Mutation analysis and audiologic assessment in six Chinese children with primary distal renal tubular acidosis

The objective of this study is to identify ATP6V1B1, ATP6V0A4 and SLC4A1 genes mutations and assess audiologic characteristics in six Chinese children with primary distal renal tubular acidosis from four unrelated families between the ages of 2 and 13 years. Both ATP6V0A4 and ATP6V1B1 genes were preferentially screened in all index cases by direct sequence analysis. If inconclusive then SLC4A1 gene should be analyzed for mutation. Their clinical features, hearing status and inner ear imaging structure were also investigated. Six loss-of-function mutations were identified in six patients. Two novel mutations were identified in either of ATP6V0A4 and ATP6V1B1 genes, respectively. Two probands from different kindreds with mutations in ATP6V1B1 presented early onset profound sensorineural hearing loss (SNHL) and enlarged vestibular aqueduct (EVA). Two from different families carrying ATP6V0A4 mutations manifested early onset moderate mixed HL and moderate SNHL, respectively, the former comorbid with EVA, while the latter not; however, both their elder sisters showed normal hearing and inner ear. These findings expand the spectrum of mutations in the ATP6V0A4 and ATP6V1B1 genes associated with primary dRTA. Our study confirms the association of EVA and mutations in either of these two genes. More studies are necessary to clarify the relationship between dRTA, SNHL, EVA, and gene mutations.     

特发性高草酸尿症并不完全性远端肾小管酸中毒1例报告及文献复习

目的:探讨特发性高草酸尿症并不完全性远端肾小管酸中毒的临床特点.方法:回顾性分析1例特发性高草酸尿症并不完全性远端肾小管酸中毒患者的临床资料,并结合文献复习予以讨论.结果:连续两次24 h尿草酸检测结果分别为89.90 mg和93.83 mg,提示为高草酸尿症,结合临床特点诊断为特发性高草酸尿症.血气分析和血电解质未见异常,肾小管酸化功能检测结果:可滴定酸(TA)为0 mmol/L,NH4 为12.93 mmol/L,净酸排泄量(NAE)为12.93 mmol/L,氯化铵负荷试验阳性,提示为不完全性远端肾小管酸中毒.结论:特发性高草酸尿症与远端肾小管酸中毒均为尿路结石形成和复发的原因之一,对尿路结石患者应积极寻找结石成因,以期进行合理的治疗和有效的预防.     

Clinical and genetic analysis of distal renal tubular acidosis in three Chinese children

Objective: Primary distal renal tubular acidosis (dRTA) is a rare genetic disease characterized by distal tubular dysfunction leading to metabolic acidosis and alkaline urine. Growth retardation is a major concern in these children. The disease is caused by defects in at least three genes (SLC4A1, ATP6V0A4, and ATP6V1B1) involved in urinary distal acidification. Several series of dRTA patients from different ethnic backgrounds have been genetically studied, but genetic studies regarding Chinese population is rare. Our aim was to investigate the clinical features and genetic basis of primary dRTA in Chinese children.

Methods: Three unrelated patients with dRTA participated in our study. Next-generation sequencing was performed, and the findings were validated using the Sanger sequencing method.

Results: All patients exhibited hyperchloraemic metabolic acidosis, abnormally high urine pH, hypokalemia, and nephrocalcinosis. Growth retardation was observed in all patients. During the follow-up (range 1–4 years), alkali replacement therapy corrected the systemic metabolic acidosis, and two patients demonstrated normal growth. rhGH therapy was administered to patient-3 at the age of 6?years, and his growth rate was significantly improved (growth velocity 9.6?cm/yr). In total, 5 mutations were identified in our cohort of three patients, and four mutations were novel.

Conclusions: We report the clinical and molecular characteristics of dRTA patients from China. The four novel mutations detected in our study extend the spectrum of gene mutations associated with primary dRTA. Furthermore, our study confirms the effect of early treatment in improving growth for dRTA patient and provides insight into the effects of rhGH on dRTA patients who were diagnosed late and exhibiting a persistent growth delay despite appropriate therapy.     

Mutation analysis of 5 children with primary distal renal tubular acidosis

Objective To analyze the mutations of causal genes in 5 children with primary distal renal tubular acidosis (dRTA), and explore their association of genotype and phenotype, so as to raise the awareness of the disease. Methods The whole exome sequencing was used to identify mutations in these 5 children from 5 families. Results A total of 4 different mutations of ATP6V0A4 gene were found in 2 dRTA children, including a novel heterozygous intron mutation (c.639+1G＞A), a reported heterozygous nonsense variant (c.580C＞T, p.Arg194*) and 2 novel heterozygous duplications (c.1504dupT, p.Tyr502Leufs*22; c.2351dupT, p.Phe785Ilefs*28). Two novel heterozygous missense mutations of ATP6V1B1 gene (c.409C＞T, p.Pro137Ser; c.904C＞T, p.Arg302Trp) were identified in the third child, and a heterozygous missense mutation of SLC4A1 gene (c.1765C＞A, p.Arg589Ser) previously reported was found in the fourth child. No mutation of the dRTA-related causal genes was found in the fifth child. Furthermore, the mutations of causal genes in each of the first three children were compound heterozygous, which were consistent with the autosomal recessive inheritance pattern, and the variant from the fourth child was de novo. Conclusions The present study has found 7 mutations, including 5 novel variants, which enriches the human gene mutation database (HGMD) and contributes to a better understanding of the disease mechanisms.     

Benign methylmalonic acidemia in a sibship with distal renal tubular acidosis

Two male infants born to consanguineous parents were investigated for feeding difficulties in the 1st month of life. Both were found to have distal renal tubular acidosis (dRTA) with hypercalciuria. Nephrocalcinosis was present in the first child but not in the second. Urinary organic acid profile demonstrated an excess of methylmalonic acid (MMA) in both children in the absence of any other organic acid. MMA mutase activity and propionate incorporation were normal. There have been no neurological symptoms in either child. The first child has normal growth and psychomotor development at 4 years. His brother, who also has significant gastro-oesophageal reflux, has failed to thrive and currently requires nasogastric feeding and caloric supplements to maintain weight along the 3rd percentile. Urinary and plasma MMA continue to be raised in both cases. The association of increased urinary and plasma MMA and dRTA presenting in the 1st month of life has not previously been reported and may represent a new syndrome of autosomal recessive inheritance. Received January 12, 1998; received in revised form and accepted March 26, 1998     

Atypical distal renal tubular acidosis confirmed by mutation analysis

In autosomal dominant distal renal tubular acidosis type I (dRTA) impaired hydrogen ion secretion is associated with metabolic acidosis, hyperchloremic hypokalemia, hypercalciuria, nephrocalcinosis, and/or nephrolithiasis. A retardation of growth is commonly observed. In this report we present a family with autosomal dominant dRTA with an atypical and discordant clinical picture. The father presented with severe nephrocalcinosis, nephrolithiasis, and isosthenuria but metabolic acidosis was absent. His 6-year-old daughter, however, suffered from metabolic acidosis, hypokalemia, and hypercalciuria. In addition, sonography revealed multiple bilateral renal cysts but no nephrocalcinosis. Mutation analysis of the AE1 gene coding for the renal Cl^–/HCO₃ ^–- exchanger AE1 displayed a heterozygous Arg589Cys exchange in both patients but not in the healthy family members. This point mutation is frequently associated with autosomal dominant dRTA. Diagnosis of autosomal dominant dRTA is supported in this family by results of AE1 mutation analysis. Received: 13 April 2000 / Revised: 23 June 2000 / Accepted: 26 June 2000     

常染色体隐性遗传性远端肾小管酸中毒患儿ATP6V0A4和ATP6V1B1基因突变分析

目的 分析常染色体隐性遗传性远端肾小管酸中毒(rdRTA)患儿ATP6V0A4和ATP6V1B1基因的突变,进行基因型和表型的相关性研究.方法 PCR扩增基因组DNA,直接测序分析来自3个家系3例患儿的ATP6V0A4和ATP6V1B1基因的突变位点,选取不相关的100例健康人作为对照.结果 1例患儿携带ATP6V0A4基因的1个新的纯合无义突变(p.R194X);1例患儿携带ATP6V1B1基因1个新的杂合无义突变(p.R114X)和1个已经报道过的杂合突变p.I386fsX441;第3例患儿未发现以上2个基因的突变.结论 对中国rdRTA患者基因突变分析有利于了解该类疾病的基因型和表型的相关性,增强临床医生对该类疾病的认识和治疗.     

Reversible low-molecular-weight proteinuria in patients with distal renal tubular acidosis

Four patients with untreated renal tubular acidosis had a urinary excretion of low-molecular-weight (LMW) proteins which was restored to normal by alkali therapy. Hypokalaemic proximal tubular damage in untreated patients with distal renal tubular acidosis is believed to be the cause of LMW proteinuria. An examination of urinary excretion of LMW proteins is useful for determining hypokalaemic proximal tubular dysfunction, as well as the efficiency of alkali therapy.     

Recessive distal renal tubular acidosis in Sarawak caused by AE1 mutations

Mutations of the AE1 (SLC4A1, Anion-Exchanger 1) gene that codes for band 3, the renal and red cell anion exchanger, are responsible for many cases of familial distal renal tubular acidosis (dRTA). In Southeast Asia this disease is usually recessive, caused either by homozygosity of a single AE1 mutation or by compound heterozygosity of two different AE1 mutations. We describe two unrelated boys in Sarawak with dRTA associated with compound heterozygosity of AE1 mutations. Both had Southeast Asian ovalocytosis (SAO), a morphological abnormality of red cells caused by a deletion of band 3 residues 400–408. In addition, one boy had a DNA sequence abnormality of band 3 residue (G701D), which has been reported from elsewhere in Southeast Asia. The other boy had the novel sequence abnormality of band 3 (Q759H) and profound hemolytic anemia.     

ATP6V1B1 mutations in distal renal tubular acidosis and sensorineural hearing loss: clinical and genetic spectrum of five families

Abstract

Distal renal tubular acidosis (DRTA) is characterized by tubular defects in urinary acidification and hyperchloremic metabolic acidosis, hypokalemia, hypercalciuria, hypocitraturia, nephrocalcinosis and nephrolithiasis. Mutations in ATP6V1B1 cause DRTA associated with sensorineural hearing loss. The objective of this multicenter study is to screen DRTA patients with sensorineural hearing loss for ATP6V1B1 gene mutations and present genotype/phenotype correlation. Clinical data in five unrelated consanguineous families with DRTA and hearing loss were obtained in Turkey. For mutation screening, all coding exons of ATP6V1B1 were PCR-amplified and sequenced from genomic DNA. In our cohort of five families, there were four different homozygous ATP6V1B1 mutations in affected individuals: c.91C>T (p.R31X), c.232G>A (p.G78R), c.497delC (p.T166RfsX9) and c.1155dupC (p.I386HfsX56). Our study shows that rare and family-specific variants in ATP6V1B1 are responsible for DRTA and sensorineural hearing loss syndrome in Turkey. While firm genotype–phenotype correlations are not available, detailed clinical and molecular analyses provide data to be used in genetic counseling.     

Hyperkalemic distal renal tubular acidosis associated with Rett syndrome

Renal function was studied in a 7-year-old girl with Rett syndrome (RS) complicated by persistent hyperchloremic hyperkalemic metabolic acidosis. The acidosis was associated with a urine pH above 5.5, positive urinary anion gap and decreased potassium excretion. Plasma renin activity, aldosterone and cortisol levels were normal. Therapy with sodium bicarbonate failed to lower urine pH below 5.5 or increase potassium excretion. Hydrochlorothiazide administration resulted in a fall in urine pH below 5.5 and an increase in potassium excretion as a result of increased distal sodium delivery and increased sodium reabsorption in the distal nephron. We conclude that a voltage-dependent type of derangement in the distal nephron, rather than aldosterone deficiency, is responsible for the impairment in urinary acidification observed in this patient. Early detection of impaired renal acidification in RS may prevent or slow the progression of growth failure.     

Distal RTA with nerve deafness: clinical spectrum and mutational analysis in five children

Distal renal tubular acidosis (RTA) with nerve deafness is caused by mutations in the ATP6V1B1 gene causing defective function of the H⁺-ATPase proton pump. We report five acidotic children (four males) from four unrelated families: blood pH 7.21–7.33, serum bicarbonate 10.8–14.7 mEq/l, minimum urinary pH 6.5–7.1 and fractional excretion of bicarbonate in the presence of normal bicarbonatemia 1.1–5.7%. Growth retardation and nephrocalcinosis, but not hypercalciuria, were common presenting manifestations. Hearing was normally preserved in one of the patients whose sister was severely deaf. One child was homozygous for a known mutation in exon 1: C>T (R31X). Three children were homozygous for a splicing mutation, intron 6 + 1G>A. The other patient was a compound heterozygote, having this mutation and a previously unreported mutation in exon 10: G>A (E330K). Our report shows that hearing loss is not always present in the syndrome of distal renal tubular acidosis with nerve deafness and the absence of hypercalciuria at diagnosis and describes a new mutation responsible for the disease in the ATP6V1B1 gene.     

Long-term follow-up in distal renal tubular acidosis with sensorineural deafness

A 20-year-old man presented with failure to thrive and bilateral genu valgum. On the basis of growth failure, skeletal deformity, hyperchloremic metabolic acidosis with alkaline urine and hypokalemia, nephrocalcinosis, and hearing loss, a diagnosis of distal renal tubular acidosis (DRTA) with sensorineural deafness was made. The genu valgum was treated by corrective osteotomy. Skeletal deformity was corrected and impaired growth improved after sustained therapy of metabolic acidosis with alkali supplementation. During an 8-year follow-up period the patient’s glomerular filtration rate remained stable, the nephrocalcinosis did not progress, and his height increased 10 cm. Although nephrolithiasis led to atrophy of the right kidney, at last follow-up, when the patient was 44 years old, his creatinine clearance was 50 ml/min per 1.73 m² body surface. Received: 17 December 1999 / Revised: 26 April 2000 / Accepted: 2 May 2000     

Val2Ala mutation in the Atp6v0a4 gene causes early-onset sensorineural hearing loss in children with recessive distal renal tubular acidosis: a case report

A young female patient born to consanguineous parents was admitted to our clinic at the age of 3 years with a 5-month history of weight loss and recurrent urinary tract infections. Based on clinical findings (delayed growth and O-bein deformity) and laboratory tests (hypokalemia, hyperchloremia, partially compensated metabolic acidosis, alkaline urine and nephrocalsinosis), a diagnosis of distal renal tubular acidosis (dRTA) was made. Then, the audiogram revealed a bilateral sensorineural hearing loss (SNHL). On follow-up, bilateral SNHL progressively worsened requiring the need for hearing aid. The ATP6V0A4 gene mutation analysis showed homozygote Val2Ala mutation. To the best of our knowledge, this is the first report describing a Turkish girl with dRTA who suffered from early-onset SNHL caused by Val2Ala mutation in the ATP6V0A4 gene.     

Transient neonatal distal renal tubular acidosis with secondary hyperparathyroidism

We describe a neonate with distal renal tubular acidosis with secondary hyperparathyroidism manifesting as hyperchloraemia, hypercalcaemia, elevated serum parathyroid hormone (PTH) and life-threatening metabolic acidosis. He exhibited general weakness, tachypnoea, dry skin and weight loss. Urinary excretion of titratable acid and ammonium was decreased. Daily alkali (2.5 mEq/kg body weight) was required to maintain a normal plasma bicarbonate (HCO₃–). With alkali therapy, the fractional excretion of HCO₃– was below 5%. Serum calcium and PTH were restored to normal promptly on initiation of alkali therapy. After 5 months of alkali therapy, normal growth and urine acidifying ability were restored and alkali therapy was discontinued. The acidification defect in this patient was transient. We consider this patient to be consistent with Lightwood's syndrome of transient infantile renal tubular acidosis.     

Hyperammonaemia in a child with distal renal tubular acidosis

A 5-month-old girl with distal renal tubular acidosis (RTA) and hyperammonaemia that had lasted for 12 days, despite metabolic acidosis correction, is presented in this report. The patient showed failure to thrive, poor feeding, hypotonia and vomiting crisis in absence of inborn errors of metabolism. Probably, hyperammonaemia was the result of an imbalance between the increased ammonia synthesis, in response to metabolic acidosis, and the impaired ammonia excretion, typical of distal RTA. Our case confirms that hyperammonaemia may be observed in distal RTA, mimicking an inborn error of metabolism, and it underlines that hyperammonaemia may persist several days after metabolic acidosis correction.     

A case report and review of hypokalemic paralysis secondary to renal tubular acidosis

A 5-year-old girl with distal renal tubular acidosis (RTA) and hypokalemic muscle paralysis is reported. RTA is a known cause of hypokalemia, but in spite of the presence of persistent hypokalemia muscular paralysis is uncommon, rarely described in children, and the onset of paralysis may initially be misinterpreted particularly if the patient is attended by a physician who is not a pediatric nephrologist. Therefore parents must be informed about this possibility. Still, as the clinical appearance of hypokalemic paralysis is quite similar to familial hypokalemic periodic paralysis, and because the emergent and prophylactic treatment of the two disorders are quite different, we discuss the diagnostic evaluation and the treatment for both of them.     

Distal type of renal tubular acidosis after anti-epileptic therapy in a girl with infantile spasms

An 11-month-old girl was referred to our hospital because of nausea and poor physical activity. She had a 5-month history of infantile spasms, which were successfully treated with valproic acid (VPA) and vitamin B6. Laboratory studies revealed hyperchloremic metabolic acidosis, mainly due to distal type renal tubular acidosis (RTA). Although a renal biopsy, performed 2 months after the onset of RTA, did not demonstrate tubulointerstitial lesions, her clinical course, in which administration of VPA led to an episode of RTA, with gradual subsidence on VPA removal, suggested that the probable causative agent of her distal type RTA was VPA. Although proximal type RTA associated with VPA administration has been reported, distal type is rarely seen. To our knowledge, a similar case has not been reported previously. Received: March 23, 1999 / Accepted: May 29, 1999     

Incomplete distal renal tubular acidosis affects growth in children.

BACKGROUND: Incomplete distal renal tubular acidosis (idRTA) is recognized as an underlying aetiology in recurrent nephrolithiasis. Until the recently reported high prevalence of idRTA in adults with osteoporosis, the effect of idRTA on skeletal parameters was not known. We hypothesize that idRTA has a potential to affect height in the paediatric population. METHODS: In a cross-sectional study, the children with posterior urethral valves (PUV), with normal estimated glomerular filtration rates, were evaluated for idRTA and complete dRTA. The idRTA evaluation was done by short ammonium chloride acidification test. The height standard deviation scores (SDS) in the idRTA group were compared with PUV children without dRTA, with complete dRTA, and to age and gender matched controls with no renal issue (n = 50). RESULTS: The idRTA group (n = 17) manifested a significantly lower mean height SDS (-1.94 +/- 0.41 vs -0.46 +/- 0.28; P < 0.001) and a higher short stature prevalence (height SDS below 2) (18% vs 0; P = 0.06) as compared with those without dRTA (n = 23). The matched controls showed a significantly higher height SDS as compared with the idRTA group (-0.39 +/- 0.25 vs -1.94 +/- 0.41; P < 0.001). As compared with the complete dRTA group (n = 9), the children with idRTA did have significantly higher height SDS (-1.94 +/- 0.41 vs -5.31 +/- 1.95; P = 0.002), and a lower short stature prevalence (18% vs 78%; P = 0.001). On multivariate analysis, dRTA was significantly associated with the height SDS (= -0.88; P < 0.001). CONCLUSIONS: Incomplete dRTA affects height in children. This observation needs validation in longitudinal studies.