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. 2019 May 1;104(5):1484-1490.
doi: 10.1210/jc.2018-02238.

SGPL1 Deficiency: A Rare Cause of Primary Adrenal Insufficiency

Nikolaos Settas  1 , Rebecca Persky  1 , Fabio R Faucz  1 , Nicole Sheanon  2 , Antonis Voutetakis  1 , Maya Lodish  1 , Louise A Metherell  3 , Constantine A Stratakis  1
Affiliations

SGPL1 Deficiency: A Rare Cause of Primary Adrenal Insufficiency

Nikolaos Settas et al. J Clin Endocrinol Metab. .

Abstract

Context: Multiple autosomal recessive genes have been etiologically linked to primary adrenal insufficiency (PAI). Recently, sphingosine-1-phosphate lyase 1 (SGPL1) gene mutations were recognized as a cause of steroid-resistant nephrotic syndrome type 14 (NPHS14), a sphingolipidosis with multisystemic manifestations, including PAI.

Objective: To check if SGPL1 mutations are involved in the pathogenesis of PAI in patients who do not exhibit nephrotic syndrome.

Methods: Sequencing of the SGPL1 gene in 21 patients with familial glucocorticoid disease or triple A syndrome.

Results: We identified two missense SGPL1 variants in four patients, two of whom were first cousins. We describe in detail the proband, a boy born to Saudi Arabian consanguineous parents with a homozygous c.665G>A, p.R222Q SGPL1 variant. The patient presented with hypoglycemia and seizures at age 2 years and was ultimately diagnosed with PAI (isolated glucocorticoid deficiency). Brain MRI showed abnormalities in the basal ganglia consistent with a degenerative process albeit the patient had no neurologic symptoms.

Conclusions: New genetic causes of PAI continue to be identified. 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. Timely diagnosis of this specific sphingolipidosis while the kidneys still function normally can lead to prompt initiation of therapy and improve outcome.

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Figures

Figure 1.
Figure 1.
Sequencing chromatograms of the SGPL1 gene. (A) Sequence of a wild-type patient. (B) Sequence from patient ALS35.03 carrying the homozygous SGPL1 missense variant (c.665 G>A, p.R222Q).
Figure 2.
Figure 2.
Pedigree of the consanguineous family ALS35 with the SGPL1 mutation described in the text. Squares indicate male family members, circles indicate female family members, black symbols indicate clinically affected family members, and arrow indicates the proband. The SGPL1 genotype is shown for family members whose DNA was available for genetic studies. NM, nonmutated allele.
Figure 3.
Figure 3.
MRI of patient ALS35.03 with findings of hyperintensity in the basal ganglia (caudate and putamen).
See this image and copyright information in PMC

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