Renal Tubular Fanconi Syndrome Research Articles

Clinical, genetic, and structural characterization of a novel TUBB4B tubulinopathy

Microtubules are cytoskeletal polymers of ⍺/β-tubulin heterodimers essential for a wide range of cellular processes. Pathogenic variations in microtubule-encoding genes (e.g., TUBB4B, which encodes the β-4B tubulin isotype) are responsible for a wide spectrum of cerebral malformations, collectively referred to as “tubulinopathies.” The phenotypic manifestation of TUBB4B-associated tubulinopathy is Leber congenital amaurosis with early-onset deafness (LCAEOD), an autosomal dominant syndrome characterized by photoreceptor and cochlear cell loss; all known patients have pathogenic variations in amino acid R391. We present the clinical and molecular genetics findings of a 16-year-old female with a de novo missense variant in exon 1 of TUBB4B, c.32 A > G (p.Gln11Arg; Q11R). In addition to hearing loss and hyperopia without retinal abnormalities, our proband presented with two phenotypes of unknown genetic etiology, i.e., renal tubular Fanconi Syndrome (FS) and hypophosphatemic rickets (HR). The Q11R variant expands the genetic basis of early sensory hearing loss; its consequences with respect to microtubule structure are described. A mechanistic explanation for the FS and rickets, involving microtubule-mediated translocation of transporter proteins to and from the apical membrane of renal proximal tubular cells, is proposed.

MO004PRIMARY BILIARY CHOLANGITIS PRESENTING WITH RENAL FANCONI SYNDROME: A FORGOTTEN PHENOTYPE

Abstract Background and Aims Primary biliary cholangitits (PBC) is an autoimmune liver disease, leading to liver fibrosis and cirrhosis. It is a rare disease affecting 1 in 3-4000 people and is more common in females. Symptoms may go unnoticed and include itch and fatigue. Most patients have anti-mitochondrial antibodies (AMA) as well as raised gamma-glutamyl transferase (GGT) and alkaline phosphatase (ALP) levels. First line treatment for PBC is ursodeoxycholic acid and is usually continued lifelong. It improves liver biochemistry, histological progression of liver disease and liver transplant-free survival. Renal complications of PBC include distal renal tubular acidosis (RTA), tubule-interstitial nephritis (TIN) and renal Fanconi syndrome. Method We reviewed a case of PBC presenting with renal Fanconi syndrome. Results A 48-year-old female was referred to the renal clinic due to progressive decline in renal function since she was diagnosed with type 2 diabetes in 2007. She was also known to have AMA (>1:640) and previously had transient transaminitis. She was clinically well with no major symptoms but reported that she had had a few episodes of urinary tract infection in the previous year. Her diabetes was managed with lifestyle modifications in the past until a few months ago when Metformin was introduced. However, her HbA1c level had never been greater than 55 mmol/mol. Urine dipstick in the clinic showed pH of 6, blood+, glucose+++, protein+++ and ketone trace. The severity of glycosuria was inconsistent with her glycaemic control. There was a disparity between her urine albumin/creatinine ration (ACR) of 18.8g/mol and protein/creatinine ratio (PCR) of 124mg/mmol. Myeloma screen was negative and further urine analysis showed generalised aminoaciduria. She also had hypouricaemia, intermittent hypophosphataemia and non-anion gap metabolic acidosis. These results are in keeping with renal Fanconi syndrome. Her eGFR was 48 ml/min/1.72m2 in 2007 and was 21 ml/min/1.72m at the time of review. A renal biopsy was undertaken, and the appearances were suggestive of mild tubulo-interstitial nephritis; the glomeruli were unremarkable; there was mild chronic tubulo-interstitial damage. She was started on oral steroid, sodium bicarbonate and ursodeoxycholic acid. The course of steroid had a slight transitory beneficial effect on the renal function. Conclusion Distal RTA is the usual renal feature of PBC, occurring in 1/3 of cases with advanced disease. In contrast, proximal RTA associating with renal Fanconi syndrome occurs rarely. Like our case, the cases that have been previously reported show that Fanconi syndrome occurred during the early phase of PBC in the absence of marked hepatic abnormalities, and were associated with CKD. Fanconi syndrome and TIN are renal features of mitochondrial cytopathies and are perhaps a forgotten association of PBC. Antimitochondrial antibodies may play a role in the onset of tubulo-interstitial nephritis and Fanconi syndrome.

Molecular based newborn screening in Germany: Follow-up for cystinosis

BackgroundNewborn screening (NBS) programs for treatable metabolic disorders have been enormously successful, but molecular-based screening has not been broadly implemented so far. MethodsThis prospective pilot study was performed within the German NBS framework. DNA, extracted from dried blood cards was collected as part of the regular NBS program. As cystinosis has a prevalence of only 1:100,000–1:200,000, a molecular genetic assay for detection of the SMN1 gene mutation with a higher prevalence was also included in the screening process, a genetic defect that leads to spinal muscular atrophy (SMA). First tier multiplex PCR was employed for both diseases. The cystinosis screening employed assays for the three most common CTNS mutations covering 75% of German patients; in case of heterozygosity for one of these mutations, samples were screened by next generation sequencing (NGS) of the CTNS exons for 101 CTNS mutations. A detection rate of 98.5% is predicted using this approach. ResultsBetween January 15, 2018 and May 31, 2019, 257,734 newborns were screened in Germany for cystinosis. One neonate was diagnosed with cystinosis, consistent with the known incidence of the disease. No false positive or false negatives were detected so far. Screening, communication of findings to parents, and confirmation of diagnosis were accomplished in a multi-disciplinary setting. This program was accomplished with the cooperation of hospitals, physicians, and parents. In the neonate diagnosed with cystinosis, oral cysteamine treatment began on day 18. After 16 months of treatment the child has no clinical signs of renal tubular Fanconi syndrome. ConclusionsThis pilot study demonstrates the efficacy of a molecular-based neonatal screening program for cystinosis using an existing national screening framework.

Mutation analysis of the CTNS gene in Iranian patients with infantile nephropathic cystinosis: identification of two novel mutations

Nephropathic cystinosis is an inherited lysosomal transport disorder caused by mutations in the CTNS gene that encodes for a lysosomal membrane transporter, cystinosin. Dysfunction in this protein leads to cystine accumulation in the cells of different organs. The accumulation of cystine in the kidneys becomes apparent with renal tubular Fanconi syndrome between 6 and 12 months of age and leads to renal failure in the first decade of life. The aim of this study was to analyze the CTNS mutations in 20 Iranian patients, from 20 unrelated families, all of whom were afflicted with infantile nephropathic cystinosis. In these patients, seven different mutant alleles were found, including two new mutations, c.517T>C; p.Y173H and c.492_515del, that have not been previously reported. In addition, we observed that c.681G>A, the common Middle Eastern mutation, was the most common mutation in our patients. Moreover, a new minisatellite or variable number of tandem repeat marker (KX499495) was identified at the CTNS gene. Seven different alleles were found for this marker, and its allele frequency and heterozygosity degree were calculated in cystinosis patients and healthy individuals.

Oculocerebrorenal syndrome phenotype in four Iraqi children

The oculocerebrorenal syndrome (OCRS) is a rare hereditary disorder characterized by ocular and cerebral defects, hypotonia, hyporeflexia and renal dysfunction. The aim of this study is to report the phenotype OCRS in four Iraqi children. From 1994 to 2005, four patients (two boys and two girls) with OCRS phenotype were observed at Al-Kadhimiyia University Hospital. All described cases had congenital cataract(s), hypotonia and hyporeflexia and renal dysfunction. It was possible to study and follow three of them for several months, while the fourth case was observed only twice and then lost to follow up. Ocular manifestations in the three cases were in the form of cataract and glaucoma; one boy had immature cataracts not affecting the vision, and bilateral congenital chorioretinal hypoplasia. Two boys had nystagmus during infancy, which was undetectable at time of referral of one case. All the patients had hypotonia and hyporeflexia, which developed after 3 years in one girl. Three patients had global developmental delay; however, intelligence and language was well developed in one girl. All the children had end stage renal failure with evidence of glomerular defect. None had any renal tubular dysfunction or Fanconi syndrome. Uremia was the cause of death in the three cases followed up during their first decade. Congenital chorioretinal hypoplasia, which had never been described in OCRS, was present in one among our cases.

Cystinosis: renal glomerular and renal tubular function in relation to compliance with cystine-depleting therapy.

Nephropathic cystinosis is a lysosomal storage disorder characterized by renal tubular Fanconi syndrome in infancy and glomerular damage leading to renal failure at ∼10 years of age. Therapy with the cystine-depleting agent cysteamine postpones renal failure, but the degree of compliance with this treatment has not been correlated with preservation of kidney function. We assessed leucocyte cystine depletion by cysteamine and created the composite compliance score that incorporates the extent of leucocyte cystine depletion, as well as duration of cysteamine treatment, into a single integer. Age at renal failure was used to gauge preservation of renal function, and the Fanconi syndrome index (FSI), a measure of aminoaciduria, was used to assess renal tubular Fanconi syndrome. Age at renal failure varied directly and linearly with the composite compliance score (y = 0.3x +8.8; R(2) = 0.61). The slope indicated that for every year of excellent cystine depletion, nearly 1 year of renal function was preserved. Age at renal failure correlated roughly with mean leucocyte cystine level, but not with mean cysteamine dosage. There was no correlation between the FSI and the composite compliance score. Greater compliance with oral cysteamine therapy yields greater preservation of renal glomerular, but not tubular, function. Oral cysteamine therapy should be given at the maximum tolerated dose, within the recommended limits.

Progressive destructive bone changes in patients with cystinosis.

Nephropathic cystinosis is an autosomal recessive lysosomal storage disorder in which intracellular cystine accumulates. It is caused by mutations in the CTNS gene. Clinical manifestations include renal tubular Fanconi syndrome in the first year of life, rickets, hypokalaemia, polyuria, dehydration and acidosis, growth retardation, hypothyroidism, photophobia and renal glomerular deterioration. Late complications include myopathy, pancreatic insufficiency and retinal blindness. Skeletal manifestations described in these patients include failure to thrive, osteomalacia, rickets and short stature. This paper describes progressive bony abnormalities in three unrelated patients with nephropathic cystinosis that have not been reported previously.

Index of Suspicion

Index of Suspicion

Tigroid pattern on magnetic resonance imaging in Lowe syndrome

Lowe (oculocerebrorenal) syndrome is an X-linked recessive disorder characterised by congenital cataract, glaucoma, cognitive developmental delay and renal tubular Fanconi syndrome. In this report we present a patient with Lowe syndrome with a tigroid pattern on cranial MRI, which has not been previously reported as an imaging feature of this syndrome.

Nephropathic cystinosis: late complications of a multisystemic disease

Cystinosis is a rare autosomal recessive disorder due to impaired transport of cystine out of cellular lysosomes. Its estimated incidence is 1 in 100,000 live births. End-stage renal disease (ESRD) is the most prominent feature of cystinosis and, along with dehydration and electrolyte imbalance due to renal tubular Fanconi syndrome, has accounted for the bulk of deaths from this disorder. Prior to renal transplantation and cystine-depleting therapy with cysteamine for children with nephropathic cystinosis, their lifespan was approximately 10 years. Now, cystinotic patients have survived through their fifth decade, but the unremitting accumulation of cystine has created significant non-renal morbidity and mortality. In this article we review the classic presentation of nephropathic cystinosis and the natural history, diagnosis, and treatment of the disorder's systemic involvement. We also emphasize the role of oral cysteamine therapy in preventing the late complications of cystinosis.

Coronary Artery and Other Vascular Calcifications in Patients with Cystinosis after Kidney Transplantation

Cystinosis, an autosomal recessive disorder of lysosomal cystine accumulation, results from mutations in the CTNS gene that encodes the lysosomal cystine transporter, cystinosin. Renal tubular Fanconi syndrome occurs in infancy, followed by rickets, growth retardation, photophobia, and renal failure, which requires renal transplantation at approximately 10 yr of age. Treatment with cysteamine decreases cellular cystine levels, retards renal deterioration, and allows for normal growth. Patients with a history of inadequate cystine depletion therapy may survive, after renal transplantation, into the third to fifth decades but will experience other, extrarenal complications of the disease. Routine chest and head computed tomography scans of 41 posttransplantation patients with cystinosis were reviewed for vascular calcification. The radiologic procedures had been performed to examine lung and brain parenchyma, so there was little ascertainment bias. Thirteen of the 41 patients had vascular calcification, including 11 with coronary artery calcification. One 25-yr-old man required three-vessel coronary artery bypass graft surgery. There were no significant differences between the 13 patients with calcification and the 28 without calcification in the following parameters: Time on dialysis, frequency of transplantation, hypertension, hypercholesterolemia, homozygosity for the 57-kb deletion in CTNS, serum creatinine, and calcium-phosphate product. However, the finding of vascular calcification correlated directly with duration of life without cysteamine therapy and inversely with duration of life under good cystine-depleting therapy. The accumulation of intracellular cystine itself maybe a risk factor for vascular calcifications, and older patients with cystinosis should be screened for this complication.

Renal epithelial traffic jams and one-way streets.

The kidney contains the body’s second largest number of different cell types, modulating the great diversity of different functions that allow complex homeostasis to occur. A feature that unites all these cell types in the postglomerular nephron is that they are highly polarized; one surface being

Early oral cysteamine therapy for nephropathic cystinosis.

Nephropathic cystinosis is an autosomal recessive lysosomal storage disorder in which intracellular cystine accumulates due to impaired transport out of lysosomes. The clinical manifestations include renal tubular Fanconi syndrome in the 1st year of life, with hypophosphatemic rickets, hypokalemia, polyuria, dehydration and acidosis, growth retardation, hypothyroidism, photophobia, renal glomerular deterioration by 10 years of age, and late complications such as myopathy, pancreatic insufficiency, and retinal blindnesss. The cystinosis gene, CTNS, codes for cystinosin, a 367 amino acid protein with seven transmembrane domains. More than 50 CTNSmutations have been identified, but approximately 50% of Northern European patients have a 57257-bp deletion which removes the first nine exons of CTNS. The mainstay of cystinosis therapy is oral cysteamine (Cystagon). This aminothiol can lower intracellular cystine content by 95%, and has proven efficacy in delaying renal glomerular deterioration, enhancing growth, preventing hypothyroidism, and lowering muscle cystine content. Its early and diligent use is critical; in one study, for every month of treatment prior to 3 years of age, 14 months' worth of later renal function were preserved. Several examples of individual patients treated early and having preserved renal function and normal growth are available. Newborn screening using a chip containing cDNA to detect common CTNSmutations may allow diagnosis and treatment in the first weeks of life. Early diagnosis and treatment of nephropathic cystinosis can change the course of this disease.

Cystinosis

Nephropathic cystinosis was first described in the early 1900s in a 21-mo-old boy who died of progressive anorexia; two siblings had previously died in infancy under similar circumstances (1). By meticulous observations and analyses, it became clear that abnormal cystine accumulation was characteristic of this autosomal recessive disease (2-4). Although some considered it to be a severe form of cystinuria, cystinosis was clearly distinguished from cystinuria by Bickel’s excellent clinical and biochemical observations (5). Clinically, untreated cystinosis patients would suffer renal tubular Fanconi syndrome, with hypophosphatemic rickets, hypokalemia, polyuria, polydypsia, dehydration, acidosis, and growth retardation followed by end-stage renal disease (ESRD) and death at approximately 10 yr of age (6,7). Shortly after the distinctive clinical aspects of cystinosis were defined, the intracellular location of cystine storage was determined. In the late 1960s, Schneider et al. (8), Schulman et al. (9), and Patrick and Lake (10) performed elegant biochemical studies to demonstrate that cystinosis cells stored cystine within the lysosome, an organelle discovered only two decades before (11). Subsequent work

Pyroglutamic aciduria and nephropathic cystinosis.

Nephropatic cystinosis (NC; McKusick 219800) is caused by impaired cystine transport across the lysosomal membrane, resulting in renal tubular Fanconi syndrome and later evolving to chronic renal failure. To prevent the progression to renal failure, treatment with cysteamine is currently used for lowering parenchymal cystine storage. Cysteamine reacts in lysosomes with cystine, producing a mixed disulphide (cysteamine-cysteine mixed disulphide) and cysteine that enter the cytosol through specific carriers. We evaluated urinary organic acids excretion in three NC patients, before and during cysteamine therapy.

Successful Pregnancy in Cystinosis

To the Editor. —Cystinosis is an autosomal recessive disorder in which accumulation of lysosomal cystine leads to renal failure, growth retardation, photophobia, endocrine dysfunction, and other late complications.1,2In their article from the National Institutes of Health reviewing the adult manifestations of the disease,2Dr Theodoropoulos and colleagues give details of endocrine manifestations but do not address the question of female fertility. We wish to report a successful pregnancy in a cystinotic woman who had received treatment with phosphocysteamine. In 1965 when this patient was 27 months old, cystinosis was diagnosed following failure to thrive and a renal tubular Fanconi syndrome. Later complications included epilepsy, corneal crystals, hypertension, and hypothyroidism. Renal impairment developed, and she received a successful living related renal transplant in November 1975. In 1987, she started treatment with phosphocysteamine, cystine levels subsequently being maintained with administration of less than 1.5 nmol of half cystine per

Muscle carnitine repletion by long-term carnitine supplementation in nephropathic cystinosis.

The renal tubular Fanconi syndrome of children with nephropathic cystinosis causes plasma and muscle carnitine depletion. L-Carnitine replacement therapy for up to 18 mo has previously been shown to normalize plasma but not muscle carnitine levels. We treated six cystinosis patients, aged 1 to 4 y, with a mean dosage of 92 mg L-carnitine/kg/d given every 6 h for an average of 62 mo. Despite fractional excretions of free carnitine ranging from 55 to 108%, plasma-free and total carnitine concentrations were maintained at or above normal levels. At the end of the carnitine replacement period, the six children had muscle-free carnitine values ranging from 16.0 to 28.0 nmol/mg noncollagen protein compared with values of 3.0 to 11.4 for cystinosis children not supplemented with carnitine [normal, 22.7 +/- 5.0 (SD) nmol/mg protein]. Total muscle carnitine values were also normalized by L-carnitine replacement. The monthly increase in total body creatinine production, a measure of muscle mass, was higher (p = 0.036) in children with normal plasma free carnitine concentrations (3.4 +/- 0.9 mg/d) than in children with low plasma free carnitine (2.3 +/- 0.7 mg/d). No serious side effects, such as severe diarrhea, were observed. We conclude that oral L-carnitine replacement can normalize muscle carnitine content in children with cystinosis.

Culture of renal tubular cells from the urine of patients with nephropathic cystinosis.

Nephropathic cystinosis represents a prototype for lysosomal storage diseases and is the most common cause of renal tubular Fanconi's syndrome. Mechanisms of the tubular transport defects in this disease have not been defined, however, in part because the cells readily cultured from affected patients, leukocytes and fibroblasts, do not express epithelial transport functions. Except for a single autopsy report, renal tubular cells from these patients have not been studied in vitro. In these studies, noninvasive harvesting and culture of renal tubular cells from the urine of patients with cystinosis is described. Cultures of renal tubular cells could be established from over 50% of the isolates which contained viable cells and which remained uncontaminated in vitro. Cells had an epithelial morphology in culture, and the majority of cultured cells expressed proximal tubular brush border marker enzyme. Cultured cells also expressed the storage defect in vitro, containing cystine levels up to 100 times those of normal cells. Cultured cells could be depleted of cystine by using the thiol cysteamine. This in vitro model system should be very useful for studying the mechanisms of renal tubular transport defects in this disease.

Ifosfamide-induced renal tubular dysfunction and rickets in children with Wilms tumor

The renal tubular Fanconi syndrome developed in five patients with Wilms tumor after treatment with ifosfamide, a derivative of cyclophosphamide. Glomerular filtration rates were severely decreased. Renal function was investigated because of the development of rickets. All patients had undergone reduction of renal mass by nephrectomy. None had preexisting renal tubular injury. The syndrome developed at cumulative doses of ifosfamide of 39 to 99 gm/m2. Low serum bicarbonate and phosphate concentrations with glucosuria, aminoaciduria, and hypochloremic metabolic acidosis were the manifestations of the Fanconi syndrome. Bicarbonate and phosphate replacement resulted in bone healing, but recovery of tubular and glomerular function did not occur. Monitoring of these laboratory values during ifosfamide therapy could allow earlier replacement therapy to prevent severe bone disease.

Electrophoretic examination of proteinuria in Lowe's syndrome and other causes of renal tubular Fanconi syndrome.

Urine samples from 26 patients with five different causes of renal tubular Fanconi syndrome were examined by zone electrophoresis on agarose gel and immunofixation. The tubular disorders associated with Lowe's syndrome, cystinosis, and idiopathic Fanconi syndrome exhibited urine protein electrophoretic characteristics that differentiated them from normal and from each other. In particular, Lowe's syndrome urine exhibited four discrete bands in the gamma globulin zone. Electrophoresis of urinary proteins may be useful in distinguishing among the different metabolic disorders causing renal tubular Fanconi syndrome.