Biallelic variants in the SLC13A1 sulfate transporter gene cause hyposulfatemia with a mild spondylo-epi-metaphyseal dysplasia

Abstract

Sulfate is the fourth most abundant anion in human plasma but is not measured in clinical practice and little is known about the consequences of sulfate deficiency. Nevertheless, sulfation plays an essential role in the modulation of numerous compounds, including proteoglycans and steroids. We report the first patient with a homozygous loss-of-function variant in the SLC13A1 gene, encoding a renal and intestinal sulfate transporter, which is essential for maintaining plasma sulfate levels. The homozygous (Arg12Ter) variant in SLC13A1 was found by exome sequencing performed in a patient with unexplained skeletal dysplasia. The main clinical features were enlargement of joints and spondylo-epi-metaphyseal radiological abnormalities in early childhood, which improved with age. In addition, autistic features were noted. We found profound hyposulfatemia due to complete loss of renal sulfate reabsorption. Cholesterol sulfate was reduced. Intravenous N-acetylcysteine administration temporarily restored plasma sulfate levels. We conclude that loss of the SLC13A1 gene leads to profound hypersulfaturia and hyposulfatemia, which is mainly associated with abnormal skeletal development, possibly predisposing to degenerative bone and joint disease. The diagnosis might be easily missed and more frequent.

Keywords: acetylcysteine; autistic disorder; cholesterol; chondroitin; joint diseases; proteoglycans; skeletal dysplasia; sulfation.

FIGURE 1

Skeletal radiographs. Panel A shows general abnormalities including ovoid‐shaped vertebral bodies, spiky widening of all metaphyses and slightly delayed epiphyseal ossification in upper limb and lower limb and irregular tarsal bones at 6 months of age. Panel B shows that at 4 years the metaphyseal abnormalities have improved but that the epiphyses are small and somewhat irregular. Panel C shows that at 11 years, flattening of the cervical vertebral bodies and irregular lumbar vertebral endplates remain. The metaphyses and epiphyses normalized (not shown).

FIGURE 2

Plasma sulfate measurements. Plasma levels in the patient compared to his parents and lab controls.

FIGURE 3

Urinary sulfate excretion. Calculated FE_sulfate in the patient and his mother is compared to SLC13A1 Arg12Ter heterozygotes and wild‐type controls from Bowling et al 2013. The FE_sulfate is expressed in % and calculated as 100 × [plasma creatinine × urine sulfate]/[urine creatinine × plasma sulfate].

FIGURE 4

intravenous N‐Acetylcysteine treatment. Panel C shows plasma levels of sulfate and cystine (oxidized form of cysteine) on a logarithmic scale during and after NAC infusion. The gray rectangles indicate NAC administration (not to scale). The concentration cystine peaked earlier than sulfate as expected from the metabolism of the drug.