Extrarenal manifestations Skeletal defects 60% of patients have absent or hypoplastic patel lae that results in lateral slippage of the patella on knee \202 exion. Joint effusions a nd osteoarthritis leading to knee pain may result. Up to 80% of patients have iliac horns t hat are pathogno- monic of NPS. These are symmetrical osseous processes arising from the il iac wings. They are asymptomatic but may be detected on clinical examination. Elbow abnorma lities are also common. These include hypoplasia of the radial heads leading to elbow sublu xa- tion, hypoplasia of the distal humerus, and formation of posterior processes from the d istal humerus leading to limitations of extension, pronation and supination of the forearm. IgA nephropathy; membranous nephropathy; anti-GBM disease; pauci-immune vasculitis. Whether these diseases occur in NPS with increased fre- quency is unknown. CHAPTER 15.9 Nail \200\223patella syndrome 615 Renal transplantation is not associated with recurrent dis- ease and is not complicated by anti-GBM disease (in con- trast to Alport \200\231s syndrome). Further reading Bennett WM, Musgrave JE, Campbell RA, et al. The nephropathy of the nail \200\223patella syndrome. Clinicopathologic analysis of 11 kindred. Am J Med 1973; 54: 304. Bongers EM, Gubler MC, Knoers NV. Nail \200\223patella syndrome. Overview on clinical and m olecular \201 ndings. Pediatr Nephrol 2002; 17: 7037 \200\2237012. Dunston JA, Hamlington JD, Zaveri J, et al. The human LMX1B gene: transcription unit, promo ter, and pathogenic mutations. Genomics 2004; 84: 565. Sweeney E, Fryer A, Mountford R, Green A, McIntosh I. Nail patella syndrome: a review of th e phenotype aided by developmental biology. J Med Genet 2003; 40: 153 \200\223162. Internet resources Nail Patella Syndrome UK: http://www.npsuk.org/ Nail Patella Syndrome Worldwide: Fig. 15.9.1 Nail \200\223patella syndrome. Electron micrograph showing the characteristic c rossbanded collagen \201 brils in the glomerular basement membrane (arrowhead). http://www.nailpatella.org/ See also Proteinuria and/or hematuria, p. 76 Alport \200\231s syndrome, p. 606 Thin membran e nephropathy, p. 602 Treatment There is no speci \201 c treatment available. A generic treatment approach with blood pressure control, the use of ACEIs and/or ARBs, and cardiovascular risk management is appropriate. P. TOPHAM 616 Congenital and infantile nephrotic syndrome Introduction Congenital nephrotic syndrome by de \201 nition develops within the \201 rs t 3 months of life. The onset of nephrotic syndrome between 3 and 12 months of age is calle d infantile nephrotic syndrome. Genetic abnormalities underlie the majority of cases of nep hrotic syndrome that develop in the \201 rst year of life. The renal outcome is generally poor. Clinical features Prematurity (35 \200\22338 weeks) is usual. Babies are small for gestatio nal age. Cranial sutures are widely separated, the nose is small and ears are low-set. Flex ion deformities of hips, knees and elbows are common. The placenta is enlarged. Edema prese nt by the end of the 1st week of life in 50%. Severe nephrosis with ascites is invariably p resent by 3 months. Profound hypoalbuminemia and hypogammaglobulinemia develops. Growth is poor. Bacterial infections (peritonitis, respiratory infections) and thromboembolism may oc cur. Hypothyroidism is common (urinary loss of thyroxine- binding proteins). End-stage rena l failure develops at 3 \200\2238 years of age. Prolonged survival is possible with support ive treatment including dialysis and transplantation. Genetics More than 85% of cases of congenital nephrotic syndrome are due to mutations of th e following genes (Table 15.10.1): NPHS1 Encodes the slit diaphragm component nephrin; mutations result in congenital nephroti c syndrome of Finnish type. NPHS2 Encodes podocin; mutations result in familial FSGS. WT1 Encodes the Wilms \200\231 tumor suppressor gene; mutations result in the Denys \200 \223Drash and Frasier syndromes. LAMB2 Encodes 2-laminin; mutations result in the Pierson syndrome. Pathology Early changes are con \201 ned to mild mesangial hypercellular- ity with increas ed mesangial matrix expansion. Later with further mesangial matrix deposition progressive g lomerulosclerosis develops. Immune deposits are absent. On electron microscopy podocytes ha ve profound foot process effacement and slit-diaphragms are absent. Tubulointerstitial chan ges are prominent, with microcystic dilatation of tubules, progressive interstitial \201 brosis and tubular atrophy developing later in the course of disease. PLCE1 Encodes phospholipase C ; mutations result in early-onset diffuse mesangial sclerosi s. NPHS1 and NPHS2 mutations account for >90% of cases of congenital nephrotic syndrome. Co ngenital nephrotic syndrome may also result from non- genetic causes and these are listed i n Table 15.10.1. Congenital nephrotic syndrome of the Finnish type (CNF) This is most frequent in Finland. T he incidence is between 0.9 and 1.2 per 10 000 live births but is now falling due to the av ailability of prenatal screening. CNF has also been described in a variety of ethnic groups throughout the world. Treatment Glucocorticoids and immunosuppressive agents are ineffective. Management includes : \200 \200 \200 \200 \200 daily or alternate day albumin infusions; gammaglobulin replacement; high-protein, low-salt diet (tube feeding/parenterally); vitamin and thyroxine supplementation; infection and thr omboembolism prophylaxis. Pathogenesis CNF results from abnormalities of the NPHS1 gene. This gene encodes for nephri n which is a component of the podocyte slit diaphragm. The absence of nephrin from the slit diaphragm is thought to result in the breakdown of glomerular permselective function and t he free movement of plasma proteins into the urine. A wide variety of nephrin mutations has been described. However, 90% of Finnish CNF patients have either the Fin-major (nt121delC T) or Fin-minor (R1109X) mutations. In non-Finnish CNF patients >30 mutations have been ide nti \201 ed. In addition, a small number of patients with fea- tures of classical CNF have no identi \201 able NPHS1 muta- tions, suggesting that the disease can be induced by prom oter or intronic mutations or mutations of proteins that interact with nephrin. Bilateral surgical nephrectomy may be required since even maximal supportive therapy may no t avoid growth retarda- tion and intercurrent complications of nephrosis. The administratio n of indomethacin and ACEIs to reduce intraglomerular pressure is an alternative approach t o sur- gery. In a small number of cases this has led to substantial reduction in proteinuri a and subsequently an improvement in nutritional status and growth. Renal transplantation c an be undertaken once the child reaches a weight of 8 \200\2239 kg. Recurrence of nephrotic syndrome can occur in 20 \200\22325% of transplants. This is more common in Fin-major rec ipi- ents (nephrin is absent in native kidneys) and has been shown to be due to the presenc e of circulating anti-nephrin CHAPTER 15.10 Congenital and infantile nephrotic syndrome 617 sclerosis may also be seen as part of Denys \200\223Drash syn- drome resulting from a mutat ion in the WT1 gene. PLCE1 encodes phospholipase C which is an enzyme that catalyzes the hydrolysis of phosphoinositides and results in the generation of signaling molecules. The m echanism through which aberrant phospholipase C activity leads to podocyte dysfunction is unclear but a causal role is supported by the observation that targeted deletion of PLCE1 gene in zebra \201 sh leads to glomerular dysfunction. Table 15.10.1 Causes of congenital nephrotic syndrome Genetic causes Congenital nephrotic syndrome of the Finnish type Diffuse mesangial sclerosi s (idiopathic) Diffuse mesangial sclerosis with Denys \200\223Drash syndrome Diffuse mesang ial sclerosis with Frasier syndrome Pierson syndrome Galloway syndrome Nail \200\223patella syndrome Nongenetic causes Clinical features Babies with diffuse mesangial sclerosis appear normal at birth, with norm al size and no placental abnormalities. Nephrotic syndrome may be present at birth but more usually develops during the \201 rst 2 years of life. Various extrarenal manifestations have been reported including muscular dystrophy, myopia, microcephaly, men- tal retardation , cataract, and nystagmus. End-stage renal failure is invariable and usually occurs before the age of 3 years. Idiopathic nephrotic syndrome Infection: \200 congenital syphilis \200 congenital toxop lasmosis \200 cytomegalovirus \200 rubella virus \200 human immunode \201 ciency vir us \200 hepatitis B Mercury exposure Membranous nephropathy due to maternal neutral Pathology Early glomerular changes include mesangial matrix expan- sion without hypercellul arity. Capillary walls become thickened due to hypertrophy of podocytes. Progression leads to massive mesangial matrix expansion, GBM thickening and reduction of capillary lumens. Me sangial sclerosis eventually contracts resulting in a sclerotic mass within a dilated Bowma n \200\231s space. Immunohistochemistry demonstrates mesangial deposi- tion of IgM, C3 and C1q probably as the result of nonspe- ci \201 c deposition in injured glomeruli. Electron microscopy demonstrates hypertrophic mesangial cells, hypertrophic podocytes containing num erous vacu- oles and irregular effacement of podocyte foot processes. The same renal pathol ogical appearances can be seen in the Denys \200\223Drash syndrome, for which screening sho uld therefore be instituted. endopeptidase mutations antibodies in the majority (analogous to the development of anti-GBM antibodies following t he transplantation of patients with Alport \200\231s syndrome). Recurrence of disease is as sociated with graft loss but graft survival may be improved by plasmapheresis and methyl- p rednisolone. Antenatal diagnosis Amniotic and maternal plasma -fetoprotein (AFP) levels are increased by 15 \200\22316 weeks gestation due to increased urinary loss of AFP by the fetus. This \201 nding is not speci \201 c but in high risk families may be suf \201 cient evidence t o con- sider termination of pregnancy. Heterozygous carrier fetuses also have increased amn iotic AFP levels, but are not at risk of developing CNF. Therefore unnecessary terminations can be undertaken on the basis of AFP testing alone. Prenatal genetic screening is now ava ilable using genetic linkage and haplotype analysis (the four major haplotypes accounting f or 90% of CNF alleles in Finland have been identi \201 ed). Haplotype testing is 95% accu rate. Treatment Diffuse mesangial sclerosis is thought to be resistant to steroid and immunosuppr essive treatment. However, a small number of instances of remission of proteinuria with ste roids or ciclosporin have been reported. Nephrotic syndrome is less severe than that seen w ith CNF, therefore the intensive supportive treatment described for CNF is generally not re quired for patients with diffuse mesangial sclerosis. Supportive treatment includes: \200 \200 \200 NPHS2 mutations A small number of patients with features typical of CNS have been found to have homozygous NPHS2 mutations. NPHS2 encodes podocin which is a podocyte-speci \201 c pr o- tein that interacts with nephrin and appears to be critical for normal slit-diaphragm fu nction. Combined NPHS1 and NPHS2 mutations have also been identi \201 ed demonstrating the genetic heterogeneity of CNS. The clinical manifestations and outcome are similar to that seen with NPHS1 mutations. Immunosuppressive treatment is ineffective. maintenance of adequate nutrition; infection prophylaxis; management of renal dysfunction. Renal transplantation is not complicated by disease recurrence. Bilateral nephrectomy is co nsidered at the time of trans- plantation given the potential risk of developing Wilms \200 \231 tumor in those with WT1 mutations. There is no consensus about this approach, however. Diffuse mesangial sclerosis Pathogenesis Mutations of the PLCE1 gene appear to be the cause of isolated diffuse mesangial sclerosis. Diffuse mesangial P. TOPHAM 618 Denys \200\223Drash syndrome (DDS) This is the combination of: \200 \200 \200 A response to steroids heralds a favorable prognosis; however, most children who present wi th INS <1 year of age are treatment resistant and tend to have progressive renal dysfunctio n. Mutations of NPHS2 can be seen in such patients. Mutations in the a-actinin-4 gene can b e identi \201 ed in some patients. The protein is involved in maintenance of the podocyte cytoskeleton and abnormalities have been iden- ti \201 ed in some families with autosomal recessive FSGS. progressive renal disease (diffuse mesangial sclerosis); male pseudohermaphroditism; Wilms \200\231 tumor. Most cases are sporadic. It is caused by mutations of the WT1 gene (chromosome 11) which en codes the Wilms \200\231 tumor suppressor gene (a zinc \201 nger protein transcription fa ctor). In DDS most mutations are missense mutations affecting exons 8 and 9. DDS patients a re heterozygous for WT1 mutations with the abnormal WT1 protein acting in a dominant negati ve manner. Loss of WT1 function predisposes to the development of Wilms \200\231 tumors (em bryonic kidney tumors arising from aberrant mesenchymal stem cell differentiation). Wilms \200\231 tumors develop when both alleles become abnor- mal (ie acquisition of a 2nd WT1 mu tation). Pierson syndrome This is also known as microcoria-congenital nephrosis syndrome. It is an a utosomal recessive syndrome resulting from muta- tions in the LAMB2 gene. LAMB2 encodes lam inin 2 which is a component of the glomerular basement membrane. Mice with a targeted del etion of LAMB2 develop congeni- tal nephrotic syndrome, retinal abnormalities, and neu- rom uscular junction defects. In children the features are: \200 Clinical features Diffuse mesangial sclerosis is invariably seen in DDS and it follows the same clinical course as described previously. Wilms \200\231 tumor may be the first manifes tation of the syndrome, may be unilateral or bilateral, and may be asso- ciated with nephro blastomatosis. Male pseudohermaphroditism (ambiguous genitalia or female phenotype, and dys genetic testes or streak gonads) is seen in all 46XY patients. 46XX children in contrast ha ve a normal female phenotype. A normal male phenotype effectively excludes a diagnosis of D DS. Progressive renal dysfunction is invariable with ESRD occurring <3 years of age. Almost all patients will develop Wilm \200\231s tumor if they retain their native kidneys. Bilate ral nephrectomy is performed prior to transplantation to avoid this complication. congenital nephrotic syndrome with diffuse mesangial sclerosis on renal biopsy; microcoria (small unreactive pupils); abnormal lens (posterior lenticonus) with cataracts; retinal abn ormalities. \200 \200 Galloway syndrome This is the constellation of: \200 \200 \200 \200 microcephaly; mental retardation; hiatus hernia; nephrotic syndrome. Probable autosomal recessive inheritance. Underlying cause is unknown. The nephrosis develo ps at 3 months of age, is treatment resistant, usually severe, and progresses to ESRD. The histological appearances resemble either minimal change disease, FSGS, mesangioproliferati ve GN, or diffuse mesangial sclerosis. Frasier syndrome This also results from WT1 mutations (point mutations in the donor splice site in intron 9). It consists of nephrotic syndrome, complete XY gonadal dysgenesis, and i ncreased susceptibility to gonadal tumors, usually gonadoblastomas. Classically, it has bee n described in 46XY patients with under- masculinized external genitalia that may range fro m ambigu- ous in appearance to normal-looking female genitalia. Recently 46XX patients have been described with a nor- mal female phenotype (and gonads) in association with nephropat hy and Wilms \200\231 tumor. The renal abnormalities may be either diffuse mesangial sclero sis or focal segmental glomerulosclerosis. Renal dysfunction is progressive with ESRD occur ring by late childhood. Infection Table 15.10.1 lists potential infectious causes of congenital nephrotic syndrome. Congenital syphilis and cytomegalovirus are the most important clinically. Renal biopsy re veals either membranous nephropathy or diffuse proliferative GN. Immune complexes containin g microbial antigen can often be identi \201 ed and probably mediate the onset of glomerul ar disease. Successful treatment of the infection usually leads to reso- lution of the glom erular disease. Other causes \200 Membranous nephropathy secondary to maternal neu- tral endopeptidase mutations; Nail \200 \223patella syndrome; Mercury exposure. Idiopathic nephrotic syndrome (INS) This is rarely seen at birth but can develop during the \201 rst year of life. Histological appearances of minimal change disease, FSGS and diff use mesangial proliferation can be seen. \200 Several cases of congenital membranous nephropathy have been described in which podocyte in jury is induced in the CHAPTER 15.10 Congenital and infantile nephrotic syndrome 619 fetus by the materno-fetal transfer of antibodies directed against the podocyte protein neu tral endopeptidase. Antibodies are generated in mothers who lack this antigen and are then sensitized by the fetus. VanDeVoorde R, Witte D, Kogan J, Goebel J. Pierson syndrome: a novel cause of congenital ne phrotic syndrome. Pediatrics 2006; 118: e501. Internet resources Congenital nephrotic syndrome: Family Factsheet: Further reading Habib R. Nephrotic syndrome in the \201 rst year of life. Pediatr Nephrol http://www.gosh.nhs.uk/factsheets/families/ F990283/index.html Orpha.net: a database of rar e diseases and orphan drugs: 1993; 7: 347. Heaton PA, Smales O, Won W. Congenital nephrotic syndrome responsive to captopril and indom etacin. Arch Dis Child 1999; 81: 174. http://www.orpha.net/ Kestil M, J rvel I. Prenatal diagnosis of congenital nephrotic See also Nail \200\223patella syndrome, p. 608 Nephrotoxic metals, p. 236 Rare syndromes wi th renal involvement, p. 640 Nephronophthisis, p. 600 syndrome (CNF, NPHS1). Prenat Diagn 2003; 23: 323 \200\223324. Little M, Wells C. A clinical overview of WT1 mutations. Hum Mutat 1997; 9: 209. Niaudet P. Genetic forms of nephrotic syndrome. Pediatr Nephrol 2004; 19: 1313 \200\2231318. Niaudet P, Gubler MC. WT1 and glomerular diseases. Pediatr Nephrol 2006; 21: 1653 \200\2231660. Patrakka J, Martin P, Salonen R, et al. Proteinuria and prenatal diag- nosis of congenital nephrosis in fetal carriers of nephrin gene mutations. Lancet 2002; 359: 1575. R.S. PATEL 620 Fabry disease Introduction Fabry (or Fabry \200\223Anderson) disease is a rare lysosomal storage disease that results from de \201 ciency of the lyso- somal enzyme A-galactosidase A (A-Gal A) and the inability to catabolize glycosphingolipids with terminal A-galactosyl residues. Glycos phingolipids are normal constituents of the plasma membrane and intracellular organelles an d often circulate in association with apolipoproteins. In the absence of suf \201 cient A- Gal A, these lipids, particu- larly globotriaosylceramide (GL-3; also known as Gb3, and cer amide trihexoside, CTH), accumulate progressively in the lysosomes of many cell types, part icularly endothelial cells. Heterozygote women may have abnormal urinary sediment, but ESRD is rare. Cardiac involvement Glycosphingolipid accumulation within the heart and coro- nary vessels leads to: \200 \200 \200 \200 \200 progressive coronary occlusive disease; ischemic cardiomyopathy; conduction abnormalities; valvular heart disease; left ventricular hypertrophy. Neurological involvement Peripheral nervous system: \200 autonomic dysfunction; \200 hy pohydrosis; \200 painful extremities (acroparesthesia, occurs early). Epidemiology Fabry disease is the second most prevalent lysosomal stor- age disorder after Gaucher \200\231s disease. Population estimates range from 1 in 80 000 to 1 in 120 000 live births. There is a slight preponderance of males with an increased incidence of 1 in 50 0 00. Central nervous system: Glycosphingolipid accumulation tends to occur in the verte- brobasi lar circulation resulting in strokes characterized by: \200 \200 \200 hemiparesis; ataxia; memory loss. Genetics The gene for A-Gal A is found on the long arm of the X chromosome (Xq21.33-q.22.1) . More than 100 mutations have been identi \201 ed in the a-Gal A gene. Most of the mutati ons described are associated with the classic Fabry phenotype, in which there is multisyste m involvement. Mutations that decrease but do not eliminate the enzyme \200\231s activity u sually cause the milder, late-onset forms of Fabry disease that affect only the heart or ki dneys. Unlike other X-linked disorders, Fabry disease causes sig- ni \201 cant medical pro blems in many females, but the signs and symptoms usually begin later in life and are milde r than those seen in their affected male relatives. Some females who carry a mutation in on e copy of the a-Gal A gene never have any of the signs and symptoms of Fabry disease. Skin involvement Angiokeratomas are small dilated veins of the upper dermis that become cov ered by hyperkeratotic epidermis (Fig. 15.11.1). They usually present early in the disease and tend to clus- ter on the lower trunk and extremities and appear as clus- ters of small, dark red spots. Ocular involvement Corneal opacities develop in the form of whitish curls that radiate from the center (corneal verticillata). Vascular lesions of the conjunctiva and retina may be i den- ti \201 ed with slit-light examination. Pulmonary involvement Deposition of glycosphingolipid in the bronchial tree causes airway n arrowing leading to: \200 \200 \200 cough; shortness of breath; a \201 xed de \201 cit with air \202 ow limitation on spiro metry. Clinical features Fabry disease may be classi \201 ed into either a classic form or a card iac variant. Classic Fabry disease is a multisystem disorder involving the: \200 \200 \200 \200 \200 Investigations Clinical examination including slit-lamp examination is often suf \201 cien t to secure the diagnosis. The serum level of globotriaosylceramide (Gb3 with GL-3) may be elevated. The urine may contain glycosphingolipid-laden epithelial cell aggregates containi ng oval fat bodies. Con \201 rmation of the diagnosis requires the demonstration of reduce d or absent A-Gal A activity in serum, leukocytes, skin or other tissue. Indeterminate resu lts may be obtained from atypical vari- ants or heterozygous females, in which case further evalu- ation is required. This may include: \200 \200 skin; eyes; kidneys; heart; neurological system. The variant form is characterized by cardiac abnormalities, most typically, conduction defe cts and cardiomyopathy. Renal involvement There is progressive glomerular damage resulting in pro- teinuria and mic roscopic hematuria. Renal function slowly declines over years with secondary hypertension a nd ESRD usually developing by the 4th or 5th decades of life. urinary ceramide digalactoside and trihexoside; molecular diagnosis. CHAPTER 15.11 Fabry disease 621 (a) Fig. 15.11.1 Angiokeratoma corporis diffusum. Renal biopsy Light microscopy This will show characteristic glomerular changes with sec- on dary tubular and vascular abnormalities (Fig. 15.11.2). Podocytes are enlarged and packed w ith small, clear vacu- oles, which represent ceramide-lipid deposits. Progressive disease l eads to capillary loop collapse and segmental or global glomerulosclerosis. Vacuoles may al so be observed in endothelial and smooth muscle cells of arterioles and arteries. Endotheli al cell enlargement leading to occlusion of the vascular lumen of arterioles and tissue isc hemia is common. (b) Electron microscopy This reveals numerous inclusions contained in lysosomes, especially wit hin podocytes (Fig. 15.11.2). These have a characteristic lamellated appearance and are kno wn as myelin (myeloid) or zebra bodies. Treatment Recombinant human a-Gal A The introduction of enzyme replacement therapy using re combinant human A-Gal A (agalsidase and ) has transformed the treatment of Fabry disea se. Randomized clinical trials have reported that treatment with enzyme replacement for \211 6 months results in: \200 reduced plasma and urine glycosphingolipid levels; \200 less neuropathic pain; \200 reduced organ deposition; \200 improved cerebral blood \202 ow; \200 better quality-of-life scores. (c) Fig. 15.11.2 Renal biopsy appearances of Fabry disease. (a) Normocellular glomeruli with pr ominent \200\230swollen \200\231 podocytes (H&E stain). (b) At higher power the podocyte c ytoplasm is voluminous and clear and has a \200\230bubbly \200\231 appearance. Similar cha nges can also be observed in endothelial cells and smooth muscle cells of blood vessels (H& E stain). (c) At the ultrastructural level the podocyte cytoplasm is packed with characteri stic concentric lysosomal inclusions known as myelin bodies. (Courtesy of Prof. Peter Furne ss and Dr Nick Mayer, Consultant Histopathologists, University Hospitals of Leicester, UK.) Deteriorating renal function is also stabilized in most patients with mild \200\223moderate CKD on treatment. Adjunctive treatments Gabapentin, carbamazepine, and opioids may be tried for neuropathic p ain. R.S. PATEL 622 enhance the activity of mutant A-Gal A enzymes with residual activity. Antihypertensive and antiplatelet therapies are useful in reducing overall cardiovascular r isk. Renal replacement therapy In those on maintenance hemodialysis, A-Gal A may be safely given and there is minimal clearance during a dialysis session. Renal transplantation is an effe ctive treatment for advanced kidney disease but will not ameliorate the extrarenal mani- fe stations. A-Gal A treatment should be continued in allograft recipients. Further reading Eng CM, Guffon N, Wilcox WR. Safety and ef \201 cacy of recombinant human alpha-galactosidase A replacement therapy in Fabry \200\231s dis- ease. N Engl J Med 2001; 345: 9 \200\22316. Eng CM, Germain DP, Banikazemi M, et al. Fabry disease: guidelines for the evaluation and m anagement of multi-organ system involvement. Genet Med 2006; 8: 539 \200\223548. Schiffmann R. Enzyme replacement in Fabry disease: the essence is in the kidney. Ann Intern Med 2007; 146: 142 \200\223144. Schiffmann R, Kopp JB, Austin HA, et al. Enzyme replacement ther- apy in Fabry disease: a r andomized controlled trial. J Am Med Assoc 2001; 285: 2743 \200\2231749. Follow-up Genetic counseling is necessary for affected individuals. A careful pedigree shou ld be obtained to identify all affected family members. In X-linked recessive disease, all daughters of affected males are carriers, and sons of affected males will not carry the gen e for Fabry disease. It is usual for mothers of affected individuals to be consid- ered car riers, and their siblings to be at risk. Internet resources Fabry Support & Information Group: http://www.fabry.org The Fabry Community: www.fabrycommunity.com National Institute of Neurological Disorders and Stroke: http://www.ninds.nih.gov/disorders/fabrys/ fabrys.htm Fabrazyme website: Prognosis In time, experience with the use of enzyme replacement therapy will determine its effectiveness in the prevention, reversal or stabilization of renal disease, which is the main determinant of morbidity in this disorder. Both renal replacement therapy and transpla ntation are now recognized treatments for Fabry disease. http://www.fabrazyme.com GeneTests website detailing centers offering genetic test- ing for Fabry disease: http://www.genetests.org/query?testid=2775 Future prospects Future research will investigate the use of gene therapy strategies for Fa bry disease. See also Chronic kidney disease in children, p. 462 Other metabolic storage disorders with renal involvement, p. 624 Investigation of inherited renal disease, p. 582 Another area for future development is the use of small molecules ( \200\230pharmacologic c haperones \200\231) that rescue and This page intentionally left blank R.S. PATEL 624 Other metabolic storage disorders with renal involvement Glycogen storage disease type I (Von Gierke \200\231s disease) (Glucose 6-phosphatase de \201 ciency) The glycogen storage disorders primarily affect the liver, heart, and muscle. Patients are able to synthesize and store glycogen but are unable to break glycogen down to release stored glucose. The principle manifestations are therefore glyco- gen accumulation in the liver and repeated episodes of hypoglycemia. More than ten distinct metabolic lesio ns contribute to this group of diseases but primary renal involvement only occurs in glycog en storage disease type 1 (GSD1). GSD1 is the commonest type of glycogen storage disease, a ccount- ing for 25% of all cases. GSD1 may be subdivided into two major forms: \200 Early hyper \201 ltration ultimately leads to secondary focal and segmental glomeruloscler osis and progressive CKD. Clinical features Presentation is usually with hypoglycemia. Abdominal pain is a common fea ture and may be due to: \200 \200 \200 hepatosplenomegaly; uric acid nephrolithiasis; pancreatitis. Large and small joint involvement may also occur. A protruding abdomen and short stature ar e the most common physical signs. Hepatomegaly is common as the number and size of ade- nom as increase with time. There may also be signs of hyperlipidemia (tendon xan- thomata) and hyperuricemia (tophi). Most patients by the time they are 20 years old will have some degre e of: \200 proteinuria; \200 hypertension; \200 nephrolithiasis; \200 renal impairm ent. Type 1a: glucose-6-phosphatase (G6P) de \201 ciency ( 80% cases); Type 1b: glucose-6-phosp hatase translocase de \201 ciency (enzyme involved in intracellular traf \201 cking of G6 P). Epidemiology The incidence of GSD1 is 1 per 100 000 live births. The incidence is higher in North Africa where it may be as high as 1 per 5000 live births. The risk of developing ESRD is variable but the likelihood is increased with increasing pro teinuria. Genetics GSD1 is an autosomal recessive disorder and therefore affects males and females eq ually. The gene for G6P lies at 17q21 and the gene for G6P trans- locase at 11q23. Diagnosis Genetic testing is possible but the gold standard for establishing the diagnosis remains a liver biopsy and com- parison of glycogen content to glucose 6-phosphatase levels . Treatment There is no cure. Treatment focuses on correcting the associated metabolic change s and promoting growth and development. Effectively this is managed through regular feeding to avoid hypoglycemia and avoidance/restriction of sucrose, fruc- tose, lactose and galact ose to prevent excessive glycogen accumulation. Pathology Glycogen and glucose-6-phosphate accumulate in the: \200 \200 \200 \200 liver; heart; kidneys; muscles. Hyperlipidemia occurs as a result of increased hepatic lipo- genesis. Hepatic adenomas may develop. These are benign tumors usually \201 rst noted around the time of puberty. They typi- cally do not cause symptoms and are identi \201 ed by routine imaging studies of the liver. In rare instances they can undergo malignant transformation. 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.