ESPE Abstracts

Background: Loss of function mutations in SGPL1 have previously been described by our group in association with a multisystemic disorder encompassing PAI and nephrotic syndrome. SGPL1 encodes, sphingosine 1-phosphate lyase (SGPL1), which irreversibly binds sphingosine 1-phosphate (S1P) and commits it to the final degradative step in sphingolipid metabolism. SGPL1 is therefore a major modulator of S1P signalling. Several sphingolipid intermediates such as ceramide, sphingosine and S1P have been purported to act as modulators of the steroidogenic pathway, as second messengers altering downstream expression of steroid responsive transcriptional elements. Under normal physiological conditions, S1P is largely pro-proliferative, suppressing the pro-apoptotic actions of ceramide. However, loss of function mutations in SGPL1 result in a pathological accumulation of both S1P and ceramide leading to induction of apoptosis.

Objective and hypotheses: Assessment of the genetic cause of PAI and congenital nephrotic syndrome in a Pakistani male (46,XY) infant who presented in early life with failure to thrive. Urinalysis revealed massive nephrotic range albuminuria. The patient was noted to be hyperpigmented with primary adrenal disease, with a low serum cortisol (61 nmol/L), markedly elevated ACTH (999 ng/L) and low normal aldosterone (190 pmol/L).

Method: Sanger sequencing of the entire coding region of SGPL1.

Results: Analysis of patient genomic DNA revealed a very rare homozygous missense mutation in SGPL1 (p.N171D, c.511A>G; gnoMAD MAF=9.86e-6 with no homozygotes), which was heterozygous in his consanguineous parents. In silico prediction tools, SIFT (score 0) and PolyPHEN (score 0.948) predicted this change to be deleterious. The patient had a wider endocrine phenotype with gonadal and thyroid disease with raised basal gonadotrophins (FSH 71 IU/L, LH 27 IU/L), an elevated TSH (25 mU/L) and low fT4 (10.7 pmol/L). Treatment included hydrocortisone, fludrocortisone, L-thyroxine and captopril. Renal function continued to deteriorate and secondary hyperparathyroidism addressed with alfacalcidol initiation. Other systemic manifestations included persistent lymphopenia, ichthyosis and motor developmental delay. Aged 9 months the patient presented with end stage renal failure and pulmonary oedema after a brief diarrhoeal illness and subsequently died.

Conclusion: The case further highlights the extent of endocrinopathy associated with this form of PAI and supports the emerging multisystemic phenotype of patients with loss of function SGPL1 mutations. Given the multisystemic and progressive nature of this form of PAI, a genetic diagnosis is crucial to accurate management and screening for comorbidities in these patients.