Familial LCAT deficiency (FLD) is an uncommon autosomal recessive disorder resulting from a heritable defect in the esterification of plasma cholesterol. Increased plasma concentrations of unesterified cholesterol, triglycerides, and phosphatidylcholine result in lipid deposition in tissues. The enzyme LCAT is carried by high-density lipoprotein (HDL) with Apolipoprotein (Apo) AI as a cofactor, and it catalyzes the esterification of free cholesterol bound to lipoproteins. Mutations in the LCAT gene, localized to chromosome 16q21-q22, cause classic familial LCAT deficiency (FLD) and fish eye disease (FED). More than 60 mutations have been described, all of which result in greatly reduced concentrations of high-density lipoprotein (HDL). The residual plasma HDL is characterized on electron microscopy by an accumulation of disk-shaped pre-β HDL that may form rouleaux. Other lipid phenotypes include morphologically abnormal low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) particles and the formation of free cholesterol and phospholipid-rich, triglyceridepoor vesicles known as lipoprotein X (LpX) (1).

Classic FLD is due to the inheritance of homozygous or complex heterozygous deletions that either abolish LCAT production or cause the synthesis of an LCAT enzyme with complete or nearly complete loss of both α-LCAT and β-LCAT activities. The disease, originally described in Norway, appears to be widely distributed. Clinical manifestations of FLD include corneal opacities, hemolytic anemia, accelerated peripheral atherosclerosis, and proteinuria with renal insufficiency. Lipid deposits also occur in the liver, spleen, and bone marrow, in which foam cells (sea-blue histiocytes) are present (2). In contrast to FLD, FED patients, whose lipid/lipoprotein profile overlaps with that seen in FLD, have reduced α-LCAT activity but preserved β-LCAT activity (1). In FED, there are no major clinical manifestations except corneal opacity. Heterozygous carriers may have a lipid/lipoprotein profile intermediate between carriers of two and zero copies of mutant alleles.

Renal involvement, the major cause of morbidity and mortality, commonly begins with proteinuria during childhood (3), and it culminates after several decades of renal insufficiency. The progression of renal disease is variable; some patients show severe proteinuria, and others experience little.

Hypertension may appear early in the course or as a late complication of renal insufficiency. Urinalysis usually shows mild hematuria, leukocyturia, and cylindruria. Renal insufficiency is not invariable (1); when present, it usually develops by the fourth decade.

Lipoprotein glomerulopathy (LPG) is a rare disorder associated with distention of glomerular capillaries by lipoprotein thrombi, proteinuria, and progression to renal failure (22). The majority of patients are of Asian ancestry, principally Japanese and Chinese, but occasional cases have been in patients with non-Asian backgrounds (23,24,25,26,27,28,29). The disease may present in childhood, and males outnumber females approximately three to two (23,30). Subjects have a characteristic biochemical finding of a twofold to threefold elevation of serum ApoE level, usually accompanied by hyperlipidemia with a predominance of triglycerides (30). Detailed analysis using electrophoresis or ultracentrifugation shows increased very low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL) fractions, which resembles type III hyperlipoproteinemia (HLP); however, hyperlipidemia is often milder than in familial type III HLP and not even recognized in some cases (23). Unlike type III HLP, systemic manifestations of hyperlipidemia, corneal arcus, cutaneous xanthomas, and atherosclerosis are very uncommon in LPG. The finding of ApoE2 heterozygosity by isoelectric focusing, rather than ApoE2 homozygosity, typical in type III HPL, also helps to differentiate the diseases.

Clinical onset is usually marked by proteinuria, and most develop steroid-resistant nephrotic syndrome. Hematuria is not typical. The disease may undergo spontaneous amelioration, but slow progression to renal failure has been observed in half of patients (23).

Type III HLP with characteristic xanthomas develops in approximately 10% of patients who are homozygous for ApoE2/2, where it is associated with combined and often severe mixed hyperlipidemia caused by the accumulation of β-VLDL, which leads to accelerated atherosclerosis. The ε2 allele is found in approximately 8% of the population (30), and ApoE2 homozygosity occurs with a frequency of about 1% in Caucasian populations. That only a minority of ApoE2 homozygotes develop type III HLP implies a multifactorial disorder, and recent studies found an increased incidence of rare ApoC3 and ApoA5 alleles in those expressing an abnormal lipid profile (48). Uncommonly, these patients develop glomerular lipidosis, manifested as proteinuria. Renal biopsies have shown large numbers of foam cells in the glomerular mesangium and distending glomerular capillaries (Fig. 27.9). Interstitial foam cells have been noted. Lipid vacuoles focally admixed with lamellated electron-dense material and occasional cholesterol clefts have been detected by electron microscopy in the cytoplasm of glomerular intracapillary foam cells, as well as in mesangial, endothelial, and tubular epithelial cells. Podocyte foot processes may be effaced. Renal lipid deposits have cleared with plasmapheresis and lipid-lowering agents. Similar renal pathology including glomerular foam cells was recently described in a patient whose lipid profile was compatible with type III HLP, but whose genotype was ApoE2/3 and in whom a novel ApoA5 mutation was discovered (49). “Lipoprotein glomerulopathy-like” disease has also been described in a few patients with type III HLP (38).

This condition, described by both Fabry and Anderson in 1898, is a rare metabolic disorder arising from a deficiency of a lysosomal exoglycohydrolase, ceramide trihexosidase, commonly referred to as α-galactosidase A (55). The enzyme catalyzes the cleavage of glycosphingolipids, especially globotriaosylceramide, which is present in most cell membranes. Deficient enzyme activity results in the systemic accumulation of neutral glycosphingolipids with terminal α-linked galactosyl moieties, primarily globotriaosylceramide (Gb3), in plasma and particularly lysosomes of vascular endothelia of the kidneys, heart, brain, and skin.

The disease is uncommon, although it is the second most prevalent inherited lysosomal storage disorder after Gaucher disease. Recent estimates of the frequency range from 1 in 40,000 to 1 in 117,000 births; however, Fabry disease may be more prevalent because of a lack of recognition in patients with isolated renal or cardiac involvement. The prevalence of previously undiagnosed Fabry disease in dialysis patients, with subsequent DNA confirmation, was shown to be 0.33% in men and 0.10% in women undergoing dialysis. Approximately 3% to 4% of patients with left ventricular hypertrophy or cardiomyopathy are discovered to have Fabry disease, and newborn screening programs with subsequent mutational analysis found an incidence of 1 in 3100 to 4700 male infants (56,57). More than 500 mutations of the α-galactosidase gene at Xq22.1 have been described, and most are family specific (55,58). About 5% of the cases are sporadic. Mutations leading to complete loss of gene product are associated with classic forms of the disease, whereas those resulting in amino acid substitutions might occasionally link to a mild phenotype or late manifestation; however, genotype-phenotype correlations are low. The X-linked disease is completely expressed in hemizygous males, but clinical presentation is quite variable, even within families. Most heterozygous females, contrary to historical accounts, are affected. Highly variable levels of enzyme activity in females and the broader range of clinical symptoms can only partly be accounted for by X inactivation (59). Although renal biopsy may be diagnostic, and EM is a reliable approach to identify the intracellular myeloid bodies, they are not pathognomonic as similar structures are present in silicon nephropathy and pseudolipidosis induced by amiodarone, chloroquine, and hydroxychloroquine (60,61,62,63). An aid to diagnosis may be immunofluorescence with a monoclonal anticeramide trihexoside; this technique has been effectively employed in routinely processed paraffin-embedded tissue (64). Affected males with classic and variant phenotypes are reliably diagnosed by the demonstration of deficient enzyme activity in plasma, leukocytes, cultured cells, or dried blood spots (65). By contrast, female carriers can exhibit normal α-galactosidase A levels, such that exclusion of a carrier status can only be done by mutational analysis of the α-galactosidase A gene. High-throughput PCR-based technologies, such as high-resolution melting analysis, may be cost-effective for newborn screening in females (66). Prenatal diagnosis is possible by amniocentesis, but preferred methods include enzyme and molecular testing on fresh fetal tissue obtained by chorionic villus sampling (67). Diagnosis by molecular probes is typically limited to patients with a positive family history and known mutation; DNA sequencing has proven to be the most reliable strategy for mutation detection. Routine mutational analysis, however, may miss deletions and duplications, which are better detected using quantitative and real-time PCR, multiplex probe amplification and hybridizations, and array comparative genome hybridization (65). New screening tools, based on measurement of urinary Gb3 isoforms via electrospray ionization mass spectrometry, as well as identification of unique proteomic biomarker profiles using capillary electrophoresis coupled to mass spectrometry, may prove relevant for screening females and monitoring response to enzyme replacement therapy (68,69).

Manifestations in hemizygous males may begin in early childhood although storage material has been observed in the prenatal period (70). The earliest and often disabling symptom is acroparesthesia. Gastrointestinal symptoms, nausea, abdominal pain, and diarrhea, commonly appear in childhood and persist into adulthood. Strokes and transient ischemic attacks are not uncommon. Cardiac disease is a well-recognized complication, classically, hypertrophic cardiomyopathy that may initially manifest as arrhythmias in childhood. The skin lesions—angiokeratomas—cluster on the lower trunk and thighs as reddish purple dark spots or papules with dilation of superficial capillaries and variable hyperkeratosis. They typically develop during adolescence and increase with age but are rarely problematic. They remain a valuable clue to the diagnosis because they are seen in only a few rare conditions. Anhidrosis or hypohidrosis and corneal opacities are seen in most patients (71). In addition to the classical phenotype, there are milder variants with residual α-galactosidase A activity that lack the characteristic features. “Cardiac” and “renal” variants present with late-onset manifestations primarily limited to the heart and kidney, respectively (55). Males generally experience onset of symptoms earlier than females, with a median age of 6 years versus 9 years in females.

Progressive nephropathy is a major feature, and ESRD can occur during adolescence (72). Clinical evolution to renal insufficiency and hypertension is variable over several decades and correlates with residual α-galactosidase activity (73). Glomerular pathology may exist, despite the presence of an apparently


normal estimated glomerular filtration rate (GFR), without manifestation of overt proteinuria or even microalbuminuria (74,75,76). As clinical parameters lack sensitivity, kidney biopsy has been employed by some to assess baseline injury (74,76). Proteinuria seems to be the most important predictor for renal progression, especially for men, in whom advanced nephropathy is more prevalent and generally occurs earlier (77,78). Most females have slowly progressive kidney disease; however, the subset (15% to 20%) that develops ESRD does so at approximately the same age as men (79). Loss of urine-concentrating ability leads to polyuria and polydipsia, and altered tubular functions have also been identified, such as impaired glucose and potassium reabsorption, to a greater degree than can be accounted for by reduced GFR (80). The urine sediment contains lipid globules showing Maltese crosses on polarization and desquamated cells containing myeloid bodies (81).

Cobalamin C (CblC) is required for conversion of dietary vitamin B₁₂ to its reduced and methylated forms, which function as coenzymes. Deficiency of cblC is a panethnic disease and the most common inborn error of cobalamin metabolism, with an estimated incidence of 1:100,000 based on expanded newborn screening (126). Cobalamin C defects lead to impaired activities of methylmalonyl-CoA mutase and methionine synthase, resulting in methylmalonic aciduria and homocystinuria. The disorder is inherited as an autosomal recessive trait, and the severity of presentation can vary considerably. CblC-deficient patients typically present in the newborn period with failure to thrive, neurologic and ophthalmologic abnormalities, and hematologic disturbances, especially megaloblastic anemia. Cardiopulmonary and gastrointestinal involvement is not uncommon. Hemolytic uremic syndrome (HUS) is characteristic, and proteinuria may be apparent. Late-onset disease is rarer and milder and can appear at any time from early childhood to adulthood, presenting as neurologic deterioration without systemic symptoms (127,128). Renal damage may be the sole manifestation of late-onset disease (129,130).
CblC defect can be difficult to diagnose on a clinical basis due to its heterogeneous manifestation but is established by finding the combination of methylmalonic aciduria, homocystinuria, and increased propionylcarnitine with normal serum vitamin B₁₂ and transcobalamin II concentrations.

Renal pathology in this group of patients has most typically been that of thrombotic microangiopathy (129,131). The glomeruli have shown mesangial expansion with mild mesangial and endothelial proliferation, endothelial swelling, capillary dilation, and basement membrane double contours (Fig. 27.23). Intracapillary fibrin or platelet thrombi can be seen. Foot process effacement, endothelial cell detachment, and expansion of the subendothelial space by granular, fibrillary material have been noted by electron microscopy (Fig. 27.24). Immunofluorescence is typically negative or nonspecific, but the peripheral glomerular membrane and primarily mesangial C3, C1q, and IgM were found in a single case, which also had widespread electron-dense deposits (131).

Nearly 60 causal mutations have been identified in the recently discovered responsible gene designated MMACHC, which maps to chromosome region 1p34.1 (132,133). The protein is involved in binding cobalamin, decyanating cyanocobalamin, and dealkylating alkylcobalamins (134). Presumed mechanisms for the renal pathology include hyperhomocysteine- and hypomethionine-induced vascular damage and methylmalonate-induced proximal tubular injury (128). Successful management requires large amounts of hydroxocobalamin and betaine. Many patients die from severe hemolytic anemia, and in those without HUS, there is often improvement of hematologic, biochemical, visceral, and growth parameters although neurologic and visual complications persist (128).

Isolated methylmalonic acidemia is an autosomal recessive disorder of branched-chain amino acid metabolism that has a varied presentation, but neonatal onset is typified by recurrent vomiting, lethargy, dehydration, failure to thrive, hypotonia, and metabolic ketoacidosis that, if untreated, results in multiorgan failure or death. It is caused by a deficiency of the enzyme methylmalonyl-CoA mutase (MCM) due to mutations in the MUT gene located on the short arm of chromosome 6 in which approximately 200 mutations have been identified (135). Defects in cobalamin metabolism (cblA, cblB, cblD variant 2) and a deficiency of methylmalonyl-CoA epimerase also yield methylmalonic acidemia (135). Children with complete MCM deficiency are cobalamin nonresponsive and typically develop renal tubular dysfunction that often progresses to ESRD by late childhood or early adolescence; partial enzyme activity correlates with lower urinary methylmalonic acid concentration, which might predict occurrence of renal failure (136,137). Assessment of nonvolatile organic acid patterns, acylcarnitine profiles, and complementation analysis are useful for diagnosis (135). Treatment is centered on dietary control and carnitine supplementation, with emergency support during times of illness.

Chronic organ damage ensues despite improved outcome of the acute metabolic crisis. Impaired renal function occurs in the majority of patients, and kidney pathology has shown tubulointerstitial nephritis with interstitial fibrosis, tubular atrophy, and interstitial mononuclear cell infiltrates (138). Mitochondrial dysfunction has been demonstrated in the MCM-deficient kidney and human proximal tubule cell models and might be implicated in renal perturbation (139,140). Chronic renal failure usually develops in the first or second decade and can be treated with dialysis. Liver transplantation provides enzyme to effectively avoid systemic metabolic derangement, but renal transplantation is required for replacement of localized kidney enzyme; neither prevents the neurologic complications that develop in some patients. The effectiveness of combined kidney and liver transplantation as a therapeutic option remains to be proven (141,142).

The glycogen storage diseases are genetic defects that result in the storage of abnormal amounts and/or abnormal forms of glycogen. Some affect several tissues, whereas others may affect only one, most commonly the liver or muscle because of their abundant quantities of glycogen.

Glycogen storage disease type I (GSD-I) is a group of autosomal recessive disorders with an incidence of 1 in 100,000. It includes two major subtypes: GSD-Ia (von Gierke disease), caused by a deficiency of glucose-6-phosphatase alpha (G6Pase-α), which accounts for about 80% of cases; and GSD-Ib, caused by a deficiency in the glucose-6-phosphate transporter (G6PT) (143,144). Glucose-6 transporter translocates glucose-6-phosphate from the cytoplasm into the lumen of the endoplasmic reticulum, where G6Pase-α hydrolyses it into glucose and phosphate; together, these enzymes maintain glucose homeostasis, and their deficiency results in an accumulation of glycogen, as conversion of glucose-6-phosphate to glucose in both glycogenolysis and gluconeogenesis is impaired. Glucose-6-phosphatase-α is expressed in high levels in the gluconeogenetic liver and kidney, whereas G6PT is ubiquitous.

Patients with GSD-I commonly become symptomatic in early infancy, presenting with hepatorenomegaly and hyperlactacidemia. They are hypoglycemic, with large abdomens and rounded faces, and some present with seizures. Hyperlipidemia, paralleling that in type IV hyperlipidemia, causes xanthomas; hyperuricemia may cause symptoms of gout in older children. The diagnosis, based on clinical and biochemical findings, is confirmed by measurement of G6Pase-α activity in fresh liver biopsy samples. More recent recommendations for diagnosis combine clinical and biochemical abnormalities with mutational analysis, the latter of which can also be used for carrier testing of at-risk families and prenatal diagnosis (144).

Renal enlargement begins early, and functional impairment is a late complication. Effective renal plasma flow (RPF) and glomerular filtration are increased at first, followed by microalbuminuria with subsequent proteinuria and hypertension. Microalbuminuria and proteinuria have been detected in children less than school age (145). The degree of hyperfiltration correlates with renal size. Patients have an incomplete form of distal tubular acidosis, and they are prone to hypercalciuria with development of nephrocalcinosis and stone disease, which can be demonstrated within the first year of life (146). Hyperuricemia, if untreated, can lead to gout. A form of Fanconi syndrome, originally thought to be associated with GSD-I, is now attributed to Fanconi-Bickel syndrome (see section later in this chapter).

Of the peroxisome biogenesis disorders, Zellweger syndrome (ZS) (cerebrohepatorenal syndrome) is the most severe and caused by various mutations in at least 13 different PEX genes that encode peroxins, proteins involved in different stages of peroxisomal protein import, and/or the biogenesis of peroxisomes. Peroxisomal enzymes, synthesized in the cytosol, fail to be incorporated into peroxisomes, resulting in a complete deficiency of functional peroxisomes and all peroxisomal functions (159). PEX1 mutations are most common in ZS, and those that induce premature stop codons correlate with the most severe phenotype and shortest survival (160). Peroxisomes are markedly reduced and sometimes absent in the kidney, liver, and other organs (161). Infants are affected at birth and show severe hypotonia, feeding disability, brain and hepatic dysfunction, periarticular calcifications, and characteristic facies. Elevated very long-chain fatty acids in blood and tissues are diagnostic, but confirmation of “ZS spectrum” patients may require complementation analysis or PEX gene testing (162,163).

More than 90% of patients have renal cortical cysts, often of glomerular origin, that may develop in utero and vary from microscopic dimensions to several centimeters in size (Figs. 27.28 and 27.29) (158,164). Most patients die within the 1st year of life. Although the renal cysts are usually asymptomatic and renal function is usually normal, occasional instances of albuminuria, aminoaciduria, and mild azotemia have been described. A high incidence of hyperoxaluria, occasionally associated with urolithiasis and nephrocalcinosis, has been observed (165).

The hypotonia, hepatic dysfunction, facial dysmorphism, and renal cysts of Zellweger could be confused with the entity of glutaric aciduria type 2 (multiple acyl-CoA dehydrogenase deficiency), a mitochondrial electron transfer disorder, but a characteristic organic acid pattern in the urine establishes the latter diagnosis. Renal anomalies in glutaric aciduria type 2 may be dramatic and include extensive cortical and medullary cyst formation, sometimes with dysplastic changes (166).

Adult (classic) Refsum disease (heredopathia atactica polyneuritiformis), a rare autosomal recessive disorder, results from an abnormal accumulation of phytanic acid owing to a defect in phytanoyl-CoA hydroxylase (PhyH). Most patients harbor mutations in the PHYH gene, although in a subset, mutations have been found in PEX7, which encodes the peroxisomal targeting signal receptor that is required for the import of PhyH into peroxisomes (167). Heterozygotes, with approximately 50% enzyme activity, do not accumulate phytanic acid.

Phytanic acid is a 20-carbon, branched-chain fatty acid derived from phytol, a component of chlorophyll. The human source of phytol and phytanic acid is entirely dietary, from dairy products and animal fats. Phytanic acid is stored in plasma and tissues, mostly adipose tissue, liver, kidney, muscle, and nerve, predominantly in triglycerides, and to a lesser extent in phospholipids and cholesterol esters (168). Phytanic acid may cause cellular toxicity by mitochondrial inhibition (169,170).

Clinical symptoms usually present in late childhood as anosmia and night blindness, caused by retinitis pigmentosa. Peripheral neuropathy, cerebellar ataxia, nerve deafness, cardiac arrhythmias, and ichthyosis often occur in the following decades (171). About 35% of patients have bone abnormalities, especially in the hands and feet, that are present at birth but typically are not recognized until other disease manifestations
become evident. High concentrations of protein are present in the spinal fluid. Full expression of the disease occurs during the fourth or fifth decade, but it can manifest in childhood.

Renal involvement is demonstrated by proteinuria, mild renal insufficiency, glycosuria, and lipiduria. Elevated plasma phytanic acid esters are demonstrated by gas chromatography, but these elevations are not specific to Refsum disease since they are seen in peroxisome biogenesis disorders; molecular genetic testing is clinically available. The condition is treated by dietary restriction and lipid apheresis (172).

Primary hyperoxaluria (PH) is a rare autosomal recessive calcium oxalate kidney stone disease with three recognized molecular causes (175). In type 1 (PH1), which is the most common, continuing renal deposition of calcium oxalate leads to nephrocalcinosis, recurrent nephrolithiasis, and chronic renal insufficiency. The disease is caused by a deficiency of the vitamin B₆-dependent liver-specific peroxisomal alanine-glyoxylate aminotransferase (AGT), which transaminates glyoxylate to glycine. Glyoxylate thus accumulates and is instead oxidized to oxalate and reduced to glycolate. Oxalate is not metabolized further and is eliminated from the body in the urine.

Crystallization occurs from highly concentrated solutions, causing urolithiasis or nephrocalcinosis with renal tubulointerstitial damage and progressive renal functional impairment. Primary hyperoxaluria type 1 is characterized by hyperoxaluria and hyperglycolic aciduria. Renal colic and hematuria, secondary to urolithiasis, often commence in childhood, although there is marked heterogeneity in the onset and severity, even within families. Five clinical presentations have been
recognized: (a) infantile oxalosis with early nephrocalcinosis and kidney failure; (b) childhood recurrent urolithiasis and rapidly progressive renal failure; (c) late onset with only occasional stone passage in adulthood; (d) post-kidney transplantation recurrence; and (d) presymptomatic discovery with family screening (176). Approximately 10% of patients have severe disease, with early infantile onset manifesting as failure to thrive, severe metabolic acidosis, anemia, and rapid progression to renal failure, whereas another 10% may not become symptomatic until the fourth or fifth decades (177). Progressive parenchymal deposition of calcium oxalate impairs renal function, which ultimately leads to systemic oxalosis. Complications include severe deforming osteopathy, arthropathy, cardiomyopathy, retinopathy, neuropathy, and pancytopenia. The kidneys are often small and may feel gritty on cut section (Fig. 27.31). Small, polyhedral or rhomboid, usually transparent, doubly refractile crystals are recognized histologically and accumulate in tubules, where they compress and destroy epithelium. The crystals can extend into the interstitium and induce fibrosis (Fig. 27.32). End-stage kidneys show extensive glomerulosclerosis and widespread interstitial fibrosis that encases abundant crystals (Fig. 27.33). Stone analysis demonstrates virtually pure (>95%) calcium oxalate monohydrate (whewellite) and a whitish or pale-yellow surface with a loose, unorganized center comprised of spherical, variably sized crystal aggregates, approximately 50 µm in diameter, that resemble balls of wool (178).

PH should be suspected in any child with a renal stone, any adult with recurrent stone disease, and anyone with oxalate crystals in tissues or body fluids or with nephrocalcinosis and decreased GFR. Renal ultrasound may disclose stones and possibly medullary or diffuse nephrocalcinosis. Markedly elevated
levels of urinary oxalate usually indicate PH in the absence of any likely causes of secondary hyperoxaluria, either increased intake (excessive star fruit and peanut ingestion), increased absorption (“enteric hyperoxaluria” related to orlistat therapy or gastrointestinal disease or surgery), or increased production (ascorbic acid or ethylene glycol ingestion). Histologic demonstration of calcium oxalate deposition in the kidney has been used for diagnosis, but it is not specific for primary disease; determining the AGT activity in a liver biopsy sample has been considered the gold standard for diagnosis. Molecular genetics has now reached a level of sensitivity and specificity that makes it useful for definitive testing and is also considered the preferred method for prenatal testing (179). More than 150 mutations have been identified in the AGXT gene, which resides on chromosome 2q37.3 (180,181). Mutations result in accelerated proteolysis, peroxisome-to-mitochondrion targeting defects, intraperoxisomal AGT aggregation, absence of AGT catalytic activity, and absence of both catalytic activity and immunoreactivity. The clinical heterogeneity may relate to great variability in enzymatic activity among patients but is clearly influenced by potential modifier genes, environmental factors, and genetic background, as the genotype-phenotype correlation is limited. However, some mutations that result in AGT mistargeting appear to be associated with responsiveness to pyridoxine treatment (181,182,183,184,185,186).

Type 2 hyperoxaluria (PH2) is caused by defective cytosolic glyoxylate/hydroxypyruvate reductase (GRHPR) due to mutations in the GRHPR gene located on chromosome 9, in which at least 15 mutations have been identified (175,187,188). Type 2 PH is rare and can be distinguished from PH1 by finding elevated glycolate and L-glycerate in addition to high oxalate levels. Clinical manifestations are less severe and consist primarily of urolithiasis, although ESRD has been documented (175,189,190). Liver enzyme analysis confirms the diagnosis. PH3 is caused by mutations in the HOGA1 gene located on chromosome 10q24. The encoded enzyme, 4-hydroxy-2-oxoglutarate aldolase, catalyzes the synthesis of mitochondrial glyoxylate and is found primarily in the liver and kidney. Patients primarily suffer from urinary stones, but urinary oxalate concentration overlaps with PH1 and PH2. The age of onset is similar, but occasional adult presentation may imply a milder disease (191,192).

Generous fluid intake and drugs that increase the urinary solubility product are important therapeutic measures (193). Pyridoxine (vitamin B₆), which affects AGT expression or activity, lowers urinary oxalate in only about one third of patients (193). Pyridoxamine, by scavenging carbonyl intermediates in the glyoxylate pathway, inhibits oxalate biosynthesis, has been shown to decrease crystal formation in hyperoxaluric animal models, and may offer therapeutic hope for the treatment of PH (194). Combined liver/kidney transplantation, which results in enzyme replacement, has achieved better outcomes than the disappointing early results from isolated kidney transplantation, in which oxalate deposits constantly recurred in the graft (179,195,196,197). Preemptive liver transplantation may be considered in some settings (198).