Hyperlipidemia Hyperlipidemia should initially be treated with dietary modi \201 cation wh ere possible. There is no long-term effective therapy although \201 brates and niacin may be useful. Statins are contraindicated as they exacerbate triglyceride levels. Renal involvement in GSD1 De \201 ciency of glucose 6-phosphatase in proximal and distal c onvoluted tubules results in glycogen accumulation and progressive renal enlargement. Clini cally this may be obscured by gross hepatosplenom- egaly. Tubular cell vacuolation leads to tubular dysfunction mani- fest by a Fanconi syndrome characterized by: \200 \200 \200 Hepatic adenomas These require ongoing surveillance. If they are complicated by pain, hemor rhage or necrosis they may need to be removed. Renal involvement There is no evidence for any speci \201 c intervention to retard progres sion of renal disease although the use of ACEIs and/ or ARBs appears to be an attractive op tion in view of the associated hyper \201 ltration and proteinuria early in the disease. aminoaciduria; glycosuria; phosphaturia. Tubular damage leading to declining renal function is not usually a major problem. CHAPTER 15.12 Other metabolic storage disorders with renal involvement 625 With time, bloodborne energy substrates such as glucose and free fatty acids enter skeletal muscle and are utilized. This may account for the \200\230second wind \200\231 phenomenon experienced by most individuals. Follow-up The importance of monitoring, detecting, and correcting hypoglycemia in order to minimize the risk of long-term brain injury from hypoglycemic episodes should be reiter- at ed at each visit. Patients with multiple hepatic adenomas should be entered into a surveill ance program. Clinical features Typical features include: \200 \200 \200 \200 exercise intolerance with myalgia; early tiredness; muscle stiffness; cramps. Prognosis In the past, many patients with GSD1 did not survive beyond infancy and childhood . Prompt recognition of this condition in the perinatal period allows effective therapy to be instituted early to improve the metabolic abnormalities and reverse the severe growth fa ilure characteristic of untreated patients. It is still unclear whether long-term complicat ions can be prevented by dietary therapy alone. With earlier diagnosis, appropriate diet, a nd better meta- bolic control, many individuals with GSD1 survive into adulthood. All of which resolve on rest. Following a short period of rest, most patients experience a \200\230second wind \200\231 phenomenon which allows for a return to activity without much dif \201 culty. Exercise may be associated with myoglobinuria in 1/3 of patients. This m ay be associated with development of AKI. Patients are of normal height and do not suffer e pisodes of hypoglycemia. Glycogen storage disease type V (McArdle disease) (Myophosphorylase de \201 ciency) Diagnosis Elevated serum creatinine kinase levels at rest are common. Lactic acid productio n after exercise is absent. 50% of patients may have nonspeci \201 c myopathic changes on EMG. Muscle biopsy shows accumulation of glycogen between myo \201 brils giving the \201 bers a vacuolar appearance. The gly- cogen is periodic acid \200\223Schiff (PAS) positive. Electron microscopy demonstrates extensive accumulation of nor- mal-appearing glycogen und er the sarcolemma and between the myo \201 laments. In 1951 McArdle \201 rst described the clinical manifestations of GSD5 in a 30-year-old m an who experienced pain, weak- ness and stiffness after exercise. Later work identi \201 e d the cause of GSD5 to be de \201 ciency of the enzyme myophos- phorylase. More than half of patients with GSD5 experi- ence acute muscle necrosis and myoglobinuria following vigoro us exercise, which can in some individuals result in AKI. Epidemiology Estimated incidence is 1 per 100 000 population, but it may be more common. Th e disorder is probably underdiagnosed because the symptoms are mild in many patients. Treatment There is no speci \201 c treatment. Branched-chain amino acids represent an alte rnative fuel source for exercising muscle. A high protein diet may therefore be useful. Str enuous and isometric exercise, which is most likely to cause symptoms and induce rhabdomyol ysis, should be avoided. Genetics There are two autosomal recessive forms of GSD5, a child- hood-onset form and an a dult-onset form. There is also a rarer autosomal dominant form. The gene for myophosphoryla se has been mapped to chromosome 11q13. Follow-up In light of the genetic basis of GSD5 it is important to offer genetic counseling for future pregnancies. Pathology Myophosphorylase (A-1,4-glucan orthophosphate glycosyl transferase) normally init iates glycogen breakdown in skeletal muscle by removing 1,4-glucosyl groups from glycogen a nd releasing glucose-1-phosphate as an energy source. Most sufferers have undetectable myop hosphorylase activ- ity and are therefore unable to release glucose from the glycogen store d in muscle. Affected individuals have dif \201 culty performing exercise, particularly an erobic exercise, as they are unable to metab- olize muscle glycogen, the main energy source in anerobic exercise. The lack of access to glycogen stores results in muscle breakdown in an attempt to release useable energy stores. Prognosis It has a relatively benign course if not complicated by severe rhabdomyolysis and AKI. Some patients have developed severe myopathies in later life. The development of CKD and ESRD has not been described. Further reading Baker L, Dahlem S, Goldfarb S, et al. Hyper \201 ltration and renal diseas e in glycogen storage disease, type I. Kidney Int 1989; 35: 1345 \200\2231350. Chen YT, Coleman RA, Scheinman JI, et al. Renal disease in type I glycogen storage disease. N Engl J Med 1988; 318: 7 \200\22311. R.S. PATEL 626 Internet resources The Children \200\231s Fund for Glycogen Storage Disease Research: See also CKD in children, p. 462 Fabry disease, p. 620 Investigation of inherited renal dis ease, p. 582 Fanconi syndrome, p. 204 Pigment-induced acute kidney injury, p. 362 http://www.curegsd.org/ Association for Glycogen Storage Diseases UK: http://www.agsdus.org.uk Association for Glycogen Storage Diseases US: http://www.agsdus.org This page intentionally left blank W. VAN T HOFF 628 Cystinosis Introduction Cystinosis is an inherited disorder of systemic cystine accu- mulation resulti ng from defective lysosomal transportation of the amino acid cystine. Lysosomes are intrace llular organelles that accumulate breakdown products from the intracellular degradation of macromolecules. Lysosome cell membranes contain a variety of distinct transporters one of w hich is cystinosin. Cystinosin acts as the lysosomal cystine/H+ symporter, mediating satura ble cystine trans- port out of the lysosome, and defects in this transporter result in lyso somal accumulation of cystine and cystinosis. Cystinosis is a multisystem disorder with wid espread cys- tine accumulation. It is not known why the kidneys and eyes are particularly s ensitive, although there is a very high lysosomal density in the cornea and proximal renal tubule. Cystinosis typically presents with features of the renal Fanconi syndrome of genera lized proximal tubular dys- function. Most cases (95% in UK Cystinosis Registry) present in early childhood but a very few patients present in adolescence or adult life. Such \200 \230late-onset \200\231 cases present with manifestations of CKD usually without features o f Fanconi syndrome. Some individuals with milder mutations can develop corneal cystine accu mulation but no renal manifestations. Rarely patients present later (adolescence/early adult- hood) with proteinuria, CKD. Long-term manifestations Whilst kidney dysfunction (initially tubular and later glomerular) predominates in the \201 rst decade, systemic cys- tine accumulation causes multiple org an dysfunction. However, many of these chronic complications have been observed in patients who have not had long-term or ade- quate cysteamine therapy. The frequency of complication s, from a variety of published sources, has been de \201 ned below as very common if >50% affected, common if 25 \200\22350%, rare if <25%, very rare if <10%. These frequencies are certainly affected by the extent and adequacy of cysteamine therapy. Endocrine Poor growth (very common): multifactorial, growth hor- mone secretion usually nor mal. Hypothyroidism (very common). Hypergonadotrophic hypogonadism (very common) with delay ed puberty (affects males more severely than females and several pregnancies have been repo rted). Impaired glucose tolerance (very common); diabetes mel- litus (common). Epidemiology This is a very rare disorder; about \201 ve children are diag- nosed each ye ar (UK Cystinosis Registry) and there are 180 patients in the UK. Cystinosis occurs in all ethnic groups and has a higher preva- lence in communities with a higher rate of consangui nity. Neurological Swallowing problems (very common, even from young age). Distal vacuolar myopat hy (common, affects hands). Respiratory insufficiency (late complication, severity related to myopathy). Subtle psychometric defects (visuospatial and visuomotor problems), e.g. dif \201 culty with writing, mathematics; although normal intelligence and speech (very common , apparent in childhood). Memory loss, seizures (rare). Stroke-like episodes (very rare). C erebral degeneration (very rare). Genetics Cystinosis is inherited as an autosomal recessive trait. Mutations in CTNS (the ge ne encoding the protein cysti- nosin, chromosome 17p13) either cause no production of cysti nosin or defective action leading to lysosomal cystine accumulation. The commonest mutation in cystinosis is a 57 kb deletion, found in 76% of patients of Northern European origin. T his deletion can be readily detected in a PCR-based rapid diagnostic test for the disorder. Other mutations, mainly causing premature termination of cystinosin, are found in the seve re, infantile-onset form of cystinosis. Ophthalmological Progressive corneal crystal deposition and clouding (very common). Retinop athy and visual impairment (rare). Narrow angle glaucoma (rare). Clinical features These often appear towards \201 rst birthday. Others Pancreatic exocrine insuf \201 ciency (extremely rare). Pancytopenia (rare but some times resistance to erythro- poetin treatment). Portal hypertension associated with nodular regenerating hyperplasia (rare). Vascular calci \201 cation with relatively low calcium-p hosphate product (compared with other ESRD patients) (common). Nonspeci \201 c symptoms \200 \200 \200 \200 \200 \200 poor feeding; vomiting; poor weight gain or weight loss; dehydration; gross salt and water craving; slow gross motor development (walking). Signs \200 \200 \200 Investigations Diagnostic con \201 rmation Leukocyte cystine concentration This test requi res specialist laboratory expertise. Usually patients have >2 nmol cystine per mg protein ( normal <0.2). poor growth; rickets (e.g. rickettic rosary); can occur in any ethnic group but often Cauca sians, blond with fair complexion; corneal crystals on slit-lamp examination (specialized t echnique). CHAPTER 15.13 Cystinosis 629 Psychosocial and other specialized support Involvement of the multidisciplinary team is ess ential for both the long-term care of patients with cystinosis (e.g. feeding programs) and their relatives. Demonstration of cystine crystals These are usually found in the cornea by slit-lamp examin a- tion but may be hard to see especially in very young, or in a biopsy material (not usual ly necessary). Speci \201 c cystine-depleting therapy with cysteamine (mercaptamine) This reacts with int ralysosomal cystine to form mixed- disul \201 de cysteamine \200\223cysteine which can the n leave the lysosome using the lysine transporter. Molecular diagnosis of CTNS deletion Use of rapid PCR assay for common deletion. Other muta tions more dif \201 cult to diagnose. Serum biochemistry \200 \200 \200 Hyperchloremic metabolic acidosis. Hypokalemia. Hypophosphatemia. For children or patients aged <12 years or 50 kg, the recommended maintenance dose is 1.3 g /m2/day divided into four doses, as equally spaced as possible but starting at low dose and building up gradually over 4 \200\2236 weeks (see \200\230Adverse effects \200\231 below) . Doses >1.9 gm/m2/day are not recommended. For patients aged >12 years or >50 kg, the maxi mal dose is 500 g four times a day. Very rarely with profound dehydration features of second- ary hyperaldosteronism predominat e with hypokalemic alkalosis ( \200\230pseudo-Bartter syndrome \200\231). Urine biochemistry \200 \200 \200 \200 Excess phosphaturia (low TmP/GFR). Aminoaciduria. Glycosuria (not always evident). Low mole cular weight proteinuria and enzymuria. Monitoring The effect should be monitored (leukocyte cystine con- centration taken 5 \200 \2236 h after dose if given 4 times per day) approximately monthly for the \201 rst 3 mon ths and thereaf- ter 3-monthly, aiming for level of <1 nmol cystine per mg protein. Pathology Renal biopsy is not routinely undertaken in cystinosis as the diagnosis is better con \201 rmed on clinical and biochemi- cal evidence. Histological sections show variatio n in size and shape of proximal tubules and irregularity of the brush border. There is also variation in the appearances of podocytes, sometimes forming a multinucleate giant cell. C ystine crystals may be identi \201 ed in the interstitium. Chronic damage is associated wi th progressive tubulointer- stitial, glomerular and vascular changes. Adverse effects of cysteamine (mercaptamine) therapy Nausea and breath smell (very common). Vomiting (common, tolerance develops at each dose level). Increased acid and gastrin produ ction (consider proton pump inhibitor). Rash, fever, lethargy (very rare and only at high d oses). Circumscribed bruising over elbows/knees and striae. Bone lesions (very rare, associ ated with high doses: biopsy shows angioendotheliomatosis). One death reported. No interfer ence with immunosuppression. Treatment General management Rehydration Rehydrate with 0.9% saline with added potassium (a void glucose solutions which may exacerbate hypokalemia). Bene \201 ts of cysteamine therapy Treatment results in: \200 \200 \200 \200 Correct acidosis Slowly correct acidosis with sodium bicarbonate sup- plements (IV or oral) or combined sodium and pot- assium citrate solutions (tricitrates/polycitra). Rapid correc tion may precipitate \200\230hungry bone disorder \200\231 with acute hypocalcemia. Improvement of GFR in \201 rst 3 years life. Retardation of progression of CKD. Improveme nt in growth. Reduced frequency of nonrenal complications. Follow-up Initial correction of electrolyte imbalances requires very close monitoring (ofte n as an inpatient) because rapid cor- rection of acidosis can precipitate hypocalcemic cram ps or seizures. Thereafter it is important to gradually increase cysteamine therapy and mon itor cystine levels (e.g. monthly in \201 rst 4 \200\2236 months, 3-monthly when stable). Effective cysteamine therapy has reduced the frequency of clinical assessment to 3 or 4 ti mes per year. Adults with cystinosis usually require standard manage- ment of their renal r eplacement therapy and more special- ist assessment of the treatment and mulitsystem proble ms of cystinosis every 3 \200\2234 months. Fluid intake and nutrition Provide high \202 uid intake (free access to water) and high c alorie intake (many children need enteral feeding sup- port). Supplementation Add supplements of potassium, phosphate and sometimes calcium and magnesium . Add 1-alfacalcidol to correct the rickets. Carnitine supplements may be used to restore t he low plasma and muscle levels, although the clinical relevance is uncertain. Growth hormone Recombinant growth hormone may be necessary in chil- dren with sustained poo r growth after optimal general management and adequate (e.g. 1 year at maintenance doses) c ysteamine therapy \200\223 see below. Prognosis Untreated children risk life-threatening dehydration and electrolyte imbalance an d progress to ESRD by 10 years. W. VAN T HOFF 630 Rickets, poor nutrition and systemic disorder contribute to poor growth. Kidney transplanta tion (deceased or live donor) are both feasible and successful; although cystine may be see n in graft biopsies, the disorder does not recur within the kidney. Systemic cystine accumu lation causes progressive multisys- tem damage and dysfunction. Kleta R, et al. First NIH/Of \201 ce of Rare Diseases Conference on Cystinosis: past, pres ent, and future. Pediatr Nephrol 2005; 20: 452 \200\223454. Van \200\231t Hoff W. Cystinosis. In: Evidence-based nephrology. In press. Internet resources The Cystinosis Foundation: http://www.cystinosisfoundation.org/ Cystinosis Research Foundation: Future prospects Effective cysteamine treatment has changed the outlook for cystinosis, fro m inevitable renal replacement therapy within the \201 rst decade to a disorder requiring intense medication but with prospects of reasonable growth and kidney survival through chi ldhood. There is also encourag- ing evidence that cysteamine ameliorates the longer-term co mplications. A better understanding of the pathogenetic mechanisms whereby cystine, accumul ated within the lysosome, affects cell dysfunction should open new avenues of therapy. http://www.natalieswish.org/page.cfm Cystinosis Foundation UK: http://www.cystinosis.org.uk/index.php See also CKD in children, p. 462 Fanconi syndrome, p. 204 Investigation of inherited renal disease, p. 582 Con \202 ict of interest The author has a contract (nonpersonal) as a medical consultant t o Orphan Europe, a distributor of Cystagon (mercaptamine). Further reading Bockenhauer D, van \200\231t Hoff W. Fanconi syndrome. In: Geary DF, Schaef fer F (eds), Clinical pediatric nephrology. Philadelphia: Mosby. Chap. 28. In press. Gahl W, Thoene J, et al. Cystinosis: a disorder of lysosomal mem- brane transportation. In: Scriver C, Beaudet A, Valle D, Sly W (eds), The metabolic and molecular basis of inherited disease. New York: McGraw-Hill; 2001. pp. 5085 \200\2235108. This page intentionally left blank D. BOCKENHAUER 632 Primary hyperoxalurias Introduction Primary hyperoxalurias are autosomal recessive disorders of hepatic enzymes le ading to increased production of oxalate. More than 90% of the body \200\231s oxalate is ex creted by the kidney with a small amount of excretion from the large intestines. Oxalate is poorly soluble and when present in excess can lead to calcium oxalate deposition in variou s tissues, primarily the kidney with formation of oxalate stones. Two forms are recognized (Fig. 15.14.1): PH type 1: defect in alanine-glycoxylate transferase (AGXT). PH type 2: def ect in glycoxylate reductase/hydroxypyru- vate reductase (GR/HPR). Enteric Fat malabsorption: fatty acids compete with oxalate to complex calcium in the gut, leaving more oxalate available for absorption. Ascorbic acid intoxication Metabolized to oxalate. De \201 ciency in intestinal Oxalobacter formigenes Normally degrades enteric oxalate, pre venting absorption. Investigations Diagnostic con \201 rmation Stone analysis and urinary oxalate excretion Th e presence of oxalate stones, especially recurrent ones, should always lead to the consider ation of PH. The diagno- sis is established by determination of oxalate and metabo- lites i n an acidi \201 ed urine sample (Table 15.14.1). Epidemiology PH1 occurs in 1 in 100 000 live births. PH2 is very rare, but may be underrep orted. Genetic testing If elevated levels of metabolites in the urine are detected, the diagnosis can be con \201 rmed by genetic testing. If no mutation is identi \201 ed or genetic test ing is not feasible, a liver biopsy needs to be considered for determination of enzyme acti vity. Genetics More than 50 different disease-causing mutations have been identi \201 ed in AGXT . The most common mutation leads to an amino acid replacement G170R. Interestingly, this mu tation is only pathogenic if occurring on the same allele together with the polymorphism P1 1L, which in Caucasians has an allelic frequency of 20%. On liver biopsy, these patients h ave demonstrable AGXT immuno- and enzyme activity (albeit reduced), but the enzyme is mista rgeted to mitochondria, instead of peroxisomes. Thus, the presence of AGXT in liver biopsy does not rule out the diagnosis of PH1. There is enormous variability in genotype \200\223p henotype correlation, even between individu- als within a family with identical genotype, m aking genetic counseling dif \201 cult. Monitoring Plasma oxalate levels With progressive CKD, renal excretion of oxalate decreases and plasma levels increase. If levels exceed 40 mol/L, saturation is reached and system ic oxalosis can occur. Imaging Calcium oxalate stones are radio-dense and thus easily imaged. Ultrasound is usuall y the preferred initial imag- ing modality. Routine imaging in the asymptomatic patient is unlikely to change management, but may be helpful in those patients with small parenchymal stones to assess the risk for dislodgement and thus obstructive urolithiasis. Clinical features Age at presentation and severity of symptoms is highly variable even with in families with identical genotype. Pathology Both AGXT and GR/HPR are hepatic enzymes involved in the metabolism of glycoxylat e to glycine (Fig. 15.14.1). Glycoxylate can be converted to glycine (AGXT), glycolate (GR/ HPR) or oxalate (lactate dehydrogenase, LDH). Decreased function of one pathway leads to ov erproduc- tion of the alternative metabolites, explaining the different patterns found in t he urine of patients with either PH1 or 2 (Table 15.14.1). AGXT is a peroxisomal enzyme tha t requires pyridoxine as cofactor, whereas GR/HPR is a cyto- plasmic enzyme. PH type 1 Most commonly presents in childhood with: \200 \200 recurrent nephrolithiasis or nephrocalcinosis; associated symptoms (polyuria, dysuria, hema turia). Rarely, is diagnosed in late adulthood based on occasional stone passage. In the most sever e form, PH1 presents in infancy with rap- idly progressive kidney failure and strikingly ec hobright kidneys (on USS), and extrarenal oxalosis, especially in bones, leading to pain an d erythropoetin-resistant anemia. Other organs may be affected including: \200 \200 \200 Treatment Treatment depends on the severity of symptoms. heart: arrhythmias, heart block; nerves: neuropathy; retina: \202 ecked retinopathy. Nephrolithiasis and normal GFR High \202 uid intake (>1.5 L/m2/day) is recommended. Citra te can be used to inhibit crystal formation (0.5 \200\2231 mmol 0.1 \200\2230.2 g/kg/day). Dietary modi \201 cation is less helpful, as the oxalate is derived from internal metabol ism. Pyridoxine, the cofactor of AGXT, in supraphysiologic doses (2 \200\2235 mg/kg startin g dose, can be increased up to 20 mg/kg) should be tried early in patients with PH1. PH type 2 Typically presents during adolescence with recurrent oxalate stones. Progressive CKD occurs in 10% of patients. Differential diagnosis Secondary hyperoxaluria Normal levels of glycolate and L-glycerate CHAPTER 15.14 Primary hyperoxalurias 633 Cytosol Peroxisome Pyruvate Alanine Glycolate Glycine D-Glycerate AGXT GR/HPR GGT pyridoxine Glycoxylate hydroxypyruvate Glycine Glycoxylate GR/HPR LDH LDH Glycolate L-Glycerate Oxalate Oxalate Fig. 15.14.1. Simpli \201 ed diagram of a hepatic cell with metabolic pathways pertinent f or the different types of primary hyperoxaluria. Decreased metabolism of glycoxylate by eit her AGXT or GR/HPR leads to increased conversion to oxalate. AGXT, alanine-glycoxylate amin otransferase (PH1); GR/HPR, glycoxylate/hydroxypyruvate reductase (PH2); LDH, lactate dehyd rogenase; GGT: -glutamyl transpeptidase. transplantation can still have elevated oxalate excretion for many months after transplanta tion, re \202 ecting the systemic oxalosis that accumulated during renal failure. A large \202 uid intake and citrate supplementation should thus be contin- ued until urinary leve ls normalize. Approximately one-third of patients experience reduction of oxalate levels with pyridoxine, sometimes back to the normal range. Typically, these are patients with the G170R mutation, but there is no complete genotype \200\223phenotype concordance (see above). Pyridoxine ca n rarely induce neuropathy and should be promptly discontinued in pyri- doxine nonresponsiv e patients. PH2 patients do not bene- \201 t from pyridoxine. Oxalobacter formigenes has been shown to decrease oxalate load in some patients, but treatment effects have been limit ed by loss of intestinal colonization with Oxalobacter over time. Prognosis Prognosis depends on the severity of symptoms. Because of poor genotype \200\223p henotype correlation, genetic analysis is not particularly helpful in determining prognosis , except that patients with PH2 seem to fare better than those with PH1, where roughly half progress to ESRD before the age of 25 years. Obviously, the earlier the presentation, the more severe the disease and the more likely progression will occur. Progressive chronic kidney disease Liver transplantation In more severe cases with progress ive CKD not halted by medical interventions, liver transplantation should be con- sidered, as it corrects the metabolic defect and thus pre- vents further excessive oxalate productio n. Future prospects PH1 is an inherited disease and gene therapy would thus be the ideal cure, but is unlikely to become available in the foreseeable future. However, identi \201 catio n of mitochon- drial mistargeting as the pathophysiologic basis of the most common mutation G170R has opened new possibilities. Already, proper targeting can be rescued in vitro. The deter- mination of the crystal structure of AGXT is helping to identify the effect of othe r missense mutations and will aid the design of novel drugs. Renal replacement therapy If liver transplantation is not feasible, renal replacement thera py should be started early (GFR 30 \200\22340 mL/min/ 1.73 m2), before systemic oxalosis oc curs (see above). Plasma oxalate levels need to be monitored and should be kept below the s aturation level of 40 mol/l. Unfortunately, oxalate is cleared poorly by dialysis. Hemod ialysis with high \202 ux membranes has the highest oxalate clearance, but even with dail y sessions is often not suf \201 cient to maintain plasma oxalate levels in the desired ra nge. Occasionally, a combination of hemo- and perito- neal dialysis has been used. Isolated renal transplantation improves oxalate clearance, but carries the high risk of graft failu re due to recurrent oxa- losis. Thus, combined liver and kidney transplantation is the pref erred option in patients with advanced renal failure. Further reading Cochat P. Primary hyperoxaluria type 1. Kidney Int 1999; 55: 2533 \200\2232547. Danpure CJ. Molecular etiology of primary hyperoxaluria type 1: new directions for treatmen t. Am J Nephrol 2005; 25: 303 \200\223310. Hoppe B, Beck B, Gatter N, et al. Oxalobacter fo rmigenes: a poten- tial tool for the treatment of primary hyperoxaluria type 1. Kidney Int 2006; 70: 1305 \200\2231311. Leumann E, Hoppe B. The primary hyperoxalurias. J Am Soc Nephrol 2001; 12: 1986 \200\2231993. Internet resources Oxalosis and Hyperoxaluria Foundation: Follow-up Follow-up depends on the severity of symptoms. It is important to recognize that patients after liver-kidney http://www.ohf.org/about_disease.html D. BOCKENHAUER 634 Genetics Home Reference (useful site for carers) Table 15.14.2 Diagnostic pattern of urine metabolites in PH1 and 2 http://ghr.nlm.nih.gov/condition+primaryhypero xaluria Urine oxalate Urine glycolate Urine L-glycerate See also Medical management of stone disease, p. 270 Surgical management of stone disease, p. 274 Renal and urinary tract stone disease in children, p. 282 Investigation of inherited renal disease, p. 582 PH1 High High Normal PH2 High Normal High Table 15.14.1 Age-appropriate reference values for oxalate and glycolate Body \202 uid <1 year 1 \200\2234 year 5 \200\22312 year Adult <0.46 <0.4 Urine Oxalate/day (mmol/1.73 m2) Oxalate/creatinine (mmol/mmol) <0.15 <0.13 <0.07 <0.08 <0.55 <0.26 Glycolate/day (mmol/1.73 m2) Glycolate/creatinine (mmol/mmol) <0.07 <0.09 <0.05 <0.04 <0.03 L-Glycerate/ creatinine (mmol/ mmol) Plasma Oxalate (mmol/l) <7.4 <5.4 Oxalate/creatinine (mmol/mmol) <0.19 <0.06 Adapted from: Cochat (1999). This page intentionally left blank J.S. CAMERON 636 Inherited disorders of purine metabolism and transportation Introduction Inherited defects of purine metbolism may lead to the overproduction of uric a cid or other purine end-products. Nephrotoxicity derives from the insolubility of uric acid and its analogs, and the ability of any crystals formed to initiate stone formation within the urinary tract, to gener- ate inflammation leading to permanent renal damage within ren al tissue, or sometimes both. Insoluble purines include in order of decreasing solubility: \200 Allopurinol should be used with care, however, since uri- nary oxypurine excretion in all H PRT-de \201 cient patients is exquisitely sensitive to allopurinol, resulting in a rapid i ncrease in concentrations of the extremely insoluble xanthine, with the possible appearance of xanthine neph- ropathy and stones. The allopurinol metabolite oxipurinol is itself also relatively insoluble, and both xanthine and oxipurinol calculi have been reported in patie nts with LNS on long-term allopurinol therapy. As in all patients with renal impairment, th e allopurinol dose must be carefully monitored, and reduced if necessary to no more than 5 mg/kg/24 h in children, or 100 mg/24 h in adults. Some patients have progressed to ESRD and transplanta- tion, but immunouppression using azathioprine will be inef- fective, and myco phenolate mofetil could have catastrophic consequences (Fig. 15.15.1); ciclosporin alone ha s proved successful. In children with the full LNS, management is dominated by the neurolog ical problems, especially the distressing self- mutilation, often by biting, which may lead to requirement for prophylactic dental extractions. The long-term progno- sis is good in c hildren and adolescents with a partial defect, but patients with the full LNS rarely surviv e beyond ado- lescence. Death is usually due to aspiration pneumonia or ESRD. No successful treatment is yet available for the severe neurological complications. uric acid > xanthine > 2,8-dihydroxyadenine. Defects of purine metabolism (Fig. 15.15.1) are often over- looked as none are common (Tabl e 15.15.1). Hypoxanthine-guanine phosphoribosyltransferase (HPRT) de \201 ciency Lesch \200\223Nyhan a nd Kelly \200\223Seegmiller syndromes HPRT catalyzes salvage transfer of the phosphoribosyl moiety of PP-ribose-P to hypoxanthine and guanine to form IMP and GMP respectively (Fig. 1 5.15.1), thus saving most of the energy required to synthesize new purine bases. This proce ss is a major downregulator of de novo purine synthesis. The presence of inactive mutant HP RT protein results in gross oversynthesis of purine nucleotides and uric acid. A number of mutations have been reported which can lead to a broad spectrum of presentations. Lesch \200\223Nyhan syndrome (LNS) One of the highest concentrations of HPRT is in the brai n. In addition to urate problems, severe neurological dif \201 cul- ties can develop, usua lly involving spasticity, developmental retardation, choreo-athetosis and self-mutilation ( LNS). The biochemical origin of this neuropathology remains unclear. Phosphoribosyl pyrophosphate synthetase (PRPS) superactivity This much rarer condition has some clinical similarities to HPRT de \201 ciency, as it is again sex-linked, leads to ura te overproduction, and there may be a neurological com- ponent to the disease. The enzyme P RPS catalyzes the transfer of the pyrophosphate group of ATP to ribose 5-phosphate to form PP-ribose-P in the de novo pathway leading to purine synthesis (Fig. 15.15.1). The mutation leads to PRPS overactivity and overproduction of urate. Kelley \200\223Seegmiller syndrome (KLS) Partial enzyme defects may be associated only with uric acid overproduction and its consequences may present (usually with gout) in adolescen ce or early adulthood; this is sometimes known as the Kelley \200\223Seegmiller syndrome. Presentation In addition to crystalluria, gout and renal impairment, affected children may present with dysmorphic features, sometimes inherited nerve deafness, a family history of r epeated attacks of bronchopneumonia and death in early infancy as well as developmental ret ardation. A much milder phenotype presents later in adolescence with kid- ney stones or sev ere gout. Presentation All degrees of HPRT de \201 ciency may present in the \201 rst weeks of lif e with crystalluria, gout and AKI, sometimes leading to ESRD or death in infancy. Diagnosis The diagnosis can be advanced by measurement of plasma urate, remembering that th e fractional excretion of \201 ltered urate (FEurate) is much higher in infants and child ren, and the plasma urate correspondingly lower than in adults. Renal failure leads to a ri se in plasma urate concentration. A better guide to diagnosis is the excretion fo urate whi lst taking a low-purine diet, to demonstrate over-production. Finally, diagnosis can be con \201 rmed by using an enzyme assay on red cell lysates. Carrier detection is unsatisfacto ry with a low yield, but preimplantation diagnosis and chori- onic villous sampling are pos sible. Diagnosis Although this defect is X-linked, it should be suspected in any child, female, or young adult of either sex with marked hyperuricemia and/or hyperuricosuria, but with norma l HPRT activity in lysed red cells. The heterozygote females can be severely affected also, particularly mothers of male children with neurological de \201 cits or urate overproduct ion who themselves have gout. These female carriers may also have sensorineural deafness. Treatment Allopurinol, again used with care to avoid xanthine neph- ropathy, will control p lasma uric acid in patients with nor- mal renal function and gout or kidney stones. A high \202 uid intake and alkalinization of the urine may help, and in CKD Treatment The elevated uric acid concentrations in either complete or partial de \201 cien cies may be controlled by a high \202 uid intake, together with alkali and allopurinol. CHAPTER 15.15 Inherited disorders of purine metabolism and transportation 637 DNA de novo ATP synthesis PRPS adenylate inosinate guanylate guanosine adenosine HPRT APRT inosine guanine hypoxanthine adenine XOR XOR 2,8-diOH adenine uric acid xanthine XOR Fig. 15.15.1 Purine metabolism in summary. The reactions catalyzed by the enzymes HPRT, PRP S, APRT, and XOR are indicated by stippled arrows. XOR, xanthine oxidoreductase; PRPS, phos phoribosyl pyrophosphate synthetase; HPRT, hypoxanthine-guanine phosphoribosyltransferase; APRT, adenine phosphoribosyltransferase; DNA, deoxyribonucleic acid; ATP, adenosine triphos phate. Table 15.15.1 Common defects of purine metabolism Homo-/hemizygote frequency Insoluble purine in crystals/stones Associated features Enzyme defect Abbreviation Gene location and mode of inheritance Uric acida HPRT Xq 1:380 000 (1/3 new mutations) Hypoxanthine-guanine ribosyltransferase de \201 ciency Choreoathetosis Self-mutilation Developmental arrest Sex-linked Uric acida PRPS Xq.21ptr (PRS1) Xp.22.3 (PRS2) ? Dysmorphia Developmental arrest Deafness Phosphoribosyl pyrophosphate synthetase overactivity Sex-linked Adenine phosphoribosy ltransferase de \201 ciency APRT 16q24 Autosomal recessive 1:33 000 to 1:250 000 2,8-Dihydroxyadenosine None Xanthine oxidoreductase de \201 ciency XOR 2p22 Autosomal recessive 1:45 000 Xanthine None a Also contain xanthine and/or oxypurinol in those treated with allopurinol. J.S. CAMERON 638 recipients will continue to need treatment with allopurinol; therefore, azathioprine should be avoided. If used, the dose of both drugs should be reduced (up to 200 mg for allopu- ri nol and 25% of the daily dose for azathioprine). the allopurinol dose must be reduced even further as indi- cated above. To date, no success ful therapy for the associated neuro- logical complications in severe cases has been devise d, and unfortunately death in childhood is frequent. Prognosis for patients presenting in a dolescence is good. Hereditary xanthinuria De \201 ciency of xanthine oxidoreductase (XOR) results in an inabi lity to oxidize hypoxanthine and xanthine to uric acid (Fig. 15.15.1). This leads to accumu lation of xanthine (and to a lesser extent hypoxanthine) in place of uric acid. Xanthine co ncentrations in plasma and especially urine are increased. The nephrotoxicity of this purin e, like that of 2,8-dihydroxyadenine, is due to its insolubility, which unlike uric acid ca n barely be increased by alkalinizing the urine. By contrast, hypoxanthine is very soluble and poses no problem. Xanthine lithiasis, like uric acid lithiasis, is climate dependent, b eing much more prevalent and associated with more severe renal complications in countries w hich fringe the Mediterranean. Adenine phosphoribosyltransferase (APRT) de \201 ciency APRT is the companion salvage enzy me of HPRT which catalyzes the conversion of adenine to AMP using PP-ribose-P (Fig. 15.15.1 ). Its prime function is the removal of adenine arising as a metabolic waste product from t he polyamine pathway. In the congenital absence of APRT, adenine accumulates in quantity an d is oxidized by xan- thine dehydrogenase to 8-hydroxyadenine and then the very insoluble 2 ,8-dihydroxyadenine. 2,8-Dihydroxyadenine is extremely insoluble at any pH, and has a high renal clearance: 2,8-dihydroxyadenine is pro- tein-bound but is actively secreted by the hu man kidney. The stones, unlike the hard, compact, yellowish urate stones, are bluish or put ty-colored and crumbly, but often have been misidenti \201 ed as uric acid because of thei r identi- cal chemical behavior, giving positive tests in both the colorimetric and murexid e reactions for urate. Type 1 xanthinuria Typically nonsense, missense, or frame-shift mutations are found in the XOR gene in patients with \200\230classical \200\231 type 1 xanthinuria. In most homozygot es uric acid is virtually undetectable in plasma and urine on a purine-free diet, and is re placed in the urine by xanthine and, to a lesser extent, hypoxanthine (which is extensively salvaged) in a ratio of 3 \200\2234:1. The potential toxicity of xanthine in xanthinuric s ub- jects relates to its high renal clearance by \201 ltration with little or no tubular reabsorption. In XOR-de \201 cient homo- zygotes with normal renal function, plasma and ur inary xanthine concentrations are generally well in excess of the solubility of xanthine in urine (0.9 mmol/L), even at pH 7.0. Therefore the potential for precipitation in the kidne y or urinary tract is high.The condition predominates in males. Type I APRT de \201 ciency Subjects are predominantly Caucasian and have no detect- able A PRT activity in lysed erythrocytes. Various substitu- tions, insertions, and deletions have been identi \201 ed in non-Japanese patients.