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PubMed1991

Clinical and laboratory findings in the oculocerebrorenal syndrome of Lowe, with special reference to growth and renal function.

BACKGROUND: The oculocerebrorenal syndrome of Lowe is an X-linked disorder whose clinical manifestations include congenital cataracts, mental retardation, and renal tubular dysfunction. We investigated growth, renal function, and serum chemistry values in patients with the oculocerebrorenal syndrome to determine the natural history of the disorder and its heterogeneity with respect to these characteristics. METHODS: Twenty-three patients with the oculocerebrorenal syndrome, ranging in age from 4 months to 31 years, were examined. Height was compared with bone age. Renal function was assessed by measurements of proteinuria, urinary volume, and fractional excretions of potassium, phosphate, carnitine, and amino acids. Creatinine clearance was determined as a measure of glomerular function. RESULTS: In the oculocerebrorenal syndrome, linear growth decreases after one year of age; bone age lies between chronologic age and height age. Renal dysfunction occurs in the first year of life, characterized by proteinuria (mean [+/- SD], 1.38 +/- 0.77 g of urinary protein per square meter of body-surface area per day; normal, less than or equal to 0.10), generalized aminoaciduria (mean, 686 +/- 505 mumol of urinary amino acid per kilogram of body weight per day; normal, 94 +/- 45), carnitine wasting (mean fractional excretion, 0.10 +/- 0.05; normal, 0.03 +/- 0.01), and phosphaturia progressing into the third decade. Urinary wasting of individual amino acids is milder than in cystinosis, and branched-chain amino acids are relatively spared. Reciprocal serum creatinine levels fall linearly with age, predicting renal failure in the fourth decade. Concentrations of the muscle enzymes creatine kinase, aspartate aminotransferase, and lactate dehydrogenase, as well as of total serum protein, serum alpha 2-globulin, and high-density lipoprotein cholesterol, are elevated. CONCLUSIONS: Renal glomerular deterioration is slowly progressive in the oculocerebrorenal syndrome. Renal tubular dysfunction begins early and persists; most patients require alkalinization therapy, and many benefit from supplemental potassium, phosphate, calcium, or carnitine. Serum enzyme elevations suggest muscle involvement in the oculocerebrorenal syndrome.

Adolescent↗

PubMed1998

Structure of the human sarco/endoplasmic reticulum Ca2+-ATPase 3 gene. Promoter analysis and alternative splicing of the SERCA3 pre-mRNA.

Human chromosome 17-specific genomic clones extending over 90 kilobases (kb) of DNA and coding for sarco/endoplasmic reticulum Ca2+-ATPase 3 (SERCA3) were isolated. The presence of the D17S1828 genetic marker in the cosmid contig enabled us to map the SERCA3 gene (ATP2A3) 11 centimorgans from the top of the short arm p of chromosome 17, in the vicinity of the cystinosis gene locus. The SERCA3 gene contains 22 exons spread over 50 kb of genomic DNA. The exon/intron boundaries are well conserved between human SERCA3 and SERCA1 genes, except for the junction between exons 8 and 9 which is found in the SERCA1 gene but not in SERCA3 and SERCA2 genes. The transcription start site (+1) is located 152 nucleotides (nt) upstream of the AUG codon. The 5'-flanking region, including exon 1, is embedded in a 1.5-kb CpG island and is characterized by the absence of a TATA box and by the presence of 14 putative Sp1 sites, 11 CACCC boxes, 5 AP-2-binding motifs, 3 GGCTGGGG motifs, 3 CANNTG boxes, a GATA motif, as well as single sites for Ets-1, c-Myc, and TFIIIc. Functional promoter analysis indicated that the GC-rich region (87% G + C) from -135 to -31 is of critical importance in initiating SERCA3 gene transcription in Jurkat cells. Exon 21 (human, 101 base pairs; mouse, 86 base pairs) can be alternatively excluded, partially included, or totally included, thus generating, respectively, SERCA3a (human and mouse, 999 amino acids (aa)), SERCA3b (human, 1043 aa; mouse, 1038 aa), or SERCA3c (human, 1024 aa; mouse, 1021 aa) isoforms with different C termini. Expression of the mouse SERCA3 isoforms in COS-1 cells demonstrated their ability to function as active pumps, although with different apparent affinities for Ca2+.

Alternative Splicing↗

PubMed1996

In vitro inhibition of the replication of human immunodeficiency virus type 1 by beta-mercaptoethylamine (cysteamine).

This study investigates the effects of cysteamine alone and in association with zidovudine or didanosine on the replication of human immunodeficiency virus type 1 (HIV-1). More than 90% viral inhibition was obtained by 200 microM cysteamine in lymphocytes and 100 microM cysteamine in macrophages against 4 primary isolates and 2 laboratory strains of HIV-1. Polymerase chain reaction analysis demonstrated that cysteamine interferes with early steps of HIV-1 replication, before proviral DNA formation. The use of cysteamine in conjunction with zidovudine or didanosine brought about an additive antiviral effect without concomitant increases in toxicity. The concentrations of cysteamine that are effective against HIV-1 in vitro have been well tolerated over long periods by patients under treatment for cystinosis, an inherited disorder. These observations suggest that cysteamine alone or in combination with zidovudine or didanosine could be a new potential treatment of HIV-1 infection.

Antiviral Agents↗

PubMed2002

Homocystine solubility and vascular disease.

There is evidence that mild elevations of tHcy are associated with an increased risk for occlusive vascular disease, thrombosis, and stroke. It is hypothesized here that cellular toxicity could indirectly result from auto-oxidation of homocysteine to homocystine. Elevated levels of total plasma homocysteine could be the primary cause of increased vascular risk, causing endothelial damage through a mechanism similar to that of cystine precipitation, which is known to cause stone formation in cystinosis and cystinuria. In fact, only traces of homocysteine circulate in plasma as the free thiol; the remainder is present as oxidation products. Of these, the symmetric disulfide homocystine is scarcely soluble at neutral pH. Its saturation limit is so close to the concentration of homocysteine in normal plasma that a transient increase of homocysteine levels could lead to precipitation of homocystine microcrystals in the bloodstream. These could damage endothelial tissue, acting as a mechanic primer for subsequent prothrombotic blood vessel alterations.

Homocysteine↗

PubMed1999

Do we really need to pay attention to the less common crystals?

In addition to monosodium urate, calcium pyrophosphate dihydrate, and apatite crystals, a wide variety of less common crystals, artifacts, and, occasionally, some unidentified birefringent materials may be seen in synovial fluids in association with acute or chronic arthritis. These unusual crystals and their associated musculoskeletal manifestations may be confused with the more common crystals and their manifestations and sometimes may provide the clue for systemic disease because they may present with a pseudovasculitis syndrome. Important advances in understanding the molecular aspect and management of primary hyperoxalurias as well as nephropathic cystinosis provide important general information to be applied in research and in the search for a more effective management of other common crystal-induced arthritis.

Arthritis↗

PubMed1994

Ocular manifestations of metabolic disorders.

Articles published during the past year on the ocular manifestations of metabolic diseases and related issues are reviewed. The focus is on clarifying the genetic or molecular basis of various metabolic disorders. Mutations of the P gene were reported in tyrosinase-positive oculocutaneous albinism and autosomal recessive ocular albinism, and were associated with a wide range of clinical phenotypes. This finding should aid in more accurate diagnosis and facilitate genetic counseling. There is no consensus but the horizontal supranuclear gaze palsy in Gaucher's disease may aid in subtyping. The report of a family with Morquio syndrome suggests that lenticular opacities should be considered as an additional finding in this syndrome. Patients with nephropathic cystinosis, which had been a fatal disease in childhood, are now surviving to adulthood. Serious ocular complications were described in adults.

Amino Acids↗

PubMed1977

1alpha-hydroxyvitamin D3 in the treatment of nutritional and metabolic rickets and osteomalacia.

Five patients with nutritional osteomalacia or rickets and six children with rickets unresponsive to physiological doses of vitamin D were treated with 1alpha-hydroxyvitamin D3 (1alpha-OHD3). Patients with nutritional osteomalacia responded to 1--2 microgram/day of 1alpha-OHD3. The most striking findings were rises in plasma calcium and, in one case, a decrease in faecal calcium. In some cases there was a rise in plasma phosphorus, alkaline phosphatase remained unchanged. There was radiological healing. In three patients with cystinosis and one with hypophosphataemia and Barrter's syndrome 2 microgram of 1alpha-OHD3 produced healing of rickets. Plasma phosphate rose on treatment, possibly by a suppression of parathyroid activity. The response to such low doses of 1alpha-OHD3 suggests impaired 1alpha-hydroxylation of 25-hydroxyvitamin D in these patients. A patient with intestinal malabsorption was resistant to high doses of 1alpha-OHD3 by mouth but responded to parenteral administration. A boy with osteopetrosis and the biochemical changes of rickets was resistant to large doses of 1alpha-OHD3 presumably because of failure of osseous response.

Adolescent↗

PubMed1999

Incidence of death in patients with intractable epilepsy during nitrazepam treatment.

PURPOSE: Increased risk of death has been reported in patients with intractable epilepsy (IE) taking nitrazepam (NZP). METHODS: Between January 1983 and March 1994, 302 patients with IE were entered into a NZP compassionate-plea protocol. NZP was discontinued if there was < 50% seizure reduction or significant side effects. In some patients with > 50% reduction, it also was discontinued for lack of sufficient effect. At the end of follow-up for this study, 62 patients remained taking NZP. Patients took NZP from 3 days to 10 years. RESULTS: Twenty-one of 302 patients died after institution of NZP. Fourteen of 21 of these were taking NZP at death, and in five of 21, the NZP had been discontinued. Two patients were excluded from analysis, because it is unclear whether NZP had been discontinued before death. Six other patients were lost from follow-up. Of the 14 deaths with NZP, seven were sudden, six were of pneumonia, and one was of cystinosis. Nine had at least one contributing factor, such as dysphagia, gastroesophageal reflux, or recurrent aspirations. The 294 patients took NZP for a total of 704 patient years (ptyrs), and were discontinued for a total of 856 ptyrs. There were 1.98 deaths/ 100 ptyrs on NZP compared with 0.58 deaths/100 ptyrs without NZP, most of the former being associated with side effects of NZP. Mortality in patients younger than 3.4 years was 3.98 with NZP compared with 0.26 deaths/100 ptyrs without NZP (p = 0.0002). Corresponding figures in patients 3.4 years or older were 0.50 and 0.86 deaths/100 ptyrs, respectively. CONCLUSIONS: NZP therapy for epilepsy apparently increases the risk of death, especially in young patients with IE. This should be considered in antiepileptic drug (AED) management decisions.

Age Factors↗

PubMed1998

A comparison of disease and gene frequencies of inborn errors of metabolism among different ethnic groups in the West Midlands, UK.

OBJECTIVE: To assess birth and gene frequencies of specific autosomal recessively inborn errors of metabolism (IEM) within different ethnic groups. DESIGN: Retrospective study in a regional centre for investigation and treatment of IEM. SUBJECTS: All children born within the West Midlands NHS Region, UK, during the decade immediately preceding the 1991 National Census. METHODS: Birth frequencies for individual IEM were calculated separately for the main ethnic groups in the West Midlands using data from the West Midlands Neonatal Screening Programme, the regional register of IEM patients, and population frequencies from the National Census. Gene frequencies were calculated using previously documented observations on parental consanguinity rates and inbreeding coefficients. RESULTS: The overall incidence of recorded IEM was tenfold higher among Pakistanis compared to white children (1:318 v 1:3760), whereas only one AfroCaribbean child was identified (incidence 1:16 887). Tyrosinaemia type 1, cystinosis, mucopolysaccharidosis type 1, non-ketotic hyperglycinaemia, and hyperchylomicronaemia all occurred more frequently among Pakistanis. An increased gene frequency was only confirmed for tyrosinaemia. The incidence of phenylketonuria was similar in Pakistani and white children (1:14 452 v 1:12 611), but the gene frequency was significantly lower in Pakistanis (1:713 v 1:112). These results illustrate the interplay between gene frequency and parental consanguinity in determining disease frequencies in different populations, and indicate anticipated disease frequencies in the absence of consanguineous marriage. These figures have implications for the organisation of services for management of inborn errors, for genetic counselling, and for the assessment of gene flow in world populations.

Ethnicity↗

PubMed1988

Effect of chronic cysteamine treatment on mouse liver aryl hydrocarbon hydroxylase activity.

Patients receive chronic cysteamine in the management of nephropathic cystinosis. In a previous report our results indicated that acute cysteamine treatment inhibited cytochrome P-450. Cysteamine (85 mg/kg i.p.) was administered daily to female Swiss mice for 1.5 and 8.5 months. Cysteamine treatment (8.5 months) did not affect hepatic microsomal aryl hydrocarbon hydroxylase (AHH) activity compared with controls. A small decrease in liver AHH activity was seen after 1.5 months of treatment with cysteamine. Liver histology, body weight, liver and spleen weights, and serum aminotransferase activity after chronic and subchronic treatment did not differ from controls. Chronic in vivo cysteamine treatment, unlike acute in vitro treatment did not decrease AHH activity. Incubation of isolated murine hepatocytes with cysteamine significantly inhibited AHH activity compared with controls. The inhibition occurred in a concentration-related manner, with 65% inhibition at 8.8 mM (1 mg/mL) (equivalent to the predicted plasma concentration using the maximally tolerable human dose), and 100% inhibition at 44 mM (5 mg/mL). The concentrations used in vitro were not cytotoxic. This suggests that chronic cysteamine treatment may not result in drug interactions and that in vitro results are not always good indicators of in vivo effects.

Animals↗

PubMed1992

Cystine dimethyl ester reduces the forces driving sodium-dependent transport in LLC-PK1 cells.

Cystinosis is an inherited metabolic disease characterized by accumulation of lysosomal cystine and renal impairment. In an attempt to better understand the link between cystine accumulation and renal functions, we studied the effects of cystine loading on the Na(+)-H+ antiporter and the sodium pump in renal epithelial cells (LLC-PK1) in culture. Incubation of LLC-PK1 with 1 mM cystine dimethyl ester (CDME) for 48 h caused lysosomal cystine loading and reduced by 22 +/- 2% the maximal velocity of sodium-hydrogen antiport with no significant change in the affinity of sodium for the transporter. Rubidium influx decreased to 46 +/- 5% of control. Ouabain binding experiments revealed a 10% reduction in the number of Na(+)-K(+)-ATPase units in the intact cells. Na(+)-K(+)-ATPase activity in the particulate fraction of the cells homogenate declined to 50 +/- 7.5% of controls. No significant change was observed in the activity of ouabain-insensitive phosphatases. The intracellular concentration of sodium increased from 20.6 +/- 3.7 to 64.8 +/- 10 mM, and potassium concentration decreased from 103 +/- 6 to 80 +/- 13 mM. In addition to the observed reduction in the sodium gradient and in agreement with the reduction in the intracellular potassium concentration, the membrane potential changed from -80.8 +/- 7.5 to -69.9 +/- 7.0 mV. The results suggest that intracellular accumulation of cystine is associated with reduction in the number and the activity of membrane transporters. The consequence of the changes in the activity of Na(+)-K(+)-ATPase is a reduction in the electrochemical forces that drive transport in the renal cells tested.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Cystine loading induces Fanconi's syndrome in rats: in vivo and vesicle studies.

To better understand the link between lysosomal cystine accumulation and the renal impairment seen in cystinosis, we have studied the effect of cystine loading in vivo, on renal function of rats, and in brush-border membrane vesicles (BBMV) prepared from the kidney cortex of the treated rats. Intraperitoneal injection of cystine dimethyl ester (CDME) (400 mumol, twice a day, for 5 days) led to an increased urine volume and excretion of glucose, phosphate, and protein. Kinetic analysis of alpha-methylglucoside initial flux in BBMV showed reduction in maximal transport capacity (Vmax, from 10.1 +/- 1.3 to 8.5 +/- 0.7 nmol.min-1.mg protein-1; P < 0.01) with no change in Michaelis constant (Km, 4.80 +/- 0.08 and 4.90 +/- 0.05 mM). The number of phlorizin binding sites declined (from 6.5 +/- 0.7 to 4.1 +/- 0.4 pmol/mg protein; P < 0.01) with no significant change in the affinity for phlorizin (0.64 +/- 0.08 and 0.59 +/- 0.06 microM). In the cortex homogenate, cystine concentration, which was undetectable in controls, increased to 0.97 +/- 0.09 nmol 1/2 cystine/mg protein. Two hours after CDME administration, ATP content declined to approximately 50% of control values. This decline was transient, and ATP content was recovered to control values 5 h after CDME administration. The treatment did not affect ouabain-sensitive adenosinetriphosphatase activity (40.0 +/- 3.9 and 38.6 +/- 4.7 nmol Pi.mg protein-1.min-1) or the number and affinity of ouabain binding sites (Bmax = 1.48 +/- 0.25 and 1.44 +/- 0.18 pmol/mg, and Kd = 0.68 +/- 0.09 and 0.72 +/- 0.12 microM, respectively). (ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗

PubMed1977

Thyroid function in children with chronic renal failure.

Thyroid function was evaluated in 24 children (aged 4-18 years) with chronic renal failure either before institution of hemodialysis or after more than 3 months of hemodialysis. 22 patients were clinically euthyroid and 2 were hypothyroid; in one case hypothyroidism was secondary to cystinosis and in the other it followed radiation therapy. The 2 hypothyroid patients had subnormal levels of T4, T3, FTI and FT4 as well as elevated serum TSH levels. Mean values for T4, T3, FTI and FT4 for the remaining 22 patients were within the normal range, but were significantly decreased, (all p values less than 0.01) when compared to controls. TSH and TBG levels were not significantly different from those of the normal population. Eleven of the euthyroid patients (50%) had either T3 or FT4, but not both, below the normal range without elevation of their TSH levels. These findings suggest that in the absence of other causes of hypothyroidism, children with chronic renal failure are able to maintain a clinically euthyroid state with either normal FT4 or T3 serum levels and can respond to primary gland failure with elevated TSH secretion.

Adolescent↗

PubMed2001

Carnitine-deficient myopathy as a presentation of tyrosinemia type I.

Carnitine deficiency secondary to renal Fanconi's tubulopathy has been described in only a few inborn errors of metabolism: cystinosis, galactosemia, and Fanconi-Bieckel syndrome. We report a 27-month-old infant who presented with a sudden change in gait owing to proximal muscle weakness. The laboratory evaluation showed carnitine deficiency associated with Fanconi's tubulopathy. Eventually, tyrosinemia type I was diagnosed. Carnitine deficiency can contribute to the clinical picture of hepatorenal tyrosinemia and should therefore be evaluated and treated.

Carnitine↗

PubMed1985

Pantethine, a cysteamine precursor, depletes immunoreactive somatostatin and prolactin in the rat.

Pantethine, a stable disulfide precursor of pantetheine, has been reported to increase intracellular concentration of cysteamine in cultured fibroblasts of patients with cystinosis. In order to determine whether pantethine acts like cysteamine in bringing about depletion of immunoreactive somatostatin (IRS) in rat neural and gastrointestinal tissues and depletion of immunoreactive PRL (IRPRL) in the anterior pituitary, groups of male rats were given pantethine by ip injection at a dose of 0.264 mM or 0.528 mM/100 g body weight or normal saline and killed 4 h later. The interval chosen corresponds to the time of maximum effect after oral cysteamine administration. In cerebral cortex, hypothalamus, duodenal and gastric mucosa, and pancreas, IRS was uniformly depressed by 50% or more as compared with control rats, the most striking changes occurring in the hypothalamus where there was a 64% depletion at the higher dose of drug. Both dosage levels depleted IRPRL in pituitary and serum. At the higher dose, IRPRL was reduced by approximately 85% in the pituitary and 75% in the serum. These findings support the hypothesis that pantethine administration leads to an accumulation of cysteamine within cells throughout the body and that the cysteamine so formed depletes IRS and IRPRL.

Animals↗

PubMedDate not supplied

Papillary pore counts: a method of studying developmental aberrations in diseased juvenile kidneys.

Counts of the number of pores of primary collecting tubules (ducts of Bellini) on renal papillae, and values calculated by adjusting the counts of compound papillae to those of "virtual" single papillae, were determined for kidneys of patients with end-stage renal failure. Values for chronic glomerulonephritis, Alport's disease, infantile polycystic disease, trisomy 18, and trisomy 13 were not abnormal. Kidneys of patients with CUTO showed significantly low pore counts, indicating that this process in some cases is a true hypoplasia, with mean reduction of number of ducts of Bellini of 26%. FGS showed a high proportion of single papillae (80% vs. normal 60%) with high virtual pore counts, suggesting that a developmental abnormality underlies this disorder (or this outcome of nephrotic syndrome). Cystinosis showed a high proportion of compound papillae (80% vs. 40%) but low virtual pore counts, implying that this genetic disorder causes both maldevelopment and postnatal functional abnormality of the kidneys. A Jeune syndrome kidney produced very low pore counts (mean 8 vs. 16.6 for virtual pore counts), and Down's syndrome also showed low pore counts (mean VPC 15.1 vs. normal 16.6), indicating that the low kidney weights demonstrated by others with Down's syndrome reflect a true hypoplasia.

Child↗

PubMed2000

Recurrent and de novo glomerulonephritis in the renal allograft.

Glomerulonephritis is a major cause of end-stage renal disease (ESRD) and is the primary disease in over a third of patients undergoing renal transplantation. An understanding of the incidence and clinical significance of recurrent glomerulonephritis posttransplantation is therefore essential. Indeed, all forms of glomerulonephritis have been reported to recur histologically after renal transplantation, but the incidence and severity of clinical recurrence varies greatly according to the type of glomerular disease. Large registries report that between 5% to 10% of allografts fail secondary to recurrence of primary disease. This review attempts to clarify some of the salient clinical features of recurrent glomerulonephritis from a body of literature full of anecdotal reports and retrospective studies. There are several excellent reviews on recurrent glomerulonephritis; this review aims to complement these by focusing on more recent developments in the field. Development of de novo glomerulonephritis in the transplant will also be discussed. The recurrence of metabolic diseases such as diabetes mellitus, cystinosis, Fabry's disease, and primary hyperoxaluria will not be discussed.

Glomerulonephritis↗

PubMed1992

[Inherited amino acid transport disorders].

Disorders due to inherited amino acids transport defect are reviewed. The disorders were categorized into three types of transport defects, namely, brush-border membrane of epithelial cells of small intestine and kidney tubules (Hartnup disease, blue diaper syndrome, cystinuria, iminoglycinuria and lysine malabsorption syndrome), basolateral membrane (lysinuric protein intolerance) and membrane of intracellular organelles (cystinosis and hyperornitinemia-hyperammonemia-homocitrullinuria syndrome). Pathogenesis, clinical feature, laboratory findings, diagnosis, genetics and treatment of these disorders are described, briefly. There is not much data for the transport systems themselves, so that further investigation in molecular and gene levels for transport systems is necessary to clarify the characteristics of the transport and heterogeneity of phenotypes in inherited amino acids transport disorders.

Amino Acid Metabolism, Inborn Errors↗