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Inherited metabolic renal disorders in children
GENETIC DISORDERS
Inherited metabolic renal disorders in children
rarely in adult practice and will require ongoing multidisciplinary management. A summary of inherited metabolic conditions affecting the kidney is provided in Table 1. This article focuses on conditions that present with renal impairment, predominantly in childhood (Table 2).
Joanna Clothier Sally-Anne Hulton
Cystinosis Cystinosis is an autosomal recessive multi-system disease, in which cystine crystals accumulate in the tissues of the body as a result of a defective cystine transporter in the lysosomal membrane. The kidney and cornea are very sensitive to this accumulation. The condition affects 1:150,000 births with both sexes affected equally. Over 100 mutations have been described in the cystinosis gene, CTNS, located on chromosome 17p13; the gene encodes a protein ‘cystinosin’. At birth, the infant appears normal and develops appropriately until 3e6 months of age, before presenting with polyuria and polydipsia, unexplained fever, anorexia, constipation, vomiting causing dehydration, and failure to thrive. Signs of rickets may be present. Caucasian infants typically have blonde hair and blue eyes. At presentation, the glomerular filtration rate (GFR) is normal. In the kidney, cystine accumulation impairs oxidative phosphorylation in proximal tubular cells and decreases the activity of Naþ-Kþ-ATPase, reducing the gradient for sodium entry into the cells and thereby decreasing the sodium-coupled transport of other solutes, manifesting as ‘Fanconi’s syndrome’. Blood and urine tests reveal a Fanconi’s syndrome pattern that includes: hypokalaemia hyponatraemia hypophosphataemia acidosis generalized aminoaciduria glycosuria. In adolescence, the multi-system effects of cystine accumulation, including growth failure, delayed puberty, hypothyroidism, insulin-dependent diabetes and mild hepatomegaly, may be present. In adulthood, additional features may include muscle weakness, increased risk of fracture, oromotor dysfunction and central nervous system (CNS) involvement (cerebellar dysfunction, cerebral atrophy, stroke), with survival expected into the fifth decade.1 The diagnosis is made by assaying white cell cystine concentration (which is typically 10e100 times above the normal range), identifying corneal crystals on slit-lamp examination and genetic analysis of the CTNS gene2 Antenatal diagnosis is possible by examining DNA from amniotic fluid or chorionic villi.
Abstract Inherited metabolic conditions of the kidney are uncommon but require consideration as diagnostic clarity informs specific treatment which improves outcomes considerably and allows children with life limiting disorders to experience greater longevity. This article focuses on four conditions, cystinosis, methylmalonic aciduria (MMA), primary hyperoxaluria and Fabry’s disease. These conditions often present with renal impairment, predominantly in childhood, but with appropriate treatments survival well into adult life is becoming more common. Recognition of the genetic mutations, phenotypic variability and specific treatment options can improve long term prognosis.
Keywords cysteamine; cystinosis; Fabry’s disease; Fanconi’s syndrome; kidney failure; kidney transplantation; methylmalonic aciduria; primary hyperoxaluria
Inheritable metabolic conditions cause considerable morbidity and mortality, but each individual disease is seldom encountered. This article focuses on four conditions: cystinosis, methylmalonic aciduria (MMA), primary hyperoxaluria and Fabry’s disease. These conditions provide a diagnostic challenge to the clinician as the initial symptoms may be non-specific or show great genetic heterogeneity. The development of treatments that can delay multi-system involvement and death, increases pressure for early identification and institution of medical management plans. Extensive communication is required with the families of children with these conditions to ensure they receive genetic counselling and the necessary knowledge to maximize compliance with treatment regimens. All these conditions are chronic and lead ultimately to multi-system involvement, making multidisciplinary and interdisciplinary working essential. Any child with chronic illness must be compliant with treatment, and management strategies should maximize the educational, social and psychological development of these young individuals. Increasing numbers of children with rare inherited metabolic conditions are reaching adulthood and effective smooth transfer to adult care is essential. Transition to adult care is always complex, but these young adults present an additional challenge as their conditions will previously have been seen
Management involves the continuing correction of dehydration and electrolyte losses with high doses of potassium, sodium, bicarbonate, phosphate, large fluid volumes and active vitamin D. Indometacin and an angiotensin converting-enzyme inhibitor may be used with care to reduce losses. To maintain nutritional intake, nasogastric or gastrostomy feeding is often required. Thyroid supplements and growth hormone are considered beneficial. Cysteamine is a treatment but not a cure for cystinosis; it acts by circumventing the defective lysosomal cystine-carrier system,
Joanna Clothier MA MB BChir MRCPCH is a Consultant in Paediatric Nephrology and Bladder Disorders at the Evelina London Children’s Hospital, Guy’s and St Thomas’ NHS Foundation Trust, London, UK. Competing interests: none declared. Sally-Anne Hulton FRCPCH MRCP FRCP is a Consultant Paediatric Nephrologist at the Birmingham Children’s Hospital NHS Foundation Trust, Birmingham, UK. Competing interests: none declared.
MEDICINE --:-
1
Crown Copyright Ó 2015 Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Clothier J, Hulton S-A, Inherited metabolic renal disorders in children, Medicine (2015), http://dx.doi.org/ 10.1016/j.mpmed.2015.04.007
GENETIC DISORDERS
stem cell transplants, which may offer a potential cure for this disease in the future.
Inherited metabolic renal disorders in children Glomerulus
Fabry’s disease Congenital disorders of glycosylation Familial lecithin-cholesterol acyltransferase deficiency Cystinosis FanconieBickel syndrome Purine transport and metabolism disorders Lowe’s syndrome Tyrosinaemia Wilson’s disease Glycogen storage disorder type 1 Nephrogenic diabetes insipidus Pyruvate carboxylase deficiency Methylmalonic acidaemia Carbonic anhydrase deficiency type II LescheNyhan syndrome Mitochondrial cytopathies Primary hyperoxaluria Cystinuria Dent’s disease
Fanconi
Tubular
Any part of kidney Renal calculi
Methylmalonic aciduria (vitamin B12 non-responsive) Methylmalonic aciduria (MMA) is an autosomal recessive defect in organic acid metabolism, leading to the accumulation of methylmalonic acid and its by-products in biological fluids. MMA is a heterogeneous group of disorders (ranging from fatal to asymptomatic) with an incidence of 1:50,000e100,000. It is caused by many different genetic defects including deficiency of the enzyme, methylmalonyl-coA mutase, and disorders of intracellular cobalamin metabolism. The gene for methylmalonyl co-A mutase is located at 6p12eq21.2. MMA usually presents in the first year of life, 80% presenting within the first week after birth with metabolic decompensation following the introduction of protein or illness. The infant presents with recurrent vomiting, lethargy, dehydration leading to profound metabolic acidosis, respiratory distress and failure to thrive, leading acutely to seizures, stroke or encephalopathy and, if left untreated, death. The mortality in the first year of life is 10% with a median survival of 6.4 years. Of those surviving, 40% have impaired development; the younger the child is at presentation, the worse the prognosis. Progressive renal failure, secondary to tubulo-interstitial disease, occurs in 20e60% of adolescents with MMA. The mechanism of the renal impairment is unknown but is thought to be secondary to dysfunction of the respiratory chain and the tricarboxylic acid cycle, secondary to the intramitochondrial accumulation of methylmalonic acid and its metabolites.4 Elevated serum glycine with raised methylmalonic acid, methylcitrate and propionic acid in urine suggests the diagnosis, which is confirmed by enzymology of fibroblasts and DNA analysis. Prenatal testing using enzyme assay on chorionic villus (CVS) and DNA analysis is available.
Table 1
thereby reducing the cystine content of lysosomes. Effectiveness is measured by monitoring white cell cystine. For greatest efficacy, it should be started as early in infancy as possible and administered every 6 hours. Unfortunately, it is unpleasant to take, as the sulphur component causes the breath to smell of rotten eggs and it can cause gastrointestinal upset, which reduces compliance. Cysteamine may delay the onset of renal failure and some of the other systemic effects of cystinosis by several years, but has no effect upon proximal tubular dysfunction.3 A modified-release cysteamine preparation given twice daily has recently been developed and may lead to improved compliance. Cysteamine eye drops are effective in the short-term reduction of corneal cystine accumulation. Before the advent of cysteamine treatment, children typically reached end-stage renal failure (ESRF) by 10 years of age; this is now delayed to late adolescence. Cystinosis accounts for around 5% of chronic renal failure in children. Kidney transplantation is successful in these patients, but cystine continues to accumulate in all tissues of the body and cysteamine treatment is required indefinitely. There is ongoing research into autologous gene-modified haematopoietic
Management aims to control methylmalonate and propionate production by limiting dietary intake of precursors (methionine, threonine, valine, isoleucine, odd chain fatty acids and cholesterol), carnitine supplementation to replete intra- and extracellular stores of free carnitine, and oral antibiotic therapy, which can be useful in decreasing gut production of propionate. During times of increased catabolism, prompt discontinuation of proteincontaining feeds and generous administration of glucosecontaining fluid to avoid decompensation leads to greater survival. Liver or combined liver/kidney transplantation are options for metabolic control. The benefit of any transplant is limited because of the ongoing systemic metabolic defect and transplantation does not normalize the concentration of methylmalonic acid in the cerebrospinal fluid and brain.5 With early diagnosis and careful medical management, these children now survive and the longer-term complications of the condition need to be considered. These include neurological impairment (secondary to deposition in the basal ganglia), mental retardation and cardiomyopathy.
Overview of inheritance, incidence and age at presentation Condition
Inheritance
Incidence
Presentation
Cystinosis Methylmalonic aciduria Primary hyperoxaluria Fabry’s disease
AR AR
1:150,000 1:50,000e100,000
Infancy Infancy
AR
1:60,000e120,000
Any age
X-L
1:40,000e117,000
Childhood
Primary hyperoxaluria Oxalate has no known useful function in man. It is derived principally from the diet and produced endogenously by the
Table 2
MEDICINE --:-
2
Crown Copyright Ó 2015 Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Clothier J, Hulton S-A, Inherited metabolic renal disorders in children, Medicine (2015), http://dx.doi.org/ 10.1016/j.mpmed.2015.04.007
GENETIC DISORDERS
metabolism of glyoxylate and ascorbic acid, and is excreted by the kidney. Hyperoxaluria can occur because of hyperabsorption of ingested oxalate or by derangement of normal metabolic pathways. The primary hyperoxalurias (PH) are inborn errors of metabolism of which three have been described at the molecular level. Primary hyperoxaluria type 1 (PH1) is caused by mutations in the AGXT gene that result in dysfunction of the vitamin B6 (pyridoxine)-dependent liver-specific peroxisomal enzyme, alanine:glyoxylate aminotransferase (AGT). Over 100 mutations have been found in the AGXT gene, located on chromosome 2q 37.3. Deficiency in AGT leads to the overproduction of oxalate and glycolate. PH2 arises from mutations in the GRHPR gene with subsequent dysfunction of the enzyme, glyoxalate/hydroxypyruvate reductase (GRHPR). PH3 arises from mutations in the HOGA1 gene, which is believed to encode the mitochondrial enzyme, 4-hydroxy-2-oxoglutarate aldolase. The investigation of any child or adult presenting with renal stones, or nephrocalcinosis must exclude PH as an underlying cause. In all such presentations a fresh urine sample must be sent for urine oxalate/creatinine ratio in the first instance, and if the measurement is borderline or elevated a 24-hour urine collection for oxalate excretion is required. All patients presenting with renal stones must also have the urine analysed for L-glyceric acid (part of a routine organic acid screen) as diagnostic of PH2. As the gene for PH3 has been identified only recently, the patient phenotypic characteristics are still being described. The main identifying feature appears to be hypercalciuria with calcium oxalate stones in early childhood. A definitive diagnosis of PH1 is made by genetic analysis or, more rarely nowadays, with liver biopsy using an immunoreactive AGT protein assay. Antenatal diagnosis is possible using DNA analysis of chorionic villi, particularly when DNA can be obtained from an affected family member or parent.6 PH1 shows phenotypic heterogeneity, presenting clinically as: infantile form, with faltering growth, anaemia, acidosis, early nephrocalcinosis and rapid progression to end-stage renal failure (ESRF) juvenile form in young children with haematuria, urinary tract infection, abdominal pain secondary to recurrent urolithiasis or nephrocalcinosis, and progressive renal failure adult or mild form, with the occasional passage of renal stones but no renal dysfunction. Investigation for nephrocalcinosis or calculi should include measurements of urinary and plasma oxalate.
favourable outcome. In those unresponsive to pyridoxine, or with early nephrocalcinosis, the condition has a progressive course; recurrent urinary calculi lead to renal damage, associated with infection and obstruction, and subsequent renal failure in the second decade of life. When the GFR drops below 40 ml/minute/1.73 m2, there is decreased excretion of oxalate and a dramatic increase in plasma oxalate, leading to systemic deposition of calcium oxalate in the heart (cardiomyopathy and conduction defects), vessel walls, skin (ulcerating lesions), nerves (peripheral neuropathy, mononeuritis multiplex), retina and joints (synovitis). Early renal replacement therapy is indicated to reduce systemic calcification but fails to clear oxalate adequately, and pre-emptive combined liver and kidney transplantation is required in PH1 to replace the enzyme deficit and support renal function. Isolated liver transplantation is advised in PH1 before systemic oxalosis develops.7 New RNAi technology will allow for targeted treatment for PH1 patients through specific liver enzyme blockade.
Fabry’s disease (also called AndersoneFabry disease) Fabry’s disease is an X-linked inborn error of glycosphingolipid metabolism, in which glycosphingolipid accumulates progressively in the vascular endothelium and viscera, as a result of a deficiency in the lysosomal enzyme, alpha-galactosidase A (alpha-Gal A). The worldwide incidence is 1:40,000e117,000.8 Symptoms typically appear in childhood in males and some female carriers, and progress in a predictable manner to multisystem involvement in adulthood. In the typical form of the disease (seen in males), first presentation occurs in childhood, initially with acroparesthesia (bouts of intense pain/tingling typically in the hands and feet), with a combination of angiokeratoma, ocular deposits (spiral streaks in corneal epithelium), hypohydrosis, intolerance of hot and cold, unexplained fevers and postprandial pain. Females usually have milder, later onset symptoms and present partly as a result of skewed inactivation of the X chromosome. Renal involvement is a predominant feature of the later stage of the disease, presenting in the second decade with proteinuria and progressing to end-stage disease in the fourth decade. Dysfunction is also seen in the central nervous and cardiovascular systems, which in the past led to death in the fourth or fifth decade. The diagnosis is often delayed or goes unrecognized owing to variable presentation and the low incidence of the condition. It is confirmed by demonstrating reduced activity levels of alpha-Gal A in peripheral leucocytes or plasma, followed by gene sequencing. Prenatal diagnosis is achieved by measuring enzyme activity in chorionic villus samples or amniotic fluid. DNA analysis is possible if the mutation within the pedigree is known.
Management involves aggressive early treatment to prevent systemic oxalate deposition in all types of PH as all groups are prone to renal failure. High fluid intake is required to maintain oxalate excretion below 0.4 mmol/litre, with oral citrate to decrease calcium oxalate deposition. Dietary restriction of oxalate has had little impact on prognosis, but ascorbic acid should be avoided Treatment with Oxalobacter formigenes to reduce gut oxalate absorption may be of benefit in some cases. A response to a 3e6-month trial of high-dose pyridoxine treatment is seen in 10e40% cases, although this may not be sustained. Certain mutations have been shown to be pyridoxine responsive (Gly170Arg and Phe152Ile) and have a more
MEDICINE --:-
Management is symptomatic, together with recombinant enzyme replacement therapy (ERT). Agalsidase alfa or agalsidase beta is given intravenously every 2 weeks, to reduce the accumulation of glycosphingolipid and thereby reduce symptoms. Chaperone molecules may have a future role in prolonging the life of the ERT. Renal failure can be treated successfully with dialysis and transplantation; recurrence of the disease in the kidney is
3
Crown Copyright Ó 2015 Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Clothier J, Hulton S-A, Inherited metabolic renal disorders in children, Medicine (2015), http://dx.doi.org/ 10.1016/j.mpmed.2015.04.007
GENETIC DISORDERS
4 Morath MA, Horster F, Sauer SW. Renal dysfunction in methylmalonic acidurias: review for the pediatric nephrologist. Pediatr Nephrol 2013; 28: 227e35. 5 Nylan WL, Gargus JJ, Boyle K, Selby R, Koch R. Progressive neurologic disability in methylmalonic acidaemia despite transplantation of the liver. Eur J Pediatr 2002; 161: 377e9. 6 Cochat P, Hulton S, Acquaviva C, et al. on behalf of OxalEurope. Primary hyperoxaluria Type 1: indications for screening and guidance for diagnosis and treatment. Nephrol Dial Transpl 2012; 27: 1729e36. 7 Hoppe B, Beck BB, Milliner DS. The primary hyperoxalurias. Kidney Int 2009; 75: 1264e71. 8 Zarate YA, Hopkin RJ. Fabry’s disease. Lancet 2008; 372: 1427e35.
uncommon, but ERT needs to be continued to control systemic accumulation. Early recognition and treatment in childhood with ERT may have a role in preventing the later phase of multi-system disease. A REFERENCES 1 Nesterova G, Gahl W. Nephropathic cystinosis: late complications of a multisystemic disease. Pediatr Nephrol 2008; 23: 863e78. 2 Emma F, Nesterova G, Langman C, et al. Nephropathic cystinosis: an international consensus document. Nephrol Dial Transpl 2014; 29: 87e94. 3 Brodin-Satorius A, Tete MJ, Niaudet P, et al. Cysteamine therapy delays the progression of nephropathic cystinosis in late adolescents and adults. Kidney Int 2012; 81: 179e89.
MEDICINE --:-
FURTHER READING Avner ED, Harmon WE, Niaudet P, Yoshikawa N. Pediatric nephrology. Springer, 2009.
4
Crown Copyright Ó 2015 Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Clothier J, Hulton S-A, Inherited metabolic renal disorders in children, Medicine (2015), http://dx.doi.org/ 10.1016/j.mpmed.2015.04.007
Inherited metabolic renal disorders in children
rarely in adult practice and will require ongoing multidisciplinary management. A summary of inherited metabolic conditions affecting the kidney is provided in Table 1. This article focuses on conditions that present with renal impairment, predominantly in childhood (Table 2).
Joanna Clothier Sally-Anne Hulton
Cystinosis Cystinosis is an autosomal recessive multi-system disease, in which cystine crystals accumulate in the tissues of the body as a result of a defective cystine transporter in the lysosomal membrane. The kidney and cornea are very sensitive to this accumulation. The condition affects 1:150,000 births with both sexes affected equally. Over 100 mutations have been described in the cystinosis gene, CTNS, located on chromosome 17p13; the gene encodes a protein ‘cystinosin’. At birth, the infant appears normal and develops appropriately until 3e6 months of age, before presenting with polyuria and polydipsia, unexplained fever, anorexia, constipation, vomiting causing dehydration, and failure to thrive. Signs of rickets may be present. Caucasian infants typically have blonde hair and blue eyes. At presentation, the glomerular filtration rate (GFR) is normal. In the kidney, cystine accumulation impairs oxidative phosphorylation in proximal tubular cells and decreases the activity of Naþ-Kþ-ATPase, reducing the gradient for sodium entry into the cells and thereby decreasing the sodium-coupled transport of other solutes, manifesting as ‘Fanconi’s syndrome’. Blood and urine tests reveal a Fanconi’s syndrome pattern that includes: hypokalaemia hyponatraemia hypophosphataemia acidosis generalized aminoaciduria glycosuria. In adolescence, the multi-system effects of cystine accumulation, including growth failure, delayed puberty, hypothyroidism, insulin-dependent diabetes and mild hepatomegaly, may be present. In adulthood, additional features may include muscle weakness, increased risk of fracture, oromotor dysfunction and central nervous system (CNS) involvement (cerebellar dysfunction, cerebral atrophy, stroke), with survival expected into the fifth decade.1 The diagnosis is made by assaying white cell cystine concentration (which is typically 10e100 times above the normal range), identifying corneal crystals on slit-lamp examination and genetic analysis of the CTNS gene2 Antenatal diagnosis is possible by examining DNA from amniotic fluid or chorionic villi.
Abstract Inherited metabolic conditions of the kidney are uncommon but require consideration as diagnostic clarity informs specific treatment which improves outcomes considerably and allows children with life limiting disorders to experience greater longevity. This article focuses on four conditions, cystinosis, methylmalonic aciduria (MMA), primary hyperoxaluria and Fabry’s disease. These conditions often present with renal impairment, predominantly in childhood, but with appropriate treatments survival well into adult life is becoming more common. Recognition of the genetic mutations, phenotypic variability and specific treatment options can improve long term prognosis.
Keywords cysteamine; cystinosis; Fabry’s disease; Fanconi’s syndrome; kidney failure; kidney transplantation; methylmalonic aciduria; primary hyperoxaluria
Inheritable metabolic conditions cause considerable morbidity and mortality, but each individual disease is seldom encountered. This article focuses on four conditions: cystinosis, methylmalonic aciduria (MMA), primary hyperoxaluria and Fabry’s disease. These conditions provide a diagnostic challenge to the clinician as the initial symptoms may be non-specific or show great genetic heterogeneity. The development of treatments that can delay multi-system involvement and death, increases pressure for early identification and institution of medical management plans. Extensive communication is required with the families of children with these conditions to ensure they receive genetic counselling and the necessary knowledge to maximize compliance with treatment regimens. All these conditions are chronic and lead ultimately to multi-system involvement, making multidisciplinary and interdisciplinary working essential. Any child with chronic illness must be compliant with treatment, and management strategies should maximize the educational, social and psychological development of these young individuals. Increasing numbers of children with rare inherited metabolic conditions are reaching adulthood and effective smooth transfer to adult care is essential. Transition to adult care is always complex, but these young adults present an additional challenge as their conditions will previously have been seen
Management involves the continuing correction of dehydration and electrolyte losses with high doses of potassium, sodium, bicarbonate, phosphate, large fluid volumes and active vitamin D. Indometacin and an angiotensin converting-enzyme inhibitor may be used with care to reduce losses. To maintain nutritional intake, nasogastric or gastrostomy feeding is often required. Thyroid supplements and growth hormone are considered beneficial. Cysteamine is a treatment but not a cure for cystinosis; it acts by circumventing the defective lysosomal cystine-carrier system,
Joanna Clothier MA MB BChir MRCPCH is a Consultant in Paediatric Nephrology and Bladder Disorders at the Evelina London Children’s Hospital, Guy’s and St Thomas’ NHS Foundation Trust, London, UK. Competing interests: none declared. Sally-Anne Hulton FRCPCH MRCP FRCP is a Consultant Paediatric Nephrologist at the Birmingham Children’s Hospital NHS Foundation Trust, Birmingham, UK. Competing interests: none declared.
MEDICINE --:-
1
Crown Copyright Ó 2015 Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Clothier J, Hulton S-A, Inherited metabolic renal disorders in children, Medicine (2015), http://dx.doi.org/ 10.1016/j.mpmed.2015.04.007
GENETIC DISORDERS
stem cell transplants, which may offer a potential cure for this disease in the future.
Inherited metabolic renal disorders in children Glomerulus
Fabry’s disease Congenital disorders of glycosylation Familial lecithin-cholesterol acyltransferase deficiency Cystinosis FanconieBickel syndrome Purine transport and metabolism disorders Lowe’s syndrome Tyrosinaemia Wilson’s disease Glycogen storage disorder type 1 Nephrogenic diabetes insipidus Pyruvate carboxylase deficiency Methylmalonic acidaemia Carbonic anhydrase deficiency type II LescheNyhan syndrome Mitochondrial cytopathies Primary hyperoxaluria Cystinuria Dent’s disease
Fanconi
Tubular
Any part of kidney Renal calculi
Methylmalonic aciduria (vitamin B12 non-responsive) Methylmalonic aciduria (MMA) is an autosomal recessive defect in organic acid metabolism, leading to the accumulation of methylmalonic acid and its by-products in biological fluids. MMA is a heterogeneous group of disorders (ranging from fatal to asymptomatic) with an incidence of 1:50,000e100,000. It is caused by many different genetic defects including deficiency of the enzyme, methylmalonyl-coA mutase, and disorders of intracellular cobalamin metabolism. The gene for methylmalonyl co-A mutase is located at 6p12eq21.2. MMA usually presents in the first year of life, 80% presenting within the first week after birth with metabolic decompensation following the introduction of protein or illness. The infant presents with recurrent vomiting, lethargy, dehydration leading to profound metabolic acidosis, respiratory distress and failure to thrive, leading acutely to seizures, stroke or encephalopathy and, if left untreated, death. The mortality in the first year of life is 10% with a median survival of 6.4 years. Of those surviving, 40% have impaired development; the younger the child is at presentation, the worse the prognosis. Progressive renal failure, secondary to tubulo-interstitial disease, occurs in 20e60% of adolescents with MMA. The mechanism of the renal impairment is unknown but is thought to be secondary to dysfunction of the respiratory chain and the tricarboxylic acid cycle, secondary to the intramitochondrial accumulation of methylmalonic acid and its metabolites.4 Elevated serum glycine with raised methylmalonic acid, methylcitrate and propionic acid in urine suggests the diagnosis, which is confirmed by enzymology of fibroblasts and DNA analysis. Prenatal testing using enzyme assay on chorionic villus (CVS) and DNA analysis is available.
Table 1
thereby reducing the cystine content of lysosomes. Effectiveness is measured by monitoring white cell cystine. For greatest efficacy, it should be started as early in infancy as possible and administered every 6 hours. Unfortunately, it is unpleasant to take, as the sulphur component causes the breath to smell of rotten eggs and it can cause gastrointestinal upset, which reduces compliance. Cysteamine may delay the onset of renal failure and some of the other systemic effects of cystinosis by several years, but has no effect upon proximal tubular dysfunction.3 A modified-release cysteamine preparation given twice daily has recently been developed and may lead to improved compliance. Cysteamine eye drops are effective in the short-term reduction of corneal cystine accumulation. Before the advent of cysteamine treatment, children typically reached end-stage renal failure (ESRF) by 10 years of age; this is now delayed to late adolescence. Cystinosis accounts for around 5% of chronic renal failure in children. Kidney transplantation is successful in these patients, but cystine continues to accumulate in all tissues of the body and cysteamine treatment is required indefinitely. There is ongoing research into autologous gene-modified haematopoietic
Management aims to control methylmalonate and propionate production by limiting dietary intake of precursors (methionine, threonine, valine, isoleucine, odd chain fatty acids and cholesterol), carnitine supplementation to replete intra- and extracellular stores of free carnitine, and oral antibiotic therapy, which can be useful in decreasing gut production of propionate. During times of increased catabolism, prompt discontinuation of proteincontaining feeds and generous administration of glucosecontaining fluid to avoid decompensation leads to greater survival. Liver or combined liver/kidney transplantation are options for metabolic control. The benefit of any transplant is limited because of the ongoing systemic metabolic defect and transplantation does not normalize the concentration of methylmalonic acid in the cerebrospinal fluid and brain.5 With early diagnosis and careful medical management, these children now survive and the longer-term complications of the condition need to be considered. These include neurological impairment (secondary to deposition in the basal ganglia), mental retardation and cardiomyopathy.
Overview of inheritance, incidence and age at presentation Condition
Inheritance
Incidence
Presentation
Cystinosis Methylmalonic aciduria Primary hyperoxaluria Fabry’s disease
AR AR
1:150,000 1:50,000e100,000
Infancy Infancy
AR
1:60,000e120,000
Any age
X-L
1:40,000e117,000
Childhood
Primary hyperoxaluria Oxalate has no known useful function in man. It is derived principally from the diet and produced endogenously by the
Table 2
MEDICINE --:-
2
Crown Copyright Ó 2015 Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Clothier J, Hulton S-A, Inherited metabolic renal disorders in children, Medicine (2015), http://dx.doi.org/ 10.1016/j.mpmed.2015.04.007
GENETIC DISORDERS
metabolism of glyoxylate and ascorbic acid, and is excreted by the kidney. Hyperoxaluria can occur because of hyperabsorption of ingested oxalate or by derangement of normal metabolic pathways. The primary hyperoxalurias (PH) are inborn errors of metabolism of which three have been described at the molecular level. Primary hyperoxaluria type 1 (PH1) is caused by mutations in the AGXT gene that result in dysfunction of the vitamin B6 (pyridoxine)-dependent liver-specific peroxisomal enzyme, alanine:glyoxylate aminotransferase (AGT). Over 100 mutations have been found in the AGXT gene, located on chromosome 2q 37.3. Deficiency in AGT leads to the overproduction of oxalate and glycolate. PH2 arises from mutations in the GRHPR gene with subsequent dysfunction of the enzyme, glyoxalate/hydroxypyruvate reductase (GRHPR). PH3 arises from mutations in the HOGA1 gene, which is believed to encode the mitochondrial enzyme, 4-hydroxy-2-oxoglutarate aldolase. The investigation of any child or adult presenting with renal stones, or nephrocalcinosis must exclude PH as an underlying cause. In all such presentations a fresh urine sample must be sent for urine oxalate/creatinine ratio in the first instance, and if the measurement is borderline or elevated a 24-hour urine collection for oxalate excretion is required. All patients presenting with renal stones must also have the urine analysed for L-glyceric acid (part of a routine organic acid screen) as diagnostic of PH2. As the gene for PH3 has been identified only recently, the patient phenotypic characteristics are still being described. The main identifying feature appears to be hypercalciuria with calcium oxalate stones in early childhood. A definitive diagnosis of PH1 is made by genetic analysis or, more rarely nowadays, with liver biopsy using an immunoreactive AGT protein assay. Antenatal diagnosis is possible using DNA analysis of chorionic villi, particularly when DNA can be obtained from an affected family member or parent.6 PH1 shows phenotypic heterogeneity, presenting clinically as: infantile form, with faltering growth, anaemia, acidosis, early nephrocalcinosis and rapid progression to end-stage renal failure (ESRF) juvenile form in young children with haematuria, urinary tract infection, abdominal pain secondary to recurrent urolithiasis or nephrocalcinosis, and progressive renal failure adult or mild form, with the occasional passage of renal stones but no renal dysfunction. Investigation for nephrocalcinosis or calculi should include measurements of urinary and plasma oxalate.
favourable outcome. In those unresponsive to pyridoxine, or with early nephrocalcinosis, the condition has a progressive course; recurrent urinary calculi lead to renal damage, associated with infection and obstruction, and subsequent renal failure in the second decade of life. When the GFR drops below 40 ml/minute/1.73 m2, there is decreased excretion of oxalate and a dramatic increase in plasma oxalate, leading to systemic deposition of calcium oxalate in the heart (cardiomyopathy and conduction defects), vessel walls, skin (ulcerating lesions), nerves (peripheral neuropathy, mononeuritis multiplex), retina and joints (synovitis). Early renal replacement therapy is indicated to reduce systemic calcification but fails to clear oxalate adequately, and pre-emptive combined liver and kidney transplantation is required in PH1 to replace the enzyme deficit and support renal function. Isolated liver transplantation is advised in PH1 before systemic oxalosis develops.7 New RNAi technology will allow for targeted treatment for PH1 patients through specific liver enzyme blockade.
Fabry’s disease (also called AndersoneFabry disease) Fabry’s disease is an X-linked inborn error of glycosphingolipid metabolism, in which glycosphingolipid accumulates progressively in the vascular endothelium and viscera, as a result of a deficiency in the lysosomal enzyme, alpha-galactosidase A (alpha-Gal A). The worldwide incidence is 1:40,000e117,000.8 Symptoms typically appear in childhood in males and some female carriers, and progress in a predictable manner to multisystem involvement in adulthood. In the typical form of the disease (seen in males), first presentation occurs in childhood, initially with acroparesthesia (bouts of intense pain/tingling typically in the hands and feet), with a combination of angiokeratoma, ocular deposits (spiral streaks in corneal epithelium), hypohydrosis, intolerance of hot and cold, unexplained fevers and postprandial pain. Females usually have milder, later onset symptoms and present partly as a result of skewed inactivation of the X chromosome. Renal involvement is a predominant feature of the later stage of the disease, presenting in the second decade with proteinuria and progressing to end-stage disease in the fourth decade. Dysfunction is also seen in the central nervous and cardiovascular systems, which in the past led to death in the fourth or fifth decade. The diagnosis is often delayed or goes unrecognized owing to variable presentation and the low incidence of the condition. It is confirmed by demonstrating reduced activity levels of alpha-Gal A in peripheral leucocytes or plasma, followed by gene sequencing. Prenatal diagnosis is achieved by measuring enzyme activity in chorionic villus samples or amniotic fluid. DNA analysis is possible if the mutation within the pedigree is known.
Management involves aggressive early treatment to prevent systemic oxalate deposition in all types of PH as all groups are prone to renal failure. High fluid intake is required to maintain oxalate excretion below 0.4 mmol/litre, with oral citrate to decrease calcium oxalate deposition. Dietary restriction of oxalate has had little impact on prognosis, but ascorbic acid should be avoided Treatment with Oxalobacter formigenes to reduce gut oxalate absorption may be of benefit in some cases. A response to a 3e6-month trial of high-dose pyridoxine treatment is seen in 10e40% cases, although this may not be sustained. Certain mutations have been shown to be pyridoxine responsive (Gly170Arg and Phe152Ile) and have a more
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Management is symptomatic, together with recombinant enzyme replacement therapy (ERT). Agalsidase alfa or agalsidase beta is given intravenously every 2 weeks, to reduce the accumulation of glycosphingolipid and thereby reduce symptoms. Chaperone molecules may have a future role in prolonging the life of the ERT. Renal failure can be treated successfully with dialysis and transplantation; recurrence of the disease in the kidney is
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Please cite this article in press as: Clothier J, Hulton S-A, Inherited metabolic renal disorders in children, Medicine (2015), http://dx.doi.org/ 10.1016/j.mpmed.2015.04.007
GENETIC DISORDERS
4 Morath MA, Horster F, Sauer SW. Renal dysfunction in methylmalonic acidurias: review for the pediatric nephrologist. Pediatr Nephrol 2013; 28: 227e35. 5 Nylan WL, Gargus JJ, Boyle K, Selby R, Koch R. Progressive neurologic disability in methylmalonic acidaemia despite transplantation of the liver. Eur J Pediatr 2002; 161: 377e9. 6 Cochat P, Hulton S, Acquaviva C, et al. on behalf of OxalEurope. Primary hyperoxaluria Type 1: indications for screening and guidance for diagnosis and treatment. Nephrol Dial Transpl 2012; 27: 1729e36. 7 Hoppe B, Beck BB, Milliner DS. The primary hyperoxalurias. Kidney Int 2009; 75: 1264e71. 8 Zarate YA, Hopkin RJ. Fabry’s disease. Lancet 2008; 372: 1427e35.
uncommon, but ERT needs to be continued to control systemic accumulation. Early recognition and treatment in childhood with ERT may have a role in preventing the later phase of multi-system disease. A REFERENCES 1 Nesterova G, Gahl W. Nephropathic cystinosis: late complications of a multisystemic disease. Pediatr Nephrol 2008; 23: 863e78. 2 Emma F, Nesterova G, Langman C, et al. Nephropathic cystinosis: an international consensus document. Nephrol Dial Transpl 2014; 29: 87e94. 3 Brodin-Satorius A, Tete MJ, Niaudet P, et al. Cysteamine therapy delays the progression of nephropathic cystinosis in late adolescents and adults. Kidney Int 2012; 81: 179e89.
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FURTHER READING Avner ED, Harmon WE, Niaudet P, Yoshikawa N. Pediatric nephrology. Springer, 2009.
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Crown Copyright Ó 2015 Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Clothier J, Hulton S-A, Inherited metabolic renal disorders in children, Medicine (2015), http://dx.doi.org/ 10.1016/j.mpmed.2015.04.007