Comprehensive Study Notes on Sphingosine Phosphate Lyase Insufficiency Syndrome (SPLIS)

Multi-Domain Clinical Manifestations of SPLIS

Sphingosine Phosphate Lyase Insufficiency Syndrome (SPLIS) is a complex, multisystemic disorder characterized by variability in symptom presentation across renal, adrenal, hematological, neurological, and audiological domains.

Renal and Adrenal Presentation

The renal and adrenal systems are often viewed as the primary anchors for SPLIS diagnosis, particularly in younger patients. Significant data points in these domains include:

Renal Findings: A $15$ -year-old and a $2$ -year-old patient exhibited the highest Urine Albumin-to-Creatinine Ratios (UACR). The $15$ -year-old presented with the most severe renal symptoms, including nephrotic syndrome. In several cases, renal symptoms resolved following kidney transplantation.
Adrenal Findings: Adrenal insufficiency is a hallmark symptom. A $42$ -year-old patient presented with a highly anomalous adrenal value of $1234\,pg/mL$ , significantly exceeding the reference range of $6-50\,pg/mL$ . Most other patients managed their symptoms using maintenance steroids.

Hematological and Neurological Symptoms

Hematological and neurological data suggest that SPLIS affects these systems independently of renal or adrenal status.

Hematological Trends: Data in this category vary widely. A notable case involves a $38$ -year-old patient presenting with pancytopenia (low counts across all blood components) as their dominant symptom. Pairwise Pearson correlations performed on a cohort of five patients indicated that White Blood Cell (WBC) counts and platelet counts move together, with an $R^2$ value of $0.96$ . This correlation may indicate stress on shared progenitor cells or joint destruction, such as splenic sequestration associated with splenomegaly or aplastic anemia.
Neurological Findings: Neural conduction studies (NCS) and reflex tests show that neurological involvement often correlates with age. Younger patients tend to have normal nerve conduction studies, whereas older patients (aged $29$ , $38$ , and $42$ ) frequently exhibit abnormal NCS and absent reflexes. This includes isolated peripheral neuropathy, which can occur even in patients with stable kidney and adrenal function.
Audiological Domain: Hearing loss in SPLIS patients ranges from mild to moderate sensory hearing loss. Exceptions include the $2$ -year-old and $42$ -year-old patients, who maintained normal hearing except at specific individual frequencies.

Impact of Kidney Transplantation and Treatment Responses

Research indicates that while kidney transplantation addresses renal failure, it does not serve as a curative measure for other SPLIS systems.

Post-Transplant Symptom Emergence

Clinical records show that new symptoms can appear or existing symptoms can worsen after a successful transplant:

Eight-year-old patient: Transplanted at age $6$ . Developed neuropathy approximately two years post-transplant.
Twenty-nine-year-old patient: Transplanted at age $27$ . Developed polyneuropathy approximately fourteen months after the transplant. Steroid treatments failed to address the neurological onset.

Vitamin B6 Therapy

Vitamin B6 has shown mixed efficacy depending on the patient and their specific sphingolipid profile. The eight-year-old patient saw significant improvement with B6 therapy, whereas the $29$ -year-old experienced only mild improvement. The lack of efficacy in some patients may be linked to baseline sphingolipid levels; for instance, patients from specific cohorts (such as the siblings from Serbia) may have lower S1P levels that limit the benefit of B6 supplementation.

Hepatic Involvement and S1P Metabolism

The liver is established as a critical site for clearing Sphingosine-1-phosphate (S1P) from the bloodstream using a hepatocyte surface enzyme to convert S1P to sphingosine, which is then degraded by S1P lyase ( $SGPL1$ ).

The Liver "Escape Hatch"

Research using knockout mouse models suggests the liver has a unique mechanism to handle excess S1P by excreting it into the bile, which then travels through the common bile duct into the intestines. In liver-specific knockout mice, high levels of S1P were found in the bile despite a lack of significant phenotype or symptom development in the liver itself. This suggests that restoring liver-specific enzyme function through gene therapy or transplant may not be as effective as expected, as S1P levels do not necessarily accumulate in liver tissue but are instead diverted to the gut.

Diagnostic Statistics and Scoring Systems

Diagnostic timing appears to be a predictive factor for patient outcomes, as highlighted by the Keller cohort study:

Diagnosis before age $1$ : Survival rate of $17\%$ .
Diagnosis after age $1$ : Survival rate of $72\%$ .

Proposed Quantifiable Scoring Models

To better track disease progression and therapeutic response, several scoring systems are considered:

Multi-Domain Responder Index (MDRI): A system designed for clinical trials to determine if patients are responding to therapeutics like B6 by scoring clinical visits on a scale of $-1$ , $0$ , and $+1$ .
Phenotype Scoring: A system to grade the severity of symptoms (e.g., distinguishing stage $1$ versus stage $3$ kidney disease, or mineralocorticoid versus glucocorticoid deficiency).
Fibroblast Lyase Activity: Assessing enzyme activity in skin fibroblasts (e.g., checking if activity is $1\%$ , $5\%$ , or $10\%$ of normal) to correlate with clinical severity.

Questions & Discussion

Question: Do these new neurological symptoms appear specifically after transplant? Response: Records indicate that neuropathies often onset or significantly increase in severity after transplantation, suggesting that normalizing renal function does not halt neurological decline.

Discussion on Adrenal Transplantation: Discussion centered on whether a combined kidney and adrenal transplant is feasible. In a historical case study involving a patient with diabetes and adrenal insufficiency, a simultaneous pancreas, kidney, and adrenal transplant was attempted. While the pancreas and kidney were successful, the adrenal gland failed to function properly, requiring the patient to remain on supplemental steroids. This suggests that adrenal transplantation may not yet be an effective alternative to steroid therapy.

Discussion on Genetic Correlation: Participants discussed the lack of a strict correlation between genotype and phenotype. For instance, the $R322Q$ mutation (also referred to as $R222Q$ in context) can lead to vastly different outcomes, ranging from isolated neuropathy in some patients to fatal kidney disease and sepsis in their siblings. This underscores the potential influence of modifying mutations or variations in enzymes like sphingosine kinase or SPT.

Discussion on Serum Analysis: It was noted that normal control ranges for S1P vary widely ( $95$ healthy pediatric controls were used for reference). Some SPLIS patients, such as those from the Pakistan or Serbia cohorts, exhibit relatively low S1P levels, making biomarkers like ceramides equally important for establishing a diagnosis.