A 26-year-old woman, with no relevant past history or chronic treatment, consulted Primary Care for general malaise, cramps and paraesthesia in the hands and feet and, for the past 2 days, she had also been unable to raise her left eyelid. An analytical control was requested in Primary Care and a creatinine level of 4.6 mg/dl was detected (the only previous control recorded in our centre was 6 years earlier with a creatinine level of 1.5 mg/dl), for which reason the patient was referred to the Emergency Department. There was no family history of renal disease in any member of the family.
Clinical course
Her blood pressure was 135/67 mmHg, heart rate 120 bpm and temperature 37.5°C, with an unremarkable physical examination. Repeat blood work in the ED confirmed impaired renal function (creatinine 5.1 mg/dl and urea 245 mg/dl), together with sodium 124 mmol/l; potassium 3.5 mmol/l; pH 7.08; bicarbonate 5.9 mmol/l; pCO2 20 mmHg; corrected ionic calcium 0.69 mmol/l (normal 1.13-1.32); magnesium 1 mg/dl; leucocytes 14.060 and the rest of the haemogram and coagulation study were normal. Other deferred analytical determinations showed: calcium 7.4 mg/dl; phosphorus 5.6 mg/dl; iPTH 298 pg/ml; vitamin D 18.27 ng/ml and uric acid 8.8 mg/dl. The immunological study (immunoglobulins, ANA) was normal. Blood electrophoresis: decreased gamma globulins. Serology for viruses B, C and HIV was negative. Urine systemic analysis showed pH 6.0, blood ++, leucocytes +++. In 24 h urine, proteinuria was 0.73 g, creatinine clearance 12 ml/min, uricosuria 600 mg, calciuria < 4 mg/kg and oxaluria 10 mg (normal: 4-31).
Electrocardiogram showed sinus rhythm, with ST elevation of 1 mm in all leads. Chest X-ray was normal. Plain abdominal X-ray showed extensive bilateral renal calcifications. After correction of hypocalcaemia, hypomagnesaemia and metabolic acidosis, the patient was discharged, with no relevant incidents during admission. Laboratory values at discharge were creatinine 3.6 mg/dl; sodium 142 mmol/l; potassium 4.4 mmol/l; pH 7.43; bicarbonate 24.6 mmol/l; calcium 8.6 mg/dl; corrected ionic calcium 1.16 mmol/l; phosphorus 2.9, iPTH 103 ng/ml and magnesium 1.9 mg/dl. Treatment at discharge was: calcium carbonate 2.5 g every 8 h; calcitriol 0.5 mcg/day; sodium bicarbonate 1 g/day and oral potassium and magnesium supplementation.

Some 48 hours after being discharged from the Nephrology Department, she consulted the Emergency Department because she was unable to speak or perform tongue movements. In addition, the patient reported that the previous night she had alterations in the control of her right hand movements. She also had difficulty swallowing and intense asthenia. She did not present fever or headache. On physical examination, blood pressure was 102/72 mmHg, heart rate 75 bpm, baseline oxygen saturation 98% and the rest of the examination was normal. Blood tests were: creatinine 3.6 mg/dl; sodium 141 mmol/l; potassium 4.4 mmol/l; pH 7.43; bicarbonate 24.6 mmol/l; calcium 8.6 mg/dl; corrected ionic calcium 1.16 mmol/l and magnesium 1.9 mg/dl. The patient was assessed by the Neurology Department and was admitted to their care for further study. This department performed an edrophonium test (negative), brain CT scan without contrast (no significant findings), EEG (abundant outbreaks of paroxysmal activity [theta waves] in the left temporal region, with propagation to the rest of the hemisphere, as well as to the contralateral homologous region, forming some bilateral paroxysmal outbreaks of sharp waves). Treatment was started with levetiracetam 250 mg/12 h, which was insufficient to control the seizures. The patient progressed to focal status, with no response to diazepam (up to 10 mg) or valproic acid boluses, requiring transfer to the ICU. Comic activity was brought under control after the start of valproic acid perfusion (1 g/24 h), since when the patient has remained asymptomatic. Subsequently, on the Neurology ward, she was monitored with oral treatment: she remained asymptomatic and was discharged with 500 mg/12 h of valproic acid orally.
Genetic study
Given the absence of a family history of renal disease, the current situation of advanced renal failure and, therefore, the diagnostic difficulties in performing specific studies to clarify the primary process that had led to the development of nephrocalcinosis, it was decided to perform a genetic study. An analysis of all known genes associated with tubulointerstitial disease was requested http://nefrochus.villaweb.es/en/ which included analysis of the gene variants found in the known genes associated with forms of nephrocalcinosis (Nephrochus, Santiago de Compostela). The study determined that the patient (II:1) was a carrier of a missense mutation in exon 14 of the SLC4A1 gene, associated with autosomal dominant distal renal tubular acidosis (ATR-AD). This mutation (c.1766G > A, fig. 2A) involves the substitution of a basic amino acid (p.R589H) arginine (Arg, R) for an amino acid histidine (His, H) not previously found in normal chromosomes of our cohort, neither in the international 1000 genomes project, nor in the dbSNP137 database, but described in the literature5,6, with a genomic code rs121912744 catalogued as CLINSIG = pathogenic and associated with families with autosomal dominant distal renal tubular acidosis. The functional study performed with various in silico prediction tools assigns pathogenicity criteria to the gene variant (SIFT: deleterious; polyphen2: deleterious; LRT: deleterious; MutationTaster: disease_causing_automatic; mutation assessor: medium; FATHMM: tolerated; RadialSVM: deleterious and LR: deleterious).

Co-segregation study
In order to be able to decide on a possible live kidney transplant donation, a cosegregation study is performed in both parents (I:1 and I:2). The fact that neither is a carrier of the R589H mutation indicates that this mutation is de novo or spontaneous, and thus they can be candidates for donation.
