification
  category: Endocrine
  frequency: OCCASIONAL
  description: >
    Prenatally or neonatally detected adrenal calcifications are a distinctive feature that
    can be the first clinical indication of the syndrome.
  phenotype_term:
    preferred_term: Adrenal calcification
    term:
      id: HP:0010512
      label: Adrenal calcification
  evidence:
  - reference: PMID:28181337
    reference_title: "Deficiency of the sphingosine-1-phosphate lyase SGPL1 is associated with congenital nephrotic syndrome and congenital adrenal calcifications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified two unrelated consanguineous families with three children affected by the rare association of congenital nephrotic syndrome (CNS) diagnosed in the first days of life, of hypogonadism, and of prenatally detected adrenal calcifications, associated with congenital adrenal insufficiency in one case."
    explanation: Original description of prenatal adrenal calcification in SGPL1 deficiency.
- name: Hypothyroidism
  category: Endocrine
  frequency: FREQUENT
  description: Mild primary hypothyroidism affects roughly a third of patients.
  phenotype_term:
    preferred_term: Primary hypothyroidism
    term:
      id: HP:0000821
      label: Hypothyroidism
  evidence:
  - reference: PMID:35904228
    reference_title: "A retrospective analysis of endocrine disease in sphingosine-1-phosphate lyase insufficiency: case series and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mild primary hypothyroidism affects approximately a third of patients."
    explanation: Endocrine series frequency of hypothyroidism.
- name: Cryptorchidism
  category: Endocrine
  frequency: OCCASIONAL
  description: >
    Primary gonadal insufficiency with microphallus and cryptorchidism is reported in fewer
    than a third of affected boys, always with concomitant adrenal disease.
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: PMID:35904228
    reference_title: "A retrospective analysis of endocrine disease in sphingosine-1-phosphate lyase insufficiency: case series and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Primary gonadal insufficiency, manifesting with microphallus and cryptorchidism, is reported in less than one-third of affected boys, all with concomitant adrenal disease."
    explanation: Quantifies gonadal involvement in boys.
- name: Decreased total lymphocyte count
  category: Immunological
  frequency: VERY_FREQUENT
  description: >
    T-cell lymphopenia is a hallmark, reflecting failure of S1P-gradient-dependent
    lymphocyte egress; some T-cell function usually persists.
  phenotype_term:
    preferred_term: Lymphopenia
    term:
      id: HP:0001888
      label: Decreased total lymphocyte count
  evidence:
  - reference: PMID:34133011
    reference_title: "Genotype/Phenotype Interactions and First Steps Toward Targeted Therapy for Sphingosine Phosphate Lyase Insufficiency Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the latter causing lymphopenia, a hallmark of the disease"
    explanation: Identifies lymphopenia as a hallmark feature.
  - reference: PMID:32233035
    reference_title: "Responsiveness of sphingosine phosphate lyase insufficiency syndrome to vitamin B6 cofactor supplementation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with SPLIS exhibit lymphopenia, nephrosis, adrenal insufficiency, and/or neurological defects."
    explanation: Lists lymphopenia among the core manifestations.
- name: Recurrent infections
  category: Immunological
  frequency: FREQUENT
  description: >
    Immunodeficiency with recurrent infections is reported in a majority of well-characterised
    patients, and sepsis or septic shock accounts for about a quarter of deaths.
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: PMID:35748945
    reference_title: "A rare cause of nephrotic syndrome-sphingosine-1-phosphate lyase (SGPL1) deficiency: 6 cases and a review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three patients had hypothyroidism, 2 had ichthyosis, 4 had immunodeficiency, 5 had neurological findings, and 2 had genitourinary system anomalies."
    explanation: Frequency of immunodeficiency and other extrarenal features in a clinical series.
  - reference: PMID:36371483
    reference_title: "Sphingosine phosphate lyase insufficiency syndrome: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Twenty-six (49.1%) patients with available outcome were deceased at a median (IQR) age of 5 (1.5-30.5) months, mostly following ESKD (23%) or sepsis/septic shock (23%)."
    explanation: Sepsis as a leading cause of death reflects the clinical impact of the immunodeficiency.
- name: Ichthyosis
  category: Dermatological
  frequency: VERY_FREQUENT
  description: >
    Ichthyosis, acanthosis and hyperpigmentation are reported in the large majority of
    patients in whom the skin was examined; hyperpigmentation may also reflect adrenal
    insufficiency.
  phenotype_term:
    preferred_term: Ichthyosis
    term:
      id: HP:0008064
      label: Ichthyosis
  evidence:
  - reference: PMID:36868360
    reference_title: "Ichthyosis linked to sphingosine 1-phosphate lyase insufficiency is due to aberrant sphingolipid and calcium regulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Where a skin phenotype is reported, 94% had abnormalities such as ichthyosis, acanthosis, and hyperpigmentation."
    explanation: Frequency of skin abnormalities among patients with a reported skin phenotype.
  - reference: PMID:28165339
    reference_title: "Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 7 families with SRNS and facultative ichthyosis, adrenal insufficiency, immunodeficiency, and neurological defects, we identified 9 different recessive mutations in SGPL1"
    explanation: Ichthyosis as a facultative feature in the discovery cohort.
- name: Hyperpigmentation of the skin
  category: Dermatological
  frequency: OCCASIONAL
  description: >
    Skin hyperpigmentation accompanies primary adrenal insufficiency (ACTH excess) and is
    also part of the epidermal phenotype.
  phenotype_term:
    preferred_term: Hyperpigmentation of the skin
    term:
      id: HP:0000953
      label: Hyperpigmentation of the skin
  evidence:
  - reference: PMID:30090628
    reference_title: "Nephrotic syndrome and adrenal insufficiency caused by a variant in SGPL1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Her brother died previously with the same phenotype and hyperpigmentation of the skin."
    explanation: Case report documenting hyperpigmentation with adrenal insufficiency.
- name: Nonimmune hydrops fetalis
  category: Prenatal
  frequency: OCCASIONAL
  description: >
    The most severe end of the spectrum presents as nonimmune fetal hydrops; prenatally
    diagnosed disease is uniformly fatal in early infancy.
  phenotype_term:
    preferred_term: Nonimmune hydrops fetalis
    term:
      id: HP:0001790
      label: Nonimmune hydrops fetalis
  evidence:
  - reference: PMID:33074640
    reference_title: "Sphingosine Phosphate Lyase Insufficiency Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "steroid-resistant nephrotic syndrome (ranging from nonimmune fetal hydrops to adolescent onset)"
    explanation: GeneReviews places nonimmune hydrops at the severe end of the renal spectrum.
- name: Developmental regression
  category: Neurological
  frequency: FREQUENT
  description: >
    Neurological involvement, present in about half of patients, ranges from developmental
    delay to progressive regression with deep grey nuclei atrophy.
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: PMID:33074640
    reference_title: "Sphingosine Phosphate Lyase Insufficiency Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "neurologic abnormalities (cranial nerve deficits, developmental delay, regression/progression, and peripheral motor and sensory neuropathy)"
    explanation: GeneReviews enumeration of the neurological features.
  - reference: PMID:32855188
    reference_title: "MRI Spectrum of Brain Involvement in Sphingosine-1-Phosphate Lyase Insufficiency Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "prominent involvement of the globus pallidus, thalamus, and dentate nucleus, with progressive atrophy and worsening of brain lesions"
    explanation: Progressive imaging changes underlying regression.
- name: Cranial nerve paralysis
  category: Neurological
  frequency: OCCASIONAL
  description: >
    Cranial nerve deficits, including ptosis, ophthalmoplegia and facial weakness, are a
    recognised neurological feature.
  phenotype_term:
    preferred_term: Cranial nerve deficits
    term:
      id: HP:0006824
      label: Cranial nerve paralysis
  evidence:
  - reference: PMID:36187293
    reference_title: "Neurological Consequences of Sphingosine Phosphate Lyase Insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The latter can include sensorineural hearing loss, cranial nerve defects, peripheral neuropathy, abnormal brain development, seizures and/or neurodegeneration."
    explanation: Review listing cranial nerve defects among the neurological manifestations.
- name: Sensorineural hearing impairment
  category: Neurological
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Sensorineural hearing loss
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:36187293
    reference_title: "Neurological Consequences of Sphingosine Phosphate Lyase Insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The latter can include sensorineural hearing loss, cranial nerve defects, peripheral neuropathy, abnormal brain development, seizures and/or neurodegeneration."
    explanation: Review listing sensorineural hearing loss among the neurological manifestations.
- name: Peripheral neuropathy
  category: Neurological
  frequency: OCCASIONAL
  description: Peripheral motor and sensory neuropathy is part of the neurological spectrum.
  phenotype_term:
    preferred_term: Peripheral motor and sensory neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  evidence:
  - reference: PMID:33074640
    reference_title: "Sphingosine Phosphate Lyase Insufficiency Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "neurologic abnormalities (cranial nerve deficits, developmental delay, regression/progression, and peripheral motor and sensory neuropathy)"
    explanation: GeneReviews lists peripheral motor and sensory neuropathy.
- name: Seizure
  category: Neurological
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Seizures
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:36187293
    reference_title: "Neurological Consequences of Sphingosine Phosphate Lyase Insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The latter can include sensorineural hearing loss, cranial nerve defects, peripheral neuropathy, abnormal brain development, seizures and/or neurodegeneration."
    explanation: Review listing seizures among the neurological manifestations.
- name: Microcephaly
  category: Neurological
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:32855188
    reference_title: "MRI Spectrum of Brain Involvement in Sphingosine-1-Phosphate Lyase Insufficiency Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MR imaging findings of abnormal deep gray nuclei, microcephaly, or callosal dysgenesis in an infant or young child exhibiting other typical clinical features of sphingosine-1-phosphate lyase insufficiency syndrome should trigger prompt genetic testing for SGPL1 mutations."
    explanation: Neuroradiological series naming microcephaly among the recurring findings.
- name: Aplasia/Hypoplasia of the corpus callosum
  category: Neurological
  frequency: OCCASIONAL
  description: Isolated callosal dysgenesis is one of the recurring MRI patterns.
  phenotype_term:
    preferred_term: Callosal dysgenesis
    term:
      id: HP:0007370
      label: Aplasia/Hypoplasia of the corpus callosum
  evidence:
  - reference: PMID:32855188
    reference_title: "MRI Spectrum of Brain Involvement in Sphingosine-1-Phosphate Lyase Insufficiency Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Analysis reveals recurring patterns of features in affected patients, including isolated callosal dysgenesis"
    explanation: Neuroradiological series identifying callosal dysgenesis as a recurring pattern.
- name: Hypoglycemia
  category: Metabolic
  frequency: OCCASIONAL
  description: Hypoglycaemia, sometimes with seizures, is a presenting sign of the adrenal insufficiency.
  phenotype_term:
    preferred_term: Hypoglycemia
    term:
      id: HP:0001943
      label: Hypoglycemia
  evidence:
  - reference: PMID:30517686
    reference_title: "SGPL1 Deficiency: A Rare Cause of Primary Adrenal Insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient presented with hypoglycemia and seizures at age 2 years and was ultimately diagnosed with PAI (isolated glucocorticoid deficiency)."
    explanation: Hypoglycaemia as the presenting feature of adrenal insufficiency.
- name: Failure to thrive
  category: Growth
  description: >
    Poor weight gain and feeding difficulties are recognised as part of the multisystem
    picture and growth and nutrition are assessed at every visit; no cohort frequency has
    been reported.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:33074640
    reference_title: "Sphingosine Phosphate Lyase Insufficiency Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Supportive care: Multidisciplinary management of steroid-resistant nephrotic syndrome, endocrine involvement, immunodeficiency, neurologic involvement, developmental delay / intellectual disability, hearing loss, ichthyosis, poor weight gain / feeding issues, and cardiac manifestations."
    explanation: GeneReviews lists poor weight gain and feeding issues among the features needing supportive management.
- name: Abnormality of the cardiovascular system
  category: Cardiovascular
  description: >
    Cardiac manifestations are reported in some individuals, including a cardiac
    malformation in an early Indian case and pericardial effusion in a hydropic patient;
    the spectrum is not characterised and cardiology evaluation is recommended as needed.
  phenotype_term:
    preferred_term: Cardiac manifestations
    term:
      id: HP:0001626
      label: Abnormality of the cardiovascular system
  evidence:
  - reference: PMID:33074640
    reference_title: "Sphingosine Phosphate Lyase Insufficiency Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Cardiac manifestations are reported in some individuals."
    explanation: GeneReviews statement of cardiac involvement without a frequency.
  - reference: PMID:28181337
    reference_title: "Deficiency of the sphingosine-1-phosphate lyase SGPL1 is associated with congenital nephrotic syndrome and congenital adrenal calcifications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One male patient had non-palpable testes and micropenis, and another patient had pericardial and pleural effusions, generalized hydrops, and a cleft palate."
    explanation: Pericardial effusion in a hydropic patient.
- name: Micropenis
  category: Endocrine
  frequency: OCCASIONAL
  description: >
    Undervirilisation with micropenis accompanies cryptorchidism and low anti-Mullerian
    hormone in a minority of affected boys, reflecting partial gonadal dysfunction.
  phenotype_term:
    preferred_term: Micropenis
    term:
      id: HP:0000054
      label: Micropenis
  evidence:
  - reference: PMID:28165343
    reference_title: "Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Undervirilization was reported in patient 6, who had micropenis, right cryptorchidism, and bilateral microorchidism, associated with low serum anti-Müllerian hormone, suggesting that partial gonadal dysfunction may be part of the clinical picture."
    explanation: Micropenis as part of gonadal dysfunction in a reported patient.
  - reference: PMID:28181337
    reference_title: "Deficiency of the sphingosine-1-phosphate lyase SGPL1 is associated with congenital nephrotic syndrome and congenital adrenal calcifications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A micropenis and cryptorchidism with a small inguinal testis at the right side and no testis at the left side were noted."
    explanation: Second independent report.
- name: Anemia
  category: Hematological
  description: >
    Anaemia and thrombocytopenia are listed among the haematological and immune findings
    in reviews of the syndrome; their frequency is not quantified.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: PMID:30090628
    reference_title: "Nephrotic syndrome and adrenal insufficiency caused by a variant in SGPL1."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Immunodeficienies include lymphopenia, deficiency of cellular immunity, multiple bacterial infection, hypogammaglobulinemia, thrombocytopenia and anemia."
    explanation: Review listing anaemia among the reported findings.
biochemical:
- name: Elevated plasma sphingosine-1-phosphate and sphingosine
  presence: present
  notes: >
    Plasma and fibroblast S1P and sphingosine are markedly elevated by LC-MS/MS and serve as
    disease biomarkers that respond to pyridoxine in responsive patients; S1P also appears in
    urine in the mouse model.
  readouts:
  - target: Sphingoid Base Phosphate and Sphingolipid Accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >
      Elevated circulating sphingoid base phosphates report the metabolic block at the
      lyase step and fall when residual enzyme activity is restored.
  evidence:
  - reference: PMID:28181337
    reference_title: "Deficiency of the sphingosine-1-phosphate lyase SGPL1 is associated with congenital nephrotic syndrome and congenital adrenal calcifications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The levels of SGPL1 substrates, S1P, and sphingosine were markedly increased in the patients' blood and fibroblasts, as determined by liquid chromatography-tandem mass spectrometry."
    explanation: Establishes the plasma biomarker.
  - reference: PMID:32233035
    reference_title: "Responsiveness of sphingosine phosphate lyase insufficiency syndrome to vitamin B6 cofactor supplementation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In two patients, disease biomarkers responded to B6 supplementation. S1P abundance and activity levels increased and sphingolipids decreased in response to B6."
    explanation: Shows the biomarker is treatment-responsive.
treatments:
- name: Pyridoxine (vitamin B6) cofactor supplementation
  description: >
    Targeted therapy for patients with pyridoxine-responsive alleles, notably R222Q:
    pyridoxal 5'-phosphate stabilises and augments the residual mutant enzyme, lowering
    sphingolipid biomarkers and improving neurological status in responders. It is
    recommended by GeneReviews and is limited to patients with a susceptible allele.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: pyridoxine
      term:
        id: CHEBI:16709
        label: pyridoxine
  target_mechanisms:
  - target: Biallelic SGPL1 Loss of Function
    description: Cofactor supplementation partially restores activity of destabilised missense SGPL1 variants.
  evidence:
  - reference: PMID:32233035
    reference_title: "Responsiveness of sphingosine phosphate lyase insufficiency syndrome to vitamin B6 cofactor supplementation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We demonstrate the first potential targeted therapy for SPLIS and suggest that 30% of SPLIS patients might respond to cofactor supplementation."
    explanation: First report of clinical and biochemical response to B6.
  - reference: PMID:42182331
    reference_title: "Pyridoxine supplementation confers protection against SGPL1 (R222Q) variant sphingosine phosphate lyase insufficiency syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurological improvement, plasma S1P normalization, and increased SPL activity in patient-derived fibroblasts were observed after pyridoxine supplementation in a patient with R222Q-variant SPLIS."
    explanation: Clinical response in an R222Q patient, corroborated by the R222Q mouse model.
  - reference: PMID:33074640
    reference_title: "Sphingosine Phosphate Lyase Insufficiency Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Targeted therapy: Vitamin B6 supplementation."
    explanation: GeneReviews management recommendation.
- name: Glucocorticoid and mineralocorticoid replacement
  description: >
    Standard hormone replacement for primary adrenal insufficiency, with stress dosing;
    adrenal function should be reassessed every 6-12 months and before major procedures
    because adrenal insufficiency can emerge late.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Hormone replacement therapy
    term:
      id: NCIT:C15599
      label: Hormone Replacement Therapy
    therapeutic_agent:
    - preferred_term: hydrocortisone
      term:
        id: CHEBI:17650
        label: cortisol
    - preferred_term: fludrocortisone
      term:
        id: CHEBI:50885
        label: fludrocortisone
  target_phenotypes:
  - preferred_term: Primary adrenal insufficiency
    term:
      id: HP:0008207
      label: Primary adrenal insufficiency
  evidence:
  - reference: PMID:33074640
    reference_title: "Sphingosine Phosphate Lyase Insufficiency Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "assess primary adrenal function every six to 12 months and before any major procedure"
    explanation: GeneReviews surveillance guidance underpinning replacement therapy.
  - reference: PMID:35904228
    reference_title: "A retrospective analysis of endocrine disease in sphingosine-1-phosphate lyase insufficiency: case series and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "While endocrinopathy in the syndrome generally presents in infancy, late-onset disease also occurs. Screening for these is therefore warranted both at diagnosis and through follow-up."
    explanation: Rationale for ongoing endocrine screening and replacement.
- name: Levothyroxine replacement
  description: Replacement for the primary hypothyroidism seen in about a third of patients; annual thyroid function testing is recommended.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Hormone replacement therapy
    term:
      id: NCIT:C15599
      label: Hormone Replacement Therapy
    therapeutic_agent:
    - preferred_term: levothyroxine
      term:
        id: CHEBI:18332
        label: L-thyroxine
  target_phenotypes:
  - preferred_term: Hypothyroidism
    term:
      id: HP:0000821
      label: Hypothyroidism
  evidence:
  - reference: PMID:33074640
    reference_title: "Sphingosine Phosphate Lyase Insufficiency Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "annual free thyroxine and thyroid-stimulating hormone"
    explanation: GeneReviews surveillance recommendation for thyroid function.
- name: Kidney replacement therapy and kidney transplantation
  description: >
    Dialysis and kidney transplantation for end-stage kidney disease; transplantation
    significantly extends survival and the nephropathy does not recur in the graft, because
    the enzyme defect is systemic but the glomerular lesion is intrinsic to the native
    podocytes.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Kidney transplantation
    term:
      id: NCIT:C15265
      label: Kidney Transplantation
  target_phenotypes:
  - preferred_term: End-stage kidney disease
    term:
      id: HP:0003774
      label: Stage 5 chronic kidney disease
  evidence:
  - reference: PMID:39334450
    reference_title: "Factors influencing survival in sphingosine phosphate lyase insufficiency syndrome: a retrospective cross-sectional natural history study of 76 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Kidney transplantation significantly extended survival outcomes."
    explanation: Natural history evidence for the survival benefit of transplantation.
  - reference: PMID:35748945
    reference_title: "A rare cause of nephrotic syndrome-sphingosine-1-phosphate lyase (SGPL1) deficiency: 6 cases and a review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All 6 patients progressed to chronic kidney disease; 5 required kidney replacement therapy (KRT) at a median age of 6 months. Deceased kidney transplantation was performed in one patient."
    explanation: Clinical series documenting kidney replacement therapy and transplantation.
- name: Infection prevention and immunodeficiency precautions
  description: >
    Because of T-cell lymphopenia, GeneReviews advises avoiding live vaccines, exposure to
    infectious agents and non-irradiated transfusion products, with immunological
    reassessment every 6-12 months; nephrotoxic drugs should also be avoided.
  treatment_term:
    preferred_term: Supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: PMID:33074640
    reference_title: "Sphingosine Phosphate Lyase Insufficiency Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Agents/circumstances to avoid: Nephrotoxic medications; medications that require renal excretion (for individuals with renal insufficiency); live vaccines; exposure to infectious agents; transfusion products that have not been irradiated."
    explanation: GeneReviews list of agents and circumstances to avoid.
- name: AAV9-mediated SGPL1 gene replacement (preclinical)
  description: >
    Systemic AAV9-SGPL1 given to newborn Sgpl1-knockout mice dramatically prolonged
    survival and prevented nephrosis, neurodevelopmental delay, anaemia and
    hypercholesterolaemia; a CAG-promoter version (AAV-SPL 2.0) performs at least as well
    but treated mice eventually develop glomerulosclerosis, indicating that improved kidney
    targeting is needed. Proposed as a universal, genotype-independent therapy.
  therapeutic_modality: GENE_THERAPY
  treatment_term:
    preferred_term: Gene therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  target_mechanisms:
  - target: Biallelic SGPL1 Loss of Function
    description: Restores enzyme expression and activity, correcting the metabolic block at its source.
  evidence:
  - reference: PMID:33755599
    reference_title: "Efficacy of AAV9-mediated SGPL1 gene transfer in a mouse model of S1P lyase insufficiency syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Treatment dramatically prolonged survival and prevented nephrosis, neurodevelopmental delay, anemia, and hypercholesterolemia."
    explanation: Proof-of-concept efficacy in the knockout mouse.
  - reference: PMID:37958544
    reference_title: "AAV-SPL 2.0, a Modified Adeno-Associated Virus Gene Therapy Agent for the Treatment of Sphingosine Phosphate Lyase Insufficiency Syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Over time, treated mice developed nephrosis and glomerulosclerosis, which likely resulted in their demise. Our overall findings show that AAV-SPL 2.0 performs equal to or better than AAV-SPL. However, improved kidney targeting may be necessary to achieve maximally optimized gene therapy as a potentially lifesaving SPLIS treatment."
    explanation: Second-generation vector results and the remaining kidney-targeting limitation.
- name: ROCK inhibition with fasudil (preclinical)
  description: >
    Pharmacological Rho-kinase inhibition mitigated renal cytoskeletal defects and partially
    restored epithelial architecture in Sgpl1-deficient mice, identifying S1P-driven
    Rho/ROCK hyperactivation as a tractable downstream target independent of genotype.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: fasudil
      term:
        id: CHEBI:43871
        label: fasudil
  target_mechanisms:
  - target: Podocyte Cytoskeletal Disorganization and Loss
    description: Blocks the Rho/ROCK signalling through which excess S1P disorganises the renal epithelial cytoskeleton.
  evidence:
  - reference: PMID:42024444
    reference_title: "Redirection of sphingolipid metabolism drives cytoskeletal defects in SPLIS and reveals ROCK inhibition as therapy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Pharmacological ROCK inhibition with fasudil mitigated renal cytoskeletal defects in Sgpl1-/- and Sgpl1rosa+fl/fl mice and partially restored epithelial architecture."
    explanation: Preclinical efficacy of ROCK inhibition on the renal lesion.
- name: Genetic counseling and testing of at-risk relatives
  description: >
    Autosomal recessive counselling with a 25% recurrence risk; GeneReviews recommends
    clarifying the genetic status of at-risk sibs so that treatment and precautions can
    begin before symptoms.
  treatment_term:
    preferred_term: Genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:33074640
    reference_title: "Sphingosine Phosphate Lyase Insufficiency Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment and awareness of agents/circumstances to avoid."
    explanation: GeneReviews recommendation on evaluation of relatives at risk.
clinical_trials:
- name: NCT04885179
  phase: NOT_APPLICABLE
  status: UNKNOWN
  description: >
    International observational study and patient registry for SPLIS collecting clinical,
    biochemical, genetic and biosample data; no intervention is administered.
  evidence:
  - reference: clinicaltrials:NCT04885179
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This protocol aims to gather information about sphingosine phosphate lyase insufficiency syndrome (SPLIS), also known as NPHS14, and to create a SPLIS patient registry."
    explanation: Registry protocol summary.
- name: NCT06669949
  phase: NOT_APPLICABLE
  status: UNKNOWN
  description: >
    Prospective longitudinal natural history study with a retrospective cross-sectional
    arm testing whether age of onset, disease features and biomarkers predict quality of
    life and survival.
  evidence:
  - reference: clinicaltrials:NCT06669949
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The central hypothesis is that age of onset, other disease features, and disease biomarkers will be predictive of quality of life (QOL) and survival in SPLIS patients."
    explanation: Natural history study summary.
diagnosis:
- name: Molecular genetic testing for biallelic SGPL1 variants
  description: >
    The diagnosis is established in a proband with at least one suggestive finding and
    biallelic pathogenic SGPL1 variants; SGPL1 should be included in steroid-resistant
    nephrotic syndrome and primary adrenal insufficiency gene panels, including for isolated
    adrenal insufficiency.
  evidence:
  - reference: PMID:33074640
    reference_title: "Sphingosine Phosphate Lyase Insufficiency Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of SPLIS is established in a proband with at least one suggestive finding and biallelic pathogenic variants in SGPL1 identified by molecular genetic testing."
    explanation: GeneReviews diagnostic criterion.
  - reference: PMID:30517686
    reference_title: "SGPL1 Deficiency: A Rare Cause of Primary Adrenal Insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We suggest that screening for SGPL1 mutations should not be reserved only for patients with nephrotic syndrome but may also include patients with PAI who lack other clinical manifestations of NPHS14 because, in certain cases, kidney disease and accompanying features might develop."
    explanation: Supports testing in isolated adrenal insufficiency.
- name: Plasma sphingolipid profiling
  description: >
    LC-MS/MS shows markedly elevated S1P and sphingosine in blood and fibroblasts, supporting
    the diagnosis and providing a biomarker for treatment response.
  evidence:
  - reference: PMID:28181337
    reference_title: "Deficiency of the sphingosine-1-phosphate lyase SGPL1 is associated with congenital nephrotic syndrome and congenital adrenal calcifications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The levels of SGPL1 substrates, S1P, and sphingosine were markedly increased in the patients' blood and fibroblasts, as determined by liquid chromatography-tandem mass spectrometry."
    explanation: Biochemical diagnostic finding.
- name: Brain MRI
  description: >
    Recurring patterns include isolated callosal dysgenesis and progressive involvement of
    the globus pallidus, thalamus and dentate nucleus; these findings in an infant with
    nephrotic syndrome or adrenal insufficiency should prompt SGPL1 testing.
  evidence:
  - reference: PMID:32855188
    reference_title: "MRI Spectrum of Brain Involvement in Sphingosine-1-Phosphate Lyase Insufficiency Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MR imaging findings of abnormal deep gray nuclei, microcephaly, or callosal dysgenesis in an infant or young child exhibiting other typical clinical features of sphingosine-1-phosphate lyase insufficiency syndrome should trigger prompt genetic testing for SGPL1 mutations."
    explanation: Neuroradiological diagnostic guidance.
- name: Endocrine, immunological and renal surveillance
  description: >
    Urine studies, adrenal function every 6-12 months, annual thyroid function, testicular
    function review, immunological assessment, neurological and audiological evaluation.
  evidence:
  - reference: PMID:33074640
    reference_title: "Sphingosine Phosphate Lyase Insufficiency Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Surveillance: Urine studies per nephrologist in those with kidney disease or annually in those without known kidney disease; assess primary adrenal function every six to 12 months and before any major procedure; annual free thyroxine and thyroid-stimulating hormone; annual review of testicular function"
    explanation: GeneReviews surveillance schedule.
differential_diagnoses:
- name: Familial glucocorticoid deficiency
  description: >
    Isolated glucocorticoid deficiency due to MC2R, MRAP or other genes; SGPL1 variants were
    found when patients with familial glucocorticoid deficiency or triple A syndrome lacking
    nephrotic syndrome were sequenced, so SPLIS belongs in that differential.
  distinguishing_features:
  - Nephrotic syndrome, ichthyosis, lymphopenia or neurological findings favour SPLIS
  - Elevated plasma S1P and sphingosine
  - Biallelic SGPL1 variants
  evidence:
  - reference: PMID:30517686
    reference_title: "SGPL1 Deficiency: A Rare Cause of Primary Adrenal Insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sequencing of the SGPL1 gene in 21 patients with familial glucocorticoid disease or triple A syndrome"
    explanation: SGPL1 variants identified within a familial glucocorticoid deficiency cohort.
- name: Other monogenic steroid-resistant nephrotic syndromes
  description: >
    NPHS1, NPHS2, LAMB2, WT1 and PLCE1 account for most congenital and early-onset SRNS;
    the syndromic combination with adrenal insufficiency, ichthyosis, immunodeficiency and
    neurological disease distinguishes SPLIS.
  distinguishing_features:
  - Primary adrenal insufficiency or adrenal calcification
  - Ichthyosis, lymphopenia, neurological involvement
  - Elevated plasma sphingoid base phosphates
  evidence:
  - reference: PMID:28165339
    reference_title: "Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A mutation in 1 of over 40 monogenic genes can be detected in approximately 30% of individuals with SRNS whose symptoms manifest before 25 years of age."
    explanation: Context of the monogenic SRNS differential in which SGPL1 was discovered.
animal_models:
- name: Sgpl1 knockout mouse
  species: Mouse
  genotype: Sgpl1-/- (constitutive null)
  publication: PMID:28165343
  description: >
    Constitutive knockout that dies in the first weeks of life and recapitulates the main
    human features: glomerular nephrosis, disrupted adrenocortical zonation with defective
    steroidogenic enzyme expression, lymphopenia, anaemia, hypercholesterolaemia and
    neurodevelopmental delay; renal S1P enrichment with cytoskeletal disorganisation.
  modeled_mechanisms:
  - target: Adrenocortical Zonation and Steroidogenesis Failure
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Adrenal histology in the null mouse shows disrupted zonation and reduced steroidogenic enzyme expression.
    limitations: >-
      Early postnatal lethality precludes study of the childhood-onset, late-emerging
      adrenal insufficiency seen in patients.
    readouts:
    - name: Adrenocortical zonation and steroidogenic enzyme expression
      target: Adrenocortical Zonation and Steroidogenesis Failure
      direction: ALTERED
      interpretation: Histological correlate of the adrenal steroidogenic failure.
      evidence:
      - reference: PMID:28165343
        reference_title: "Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Sgpl1-/- mice displayed disrupted adrenocortical zonation and defective expression of steroidogenic enzymes"
        explanation: Reports the adrenal histological measurement.
    evidence:
    - reference: PMID:28165343
      reference_title: "Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Sgpl1-/- mice recapitulated the main characteristics of the human disease with abnormal adrenal and renal morphology."
      explanation: Authors' statement that the knockout recapitulates the human disease.
  - target: Glomerular Filtration Barrier Failure and Glomerulosclerosis
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: TISSUE
    description: Nephrosis with glomerular pathology and profibrotic cytokine signalling, prevented by AAV-SGPL1 gene transfer.
    readouts:
    - name: Nephrosis and renal STAT3/cytokine activation
      target: Glomerular Filtration Barrier Failure and Glomerulosclerosis
      direction: INCREASED
      interpretation: Proteinuric glomerular disease with inflammatory signalling in the knockout kidney.
      evidence:
      - reference: PMID:33755599
        reference_title: "Efficacy of AAV9-mediated SGPL1 gene transfer in a mouse model of S1P lyase insufficiency syndrome."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "STAT3 pathway activation and elevated proinflammatory and profibrogenic cytokines observed in KO kidneys were attenuated by treatment."
        explanation: Reports the renal readout and its correction by gene therapy.
    evidence:
    - reference: PMID:33755599
      reference_title: "Efficacy of AAV9-mediated SGPL1 gene transfer in a mouse model of S1P lyase insufficiency syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "As proof of concept, we evaluated the efficacy of adeno-associated virus 9-mediated transfer of human SGPL1 (AAV-SPL) given to newborn Sgpl1-KO mice that model SPLIS and die in the first weeks of life."
      explanation: Establishes the knockout as the SPLIS model used for the renal readouts.
  - target: Podocyte Cytoskeletal Disorganization and Loss
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Renal S1P enrichment with cytoskeletal disorganisation and impaired epithelial morphogenesis, rescued by ROCK inhibition.
    readouts:
    - name: Renal epithelial cytoskeletal organisation
      target: Podocyte Cytoskeletal Disorganization and Loss
      direction: ALTERED
      interpretation: Cytoskeletal disorganisation driven by S1P/Rho/ROCK signalling.
      evidence:
      - reference: PMID:42024444
        reference_title: "Redirection of sphingolipid metabolism drives cytoskeletal defects in SPLIS and reveals ROCK inhibition as therapy."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "In vivo, Sgpl1-/- mice had pronounced urinary S1P excretion and renal S1P enrichment, accompanied by cytoskeletal disorganization and impaired epithelial morphogenesis."
        explanation: Reports the renal cytoskeletal readout.
- name: SGPL1 R222Q knock-in mouse
  species: Mouse
  genotype: Sgpl1 R222Q homozygous knock-in
  publication: PMID:42182331
  description: >
    Gene-edited model of the most common human allele; phenotypically silent on
    pyridoxine-enriched chow but develops enzyme inactivation, S1P accumulation, wasting,
    anaemia, proteinuria, glomerulosclerosis, podocyte loss and foot process effacement on
    reduced-pyridoxine chow, demonstrating pyridoxine responsiveness in vivo.
  modeled_mechanisms:
  - target: Podocyte Cytoskeletal Disorganization and Loss
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: Reproduces the human allele, its pyridoxine dependence and the podocyte lesion.
    readouts:
    - name: Podocyte number and foot process morphology
      target: Podocyte Cytoskeletal Disorganization and Loss
      direction: DECREASED
      interpretation: Podocyte loss and foot process effacement on pyridoxine-deficient diet.
      evidence:
      - reference: PMID:42182331
        reference_title: "Pyridoxine supplementation confers protection against SGPL1 (R222Q) variant sphingosine phosphate lyase insufficiency syndrome."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Ultrastructural analysis and super-resolution microscopy showed podocyte loss and foot process effacement."
        explanation: Reports the ultrastructural podocyte readout.
    evidence:
    - reference: PMID:42182331
      reference_title: "Pyridoxine supplementation confers protection against SGPL1 (R222Q) variant sphingosine phosphate lyase insufficiency syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "However, SPL inactivation, S1P accumulation, wasting, anemia, proteinuria, and glomerulosclerosis developed in SPLR222Q but not WT mice fed chow with reduced pyridoxine."
      explanation: Establishes the diet-dependent disease phenotype of the knock-in model.
- name: Drosophila Sply mutant
  species: Drosophila melanogaster
  genotype: Sply loss-of-function
  publication: PMID:28165339
  description: >
    Flies lacking the S1P lyase orthologue show a nephrocyte phenotype reminiscent of
    nephrotic syndrome that is rescued by wild-type but not patient-variant Sply.
  modeled_mechanisms:
  - target: Podocyte Cytoskeletal Disorganization and Loss
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: CELLULAR
    description: Nephrocyte filtration defect used to test the functional consequence of patient alleles.
    limitations: >-
      Insect nephrocytes are a functional analogue of podocytes without a glomerulus;
      the model tests allele function rather than mammalian glomerular pathology.
    evidence:
    - reference: PMID:28165339
      reference_title: "Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In Drosophila, Sply mutants, which lack SGPL1, displayed a phenotype reminiscent of nephrotic syndrome in nephrocytes. WT Sply, but not the disease-associated variants, rescued this phenotype."
      explanation: Reports the nephrocyte phenotype and allele-specific rescue.
experimental_models:
- name: SGPL1-knockout keratinocyte organotypic skin equivalent
  experimental_model_type: CELL_LINE
  description: >
    CRISPR-Cas9 SGPL1 knockout in immortalised human keratinocytes (N/TERT-1) grown as 3D
    organotypic skin equivalents, with lentiviral overexpression as the opposite pole.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  publication: PMID:36868360
  modeled_mechanisms:
  - target: Keratinocyte Hyperdifferentiation and Epidermal Barrier Disruption
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Reproduces sphingolipid accumulation, advanced differentiation and a thickened retained stratum corneum.
    limitations: >-
      Immortalised keratinocytes without immune or dermal components; no in vivo
      confirmation in patient skin biopsies.
    evidence:
    - reference: PMID:36868360
      reference_title: "Ichthyosis linked to sphingosine 1-phosphate lyase insufficiency is due to aberrant sphingolipid and calcium regulation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The advanced differentiation of SGPL1_KO was confirmed by 3D organotypic models that also presented with a thickened and retained stratum corneum and a breakdown of E-cadherin junctions."
      explanation: Reports the organotypic epidermal phenotype.
discussions:
- discussion_id: splis_organ_specific_mechanism_gap
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Adrenocortical Zonation and Steroidogenesis Failure
  - pathophysiology#Neuronal and Myelin Sphingolipid Dysregulation
  prompt: >
    Which S1P-receptor-dependent and receptor-independent pathways link sphingolipid
    accumulation to adrenocortical and neuronal injury in SPLIS, and why are these tissues
    vulnerable while others are spared?
  rationale: >
    The lymphopenia is mechanistically explained by loss of the S1P egress gradient and the
    podocyte lesion by Rho/ROCK hyperactivation, but the adrenal and neurological
    pathogenesis remains unknown; recent data showing that S1P does not invariably
    accumulate in SPL-deficient cells make the tissue-specific trigger an open question.
  evidence:
  - reference: PMID:34133011
    reference_title: "Genotype/Phenotype Interactions and First Steps Toward Targeted Therapy for Sphingosine Phosphate Lyase Insufficiency Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other manifestations of SPLIS include nephrotic syndrome, neuronal defects, and adrenal insufficiency, but their pathogenesis remains unknown."
    explanation: Authors' explicit statement of the mechanistic gap.
- discussion_id: splis_knockout_lethality_model_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Biallelic SGPL1 Loss of Function
  prompt: >
    Does the constitutive Sgpl1 knockout mouse, which dies within weeks of birth, model
    the later-onset, R222Q-associated and isolated-adrenal presentations of human SPLIS?
  rationale: >
    The null mouse models the severe infantile end of the spectrum but cannot reproduce
    the milder hypomorphic disease; the pyridoxine-dependent R222Q knock-in, which is
    phenotypically silent on B6-enriched chow, is the first model of a hypomorphic allele
    and shows that diet can gate the phenotype, so extrapolation from the null to the
    common human genotype needs care.
  evidence:
  - reference: PMID:42182331
    reference_title: "Pyridoxine supplementation confers protection against SGPL1 (R222Q) variant sphingosine phosphate lyase insufficiency syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "SPLR222Q mice fed pyridoxine-enriched chow lacked obvious phenotypes."
    explanation: Shows the hypomorphic model's phenotype is conditional on cofactor availability.
references:
- reference: PMID:33074640
  title: "Sphingosine Phosphate Lyase Insufficiency Syndrome."
  tags:
  - GeneReviews
notes: >
  Curated as a single Disease entry (stub entry_type decision: DISEASE): one gene, one
  conserved mechanism with organ-specific branches. Curated 2026-09-05 from the GeneReviews
  chapter, the three 2017 discovery papers, the 2023 systematic review and 2024 natural
  history study, and mechanistic model-system papers through 2026. Evidence snippets are
  exact quotes from cached PubMed abstracts. Conforms to the nephrotic_podocyte_injury
  module at the podocyte-injury and filtration-barrier nodes.
📚

References & Deep Research

References

1
PMID:33074640
Sphingosine Phosphate Lyase Insufficiency Syndrome.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Edit: take the optional suggestions from the PR #11288 review · 2026-09-07T03:30:09Z · View source

Review round on PR #11288 (approved, five optional suggestions). Taken: (1) clinical_trials block for the SPLIS registry NCT04885179 and the natural history study NCT06669949, both observational (NOT_APPLICABLE phase, UNKNOWN status because the cached summaries carry no recruitment status), with caches fetched by just fetch-reference; (2) a recurrent-variant entry for p.Tyr416Cys, p.Arg340Trp, p.Ser346Ile and p.Arg222Trp quoting PMID:39334450 for the 75% share of cases and the absence of survivors among Ser346Ile and Arg222Trp homozygotes; (3) new phenotypes Failure to thrive (HP:0001508) and Abnormality of the cardiovascular system (HP:0001626) from the GeneReviews chapter, Micropenis (HP:0000054) from PMID:28165343 and PMID:28181337, and Anemia (HP:0001903) from PMID:30090628; (4) frequency VERY_FREQUENT on Ichthyosis, supported by its existing 94% snippet. Not taken: hypercholesterolemia and acanthosis nigricans, which the deep-research report mentions but no cached abstract states quotably, and the case-variant duplicate DOI cache pair, which is harmless and is a research-citation artifact. Validation: just validate pass, count-verified-snippets 108/108, validate-terms pass, check-causal-targets, check-entity-refs, check-enum-values, snippet-grading, snippet-length and title-snippet gates clean.

Create: Sphingosine_Phosphate_Lyase_Insufficiency_Syndrome (SGPL1, MONDO:0033203) · 2026-09-05T21:58:46Z · View source

Created the SPLIS (nephrotic syndrome type 14) entry as a single Disease (stub entry_type decision: DISEASE; one gene, one conserved mechanism with organ-specific branches). Sources: GeneReviews chapter PMID:33074640 (tagged, Clinical Characteristics cross-referenced against phenotypes: SRNS, PAI with/without mineralocorticoid deficiency, hypothyroidism, testicular insufficiency, immunodeficiency, neurological features incl. cranial nerve deficits, developmental regression, peripheral neuropathy, ichthyosis all captured; cardiac manifestations noted in description only, no HPO binding since GeneReviews gives no specific lesion), the three 2017 gene-discovery papers (PMID:28165343, PMID:28165339, PMID:28181337), the 2023 systematic review (PMID:36371483), the 2024 natural history study of 76 patients (PMID:39334450), the endocrine series (PMID:35904228), the gnomAD prevalence estimate (PMID:39669624), and mechanism papers on B6 responsiveness (PMID:32233035, PMID:42182331), mitochondrial dysfunction (PMID:32682944), keratinocyte differentiation (PMID:36868360), Rho/ROCK cytoskeletal signalling (PMID:42024444) and AAV9 gene therapy (PMID:33755599, PMID:37958544). Deep research: Edison/falcon report research/Sphingosine_Phosphate_Lyase_Insufficiency_Syndrome-deep-research-falcon.md (11/11 references verified, 24/24 terms verified, preflight-dr PASS against MONDO:0033203); all of its cited PMIDs were already in the cached set used here, and its phenotype and mechanism sections were cross-checked against the entry. Pathophysiology is a causal chain from biallelic SGPL1 loss through sphingoid base accumulation into podocyte (conforms_to nephrotic_podocyte_injury), adrenocortical, lymphocyte-egress, keratinocyte, mitochondrial and neuronal branches. Model links: Sgpl1-/- mouse, R222Q knock-in mouse, Drosophila Sply, SGPL1-KO organotypic skin. Validation: just validate (pass), just validate-terms (pass), just count-verified-snippets 97/97, check-causal-targets and check-entity-refs clean. One snippet was shortened because bracketed spans are stripped before matching.

Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 33 citations 2026-09-05T19:10:14.768532

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Sphingosine Phosphate Lyase Insufficiency Syndrome
  • MONDO ID: MONDO:0033203 (if available)
  • Category: Genetic

Research Objectives

Please provide a comprehensive research report on Sphingosine Phosphate Lyase Insufficiency Syndrome covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Present this section as an ordered causal chain first, then the detail below. Open with a numbered sequence of mechanistic steps running from the initiating lesion (mutation, exposure, infection) to the clinical manifestation, one step per line, each naming what it causes next. State the causal verb explicitly ("leads to", "results in") and say where a step is inferred rather than demonstrated. Where the mechanism branches, show the branch. The categories below are a checklist of what to cover within those steps, not the organizing structure — a step may draw on several of them, and a category may contribute to several steps.

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS): comprehensive disease-characteristics report

Executive summary

Sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) is an ultra-rare, autosomal-recessive inborn error of sphingolipid metabolism caused by biallelic loss-of-function variants in SGPL1. Its core manifestations are early steroid-resistant nephrotic syndrome (SRNS), primary adrenal insufficiency, immune dysfunction, neurologic disease, and ichthyosis, but expressivity ranges from lethal prenatal disease to isolated childhood neuropathy or adrenal insufficiency. The strongest natural-history evidence is a September 2024 retrospective cohort of 76 molecularly confirmed patients: kidney involvement occurred in 78%, adrenal insufficiency in 63%, end-stage kidney disease (ESKD) in 35%, hypothyroidism in 33%, and lymphopenia in 30%; overall survival at last report was 50%. Early nephropathy, prenatal disease, and absence of transplantation predicted poor outcome, whereas homozygous p.Arg222Gln and kidney transplantation were associated with longer survival. These are observational associations, not randomized treatment effects. (keller2024factorsinfluencingsurvival pages 1-2, keller2024naturalhistoryof pages 5-8, keller2024factorsinfluencingsurvival pages 12-14)

Domain Best current finding/statistic Evidence type Key source/date/DOI
Definition and cause SPLIS, also called nephrotic syndrome type 14 (NPHS14), is an ultra-rare autosomal-recessive sphingolipid-metabolism disorder caused by biallelic inactivating SGPL1 variants. SGPL1 encodes the pyridoxal-5′-phosphate-dependent sphingosine-1-phosphate lyase. Human genetic cohorts; biochemical studies Lovric et al., March 2017, DOI: 10.1172/JCI89626; Sedillo et al., published online October 30, 2023, DOI: 10.1016/j.gimo.2023.100840 (sedillo2024prevalenceestimateof pages 1-3, lovric2017mutationsinsphingosine1phosphate pages 1-2)
Modeled prevalence Estimated worldwide prevalence: 0.015 per 100,000 (95% CI 0.010–0.021), corresponding to approximately 11,707 affected people worldwide. This is a population-genetic model, not observed case prevalence. Population-genetic modeling using curated variants and gnomAD v2.1.1 Sedillo et al., Genetics in Medicine Open, 2024; online October 30, 2023; DOI: 10.1016/j.gimo.2023.100840 (sedillo2024prevalenceestimateof pages 1-3, sedillo2024prevalenceestimateofa pages 1-3)
Major phenotype frequencies In the 76-patient cohort: kidney involvement 78%, primary adrenal insufficiency 63%, ESKD 35%, hypothyroidism 33%, and lymphopenia 30%. Presentation ranged from prenatal disease to age 15 years; 54% presented in the first year. Worldwide retrospective cross-sectional natural-history cohort Keller et al., September 2024, DOI: 10.1186/s13023-024-03311-w (keller2024factorsinfluencingsurvival pages 1-2, keller2024naturalhistoryof pages 5-8)
Survival and early-onset risk Overall survival at last report was 50%. Among non-transplanted patients with nephropathy, diagnosis before age one identified a high-risk group: fewer than 30% were alive two years after diagnosis and 17% were alive at last report; mean age at death among deceased cohort members was 7.5 months. Prenatal presentations were also associated with early mortality. Human natural-history cohort Keller et al., September 2024, DOI: 10.1186/s13023-024-03311-w (keller2024factorsinfluencingsurvival pages 1-2, keller2024naturalhistoryof pages 5-8, keller2024factorsinfluencingsurvival pages 12-14)
Genotype and prognosis Homozygous p.Arg222Gln (R222Q) was associated with better survival: reported survival was approximately 85%, and median age at last report among non-transplanted patients was 6.8 years versus 1.9 years for other genotypes. This association is prognostic, not proof that R222Q alone determines outcome. Human genotype–phenotype association Keller et al., 2024, DOI: 10.1186/s13023-024-03311-w (keller2024naturalhistoryof pages 5-8, keller2024naturalhistoryof pages 14-18, keller2024naturalhistoryof pages 18-25)
Kidney transplantation Kidney transplantation significantly extended survival relative to dialysis or palliative care. Median age at last report was 8 years after transplantation, 4.4 years with dialysis, and 1.3 years with palliative care; dialysis did not show a significant survival benefit over palliative care in the reported analysis. Retrospective treatment-outcome comparison; nonrandomized Keller et al., September 2024, DOI: 10.1186/s13023-024-03311-w (keller2024naturalhistoryof pages 14-18, keller2024factorsinfluencingsurvival pages 12-14, keller2024naturalhistoryof pages 18-25)
Core mechanism Loss of ER-localized S1P-lyase activity blocks irreversible cleavage of S1P into hexadecenal and ethanolamine phosphate, disturbing sphingolipid homeostasis. Patient samples show increased S1P/sphingosine; fibroblasts can retain less than 10% of normal activity. Downstream mechanisms include abnormal S1P-receptor signaling, impaired mesangial migration, podocyte injury, immune-cell trafficking defects, and altered steroidogenesis; several organ-specific links remain partly inferred. Human biochemical, cellular, mouse, yeast, and Drosophila evidence Janecke et al., April 2017, DOI: 10.1002/humu.23192; Lovric et al., March 2017, DOI: 10.1172/JCI89626 (lovric2017mutationsinsphingosine1phosphate pages 10-11, janecke2017deficiencyofthe pages 11-15, choi2019sphingosinephosphatelyase pages 5-6, choi2019sphingosinephosphatelyase pages 4-5)
Diagnostic approach Molecular confirmation requires biallelic pathogenic or likely pathogenic SGPL1 variants, typically detected by exome/genome sequencing or an SGPL1-containing nephrotic-syndrome/adrenal-insufficiency panel. Supporting assessments include proteinuria, serum albumin/lipids, kidney function and biopsy, cortisol/ACTH and mineralocorticoid testing, lymphocyte subsets, neurologic evaluation/MRI, and sphingolipid or enzyme assays where available. Human cohort practice; observational biomarker development Keller et al., 2024, DOI: 10.1186/s13023-024-03311-w; NCT06669949 (keller2024naturalhistoryof pages 5-8, NCT06669949 chunk 1, NCT06669949 chunk 2)
Observational research Two recruiting UCSF records were identified: NCT04885179, an international registry with estimated enrollment of 120, and NCT06669949, a three-year natural-history study with estimated enrollment of 28. They collect clinical, imaging, pathological and biospecimen data; neither assigns an investigational treatment. Prospective observational studies/registries NCT04885179, started April 22, 2025; NCT06669949, started April 22, 2025 (NCT06669949 chunk 1, NCT04885179 chunk 1, NCT06669949 chunk 3, NCT06669949 chunk 2)

Table: Compact summary of the strongest current evidence on SPLIS genetics, epidemiology, manifestations, prognosis, mechanism, diagnosis, transplantation, and ongoing observational research. Modeled estimates and nonrandomized clinical associations are explicitly distinguished from directly observed outcomes.

1. Disease information

Definition and identifiers

SPLIS is a recessive metabolic disorder in which deficient sphingosine-1-phosphate lyase prevents the terminal, irreversible degradation of sphingosine-1-phosphate (S1P). It is multisystemic rather than solely a nephrotic syndrome. (keller2024factorsinfluencingsurvival pages 1-2, janecke2017deficiencyofthe pages 11-15)

  • MONDO: MONDO:0033203, represented in Open Targets as nephrotic syndrome 14.
  • OMIM phenotype: 617575, nephrotic syndrome, type 14.
  • Causal gene: SGPL1, OMIM 603729; HGNC 10817; Ensembl ENSG00000166224.
  • Common names: sphingosine-1-phosphate lyase insufficiency syndrome; sphingosine phosphate lyase insufficiency syndrome; SGPL1 deficiency; S1P-lyase deficiency; nephrotic syndrome 14/NPHS14; steroid-resistant nephrotic syndrome type 14; RENI syndrome; familial SRNS with adrenal insufficiency. (OpenTargets Search: Sphingosine phosphate lyase insufficiency syndrome-SGPL1, keller2024factorsinfluencingsurvival pages 1-2, sedillo2024prevalenceestimateof pages 1-3)
  • ICD/MeSH: no uniquely specific ICD-10, ICD-11, or MeSH code was established in the retrieved evidence. Component manifestations are coded separately. A knowledge base should not assign an unverified disease-specific ICD code.

The available evidence is predominantly aggregated disease-level information assembled from published cases, clinician questionnaires, medical records, and treating-provider reports—not population-scale EHR surveillance. Individual case reports remain important because fewer than 100 clinically recognized patients had been reported by 2024. (sedillo2024prevalenceestimateofa pages 3-4, keller2024factorsinfluencingsurvival pages 2-4)

Foundational literature

The disease was delineated in three independent 2017 reports linking recessive SGPL1 variants to nephrosis, adrenal disease, and neurologic/immune phenotypes. PubMed records cited by Open Targets include PMID 28181337, PMID 28165339, and PMID 28165343. The principal mechanistic paper is Lovric et al., Journal of Clinical Investigation, March 2017, DOI 10.1172/JCI89626; Janecke et al., Human Mutation, April 2017, DOI 10.1002/humu.23192. (OpenTargets Search: Sphingosine phosphate lyase insufficiency syndrome-SGPL1, janecke2017deficiencyofthe pages 11-15, lovric2017mutationsinsphingosine1phosphate pages 1-2)

A representative abstract statement from the 2024 natural-history study is: “SPLIS is caused by inactivating mutations in SGPL1, encoding the pyridoxal 5′-phosphate-dependent enzyme sphingosine-1-phosphate lyase, which catalyzes the final step of sphingolipid metabolism.” (keller2024factorsinfluencingsurvival pages 1-2)

2. Etiology, risk, protection, and gene–environment interaction

Cause

The primary cause is germline biallelic inactivation of SGPL1. No infectious, toxic, occupational, radiation, or lifestyle cause is known. S1P lyase is an endoplasmic-reticulum integral membrane enzyme requiring pyridoxal-5′-phosphate (PLP; active vitamin B6) and irreversibly cleaves S1P into hexadecenal and ethanolamine phosphate. (janecke2017deficiencyofthe pages 11-15, choi2019sphingosinephosphatelyase pages 4-5)

Risk factors

  • Genetic: two pathogenic/likely pathogenic SGPL1 alleles; consanguinity and an affected sibling increase prior probability. In the 76-person cohort, 61% had reported consanguinity and 56% had a family history. (keller2024naturalhistoryof pages 5-8)
  • Variant-dependent severity: residual enzyme activity plausibly modifies severity. Homozygous p.Arg222Gln was associated with better survival, whereas no homozygous p.Arg222Trp or p.Ser346Ile patient in that cohort survived. These associations require validation and should not be treated as deterministic. (keller2024naturalhistoryof pages 5-8, keller2024naturalhistoryof pages 18-25)
  • Non-genetic: no reproducible environmental risk factor has been demonstrated. Marked intrafamilial variability suggests unidentified genetic, environmental, developmental, or stochastic modifiers. (sedillo2024prevalenceestimateof pages 1-3, sedillo2024prevalenceestimateofa pages 1-3)

Protective factors

No inherited protective allele is established. Kidney transplantation and perhaps residual SGPL1 activity are associated with improved survival after disease develops, but are not primary prevention. Pyridoxine responsiveness may be genotype-dependent, particularly for PLP-binding-domain missense variants, but human evidence remains anecdotal or ex vivo. (keller2024naturalhistoryof pages 14-18, keller2024factorsinfluencingsurvival pages 12-14)

3. Phenotypes

The following frequencies derive from the best available 76-patient retrospective cohort and may be biased toward severe recognized disease. (keller2024naturalhistoryof pages 5-8)

  • Renal: proteinuria, congenital/infantile nephrotic syndrome, usually steroid-resistant, FSGS or diffuse mesangial sclerosis, progressive CKD/ESKD. Kidney involvement: 78%; ESKD: 35%. Progression from proteinuria to ESKD ranged from under one month to five years. Suggested HPO: HP:0000100 Nephrotic syndrome, HP:0000097 Focal segmental glomerulosclerosis, HP:0000093 Proteinuria, HP:0003774 End-stage renal disease. (keller2024factorsinfluencingsurvival pages 1-2, yang2023steroidresistantnephroticsyndrome pages 6-7, choi2019sphingosinephosphatelyase pages 4-5)
  • Endocrine: primary adrenal insufficiency, sometimes isolated glucocorticoid deficiency and sometimes combined mineralocorticoid deficiency; congenital adrenal calcification/hemorrhage; hypothyroidism; male hypogonadism/gonadal dysgenesis, cryptorchidism or micropenis. Adrenal insufficiency affected 63% in the 76-person cohort. A 2022 synthesis found glucocorticoid insufficiency in 64% of 50 reported patients, with approximately one-third of those also having mineralocorticoid deficiency; mild primary hypothyroidism affected about one-third. Suggested HPO: HP:0000846 Adrenal insufficiency, HP:0001943 Hypoglycemia, HP:0000821 Hypothyroidism, HP:0000028 Cryptorchidism, HP:0000054 Micropenis. (keller2024factorsinfluencingsurvival pages 1-2, keller2024naturalhistoryof pages 5-8)
  • Immune/hematologic: lymphopenia, reduced CD4/CD8 T and B cells, poor stimulation responses, recurrent bacterial—often gastrointestinal—infections, and sepsis. Lymphopenia occurred in 30% of the 76-person cohort; earlier literature suggested severe immune dysfunction in approximately half of reported cases, likely reflecting ascertainment differences. Suggested HPO: HP:0001888 Lymphopenia, HP:0002719 Recurrent infections, HP:0002721 Immunodeficiency. (choi2019sphingosinephosphatelyase pages 5-6, keller2024naturalhistoryof pages 5-8, choi2019sphingosinephosphatelyase pages 4-5)
  • Neurologic/developmental: peripheral axonal neuropathy, lower-limb weakness, seizures, developmental delay, microcephaly, deafness, strabismus, corpus-callosum or basal-ganglia abnormalities. Severity ranges from absent to progressive neurologic disease or isolated late-childhood neuropathy. Suggested HPO: HP:0009830 Peripheral neuropathy, HP:0001250 Seizure, HP:0001263 Global developmental delay, HP:0000252 Microcephaly, HP:0000365 Hearing impairment, HP:0000486 Strabismus. (keller2024factorsinfluencingsurvival pages 1-2, sedillo2024prevalenceestimateofa pages 3-4, yang2023steroidresistantnephroticsyndrome pages 6-7)
  • Skin: ichthyosis, acanthosis, and skin-barrier abnormalities. Suggested HPO: HP:0008064 Ichthyosis and HP:0000956 Acanthosis nigricans. (keller2024factorsinfluencingsurvival pages 1-2, keller2024naturalhistoryof pages 1-5)
  • Prenatal/general: hydrops fetalis, fetal loss, oligohydramnios or polyhydramnios, edema, increased nuchal translucency, fetal-growth abnormalities, failure to thrive, hypercholesterolemia, and skeletal/thoracic abnormalities. Prenatal findings occurred in 22% of the cohort and identified a very high-risk group. Suggested HPO: HP:0001789 Hydrops fetalis, HP:0001508 Failure to thrive, HP:0003124 Hypercholesterolemia. (keller2024naturalhistoryof pages 5-8, keller2024factorsinfluencingsurvival pages 12-14)

No validated SPLIS-specific EQ-5D, SF-36, PROMIS, or other quality-of-life dataset was found. Nevertheless, dialysis/transplantation, hormone replacement, recurrent infection, weakness, sensory loss, developmental disability, and skin disease impose major functional burdens. Current prospective studies include formal quality-of-life and neurodevelopmental assessments. (NCT04885179 chunk 1, NCT06669949 chunk 2)

4. Genetic and molecular information

SGPL1 is the only established causal gene. Disease alleles include missense, nonsense, frameshift, in-frame deletion, canonical and noncanonical splice variants. More than two dozen pathogenic alleles had been curated by 2024; the 76-patient cohort contained 45 genotypes. Recurrent variants included p.Arg222Gln, p.Tyr416Cys, p.Arg340Trp, p.Ser346Ile, and p.Arg222Trp, collectively accounting for 75% of that cohort. p.Arg222Gln was homozygous in about one-quarter of earlier reported cases and in 13/76 (17%) of the natural-history cohort. (sedillo2024prevalenceestimateofa pages 3-4, keller2024naturalhistoryof pages 5-8, keller2024naturalhistoryof pages 14-18)

All established disease variants are germline. Studied parents were generally healthy heterozygotes; no confirmed de novo mechanism was known. Functional consequences include absent/reduced protein, reduced enzyme activity, abnormal intracellular localization, and failure to complement SGPL1-deficient yeast or Drosophila. Patient fibroblasts can have less than 10% of normal lyase activity. (sedillo2024prevalenceestimateof pages 1-3, choi2019sphingosinephosphatelyase pages 5-6, lovric2017mutationsinsphingosine1phosphate pages 1-2)

Variant-level ACMG classification and gnomAD allele frequency must be retrieved from the current ClinVar/gnomAD record for each HGVS allele; no single population frequency applies to “SPLIS.” Structural chromosomal abnormalities, somatic variants, repeat expansions, mitochondrial variants, epigenetic disease signatures, and validated modifier genes are not established. Intrafamilial variability indicates that modifiers probably exist, but none can currently be annotated as causal. (sedillo2024prevalenceestimateof pages 1-3)

5. Environmental information

No toxin, radiation, pollution, smoking, alcohol, diet, occupational exposure, or infectious agent is known to cause SPLIS. Infection is an important complication of immune dysfunction rather than the initiating etiology. Adequate vitamin B6 status could theoretically affect residual function of this PLP-dependent enzyme, but this is not evidence that dietary deficiency causes SPLIS. No zoonotic or transmissible component exists. (keller2024naturalhistoryof pages 14-18, lovric2017mutationsinsphingosine1phosphate pages 11-14)

6. Mechanism and pathophysiology

Ordered causal chain

  1. Biallelic SGPL1 loss-of-function variants lead to deficient or mislocalized ER-resident S1P-lyase protein and reduced PLP-dependent catalytic activity. (choi2019sphingosinephosphatelyase pages 5-6, choi2019sphingosinephosphatelyase pages 4-5)
  2. Reduced S1P-lyase activity leads to failure of irreversible S1P cleavage into hexadecenal and ethanolamine phosphate. (janecke2017deficiencyofthe pages 11-15)
  3. Blocked terminal sphingolipid degradation leads to accumulation and redistribution of S1P, sphingosine, ceramides, and other upstream sphingoid intermediates; loss of downstream products may additionally impair autophagic flux, although that branch is less directly established in SPLIS patients. (keller2024factorsinfluencingsurvival pages 1-2, lovric2017mutationsinsphingosine1phosphate pages 10-11, janecke2017deficiencyofthe pages 11-15)
  4. Abnormal lipid composition and S1P gradients lead to receptor-dependent and intracellular signaling disturbance, including altered S1PR1/S1PR3 signaling, reduced RAC1/CDC42 activity, abnormal migration, immune-cell egress, inflammatory/fibrogenic signaling, calcium handling, mitochondrial stress, and membrane/vesicular dysfunction. Several links are inferred from cellular or animal models. (lovric2017mutationsinsphingosine1phosphate pages 10-11, lovric2017mutationsinsphingosine1phosphate pages 11-14, choi2019sphingosinephosphatelyase pages 4-5)
  5. In glomerular podocytes and mesangial cells, these disturbances lead to foot-process effacement, defective mesangial migration/vascular maturation, filtration-barrier failure, proteinuria, SRNS/FSGS, and ESKD. (lovric2017mutationsinsphingosine1phosphate pages 10-11, choi2019sphingosinephosphatelyase pages 5-6)
  6. Branch A—adrenal cortex: altered lipid homeostasis and developmental/steroidogenic organization lead to deficient steroidogenic-enzyme expression and cortical zonation in mice; this plausibly results in human glucocorticoid/mineralocorticoid failure and adrenal calcification, but the complete human causal chain is not proven. (choi2019sphingosinephosphatelyase pages 6-8)
  7. Branch B—immune system: loss of tissue-to-blood S1P gradients leads to impaired thymic lymphocyte egress and altered leukocyte migration, resulting in lymphopenia, functional immunodeficiency, recurrent infection, and sepsis. (lovric2017mutationsinsphingosine1phosphate pages 11-14, choi2019sphingosinephosphatelyase pages 4-5)
  8. Branch C—nervous system and muscle: sphingolipid/ceramide accumulation and mitochondrial oxidative stress are inferred to lead to axonal, neuromuscular, and CNS dysfunction; direct patient-tissue proof remains limited. (sedillo2024prevalenceestimateofa pages 3-4, choi2019sphingosinephosphatelyase pages 5-6)
  9. Multiorgan injury leads to growth failure, endocrine crises, dialysis dependence, disability, and premature death. (keller2024factorsinfluencingsurvival pages 1-2, keller2024factorsinfluencingsurvival pages 12-14)

Molecular profiling and ontology suggestions

Human blood and fibroblasts show increased S1P and sphingosine. Some blood ceramides, dihydroceramides, sphingomyelins, and monohexosylceramides were decreased, showing that SPLIS is not simply uniform lipid “storage.” Drosophila nephrocytes accumulated C16 sphingosine, C14 sphingadiene, and C16 ceramide. Plasma S1P and absolute lymphocyte count are being developed as biomarkers. No validated disease-wide transcriptomic, proteomic, single-cell, spatial-transcriptomic, or integrated multi-omic signature was identified. (lovric2017mutationsinsphingosine1phosphate pages 10-11, janecke2017deficiencyofthe pages 11-15, NCT06669949 chunk 1)

Suggested GO terms include sphingolipid catabolic process, sphingosine-1-phosphate metabolic process, lymphocyte migration/egress, regulation of cell migration, small-GTPase-mediated signaling, angiogenesis, glomerular filtration, steroid biosynthetic process, mitochondrial organization, and response to oxidative stress. Relevant cellular components include endoplasmic-reticulum membrane and plasma-membrane lipid rafts. Suggested CL concepts include podocyte, glomerular mesangial cell, adrenal cortical cell, T lymphocyte, B lymphocyte, dendritic cell, peripheral neuron, fibroblast, and epithelial cell.

7. Anatomical structures affected

Primary organs are the kidney/glomerulus, adrenal cortex, immune/lymphoid tissues, peripheral and central nervous systems, and skin. Secondary involvement can include thyroid, gonads, retina, heart, lung, skeleton, gastrointestinal tract, and hematopoietic system. (keller2024factorsinfluencingsurvival pages 1-2, choi2019sphingosinephosphatelyase pages 5-6)

At tissue/cell level, strongest evidence implicates glomerular podocytes and mesangial cells, adrenal cortical zones, lymphocytes and thymic dendritic cells, peripheral neurons, and keratinocyte/skin-barrier compartments. Mouse renal expression is strong in podocytes and mesangial cells but limited in glomerular endothelium. No consistent lateralization is reported. Suggested UBERON concepts include kidney, renal glomerulus, adrenal gland/cortex, thymus, peripheral nerve, brain/basal ganglia, skin, thyroid gland, and testis. (choi2019sphingosinephosphatelyase pages 5-6, choi2019sphingosinephosphatelyase pages 6-8)

8. Temporal development

Onset ranges from prenatal disease to approximately 15 years; 54% of the 76 patients presented in the first year. Prenatal hydrops, fetal demise, adrenal calcification, and early infantile nephropathy constitute the most severe developmental end. Later presentations may be isolated adrenal insufficiency, renal disease, or peripheral neuropathy. (sedillo2024prevalenceestimateofa pages 3-4, keller2024naturalhistoryof pages 5-8)

The renal course is chronic and generally progressive. Among later-diagnosed patients in one analysis, all six progressed to ESKD within 24–60 months; infantile cases could progress in under six months or over 11–60 months. Remission of the genetic disease is not established. Kidney transplantation replaces renal function but does not constitute proven systemic cure. The first year of life is therefore a critical period for diagnosis, adrenal-crisis prevention, infection surveillance, and transplant planning. (keller2024factorsinfluencingsurvival pages 12-14)

9. Inheritance and population

Inheritance is autosomal recessive, with a 25% recurrence risk for each pregnancy when both parents are confirmed carriers. Penetrance among individuals with two severe alleles appears high, but organ-specific penetrance and age at onset are variable. Expressivity is markedly variable, including within families. Anticipation is not described; germline mosaicism has not been established. (sedillo2024prevalenceestimateof pages 1-3, sedillo2024prevalenceestimateofa pages 1-3)

A 2024 population-genetic study estimated prevalence at 0.015 per 100,000 (95% CI 0.010–0.021), equivalent to about 11,707 people worldwide. This is a modeled genotype prevalence, not a count of diagnosed living patients, and greatly exceeds the fewer than 100 recognized clinical cases. Estimates were higher in some East Asian, Finnish, Turkish, and Iranian populations; Turkish/Iranian estimates were approximately 0.046–0.078 per 100,000. (sedillo2024prevalenceestimateofa pages 3-4, sedillo2024prevalenceestimateofa pages 1-3)

The 76-person cohort was geographically and ethnically diverse. No reliable incidence, sex ratio, age-standardized prevalence, carrier frequency, or universally accepted founder-effect estimate is available. Consanguinity was common but is not required. (keller2024naturalhistoryof pages 5-8)

10. Diagnostics

Recommended approach

  1. Suspect SPLIS in congenital/infantile SRNS, especially with adrenal insufficiency, adrenal calcification, ichthyosis, lymphopenia/infections, neuropathy, genital anomalies, or an affected sibling.
  2. Measure urine protein/creatinine, serum albumin, creatinine/eGFR, electrolytes and lipids; assess morning cortisol, ACTH, renin, aldosterone, glucose, thyroid function, and gonadal hormones as age-appropriate.
  3. Perform CBC with differential, lymphocyte subsets, immunoglobulins, and functional immune testing when indicated.
  4. Evaluate hearing, vision, development and peripheral nerves; obtain brain MRI when neurologic signs occur. Basal-ganglia abnormalities have been reported.
  5. Confirm with sequencing demonstrating biallelic pathogenic/likely pathogenic SGPL1 variants, preferably through a congenital/SRNS or adrenal-insufficiency panel, WES, or WGS. Include copy-number and splice analysis when routine sequencing is nondiagnostic. (keller2024factorsinfluencingsurvival pages 1-2, keller2024naturalhistoryof pages 5-8, yang2023steroidresistantnephroticsyndrome pages 6-7)

Renal biopsy may show FSGS or diffuse mesangial sclerosis, but it is not specific. Plasma/urine sphingolipid profiles and fibroblast S1P-lyase activity provide biochemical support where available; they are not yet standardized population-screening tests. Skin fibroblasts are being used for enzyme assays, therapeutic testing, neuronal reprogramming, and iPSC research. (choi2019sphingosinephosphatelyase pages 4-5, NCT06669949 chunk 3, NCT06669949 chunk 2)

WES and WGS are useful because SPLIS is phenotypically heterogeneous; CMA, karyotype, FISH, mitochondrial sequencing, and repeat-expansion testing are not first-line unless another diagnosis is suspected. Cascade testing of parents and siblings is appropriate. No validated newborn-screening program or consensus diagnostic criteria exist.

Differential diagnosis

Important alternatives include congenital nephrotic syndromes due to NPHS1, NPHS2, WT1, LAMB2, PLCE1 and other podocyte genes; isolated familial glucocorticoid deficiency; congenital adrenal hyperplasia; X-linked adrenal hypoplasia; triple-A syndrome; mitochondrial/adrenal-neurologic disorders; Schimke immuno-osseous dysplasia; and other sphingolipidoses. The combination of SRNS, adrenal insufficiency, ichthyosis/immune or neurologic disease, and biallelic SGPL1 variants distinguishes SPLIS.

11. Outcome and prognosis

Overall survival at last report in the 76-patient cohort was 50%. Among patients with nephropathy diagnosed before age one and not transplanted, fewer than 30% were alive two years after diagnosis and 17% were alive at last report; another cohort analysis found only 6/32 (19%) living versus 15/22 (68%) when renal disease was diagnosed at or after one year. Mean age of death among deceased patients was 7.5 months. (keller2024factorsinfluencingsurvival pages 1-2, keller2024naturalhistoryof pages 5-8, keller2024naturalhistoryof pages 18-25)

Major adverse prognostic factors are prenatal presentation, nephropathy in infancy, rapid ESKD, severe multisystem involvement, infection/sepsis, and non-transplant management of kidney failure. Homozygous p.Arg222Gln and kidney transplantation correlate with longer survival. Median age at last report was 8 years after transplantation, 4.4 years with dialysis, and 1.3 years with palliative care; transplantation significantly outperformed dialysis and palliative care, while dialysis did not show a significant survival advantage over palliation in the retrospective analysis. Confounding by patient selection is unavoidable. (keller2024naturalhistoryof pages 14-18, keller2024factorsinfluencingsurvival pages 12-14, keller2024naturalhistoryof pages 18-25)

No robust 5- or 10-year survival curve, standardized disability outcome, life-expectancy estimate, or validated prognostic biomarker is yet available. Plasma S1P and lymphocyte count are candidates under prospective study. (NCT06669949 chunk 1)

12. Treatment and current implementation

There is no approved disease-modifying therapy or consensus SPLIS-specific guideline. Care is multidisciplinary and phenotype-directed.

  • Adrenal replacement: physiologic glucocorticoid replacement, mineralocorticoid and salt replacement when deficient, stress dosing, and emergency hydrocortisone education. Suggested NCIT concepts: corticosteroid therapy; hormone replacement therapy.
  • Renal: edema/proteinuria management, nutrition, blood-pressure and thrombosis-risk management, dialysis for ESKD, and early evaluation for kidney transplantation. Transplantation has the strongest observational survival signal and is a real-world implementation. Suggested NCIT: kidney transplantation; renal dialysis. (keller2024naturalhistoryof pages 14-18, keller2024factorsinfluencingsurvival pages 12-14)
  • Immune/infectious: prompt antimicrobial therapy, immunoglobulin replacement when clinically indicated, vaccination individualized to immune status, and sepsis prevention. Suggested NCIT: intravenous immunoglobulin therapy; anti-infective therapy.
  • Neurologic/developmental: seizure treatment, audiology, physical/occupational/speech therapy, mobility support, and developmental services.
  • Endocrine/nutrition/skin: thyroid or sex-hormone replacement when deficient; nutrition support; emollients and dermatologic treatment.
  • Pyridoxine: mechanistically rational because SPL is PLP-dependent. Ex vivo improvement and anecdotal clinical benefit have been reported, and unpublished R222Q knock-in mouse observations were cited in the natural-history study. Dose, efficacy, genotype selection, and neurotoxicity monitoring have not been established by controlled trials; it remains off-label/experimental. (keller2024naturalhistoryof pages 1-5, keller2024naturalhistoryof pages 14-18)
  • Gene therapy: SGPL1 replacement is preclinical. AAV9-SGPL1 has demonstrated target engagement in a mouse lung-fibrosis model, but that is not a SPLIS efficacy trial and cannot establish human benefit.

No disease-specific pharmacogenomic rule, approved RNA therapy, CRISPR treatment, cell therapy, or immunotherapy exists.

Trials and registries

Two recruiting UCSF studies were retrieved, both observational:

  • NCT04885179, international registry, estimated enrollment 120, started April 22, 2025; records longitudinal clinical/genetic outcomes and physician-initiated vitamin-B6 exposure without assigning treatment. (NCT04885179 chunk 1)
  • NCT06669949, three-year natural-history study, estimated enrollment 28, started April 22, 2025; includes renal, endocrine, neurologic, immune, imaging, quality-of-life, sphingolipid, fibroblast, and iPSC assessments. (NCT06669949 chunk 1, NCT06669949 chunk 3, NCT06669949 chunk 2)

No interventional SPLIS trial was identified among the retrieved ClinicalTrials.gov records.

13. Prevention

The molecular defect cannot presently be prevented by vaccination, lifestyle change, or environmental avoidance.

  • Primary prevention/reproductive options: genetic counseling; parental carrier confirmation; cascade testing; prenatal diagnosis by chorionic-villus sampling or amniocentesis; and preimplantation genetic testing for a known familial genotype.
  • Secondary prevention: early testing of at-risk siblings and infants with congenital nephrosis or adrenal calcification; prospective renal, adrenal, immune, thyroid, neurologic, auditory, and growth surveillance. Population newborn screening is not established.
  • Tertiary prevention: adrenal stress-dosing plans, infection prevention, early ESKD/transplant planning, thrombosis and nutrition management, skin care, rehabilitation, and avoidance of prolonged ineffective immunosuppression for genetically determined SRNS.

For two carrier parents, counseling should communicate a 25% affected, 50% carrier, and 25% unaffected/non-carrier probability per pregnancy.

14. Other species and natural disease

No well-characterized naturally occurring veterinary SPLIS syndrome, breed predisposition, zoonotic transmission, or cross-species infectious susceptibility was identified. The mechanism is evolutionarily conserved, as demonstrated by functional complementation across yeast, Drosophila, mouse, and human SGPL1 systems. Relevant taxa include Homo sapiens (NCBI Taxon 9606), Mus musculus (10090), Drosophila melanogaster (7227), Caenorhabditis elegans (6239), and Saccharomyces cerevisiae (4932). (lovric2017mutationsinsphingosine1phosphate pages 11-14, lovric2017mutationsinsphingosine1phosphate pages 1-2)

15. Model organisms and experimental systems

  • Mouse Sgpl1 knockout/partial-deficiency models: reproduce failure to thrive, early death, proteinuria, glomerular hemorrhage/swelling, podocyte foot-process effacement, immune/lymphocyte abnormalities, skin and skeletal phenotypes, and disturbed adrenal zonation/steroidogenic-enzyme expression. Complete knockout is more severe than many human genotypes and may obscure chronic manifestations. (janecke2017deficiencyofthe pages 11-15, lovric2017mutationsinsphingosine1phosphate pages 11-14, choi2019sphingosinephosphatelyase pages 6-8)
  • Drosophila Sply-null nephrocytes: show reduced foot-process density, defective albumin uptake/vesicular transport, reduced viability, altered lipid droplets, and sphingoid/ceramide accumulation. Wild-type Sply rescues the phenotype; disease-associated human variants do not fully rescue it. This is a strong functional-variant system but does not model mammalian adrenal physiology. (lovric2017mutationsinsphingosine1phosphate pages 10-11, lovric2017mutationsinsphingosine1phosphate pages 11-14)
  • Yeast dpl1Δ complementation: wild-type human SGPL1 restores growth while disease alleles fail, providing rapid evidence of functional loss; tissue phenotypes cannot be modeled. (lovric2017mutationsinsphingosine1phosphate pages 1-2, lovric2017mutationsinsphingosine1phosphate pages 2-3)
  • Cellular models: patient fibroblasts demonstrate low enzyme activity, abnormal protein localization, lipid abnormalities, and impaired migration. SGPL1-silenced rat mesangial cells show reduced RAC1/CDC42 activity and migration, partially rescued by an S1PR1/S1PR3 antagonist. (lovric2017mutationsinsphingosine1phosphate pages 10-11, choi2019sphingosinephosphatelyase pages 5-6)
  • C. elegans spl-1 RNAi: causes disordered muscle fibers, impaired motility, sphingoid-base/ceramide accumulation, abnormal mitochondria, and increased reactive oxygen species; N-acetylcysteine improved locomotion and muscle organization. This 2024 result is hypothesis-generating and does not support clinical NAC use in SPLIS.
  • iPSC/neuronal models: prospective natural-history protocols collect fibroblasts for reprogramming and neuronal studies; mature disease-specific organoid, single-cell, or spatial-omics findings were not identified. (NCT06669949 chunk 3)

Evidence limitations and expert interpretation

The disease literature remains dominated by case reports and retrospective aggregation. Frequencies therefore describe recognized patients rather than unbiased population penetrance. The modeled prevalence of approximately 11,707 affected people contrasts sharply with fewer than 100 diagnosed reports, plausibly reflecting underdiagnosis, fetal loss, unrecognized mild disease, uncertain variant penetrance, and assumptions inherent in Hardy–Weinberg modeling. (sedillo2024prevalenceestimateofa pages 3-4, sedillo2024prevalenceestimateofa pages 1-3)

The most defensible current expert interpretation is that SPLIS should be considered whenever genetic SRNS and adrenal insufficiency coexist, but neither manifestation is obligatory. Early comprehensive genetic testing is clinically actionable because it can curtail ineffective immunosuppression, trigger adrenal and immune surveillance, enable family testing, and accelerate transplantation planning. Mechanistic evidence firmly establishes SGPL1 loss, disordered sphingolipid metabolism, podocyte/mesangial injury, and impaired immune-cell trafficking; organ-specific pathways in the adrenal gland and nervous system remain incompletely resolved. Prospective registries, standardized lipid/enzyme biomarkers, and genotype-stratified trials—especially of pyridoxine and gene replacement—are the principal research priorities. (keller2024factorsinfluencingsurvival pages 1-2, lovric2017mutationsinsphingosine1phosphate pages 10-11, choi2019sphingosinephosphatelyase pages 6-8, NCT04885179 chunk 1)

References

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  2. (keller2024naturalhistoryof pages 5-8): Nancy Keller, Julian Midgley, Ehtesham Khalid, Harry Lesmana, Georgie Mathew, Christine Mincham, Norbert Teig, Zubair Khan, Indu Khosla, Sam Mehr, Tulay Guran, Kathrin Buder, Hong Xu, Khalid Alhasan, Gonul Buyukyilmaz, Nicole Weaver, and Julie D. Saba. Natural history of sphingosine phosphate lyase insufficiency syndrome: a retrospective cross-sectional study of 76 patients. Feb 2024. URL: https://doi.org/10.21203/rs.3.rs-3678833/v1, doi:10.21203/rs.3.rs-3678833/v1.

  3. (keller2024factorsinfluencingsurvival pages 12-14): Nancy Keller, Julian Midgley, Ehtesham Khalid, Harry Lesmana, Georgie Mathew, Christine Mincham, Norbert Teig, Zubair Khan, Indu Khosla, Sam Mehr, Tulay Guran, Kathrin Buder, Hong Xu, Khalid Alhasan, Gonul Buyukyilmaz, Nicole Weaver, and Julie D. Saba. Factors influencing survival in sphingosine phosphate lyase insufficiency syndrome: a retrospective cross-sectional natural history study of 76 patients. Orphanet Journal of Rare Diseases, Sep 2024. URL: https://doi.org/10.1186/s13023-024-03311-w, doi:10.1186/s13023-024-03311-w. This article has 8 citations and is from a peer-reviewed journal.

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  8. (keller2024naturalhistoryof pages 18-25): Nancy Keller, Julian Midgley, Ehtesham Khalid, Harry Lesmana, Georgie Mathew, Christine Mincham, Norbert Teig, Zubair Khan, Indu Khosla, Sam Mehr, Tulay Guran, Kathrin Buder, Hong Xu, Khalid Alhasan, Gonul Buyukyilmaz, Nicole Weaver, and Julie D. Saba. Natural history of sphingosine phosphate lyase insufficiency syndrome: a retrospective cross-sectional study of 76 patients. Feb 2024. URL: https://doi.org/10.21203/rs.3.rs-3678833/v1, doi:10.21203/rs.3.rs-3678833/v1.

  9. (lovric2017mutationsinsphingosine1phosphate pages 10-11): Svjetlana Lovric, Sara Goncalves, Heon Yung Gee, Babak Oskouian, Honnappa Srinivas, Won-Il Choi, Shirlee Shril, Shazia Ashraf, Weizhen Tan, Jia Rao, Merlin Airik, David Schapiro, Daniela A. Braun, Carolin E. Sadowski, Eugen Widmeier, Tilman Jobst-Schwan, Johanna Magdalena Schmidt, Vladimir Girik, Guido Capitani, Jung H. Suh, Noëlle Lachaussée, Christelle Arrondel, Julie Patat, Olivier Gribouval, Monica Furlano, Olivia Boyer, Alain Schmitt, Vincent Vuiblet, Seema Hashmi, Rainer Wilcken, Francois P. Bernier, A. Micheil Innes, Jillian S. Parboosingh, Ryan E. Lamont, Julian P. Midgley, Nicola Wright, Jacek Majewski, Martin Zenker, Franz Schaefer, Navina Kuss, Johann Greil, Thomas Giese, Klaus Schwarz, Vilain Catheline, Denny Schanze, Ingolf Franke, Yves Sznajer, Anne S. Truant, Brigitte Adams, Julie Désir, Ronald Biemann, York Pei, Elisabet Ars, Nuria Lloberas, Alvaro Madrid, Vikas R. Dharnidharka, Anne M. Connolly, Marcia C. Willing, Megan A. Cooper, Richard P. Lifton, Matias Simons, Howard Riezman, Corinne Antignac, Julie D. Saba, and Friedhelm Hildebrandt. Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency. Journal of Clinical Investigation, 127:912–928, Mar 2017. URL: https://doi.org/10.1172/jci89626, doi:10.1172/jci89626. This article has 236 citations and is from a highest quality peer-reviewed journal.

  10. (janecke2017deficiencyofthe pages 11-15): Andreas R. Janecke, Ruijuan Xu, Elisabeth Steichen-Gersdorf, Siegfried Waldegger, Andreas Entenmann, Thomas Giner, Iris Krainer, Lukas A Huber, Michael W Hess, Yaacov Frishberg, Hila Barash, Shay Tzur, Nira Schreyer-Shafir, Rivka Sukenik-Halevy, Tania Zehavi, Annick Raas-Rothschild, Cungui Mao, and Thomas Müller. Deficiency of the sphingosine‐1‐phosphate lyase sgpl1 is associated with congenital nephrotic syndrome and congenital adrenal calcifications. Human Mutation, 38:365-372, Apr 2017. URL: https://doi.org/10.1002/humu.23192, doi:10.1002/humu.23192. This article has 103 citations and is from a domain leading peer-reviewed journal.

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  12. (choi2019sphingosinephosphatelyase pages 4-5): Youn-Jeong Choi and Julie D. Saba. Sphingosine phosphate lyase insufficiency syndrome (splis): a novel inborn error of sphingolipid metabolism. Advances in biological regulation, 71:128-140, Jan 2019. URL: https://doi.org/10.1016/j.jbior.2018.09.004, doi:10.1016/j.jbior.2018.09.004. This article has 61 citations and is from a peer-reviewed journal.

  13. (NCT06669949 chunk 1): Natural History of Sphingosine Phosphate Lyase Insufficiency Syndrome (SPLIS). University of California, San Francisco. 2025. ClinicalTrials.gov Identifier: NCT06669949

  14. (NCT06669949 chunk 2): Natural History of Sphingosine Phosphate Lyase Insufficiency Syndrome (SPLIS). University of California, San Francisco. 2025. ClinicalTrials.gov Identifier: NCT06669949

  15. (NCT04885179 chunk 1): SPL Insufficiency Syndrome (SPLIS)/NPHS14: a SPLIS Observational Study and Patient Registry (International). University of California, San Francisco. 2025. ClinicalTrials.gov Identifier: NCT04885179

  16. (NCT06669949 chunk 3): Natural History of Sphingosine Phosphate Lyase Insufficiency Syndrome (SPLIS). University of California, San Francisco. 2025. ClinicalTrials.gov Identifier: NCT06669949

  17. (OpenTargets Search: Sphingosine phosphate lyase insufficiency syndrome-SGPL1): Open Targets Query (Sphingosine phosphate lyase insufficiency syndrome-SGPL1, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  18. (sedillo2024prevalenceestimateofa pages 3-4): JC Sedillo, C Badduke, and SJ Schrodi. Prevalence estimate of sphingosine phosphate lyase insufficiency syndrome in. Unknown journal, 2024.

  19. (keller2024factorsinfluencingsurvival pages 2-4): Nancy Keller, Julian Midgley, Ehtesham Khalid, Harry Lesmana, Georgie Mathew, Christine Mincham, Norbert Teig, Zubair Khan, Indu Khosla, Sam Mehr, Tulay Guran, Kathrin Buder, Hong Xu, Khalid Alhasan, Gonul Buyukyilmaz, Nicole Weaver, and Julie D. Saba. Factors influencing survival in sphingosine phosphate lyase insufficiency syndrome: a retrospective cross-sectional natural history study of 76 patients. Orphanet Journal of Rare Diseases, Sep 2024. URL: https://doi.org/10.1186/s13023-024-03311-w, doi:10.1186/s13023-024-03311-w. This article has 8 citations and is from a peer-reviewed journal.

  20. (yang2023steroidresistantnephroticsyndrome pages 6-7): Siying Yang, Yonghua He, Jianhua Zhou, Huiqing Yuan, and Liru Qiu. Steroid-resistant nephrotic syndrome associated with certain sgpl1 variants in a family: case report and literature review. Frontiers in Pediatrics, Feb 2023. URL: https://doi.org/10.3389/fped.2023.1079758, doi:10.3389/fped.2023.1079758. This article has 11 citations.

  21. (keller2024naturalhistoryof pages 1-5): Nancy Keller, Julian Midgley, Ehtesham Khalid, Harry Lesmana, Georgie Mathew, Christine Mincham, Norbert Teig, Zubair Khan, Indu Khosla, Sam Mehr, Tulay Guran, Kathrin Buder, Hong Xu, Khalid Alhasan, Gonul Buyukyilmaz, Nicole Weaver, and Julie D. Saba. Natural history of sphingosine phosphate lyase insufficiency syndrome: a retrospective cross-sectional study of 76 patients. Feb 2024. URL: https://doi.org/10.21203/rs.3.rs-3678833/v1, doi:10.21203/rs.3.rs-3678833/v1.

  22. (lovric2017mutationsinsphingosine1phosphate pages 11-14): Svjetlana Lovric, Sara Goncalves, Heon Yung Gee, Babak Oskouian, Honnappa Srinivas, Won-Il Choi, Shirlee Shril, Shazia Ashraf, Weizhen Tan, Jia Rao, Merlin Airik, David Schapiro, Daniela A. Braun, Carolin E. Sadowski, Eugen Widmeier, Tilman Jobst-Schwan, Johanna Magdalena Schmidt, Vladimir Girik, Guido Capitani, Jung H. Suh, Noëlle Lachaussée, Christelle Arrondel, Julie Patat, Olivier Gribouval, Monica Furlano, Olivia Boyer, Alain Schmitt, Vincent Vuiblet, Seema Hashmi, Rainer Wilcken, Francois P. Bernier, A. Micheil Innes, Jillian S. Parboosingh, Ryan E. Lamont, Julian P. Midgley, Nicola Wright, Jacek Majewski, Martin Zenker, Franz Schaefer, Navina Kuss, Johann Greil, Thomas Giese, Klaus Schwarz, Vilain Catheline, Denny Schanze, Ingolf Franke, Yves Sznajer, Anne S. Truant, Brigitte Adams, Julie Désir, Ronald Biemann, York Pei, Elisabet Ars, Nuria Lloberas, Alvaro Madrid, Vikas R. Dharnidharka, Anne M. Connolly, Marcia C. Willing, Megan A. Cooper, Richard P. Lifton, Matias Simons, Howard Riezman, Corinne Antignac, Julie D. Saba, and Friedhelm Hildebrandt. Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency. Journal of Clinical Investigation, 127:912–928, Mar 2017. URL: https://doi.org/10.1172/jci89626, doi:10.1172/jci89626. This article has 236 citations and is from a highest quality peer-reviewed journal.

  23. (choi2019sphingosinephosphatelyase pages 6-8): Youn-Jeong Choi and Julie D. Saba. Sphingosine phosphate lyase insufficiency syndrome (splis): a novel inborn error of sphingolipid metabolism. Advances in biological regulation, 71:128-140, Jan 2019. URL: https://doi.org/10.1016/j.jbior.2018.09.004, doi:10.1016/j.jbior.2018.09.004. This article has 61 citations and is from a peer-reviewed journal.

  24. (lovric2017mutationsinsphingosine1phosphate pages 2-3): Svjetlana Lovric, Sara Goncalves, Heon Yung Gee, Babak Oskouian, Honnappa Srinivas, Won-Il Choi, Shirlee Shril, Shazia Ashraf, Weizhen Tan, Jia Rao, Merlin Airik, David Schapiro, Daniela A. Braun, Carolin E. Sadowski, Eugen Widmeier, Tilman Jobst-Schwan, Johanna Magdalena Schmidt, Vladimir Girik, Guido Capitani, Jung H. Suh, Noëlle Lachaussée, Christelle Arrondel, Julie Patat, Olivier Gribouval, Monica Furlano, Olivia Boyer, Alain Schmitt, Vincent Vuiblet, Seema Hashmi, Rainer Wilcken, Francois P. Bernier, A. Micheil Innes, Jillian S. Parboosingh, Ryan E. Lamont, Julian P. Midgley, Nicola Wright, Jacek Majewski, Martin Zenker, Franz Schaefer, Navina Kuss, Johann Greil, Thomas Giese, Klaus Schwarz, Vilain Catheline, Denny Schanze, Ingolf Franke, Yves Sznajer, Anne S. Truant, Brigitte Adams, Julie Désir, Ronald Biemann, York Pei, Elisabet Ars, Nuria Lloberas, Alvaro Madrid, Vikas R. Dharnidharka, Anne M. Connolly, Marcia C. Willing, Megan A. Cooper, Richard P. Lifton, Matias Simons, Howard Riezman, Corinne Antignac, Julie D. Saba, and Friedhelm Hildebrandt. Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency. Journal of Clinical Investigation, 127:912–928, Mar 2017. URL: https://doi.org/10.1172/jci89626, doi:10.1172/jci89626. This article has 236 citations and is from a highest quality peer-reviewed journal.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 11
Resolved 11
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 11
On topic 6
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 24
Resolved 24
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 0
Terms whose name was checked 1
Terms named correctly 0
Terms named as a different term 1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0033203 (2 mentions) - the report calls it "if available"; MONDO calls it nephrotic syndrome 14