Retinal Abnormalities Characteristic of Inherited Renal Disease

BRIEF REVIEW

www.jasn.org

Retinal Abnormalities Characteristic of Inherited Renal Disease Judy Savige, Sujiva Ratnaike, and Deb Colville Department of Medicine, Northern Health, The University of Melbourne, Epping, Victoria, Australia

ABSTRACT Many inherited renal diseases have retinal features that are helpful diagnostically. These include coloboma, drusen, atrophy and pigmentation (retinitis pigmentosa), hamartoma, vascular anomalies, and crystals. Retinal abnormalities occur because the kidney and retina share developmental pathways and structural features including basement membrane collagen IV protomer composition and their vascularity, and because both the kidney and retina are functionally dependent on ciliated cells. Diagnosis of inherited renal disease is important because of the risks of further renal and systemic complications, the implications for other family members, the predictability of the clinical course, and the possibility of treatment. Furthermore, retinal abnormalities may help explain the pathogenesis of the renal disease, and can sometimes be used to monitor its course. J Am Soc Nephrol 22: ●●●–●●●, 2011. doi: 10.1681/ASN.2010090965

Inherited disease accounts for half of all children and 1 in 5 adults with endstage renal failure (Table 1).1 The prevalence of individual diseases varies from 1 in 5 to 10,000 for Alport syndrome and membranoproliferative glomerulonephritis type 2, to 1 in 50,000 for the rarer conditions such as Fabry disease.2 The challenge is to identify inherited renal disease when the phenotype is mild or atypical, or when there is no family history, which occurs with de novo mutations, recessive inheritance, and dominant disease with variable expression or penetrance. Inherited renal disease is suspected when there is a family history of similar features, or when abnormalities affect multiple systems without another obvious explanation.3 Databases such as ORPHANET (http://www.orpha.net) and OMIM (http://www.ncbi.nlm.nih.gov/ omim) suggest patterns of organ involvement. Many inherited renal diseases have hearing loss (Table 2), and ocular, espeJ Am Soc Nephrol 22: ●●●–●●●, 2011

cially retinal, abnormalities. Notable exceptions, based on current knowledge, are the autosomal dominant and recessive forms of polycystic kidney disease, medullary cystic kidney disease, and thin basement membrane nephropathy.

WHY THE KIDNEY AND RETINA SHARE INVOLVEMENT IN INHERITED DISEASES

Inherited renal disease often also involves the retina because the kidney and retina develop at the same embryonic stage and share developmental pathways;4 the glomerular filtration barrier and retinochoroidal junction are structurally similar;5 the glomerulus and chorioretina are both large capillary beds, and the renal epithelial (podocyte) and retinal pigment epithelial (RPE) cells are critically dependent on cilia to function.

The Kidney and Eye Share Developmental Pathways

Both the PAX and WT1 pathways are important in the embryogenesis of the kidney and retina.4 The PAX genes encode nuclear transcription factors that control development of the kidney, eye, ear, brain, vertebral column and limb muscles.6 PAX2 is required for development of the urogenital tract, eye, ear, and brain. The WT1 gene is necessary for ureteric bud formation and retinal ganglion cell differentiation.7,8 Mutations in PAX2 result in the renal-coloboma syndrome with vesicoureteric reflux, and WT1 mutations produce Wilm’s tumor, and the WAGR, Frasier, and Denys-Drash syndromes.9 –11 The Retinochoroidal Junction Resembles the Glomerular Filtration Barrier

RPE cells, Bruch’s membrane, and the fenestrated choriocapillaries of the retina resemble the podocytes, glomerular basement membrane (GBM), and fenestrated capillaries of the glomerular tuft, respectively. The epithelial cells have organ-specific functions, the basement membranes support the adjacent structures and form a barrier that prevents the Published online ahead of print. Publication date available at www.jasn.org. Correspondence: Dr. Judy Savige, Department of Medicine, Northern Health, The University of Melbourne, The Northern Hospital, Epping, Victoria 3076, Australia. Phone: ⫹613 8405 8823; Fax: ⫹613 8405 8724; E-mail: [email protected] Copyright © ●●●● by the American Society of Nephrology

ISSN : 1046-6673/2204-●●●

1

BRIEF REVIEW

www.jasn.org

Table 1. Inherited renal diseases that present in adults as well as children Autosomal recessive polycystic kidney disease140 Alport syndrome46 Membranoproliferative glomerulonephritis Nephronophthisis141 Bardet-Biedl syndrome142 Alagille syndrome143,77 MELAS syndrome80,81 Kearns-Sayre syndrome82 LCAT deficiency115 Cystinosis129 Oxalosis121 Fabry disease144,145

Table 2. Inherited renal diseases associated with hearing loss Renal coloboma syndrome146 CHARGE syndrome24 Alport syndrome47 MELAS syndrome80,81 Kearns-Sayre syndrome82 Leber Amaurosis Alstrom syndrome72 Fabry disease94 Charcot-Marie-Tooth disease Bartter syndrome147 Wolfram syndrome Hurler syndrome Nephronophthisis63 Bardet-Biedl syndrome142

passage of macromolecules, and the capillaries provide nutrition and remove waste from nearby metabolically active cells. After infancy, the GBM, and the internal limiting and Bruch’s membranes in the retina comprise the same specialized collagen IV ␣3␣4␣5 protomers.12,13 Mutations in the collagen IV genes (COL4A1 and COL4A3 through COL4A5) result in Hereditary Angiopathy with retinal tortuosities, Nephropathy, Aneurysms, and muscular Cramps (HANAC), and in X-linked and the autosomal recessive forms of Alport syndrome, respectively. Ciliated Cells

Cilia transmit mechanosensory, visual, and osmotic stimuli, and both podocytes and RPE cells depend on their primary cilia for specialized cell functions. Mutations affecting proteins in 2

the podocyte cilia or related structures result in cystic kidney disease14 including nephronophthisis and its variants (the nephrocystins) and Bardet-Biedl syndrome (BBS1 through BBS12 etc.). The retina is commonly affected,15 and other clinical features include hearing loss, abnormal limb and digit development, developmental delay, situs inversus, liver and respiratory disease, and infertility.16

RETINAL ABNORMALITIES IN INHERITED RENAL DISEASE

Retinal abnormalities in inherited renal disease include coloboma, drusen, atrophy and pigmentation (retinitis pigmentosa), hamartoma, vascular anomalies, and crystals (Table 3; Figure 1). These changes may also be accompanied by the retinal associations of renal failure such as hemorrhage,17 arteriolar narrowing, exudates, infarcts,18 calcification,19,20 and macular degeneration.21

COLOBOMA

Coloboma result from defective closure of the embryonic fissure of the optic cup. These defects are typically located in the lower part of the iris, chorioretina, or optic disc. Optic disc coloboma occur in vesicoureteric reflux and other structural urinary tract disease.22 Optic disc and chorioretinal and iris coloboma are found in the CHARGE and COACH syndromes, and possibly in nephronophthisis and tuberous sclerosis.23–26 Coloboma are identified by careful ophthalmoscopic examination and photography of both fundi of the presenting individual and their family members. Coloboma are typically asymmetrical with, for example, a normal eye or mild defect in one eye, and a severe central abnormality in the other.27 Likewise, the severity of the defect varies in individual members of a family. There is no treatment and they may be complicated by glaucoma, retinal detachment, and central serous retinopathy.28

Journal of the American Society of Nephrology

Renal-Coloboma Syndrome (Papillorenal Syndrome, OMIM 120330)

Coloboma are found in ⬍5% of patients with reflux nephropathy or other renal structural defects but many are probably unrecognized. Inheritance is autosomal dominant, but only 50% of patients with the renal-coloboma syndrome have PAX2 mutations.22,27 The other genes are not known. PAX2 mutations are different in each family and have their effect through interfering with the vascular supply of the urinary tract and eye. Some mutations cause reflux only without coloboma29 but none causes isolated coloboma. The renal abnormalities in renal-coloboma syndrome include vesicoureteric reflux, renal hypoplasia, multicystic or dysplastic kidneys, and renal failure.30,31 The age at presentation and rate of progression to renal failure vary even within families. Ocular features vary from optic disc pits to large chorioretinal coloboma, and abnormalities are usually asymmetrical.27 Pits are subtle and may be overlooked on ophthalmoscopy. In more severe disease the retinal vessels emerge from the periphery of the optic disc.32 The surrounding retina appears atrophic. Vision varies from normal to severely impaired.33 Fewer than 20% patients have associated sensorineural hearing loss, seizures, Arnold-Chiari malformations, or skin and joint laxity.30 Patients with papillorenal syndrome should be monitored for ophthalmic complications and other family members screened carefully for optic disc defects. PAX2 mutations do not occur in the CHARGE or COACH syndromes and do not cause iris coloboma. CHARGE Syndrome (OMIM 214800)

This comprises Coloboma of the iris, Heart anomalies, Atresia of the nasal choanae, Retardation of growth and/or development, Genital and/or urinary abnormalities (hypogonadism), and Ear abnormalities with deafness.24 This condition affects 1 in 10,000 individuals and demonstrates autosomal dominant inheritance. Sixty percent of patients have a mutation in the CHD7 gene34 which codes for a DNAbinding protein involved in early embryonic development. Ninety percent of chilJ Am Soc Nephrol 22: ●●●–●●●, 2011

www.jasn.org

BRIEF REVIEW

Table 3. Inherited renal diseases associated with retinal abnormalities Retinal Abnormality

Disease

Retinal Features

Vision

Coloboma or cavitary abnormality of the optic disc

PAX2 mutations (“papillorenal syndrome”)

Includes optic pits, optic disc coloboma, the morning glory anomaly, and the papillorenal syndrome Optic disc, chorioretinal and iris coloboma

Normal to severe impairment depending on the defect

COACH syndrome CHARGE syndrome Nephronophthisis (uncommonly) Tuberous sclerosis (uncommonly) Drusen

No treatment available

Membranoproliferative glomerulonephritis type II

Perimacular dots and flecks and peripheral coalescing flecks; these are not technically drusen Macular drusen, eventually retinal atrophy and hemorrhage

MELAS syndrome Nephronophthisis

Retinal atrophy Atrophy, pigmentation

LCAT deficiency Alstrom syndrome Alagille syndrome

Usually normal, sometimes macular degeneration and hemorrhage Retinal atrophy Retinal atrophy, optic disc drusen

Phakomatoses

Tuberous sclerosis Neurofibromatosis

Hamartoma, useful diagnostically Hamartoma, optic nerve glioma

Normal Normal

Vascular abnormalities

HANAC Fabry disease Von Hippel Lindau syndrome Amyloidosis

Tortuous retinal vessels Tortuous retinal vessels Haemangioblastoma, tortuous vessels

Normal Normal Normal

Plaques around blood vessels, hemorrhage, infarcts Tortuous retinal vessels Angioid streaks

Normal

Highly refractile crystals Highly refractile crystals Yellow-white calcium deposits in the mid-periphery

Normal Normal Normal

Retinal pigmentation/atrophy

Alport syndrome

No treatment available

Sturge-Weber syndrome Ehlers Danlos syndrome Crystals

Oxalosis Cystinosis Bartter/Gitelman syndromes

dren have coloboma of the optic disc, chorioretina or iris, 20% to 40% have a structural urinary tract anomaly including solitary kidney, renal hypoplasia, duplex kidney, or vesicoureteric reflux, and 60% have heart defects (often Fallot’s tetralogy). Kidney problems are often associated with ipsilateral facial palsy.35

in the cerebral cortex.39 Loss of these genes produces ocular and genitourinary anomalies, respectively. The iris is deficient, and the optic nerve and fovea are hypoplastic. These abnormalities may be complicated by a fragile cornea, glaucoma, and retinal detachment.40 Fifty percent of patients develop renal cancer.

WAGR Syndrome (OMIM 194072)

COACH Syndrome (OMIM 216360)

This is a rare genetic syndrome with Wilm’s tumor, Aniridia, Genitourinary anomalies including gonadal tumors, mental Retardation, and obesity.36,37 It results from a deletion involving the contiguous genes, PAX6 and WT1, on chromosome 11.38 PAX6 regulates neuronal migration

Cerebellar vermis hypo/aplasia, Oligophrenia, congenital Ataxia, ocular Coloboma, and Hepatic fibrosis. This affects 1 in 200,000 individuals and inheritance is autosomal recessive. It probably represents a subtype of Joubert syndrome with liver disease.41 Mutations affect one of the

J Am Soc Nephrol 22: ●●●–●●●, 2011

Normal

Needs regular review; may deteriorate Normal to severe impairment Night blindness to severe impairment May become severe May become severe May become severe

Normal Normal

MKS3, CC2D2A, or RPGRIP1L genes.42 MSK3 mutations account for nearly 60% of cases.43 Patients may have the molar tooth sign, a midbrain-hindbrain malformation also seen in Joubert syndrome and congenital hepatic fibrosis. Although they have medullary renal cysts, they do not necessarily develop renal failure. Optic nerve coloboma,44,41 mental retardation, nystagmus, and congenital ataxia occur.

DRUSEN

Drusen are yellowish-white deposits of cellular and inflammatory debris

Retinal Abnormalities in Inherited Renal Disease

3

BRIEF REVIEW

www.jasn.org

A a

B

iI

jJ

C

D

Kk

L

E

F

M

n N

G

H

O

P p

Figure 1. Retinal abnormalities in inherited renal disease. (A) Optic pit. This is a mild form of the optic disc coloboma that occurs with reflux nephropathy due to PAX2 mutations. It may also be found in the CHARGE and COACH syndromes. Vision was normal in this eye but coloboma are typically asymmetrical. (B) Morning glory anomaly. Vision is impaired. (C) Normal central retina. The central retina was also normal in the fellow eye. This individual had a child with an iris coloboma and single kidney. (D) This is the peripheral retina of the individual whose fundus is shown in (C). Retinal coloboma were present in the periphery bilaterally. (E) Dot and fleck retinopathy in Alport syndrome. The retinopathy spares the macula and is bilateral. Vision is not affected; (F) Peripheral retinopathy in Alport syndrome. This is more common than the central retinopathy and comprises confluent dots and flecks ⬎2 disc diameters from the macula. Again vision is not affected. (G) Widespread large soft macular drusen in membranoproliferative glomerulonephritis (dense deposit disease). These are identical to the drusen in macular degeneration but are present from early adulthood. (H) Late form of dense deposit disease with extensive retinal drusen, hemorrhage, and atrophy. These individuals should be assessed and monitored by an ophthalmologist because of the risk of complications and the possibility of treatment. (I) Retinal drusen and atrophy in Jeune syndrome, a form of nephronophthisis. (J) Red-free images of Jeune syndrome in which the abnormalities are more obvious. (K) Retinal atrophy in Joubert syndrome, another form of nephronophthisis, demonstrated by optical coherence tomography. The black line indicates peripapillary thickness is 1% normal. (L) Retinal atrophy in MELAS syndrome. The patient initially had poor vision that progressed. (M) Chorio-retinal atrophy in Kearns Sayre syndrome. The retina is thinned and depigmented. Vision is affected. (N) Hamartoma in tuberous sclerosis. A white tuber with fine linear hemorrhage was present unilaterally. This abnormality is present in the majority of patients with tuberous sclerosis and must be distinguished from retinal infarcts due to hypertension, diabetes, or lupus. (O) Corkscrew vessels in Fabry syndrome. These are asymptomatic but sudden visual loss may occur with central artery occlusion. These must be distinguished from the changes in hypertension. (P) Von Hippel Lindau syndrome. Tortuous vessels are seen leading to a hemangioblastoma just outside the field. The obvious macular lipid exudates are due to leakage from abnormal vessels. Vision is impaired.

located beneath the RPE. They are obvious on fundus ophthalmoscopy and photographs especially red-free images. Occasional drusen occur normally with aging and increased numbers are 4

found with some forms of glomerulonephritis.45 The dots and flecks in Alport syndrome are not technically drusen because they affect the internal limiting membrane rather than the


RPE. 46 They are smaller than the drusen in membranoproliferative glomerulonephritis type 2 and do not involve the macula. The drusen in dense deposit disease are large and soft and J Am Soc Nephrol 22: ●●●–●●●, 2011

www.jasn.org

located at the macula. They resemble the drusen in macular degeneration but occur in early adulthood and are accompanied by renal manifestations.

Alport Syndrome (X-Linked OMIM 301050; Autosomal Recessive OMIM 203780)

Alport syndrome affects 1 in 10,000 individuals47 and accounts for 2% of adults with ESRD. At least 80% of patients have X-linked disease with COL4A5 mutations and the others have autosomal recessive or dominant inheritance with mutations in the COL4A3 or COL4A4 genes. These genes code for the chains that comprise the collagen IV ␣3␣4␣5 protomer which is found in the GBM, the stria vascularis of the cochlea, cornea, lens capsule, and internal limiting membrane, and Bruch’s membrane of the retina.48 Individuals with Alport syndrome have hematuria and develop kidney failure, hearing loss, corneal dystrophy, lenticonus, and retinopathy. Retinopathy is present in half the males and 1 in 5 females with X-linked disease, and probably the majority of those with recessive disease.47 Central perimacular dots and flecks and retinal thinning are typical and, rarely, a macular hole occurs especially in the temporal macula.49 –51,46 In severe disease the flecks outline a perimacular lozenge.52,53 Peripheral flecks are more common than the perimacular retinopathy. Retinal abnormalities are best visualized using red-free photographs and the peripheral retinopathy requires multiple images. Vision is not affected. The central and peripheral retinopathies are diagnostic for Alport syndrome, but the diagnosis may also be confirmed with a positive family history, GBM lamellation, and absence of the ␣3␣4␣5 protomers from the kidney or skin, or genetic testing. Many mutations have been described in X-linked Alport syndrome, and they are generally different in each family. Certain variants, such as large deletions and rearrangements, nonsense mutations, and carboxy terminus missense mutations, result in early onset renal failure and retinopathy in males.54 –56 Many fewer mutations have J Am Soc Nephrol 22: ●●●–●●●, 2011

been described in recessive and the rare dominant forms, and the effect on phenotype is not clear. Membranoproliferative Glomerulonephritis Type 2 (Dense Deposit Disease, or Mesangiocapillary Glomerulonephritis, Associated with Factor H Deficiency, OMIM 609814)

This accounts for 2% of all glomerular disease.57 Patients have hematuria and proteinuria and develop renal impairment by early adulthood. Facial and shoulder girdle lipodystrophy, and C3 nephritic factor, and low C3 levels may occur.5,58 At least some forms of this disease are inherited, and mutations and disease haplotypes have been identified in the complement Factor H (CFH) gene.59,60 The intramembranous GBM deposits and retinal drusen have an identical composition.61 Vision is affected, and patients should be assessed and reviewed regularly by an ophthalmologist because of the risk of retinal complications such as neovascular membranes.62

RETINAL ATROPHY AND PIGMENTATION (RETINITIS PIGMENTOSA)

Individuals with renal disease and retinal atrophy first complain of poor night vision and even tunnel vision. Initially, the abnormality is only demonstrated with an electroretinogram but subsequently the retinal appearance is abnormal with pallor, pigmentation and mottling, attenuated arterioles and venules, and obvious choroidal vessels. Nephronophthisis

These diseases affect 1 in 50,000 individuals and account for 10% to 25% of all children with inherited renal failure.63 Inheritance is autosomal recessive. Mutations affect the NPHP1 through NPHP10 (nephrocystin) genes. Homozygous NPHP1 mutations account for 25% of patients, and mutations in the other genes, each for ⬍3%.64 These genes code for proteins found in the primary cilia or centrosome, and result in defective signal-

BRIEF REVIEW

ing and abnormal tissue differentiation and maintenance. Additional genes still have to be identified. Patients present from 1 year of age through to the fourth decade with polyuria and polydipsia but not hematuria, proteinuria, or hypertension. Their kidneys are small- or normal-sized with corticomedullary cysts. The ciliary theory explains the pattern of organs involved with retinal dystrophy/retinitis pigmentosa, ataxia, situs inversus, liver fibrosis, and mental retardation. Hearing loss may be present.65 Retinitis pigmentosa (Senior Loken syndrome) occurs with 10% to 30% NPHP1 through NPHP4 mutations, and all NPHP5 and NPHP6 mutations.16,64 The retinal defects vary from abnormal retinal function tests to blindness. There may also be tunnel vision early,16 nystagmus and poor pupillary reflexes, and fundus abnormalities. Vision deteriorates in parallel with worsening renal function. Rare related disorders result from recessive mutations in genes coding for other proteins in the cilia, basal bodies, or centrosomes of renal and retinal epithelial cells. Most of these disorders also feature renal medullary cysts and retinal atrophy/ pigmentation. Bardet-Biedl syndrome (BBS, OMIM 209900) affects 1 in 50,000 individuals. Mutations affect the 14 BBS genes, one of which accounts for 50% of all mutations (BBS1, BBS10). Sometimes mutations affect two different genes, and disease severity may also depend on a modifier gene.66 This syndrome is characterized clinically by focal and segmental glomerular sclerosis (FSGS), obesity, impaired cognition, and polydactyly. The phenotype varies within families and individuals may not present until the fifth decade. The retina is normal early, but atrophy without much pigmentation occurs later. The visual abnormalities include abnormal electroretinogram, night blindness, peripheral field defects, and blindness in early adulthood.67 Carriers probably have subtle defects of retinal function.68 Joubert syndrome and related disorders (OMIM 213300) are due to mutations in the NPHS1, NPHS6, AHI1, CEP290, and additional unidentified


5

BRIEF REVIEW

www.jasn.org

genes.69,70 The kidneys are often cystic. Other clinical features include hepatic fibrosis, polydactyly, cerebellar ataxia (with cerebellar vermis hypoplasia and the molar tooth sign on MRI), and abnormal eye movements including rotary nystagmus, psychomotor retardation, and developmental delay. Retinal abnormalities include retinitis pigmentosa and possibly chorioretinal coloboma.16 As with the Senior Loken syndrome, the retinitis pigmentosa is often severe and the electroretinogram is abnormal early.16 Cogan syndrome (oculomotor apraxia; OMIM 257550) is also due to NPHS mutations and may be a mild form of Joubert syndrome. Renal failure, poor hearing, and reduced muscle tone occur but there are no retinal abnormalities.71 Meckel-Gruber syndrome (OMIM 249000) may be caused by the same mutations as Joubert syndrome but is fatal in early life. It is characterized by cystic kidney dysplasia, liver fibrosis, occipital encephalocoele, and polydactyly. Jeune syndrome (asphyxiating thoracic dystrophy; OMIM 208500) is characterized by cystic kidney disease, a long narrow thorax, short limb dwarfism, brachydactyly, and other skeletal defects. Respiratory distress may be severe.72 Retinal atrophy occurs, but is mild. Alstrom disease (OMIM 203800) is due to mutations in the ALMS1 gene and clinically resembles the BardetBiedl syndrome. Affected individuals have renal failure with FSGS and tubulointerstitial fibrosis.73 They also have hearing loss, liver dysfunction, dilated cardiomyopathy, delayed puberty, obesity, and diabetes without mental retardation, polydactyly, or hypogonadism. Retinal atrophy occurs with large pigment clumps,73 vascular attenuation, and optic disc pallor. Vision is poor. Nephronophthisis and its variants must be distinguished from Medullary cystic kidney disease (OMIM 191845), which presents in adulthood, and demonstrates autosomal dominant inheritance. It is often caused by mutations in the UMOD gene, which codes for uromodulin, or Tamm Horsfall pro6

tein.74 –76 This disease typically results in renal failure in middle age, sometimes with a high serum urate, but there are no known retinal associations.

muscle biopsy demonstrating raggedred fibers, or on mitochondrial DNA sequencing.

Alagille Syndrome (Arteriohepatic Dysplasia, OMIM 118450)

Kearns-Sayre is a rare mitochondrial disease affecting 1 in 30,000 to 100,000 individuals. It typically results from a 4.9-kb deletion in mito-chondrial DNA. Many cases occur de novo. The onset is usually before the age of 20 but sometimes later.82 Kearns-Sayre syndrome is associated with a Bartter-like tubular defect,83 together with chronic progressive external ophthalmoplegia, ptosis, hearing loss, cardiac conduction abnormalities, cerebellar ataxia, and diabetes. Despite retinal atrophy and pigmentation, visual loss is usually mild. Again the diagnosis is confirmed with ragged-red fibers on muscle biopsy, or with mitochondrial DNA sequencing.

This is very rare and ⬍50 families have been described worldwide. Inheritance is autosomal dominant, and the diagnosis is usually made in children with cholestasis or their adult relatives, but sometimes in isolated adults.77 It results from mutations in the JAG1 gene, which encodes a ligand for Notch1. This stimulates a signaling pathway that determines cell fate in embryogenesis.78 Clinical features include renal arterial stenosis, hypertension, and renal failure but the kidneys may not be involved. There are reduced intrahepatic bile ducts and liver failure that typically presents with neonatal jaundice. In addition, peripheral pulmonary artery hypoplasia results in pulmonary hypertension, and various cardiac anomalies, vertebral arch defects, and a peculiar facies are present. The retina is commonly diffusely hypopigmented or speckled, and optic disc anomalies, especially drusen, are present in nearly all affected individuals.79 MELAS (Myopathy, Encephalopathy, Lactic Acidosis, Stroke-like Episodes Syndrome, OMIM 540000)

This condition affects 1 in 5 to 10,000 individuals and is due to an A3243G mutation in the mitochondrial DNA coding for tRNA (Leu).80,81 Inheritance is mitochondrial with transmission from mother to child. Presentation occurs from childhood through early adulthood. In addition to the classical features, patients usually have FSGS and steroid-resistant nephrotic syndrome that progresses to end-stage renal failure before middle age. Hearing loss, cardiomyopathy, and diabetes are also common but clinical features vary between families. Retinal atrophy occurs in at least half the patients80 but the electroretinogram is abnormal in 90%. The diagnosis is confirmed with a


Kearns-Sayre Syndrome (OMIM 530000)

PHAKOMATOSES (NEUROCUTANEOUS SYNDROMES)

These disorders include neurofibromatosis, tuberous sclerosis, von Hippel Lindau disease, and Sturge-Weber syndrome. Von Hippel Lindau and Sturge-Weber syndromes also cause vascular anomalies and are considered later. Neurofibromatosis (NF) Types I and 2 (OMIM 162200 and 101000)

Neurofibromatosis 1 and 2 affect 1 in 3000 and 1 in 100,000 live births and are due to mutations in the NF1 or NF2 genes, which code for neurofibromin, a GTP-ase-activating enzyme, or merlin, a cytoskeletal protein, respectively. Inheritance is autosomal dominant but about half of all mutations occur de novo. NF1 and NF2 mutations are characterized by pigmented skin lesions, neurofibromas, and acoustic neuroma (NF2). Hypertension occurs because of proximal renal artery stenosis, coarctation of the aorta, or phaemochromocytoma.84 Retinal abnormalities include ischemia,85 hamartoma including Combined Hamartoma of the Retina and Retinal Pigment Epithelium J Am Soc Nephrol 22: ●●●–●●●, 2011

www.jasn.org

(CHRRPE, both NF1 and NF286), optic glioma (NF1), and optic atrophy secondary to pressure on the optic nerve. Tuberous Sclerosis (TSC) Types 1 and 2 (OMIM 191100 and 191092)

TSC affects 1 in 10,000 individuals, and inheritance is autosomal dominant. Mutations occur in the TSC1 gene or more commonly the TSC2 gene, which code for hamartin and tuberin, respectively. 87 Twenty percent of patients have no mutation identified. Both TSC1 and TSC2 are tumor suppressor genes that require a second hit before tumors develop. TSC mutations are highly penetrant but have variable expression. TSC2 is contiguous with the PKD1 gene for polycystic kidney disease, and patients with large deletions have both TSC and renal cysts.88 Sixty to 80% of patients with TSC have multiple bilateral angiomyolipoma in the kidney.89 These result in hematuria, and sometimes cancer. Thirty percent of patients have renal cysts. Facial adenoma sebaceum, cardiac rhabodomyoma, and pulmonary cysts are common. Ocular coloboma and eyelid tumors are rare. Most patients have at least one retinal or optic nerve hamartoma. 90 These are highly vascular and eventually calcify, and must be differentiated from hypertensive infarcts. Vision remains normal. Retinal hamartoma are helpful diagnostically, but the diagnosis of TSC is also confirmed with genetic testing.

VASCULAR ABNORMALITIES

Some inherited renal diseases are associated with tortuous retinal vessels with hemorrhages and infarcts (cotton wool spots). These are evident on ophthalmoscopy and in retinal photographs. The major differential diagnoses are hypertension and diabetes, which are usually obvious on history. However, retinal abnormalities can persist for months after a single episode of severe hypertension, and the diagnosis of diabetes may not be obvious if glucose control J Am Soc Nephrol 22: ●●●–●●●, 2011

improves as renal function deteriorates. HANAC (Hereditary Angiopathy with Retinal Tortuosities, Nephropathy (Manifesting as Hematuria or Cysts), Aneurysms, and Muscular Cramps Syndrome, OMIM 611773)

To date, only a few families have been described with this disease.91–93 It results from mutations in the COL4A1 gene. Affected individuals have hematuria, renal cysts, and GBM defects. Small and large arteries are tortuous. Other features include headache, muscle cramps with elevated levels of creatine kinase, supraventricular cardiac arrhythmia, Raynaud’s phenomenon, and leukoencephaly. The retina has tortuous vessels, and repeated retinal hemorrhage results in transient visual impairment that resolves spontaneously. Fabry Disease (OMIM 301500)

This lysosomal storage disorder affects at least 1 in 50,000 males but milder forms are probably more common.94 Inheritance is X-linked and disease results from mutations in the GLA gene encoding ␣Galactosidase A. Mutations result in the accumulation of the glycolipid, ceramide, in blood vessels and other tissues.95 Mutations are different in each family but missense variants are most common (76%). Mutation type correlates with age at onset of renal failure. Symptoms appear in childhood but become particularly troublesome in the fourth decade. Fifty percent of patients have proteinuria by 35 years of age, and renal failure by 42.96 The renal biopsy demonstrates FSGS with lamellated zebra bodies. Other features include angiokeratoma on the lower abdomen and thighs, cardiomyopathy, mitral valve prolapse, painful peripheral neuropathy, hearing loss, stroke, and lack of sweating. Patients with atypical disease (cardiac or visceral features without angiokeratoma, renal disease, or corneal keratopathy) are recognized increasingly.97,98 Features in females vary from asymptomatic to severe.99 Fabry disease is also found in a

BRIEF REVIEW

series of patients with renal failure on dialysis, with cardiomyopathy, and in young patients with stroke.100 –102 The retinal vessels are tortuous. Other ocular abnormalities include corneal verticillata or horse tails, and tortuous conjunctival vessels. Vision is normal. The diagnosis is confirmed on renal biopsy, with low enzyme levels (which may be normal in affected symptomatic females), or with genetic testing. Von Hippel Lindau Disease (OMIM 193300)

This condition affects 1 in 36,000 individuals. It results from mutations in the VHL gene, which codes for the protein that regulates hypoxia-inducible factor activity.103 Mutations result in upregulation of vascular endothelial growth factor and increased endothelial cell growth and migration.104 Inheritance is autosomal dominant, but 20% of mutations occur de novo. However, two mutations are required for disease, one germline and one somatic. Germline mutations are different in each family. Nonsense mutations and deletions result in more severe disease.105 The timing of the somatic mutation probably determines the age at onset of disease, the organs affected, and severity. Thus, phenotypes vary even within families but penetrance is nearly 100% by age 60. Affected individuals develop renal cysts, and sometimes clear cell renal cancer. They also have cafe au lait spots, nervous system hemangioblastomas, and sometimes, phemochromocytoma and pancreatic islet cell tumors. Fifty percent of patients have retinal hemangioblastoma.106 These are usually multiple, vary in size, and are located in the central and mid-peripheral retina. They have a globular reddish appearance (sugar-coated raspberries) and adjoining vessels are tortuous. They may be asymptomatic for years and regress spontaneously. However, they may be complicated by retinal hemorrhage, tears, and detachment. Even small asymptomatic lesions should be treated. Early detection and treatment helps preserve vision,107 and in the future, antian-


7

BRIEF REVIEW

www.jasn.org

giogenic factors may prove helpful. The diagnosis of von Hippel Lindau syndrome is usually made clinically, but may be confirmed also with genetic testing. Sturge-Weber Syndrome (OMIM 185300)

One in 50,000 individuals are affected and many cases are sporadic. No mutant gene has been identified. The condition is characterized by facial nevi, cerebral hemangioma, and intracranial calcification. Vascular malformations occur in the kidney, within the renal pelvis, papilla, or urinary bladder.108 These are typically solitary and result in hematuria. They can be treated with laser. Vascular malformations of the retina and choroid may be complicated by retinal detachment or optic neuropathy.109,110

mutation, and carriers are usually asymptomatic.116 LCAT deficiency produces steroid-resistant FSGS and ESRD by the fourth decade, but sometimes the kidneys are not affected. Other features include dyslipidemia and xanthelasma, corneal opacities, and stomatocytes with increased membrane phospholipid, resulting in hemolytic anemia. Retinal manifestations include macular degeneration and hemorrhage from involvement and rupture of Bruch’s membrane.117 LCAT deficiency is diagnosed when LCAT levels are negligible, unesterified cholesterol and cholesterol ester levels are low, and LDL and triglyceride levels are increased. The diagnosis is also made with genetic testing.

RETINAL CRYSTALS Amyloidosis

Amyloid deposits are rigid, linear nonbranching aggregated fibrils with an antiparallel ␤-pleated sheet configuration. The inherited forms (AA) include those due to transthyretin mutations, familial amyloidotic polyneuropathy, and familial Mediterranean fever. Inheritance is autosomal recessive or dominant depending on the type. Inherited amyloidosis affects many tissues including the kidney and eye.111,112 It commonly results in kidney failure, but other features include cardiomyopathy, polyneuropathy, and autonomic dysfunction. Retinal changes include tortuous vessels, vessel cuffing, hemorrhage, and infarcts.112–114 The diagnosis is confirmed with the demonstration of Congo red deposits with apple green birefringence under polarized light in a conjunctival biopsy, or with genetic testing. Lecithin-Cholesterol Acyltransferase (LCAT) Deficiency (OMIM 606967)

This condition appears to be very rare, affecting ⬍1 in 1,000,000 individuals, but is also probably under-recognized.115 Inheritance is autosomal recessive, and more than 40 mutations have been described. LCAT catalyzes the formation of cholesterol esters and its deficiency results in lipid deposition in the kidney and other tissues. Clinical features vary in different members of a family with the same 8

Retinal crystals are small and highly refractile, often with associated pigmentation (cystinosis, oxalosis) or large and dull (ectopic calcium deposits in chronic renal failure, Bartter and Gitelman syndrome). Vascular deposits may result in ischemia. The crystals must be distinguished from the normal youthful retinal sheen. Other causes of crystals are usually obvious on history (cholesterol emboli, tamoxifen, talc in intravenous drug users, and calcified drusen).118 Oxalosis (OMIM 260000)

Oxalosis affects 1 in 100,000 individuals.119 Inheritance is autosomal recessive and due to mutations in the alanine glyoxylate aminotransferase (AGT) or the glyoxylate reductase/hydroxypyruvate reductase (GRHPR) genes.120 AGT deficiency is more common and causes more serious disease. Mutations result in increased synthesis of oxalate and subsequent urinary excretion and deposition of insoluble calcium oxalate in the kidney. As renal function deteriorates with progressive involvement, oxalate accumulates in other organs. Oxalosis results in nephrolithiasis, nephrocalcinosis, and renal failure. Renal failure occurs from infancy through to the sixth decade.121 The characteristic retinal findings are highly refractile crystals often in the arte-


rioles, producing a flecked retinopathy,122 and crystals in the RPE layer, producing a hyperpigmented center surrounded by hypopigmentation (ringlets).123 Optic atrophy occurs with severe disease. Vision is usually normal, but may be impaired. The diagnosis of oxalosis is suspected in patients with stones or nephrocalcinosis in childhood, recurrent calcium oxalate stones in adulthood, or renal insufficiency associated with stones or nephrocalcinosis. The diagnosis is confirmed with urinary oxalate levels and genetic testing. Cystinosis (OMIM 219800)

This condition also affects about 1 in 100,000 individuals124 and accounts for 5% of children with renal failure.125 Inheritance is autosomal recessive, and mutations occur in the CTNS gene for cystinosin.126 Many Caucasians have the same mutation consistent with a founder effect.127 Compound heterozygotes have milder, usually adult-onset, disease and carriers are asymptomatic. Affected children typically present in infancy with polyuria and dehydration from damaged proximal tubular cells. Untreated, they develop renal failure before the teenage years.124 However, retinal (and corneal and iris) crystals occur even without systemic features. Affected individuals complain of gritty eyes and, if severely affected, have poor night and color vision and reduced visual acuity. They also have retinal crystals with hypopigmentation, and pigmentary stippling.128 Adult-onset disease was formerly considered primarily ocular but probably all patients have at least some renal involvement.129 The diagnosis is based on clinical features, increased leukocyte cystine levels, and genetic testing.124,125 Tubular Defects (Bartter Syndrome, OMIM 607364 and Gitelman Syndrome, OMIM 263800)

These each affect about 1 in 50,000 individuals and inheritance is autosomal recessive.130 Bartter syndrome130 is due to mutations in genes coding for proteins found in the thick ascending limb of the loop of Henle and is characterized by hypokalemia, alkalosis, and normal or low J Am Soc Nephrol 22: ●●●–●●●, 2011

www.jasn.org

blood pressure. Patients present in utero or before school age. They typically have polyuria, polydipsia, and a tendency for dehydration, features also seen with loop diuretics such as furosemide. Mutations affect the NKCC2, ROMK, CLCNKB, BSND, and CASR genes. Patients also often have a magnesium deficiency and develop widespread calcium deposits. Gitelman syndrome results from mutations in the SLC12A3 gene, which codes for the thiazide-sensitive Na-Cl cotransporter in the distal convoluted tubule.131 This disease is mild and patients present in adolescence or later. They are asymptomatic or have fatigue, muscle cramps, and rarely seizures or cardiac arrhythmias. Symptoms are due mainly to hypokalemia. BP is normal. Carriers may have mild features. Patients with both conditions may have large dullish yellow-white deposits in the retinal midperiphery,132,133 sometimes with pigment deposition. Visual fields and acuity are normal.

INCIDENTAL RETINAL FINDINGS Nail Patella Syndrome (Hereditary Osteo-onychodysplasis, OMIM 161200)

This affects about 1 in 50,000 individuals134 and inheritance is autosomal dominant. It is due to mutations in the LMX1B gene, which encodes the transcription factor that regulates expression of collagen IV, and determines dorsal limb and eye development in the embryo.135 However, LMX1B is also expressed after birth in the glomerular podocyte, suggesting it has a regulatory role in that cell.136 Mutations affect a critical region of the gene (the LIM or homeodomain) and result in haploinsufficiency. Most patients have thumb nail hypoplasia, absent patellae, radial head dislocation, and iliac horns. The presence of renal disease (hematuria and proteinuria in 40% to 60%) depends on the underlying mutation and 15% of patients develop renal failure by middle age.134 The renal biopsy demonstrates variable amounts of glomerulosclerosis, with GBM thickening, rarefaction, and collagen III fibrils. J Am Soc Nephrol 22: ●●●–●●●, 2011

About one third of patients develop primary open-angle glaucoma by the age of 40, and sometimes optic atrophy.137 Other ocular associations are ptosis, epicanthal folds, microcornea, keratoconus, cataracts, and possibly cloverleaf iris pigmentation.138 Individuals with the nail and bone manifestations of the nail-patella syndrome should be screened for hematuria and proteinuria, and reviewed annually for increased intraocular pressure and glaucoma.139

CONCLUSIONS

Many inherited renal diseases are diagnosed with expensive and labor-intensive laboratory techniques. However, retinal abnormalities in inherited renal disease are sufficiently common and characteristic to help with the diagnosis. Most of these features are obvious on ophthalmoscopy or in retinal photographs. Some are easier to identify with red-free images or peripheral retinal views. Retinal abnormalities may affect vision, and most patients with inherited renal disease require an ophthalmological assessment and sometimes further testing, monitoring, and treatment. The diagnosis of inherited renal disease is important because of the risk of complications, the implications for family members, and the possibility of treatment. Retinal abnormalities may also assist with assessing disease progression and the response to treatment, and in explaining the pathogenesis of the renal lesions. Inherited forms of renal disease where, currently, there are no known retinal associations, warrant further ophthalmic investigation.

ACKNOWLEDGMENT This project was supported by the National Health and Research Council of Australia and Kidney Health Australia. We would like to thank the many patients who took part in these studies and their clinicians, especially Prof. David Power, A/Prof. James

BRIEF REVIEW

Elder, A/Prof. Justin O’Day, and Dr. Kathy Nicholls.

DISCLOSURES None.

REFERENCES 1. Gru¨nfeld, J-P: Congenital/inherited kidney diseases: How to identify them early and how to manage them. Clin Exp Nephrol 9: 192–194, 2005 2. Levy M, Feingold J: Estimating prevalence in single-gene kidney diseases progressing to renal failure. Kidney Int 58: 925–943, 2000 3. Grunfeld JP, Chauveau D, Levy M: Anderson-Fabry disease: Its place among other genetic causes of renal disease. J Am Soc Nephrol 13: S126 –S129, 2002 4. Izzedine H, Bodaghi B, Launay-Vacher V, Deray G: Eye and kidney: From clinical findings to genetic explanations. J Am Soc Nephrol 14: 516 –529, 2003 5. Appel GB, Cook HT, Hageman G, Jennette JC, Kashgarian M, Kirschfink M, Lambris JD, Lanning L, Lutz HU, Meri S, Rose NR, Salant DJ, Sethi S, Smith RJH, Smoyer W, Tully HF, Tully SP, Walker P, Welsh M, Wurzner R, Zipfel PF: Membranoproliferative glomerulonephritis type II (dense deposit disease): An update. J Am Soc Nephrol 16: 1392–1403, 2005 6. Dahl E, Koseki H, Balling R: Pax genes and organogenesis. Bioessays 19: 755–765, 1997 7. Mrowka C, Schedl A: Wilms’ tumor suppressor gene WT1: From structure to renal pathophysiologic features. J Am Soc Nephrol 11: S106 –S115, 2000 8. Wagner N, Wagner KD, Schley G, Coupland SE, Heimann H, Grantyn R, Scholz H: The Wilms’ tumor suppressor Wt1 is associated with the differentiation of retinoblastoma cells. Cell Growth Differ 13: 297–305, 2002 9. Pelletier J, Bruening W, Li FP, Haber DA, Glaser T, Housman DE: WT1 mutations contribute to abnormal genital system-development and hereditary Wilms-tumor. Nature 353: 431– 434, 1991 10. Pelletier J, Bruening W, Kashtan CE, Mauer SM, Manivel JC, Striegel JE, Houghton DC, Junien C, Habib R, Fouser L, Fine RN, Silverman BL, Haber DA, Housman D: Germline mutations in the Wilms-tumour suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome. Cell 67: 437– 447, 1991 11. Barbaux S, Niaudet P, Gubler MC, Grunfeld JP, Jaubert F, Kuttenn F, Fekete CN,


9

BRIEF REVIEW

12.

13.

14. 15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

10

www.jasn.org

Souleyreau-Therville N, Thibaud E, Fellous M, McElreavey K: Donor splice-site mutations in WT1 are responsible for Frasier syndrome. Nat Genet 17: 467– 470, 1997 Harvey SJ, Zheng KQ, Sado Y, Naito I, Ninomiya Y, Jacobs RM, Hudson BG, Thorner PS: Role of distinct type IV collagen networks in glomerular development and function. Kidney Int 54: 1857–1866, 1998 Ljubimov AV, Burgeson RE, Butkowski RJ, Couchman JR, Zardi L, Ninomiya Y, Sado Y, Huang ZS, Nesburn AB, Kenney MC: Basement membrane abnormalities in human eyes with diabetic retinopathy. J Histochem Cytochem 44: 1469–1479, 1996 Watnick T, Germino G: From cilia to cyst. Nat Genet 34: 355–356, 2003 Hildebrandt F, Otto E: Cilia and centrosomes: A unifying pathogenic concept for cystic kidney disease? Nat Rev Genet 6: 928 –940, 2005 Adams NA, Awadein A, Toma HS: The retinal ciliopathies. Ophthalmol Genet 28: 113–125, 2007 Evans RD, Rosner M: Ocular abnormalities associated with advanced kidney disease and hemodialysis. Semin Dial 18: 252–257, 2005 Bajracharya L, Shah D, Raut K, Koirala S: Ocular evaluation in patients with chronic renal failure–a hospital based study. Nepal Med Coll J 10: 209 –214, 2008 Haddad R, Witzmann K, Braun O: Metastatic calcification to the peripheral fundus in chronic renal failure. Ophthalmologica 179: 178 –183, 1979 Patel DV, Snead MP, Satchi K: Retinal arteriolar calcification in a patient with chronic renal failure. Br J Ophthalmol 86: 1063, 2002 Liew G, Mitchell P, Wong TY, Iyengar SK, Wang JJ: CKD increases the risk of agerelated macular degeneration. J Am Soc Nephrol 19: 806 – 811, 2008 Sanyanusin P, Schimmenti LA, McNoe LA, Ward TA, Pierpont MEM, Sullivan MJ, Dobyns WB, Eccles MR: Mutation of the PAX2 gene in a family with optic-nerve colobomas, renal anomalies and vesicoureteral reflux. Nat Genet 9: 358 –364, 1995 Alsing A, Christensen C: Atypical macular coloboma (dysplasia) associated with familial juvenile nephronophthisis and skeletal abnormality. Ophthalmol Pediatr Genet 9: 149 –155, 1988 Pagon RA, Graham JM, Zonana J, Yong SL: Coloboma, congenital heart disease, and choanal atresia with multiple anomalies: CHARGE association. J Pediatr 99: 223– 227, 1981 Verloes A, Lambotte C: Further delineation of a syndrome of cerebellar vermis hypo/ aplasia, oligophrenia, congenital ataxia,

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.


coloboma, and hepatic fibrosis. Am J Med Genet 32: 227–232, 1989 Mullaney PB, Jacquemin C, Abboud E, Karcioglu ZA: Tuberous sclerosis in infancy. J Pediatr Ophthalmol Strabismus 34: 372– 375, 1997 Dureau P, Attie-Bitach T, Salomon R, Bettembourg O, Amiel J, Uteza Y, Dufier JL: Renal coloboma syndrome. Ophthalmology 108: 1912–1916, 2001 Bron AJ, Burgess SEP, Awdry PN, Oliver D, Arden G: Papillo-renal syndrome. An inherited association of optic disk dysplasia and renal-disease. Report and review of the literature. Ophthalmol Pediatr Genet 10: 185–198, 1989 Nishimoto K, Iijima K, Shirakawa T, Kitagawa K, Satomura K, Nakamura H, Yoshikawa N: PAX2 gene mutation in a family with isolated renal hypoplasia. J Am Soc Nephrol 12: 1769 –1772, 2001 Fletcher J, Hu M, Berman Y, Collins F, Grigg J, McIver M, Juppner H, Alexander SI: Multicystic dysplastic kidney and variable phenotype in a family with a novel deletion mutation of PAX2. J Am Soc Nephrol 16: 2754 –2761, 2005 Cheong HI, Cho HY, Kim JH, Yu YS, Ha IS, Choi Y: A clinico-genetic study of renal coloboma syndrome in children. Pediatr Nephrol 22: 1283–1289, 2007 Eccles MR, Schimmenti LA: Renal-coloboma syndrome: A multi-system developmental disorder caused by PAX2 mutations. Clin Genet 56: 1–9, 1999 Parsa CF, Silva ED, Sundin OH, Goldberg MF, De Jong MR, Sunness JS, Zimer R, Hunter DG: Redefining papillorenal syndrome: An underdiagnosed cause of ocular and renal morbidity. Ophthalmology 108: 738 –749, 2001 Vissers L, van Ravenswaaij CMA, Admiraal R, Hurst JA, de Vries BBA, Janssen IM, van der Vliet WA, Huys E, de Jong PJ, Hamel BCJ, Schoenmakers E, Brunner HG, Veltman JA, van Kessel AG: Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nat Genet 36: 955–957, 2004 Ragan DC, Casale AJ, Rink RC, Cain MP, Weaver DD: Genitourinary anomalies in the CHARGE association. J Urol 161: 622– 625, 1999 Fischbach BV, Trout KL, Lewis J, Luis CA, Sika M: WAGR syndrome: A clinical review of 54 cases. Pediatrics 116: 984 –988, 2005 Clericuzio, C: WAGR syndrome. In: Management of Genetic Syndromes. 2nd ed. edited by Cassidy S, Allanson J, New York,: John Wiley & Sons, 2004 Glaser T, Jepeal L, Edwards JG, Young SR, Favor J, Maas RL: PAX6 gene dosage effect in a family with congenital cataracts, aniridia, anophthalmia and centra-nervous-system defects. Nat Genet 7: 463–471, 1994 Talamillo A, Quinn JC, Collinson JM, Caric

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

D, Price DJ, West JD, Hill RE: PAX6 regulates regional development and neuronal migration in the cerebral cortex. Dev Biol 255: 151–163, 2003 Lee H, Khan R, O’Keefe M: Aniridia: Current pathology and management. Acta Ophthalmol 86: 708 –715, 2008 Satran D, Pierpont MEM, Dobyns WB: Cerebello-oculo-renal syndromes including Arima, Senior-Loken and COACH syndromes: More than just variants of Joubert syndrome. Am J Med Genet 86: 459 – 469, 1999 Doherty D, Parisi M, Finn L, Gunay-Aygun M, Al-Mateen M, Bates D, Clericuzio C, Demir H, Dorschner M, van Essen A, Gahl WA, Gentile M, Gorden N, Hikida A, Knutzen D, Ozyurek H, Phelps I, Rosenthal P, Verloes A, Weigand H, Chance P, Dobyns WB, Glass I: Mutations in 3 genes (MKS3, CC2D2A, RPGRIP1L) cause COACH syndrome (Joubert syndrome with congenital hepatic fibrosis). J Med Genet 47: 8 –21, 2010 Brancati F, Iannicelli M, Travaglini L, Mazzotta A, Bertini E, Boltshauser E, D’Arrigo S, Emma F, Fazzi E, Gallizzi R, Gentile M, Loncarevic D, Mejaski-Bosnjak V, Pantaleoni C, Rigoli L, Salpietro DC, Signorini S, Stringini G, Verloes A, Zabloka D, the International JSRD Study Group, Dallapiccola B, Gleeson J, Valente EM: MKS3/ TMEM67 mutations are a major cause of COACH Syndrome, a Joubert Syndrome related disorder with liver involvement. Hum Mutat 30: E432–E442, 2009 Kumar S, Rankin R: Renal insufficiency is a component of COACH syndrome. Am J Med Genet 61: 122–126, 1996 Mullins RF, Aptsiauri N, Hageman GS: Structure and composition of drusen associated with glomerulonephritis: Implications for the role of complement activation in drusen biogenesis. Eye 15: 390 –395, 2001 Savige J, Liu J, Cabrera DeBuc D, Handa JT, Hageman GS, Wang YY, Parkin JD, Vote B, Fassett R, Sarks S, Colville, D: Retinal basement membrane abnormalities and the retinopathy of Alport syndrome. Invest Ophthalmol Vis Sci 51: 1621–1627, 2010 Savige J, Colville D: Ocular features aid the diagnosis of Alport syndrome. Nat Rev Nephrol 5: 356 –360, 2009 Chen L, Miyamura N, Ninomiya Y, Handa JT: Distribution of the collagen IV isoforms in human Bruch’s membrane. Br J Ophthalmol 87: 212–215, 2003 Shaw EA, Colville D, Wang YY, Zhang KW, Dagher H, Fassett R, Guymer R, Savige J: Characterization of the peripheral retinopathy in X-linked and autosomal recessive Alport syndrome. Nephrol Dial Transplant 22: 104 –108, 2007 Usui T, Ichibe M, Hasegawa S, Miki A, Baba

J Am Soc Nephrol 22: ●●●–●●●, 2011

www.jasn.org

51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

E, Tanimoto N, Abe H: Symmetrical reduced retinal thickness in a patient with Alport syndrome. Retina 24: 977–979, 2004 Rahman W, Banerjee S: Giant macular hole in Alport syndrome. Can J Ophthalmol 42: 314 –315, 2007 Cervantes-Coste G, Fuentes-Paez G, Yeshurun I, Jimenez-Sierra JM: Tapetal-like sheen associated with fleck retinopathy in Alport syndrome. Retina 23: 245–247, 2003 Colville D, Wang YY, Tan R, Savige J: The retinal “lozenge’’ or ”dull macular reflex’’ in Alport syndrome may be associated with a severe retinopathy and early-onset renal failure. Br J Ophthalmol 93: 383– 386, 2009 Jais JP, Knebelmann B, Giatras I, De Marchi M, Rizzoni G, Renieri A, Weber M, Gross O, Netzer KO, Flinter F, Pirson Y, Verellen C, Wieslander J, Persson U, Tryggvason K, Martin P, Hertz JM, Schroder C, Sanak M, Krejcova S, Carvalho MF, Saus J, Antignac C, Smeets H, Gubler MC: X-linked Alport syndrome: Natural history in 195 families and genotype-phenotype correlations in males. J Am Soc Nephrol 11: 649–657, 2000 Gross O, Netzer KO, Lambrecht R, Seibold S, Weber M: Meta-analysis of genotype-phenotype correlation in X-linked Alport syndrome: Impact on clinical counselling. Nephrol Dial Transplant 17: 1218 –1227, 2002 Tan R, Colville D, Wang YY, Rigby L, Savige, J: Alport retinopathy results from “severe” COL4A5 mutations and predicts early renal failure. Clin J Am Soc Nephrol 5: 34 –38, 2010 Simon P, Ramee MP, Autuly V, Laruelle E, Charasse C, Cam G, Ang KS: Epidemiology of primary glomerular-diseases in a French region. Variations according to period and age. Kidney Int 46: 1192–1198, 1994 Smith RJH, Alexander J, Barlow PN, Botto M, Cassavant TL, Cook HT, de Cordoba SR, Hageman GS, Jokiranta TS, Kimberling WJ, Lambris JD, Lanning LD, Levidiotis V, Licht C, Lutz HU, Meri S, Pickering MC, Quigg RJ, Rops AL, Salant DJ, Sethi S, Thurman JM, Tully HF, Tully SP, van der Vlag J, Walker PD, Wurzner R, Zipfel PF: New approaches to the treatment of dense deposit disease. J Am Soc Nephrol 18: 2447–2456, 2007 Licht C, Heinen S, Jozsi M, Loschmann I, Saunders RE, Perkins SJ, Waldherr R, Skerka C, Kirschfink M, Hoppe B, Zipfel PF: Deletion of Lys224 in regulatory domain 4 of Factor H reveals a novel pathomechanism for dense deposit disease (MPGN II). Kidney Int 70: 42–50, 2006 Abrera-Abeleda MA, Nishimura C, Smith JLH, Sethi S, McRae JL, Murphy BF, Silvestri G, Skerka C, Jozsi M, Zipfel PF, Hageman GS, Smith RJH: Variations in the com-

J Am Soc Nephrol 22: ●●●–●●●, 2011

61.

62.

63.

64.

65.

66.

67.

68.

69.

70.

71.

plement regulatory genes factor H (CFH) and factor H related 5 (CFHR5) are associated with membranoproliferative glomerulonephritis type II (dense deposit disease). J Med Gen 43: 582–589, 2006 Duvall-Young J, Short CD, Raines MF, Gokal R, Lawler W: Fundus changes in mesangiocapillary glomerulonephritis type II: Clinical and fluorescein angiographic findings. Br J Ophthalmol 73: 900 –906, 1989 Colville D, Guymer R, Sinclair RA, Savige, J: Visual impairment caused by retinal abnormalities in mesangiocapillary (membranoproliferative) glomerulonephritis type II (“dense deposit disease”). Am J Kidney Dis 42: E2–E5, 2003 Hildebrandt F, Zhou WB: Nephronophthisis-associated ciliopathies. J Am Soc Nephrol 18: 1855–1871, 2007 Hildebrandt F, Attanasio M, Otto E: Nephronophthisis: Disease mechanisms of a ciliopathy. J Am Soc Nephrol 20: 23–35, 2009 Clarke MP, Sullivan TJ, Francis C, Baumal R, Fenton T, Pearce WG: Senior-Loken syndrome. Case reports of two siblings and association with sensorineural deafness. Br J Ophthalmol 76: 171–172, 1992 Badano JL, Leitch CC, Ansley SJ, MaySimera H, Lawson S, Lewis RA, Beales PL, Dietz HC, Fisher S, Katsanis N: Dissection of epistasis in oligogenic Bardet-Biedl syndrome. Nature 439: 326 –330, 2006 Beales PL, Elcioglu N, Woolf AS, Parker D, Flinter FA: New criteria for improved diagnosis of Bardet-Biedl syndrome: Results of a population survey. J Med Genet 36: 437– 446, 1999 Kim LS, Fishman GA, Seiple WH, Szlyk JP, Stone EM: Retinal dysfunction in carriers of Bardet-Biedl syndrome. Ophthalmic Genet 28: 163–168, 2007 Ferland RJ, Eyaid W, Collura RV, Tully LD, Hill RS, Al-Nouri D, Al-Rumayyan A, Topcu M, Gascon G, Bodell A, Shugart YY, Ruvolo M, Walsh CA: Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome. Nat Genet 36: 1126, 2004 Valente EM, Brancat F, Silhavy JL, Castori M, March SE, Barrano G, Bertini E, Boltshauser E, Zaki MS, Abdel-Aleem A, AbdelSalam GMH, Bellacchlo E, Battini R, Cruse RP, Dobyns WB, Krishnamoorthy KS, Lagier-Tourenne C, Magee A, Pascual-Castroviejo I, Salpietro CD, Sarco D, Dallapiccola B, Gleeson JG: AHI1 gene mutations cause specific forms of Joubert syndromerelated disorders. Ann Neurol 59: 527–534, 2006 Mollet G, Salomon R, Gribouval O, Silbermann F, Bacq D, Landthaler G, Milford D, Nayir A, Rizzoni G, Antignac C, Saunier S: The gene mutated in juvenile nephronophthisis type 4 encodes a novel protein that

72.

73.

74.

75.

76.

77.

78.

79.

80.

81.

BRIEF REVIEW

interacts with nephrocystin. Nat Genet 32: 459, 2002 Tuysuz B, Baris S, Aksoy F, Madazli R, Ungur S, Sever L: Clinical variability of asphyxiating thoracic dystrophy (Jeune) syndrome: Evaluation and classification of 13 patients. Am J Med Genet 149A: 1727–1733, 2009 Marshall JD, Bronson RT, Collin GB, Nordstrom AD, Maffei P, Paisey RB, Carey C, MacDermott S, Russell-Eggitt I, Shea SE, Davis J, Beck S, Shatirishvili G, Mihai CM, Hoeltzenbein M, Pozzan GB, Hopkinson I, Sicolo N, Nagget JK, Nishina PM: New Alstrom syndrome phenotypes based on the evaluation of 182 cases. Arch Int Med 165: 675– 683, 2005 Kottgen A, Hwang SJ, Larson MG, Van Eyk JE, Fu Q, Benjamin EJ, Dehghan A, Glazer NL, Kao WH, Harris TB, Gudnason V, Shlipak MG, Yang Q, Coresh J, Levy D, Fox CS: Uromodulin levels associate with a common UMOD variant and risk for incident CKD. J Am Soc Nephrol 21: 337–344, 2010 Bleyer AJ: Improving the recognition of hereditary interstitial kidney disease. J Am Soc Nephrol 20: 11–13, 2009 Dahan K, Devuyst O, Smaers M, Vertommen D, Loute G, Poux JM, Viron B, Jacquot C, Gagnadoux MF, Chauveau D, Buchler M, Cochat P, Cosyns JP, Mougenot B, Rider MH, Antignac C, Verellen-Dumoulin C, Pirson Y: A cluster of mutations in the UMOD gene causes familial juvenile hyperuricemic nephropathy with abnormal expression of uromodulin. J Am Soc Nephrol 14: 2883–2893, 2003 Jacquet A, Guiochon-Mantel A, Noel LH, Sqalli T, Bedossa P, Hadchouel M, Grunfeld JP, Fakhouri F: Alagille syndrome in adult patients: It is never too late. Am J Kidney Dis 49: 705–709, 2007 Li LH, Krantz ID, Deng Y, Genin A, Banta AB, Collins CC, Qi M, Trask BJ, Kuo WL, Cochran J, Costa T, Pierpont MEM, Rand EB, Piccoli DA, Hood L, Spinner NB: Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet 16: 243–251, 1997 Hingorani M, Nischal KK, Davies A, Bentley C, Vivian A, Baker AJ, Mieli-Vergani G, Bird AC, Aclimandos WA: Ocular abnormalities in Alagille syndrome. Ophthalmology 106: 330 –337, 1999 Sue CM, Mitchell P, Crimmins DS, Moshegov C, Byrne E, Morris JGL: Pigmentary retinopathy associated with the mitochondrial DNA 3243 point mutation. Neurology 49: 1013–1017, 1997 Jansen JJ, Maassen JA, van der Woude FJ, Lemmink HA, van den Ouweland JM, t’ Hart LM, Smeets HJ, Bruijn JA, Lemkes HH: Mutation in mitochondrial tRNA(Leu(UUR)) gene associated with progressive kidney


11

BRIEF REVIEW

82.

83.

84.

85.

86.

87.

88.

89.

90.

91.

92.

93.

94.

12

www.jasn.org

disease. J Am Soc Nephrol 8: 1118 –1124, 1997 Yerdelen D, Koc F, Koc Z: Delayed diagnosis of Kearns-Sayre syndrome in a 38-yearold male patient: A case report. Int J Neurosci 118: 267–275, 2008 Emma F, Pizzini C, Tessa A, Di Giandomenico S, Onetti-Muda A, Santorelli FM, Bertini E, Rizzoni G: “Bartter-like” phenotype in Kearns-Sayre syndrome. Pediatr Nephrol 21: 355–360, 2006 Booth C, Preston R, Clark G, Reidy J: Management of renal vascular disease in neurofibromatosis type 1 and the role of percutaneous transluminal angioplasty. Nephrol Dial Transplant 17: 1235–1240, 2002 Lecleire-Collet A, Cohen SY, Vignal C, Gaudric A, Quentel G: Retinal ischaemia in type 1 neurofibromatosis. Br J Ophthalmol 90: 117, 2006 Vianna RNG, Pacheco DF, Vasconcelos MM, de Laey, J-J: Combined hamartoma of the retina and retinal pigment epithelium associated with neurofibromatosis type-1. Int Ophthalmol 24: 63– 66, 2001 Crino PB, Nathanson KL, Henske EP: The tuberous sclerosis complex. N Engl J Med 355: 1345–1356, 2006 Brook-Carter PT, Peral B, Ward CJ, Thompson P, Hughes J, Maheshwar MM, Nellist M, Gamble V, Harris PC, Sampson JR: Deletion of the TSC2 and PKD1 genes associated with severe infantile polycystic kidney disease: A contiguous gene syndrome. Nat Genet 8: 328 –332, 1994 Rakowski SK, Winterkorn EB, Paul E, Steele DJR, Halpern EF, Thiele EA: Renal manifestations of tuberous sclerosis complex: Incidence, prognosis, and predictive factors. Kidney Int 70: 1777–1782, 2006 Robertson D: Ophthalmic manifestations of tuberous sclerosis. Ann N Y Acad Sci 615: 17–25, 1991 Gould DB, Marchant JK, Savinova OV, Smith RS, John SWM: COL4A1 mutation causes endoplasmic reticulum stress and genetically modifiable ocular dysgenesis. Hum Mol Genet 16: 798 – 807, 2007 Plaisier E, Alamowitch S, Gribouval O, Mougenot B, Gaudric A, Antignac C, Roullet E, Ronco P: Autosomal-dominant familial hematuria with retinal arteriolar tortuosity and contractures: A novel syndrome. Kidney Int 67: 2354 –2360, 2005 Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, Marro B, Desmettre T, Cohen SY, Roullet E, Dracon M, Fardeau M, Van Agtmael T, Kerjaschki D, Antignac C, Ronco P: COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. N Engl J Med 357: 2687–2695, 2007 Clarke JTR: Narrative review: Fabry disease. Ann Intern Med 146: 425– 433, 2007

95. Nance CS, Klein CJ, Banikazemi M, Dikman SH, Phelps RG, McArthur JC, Rodriguez M, Desnick RJ: Later-onset Fabry disease: An adult variant presenting with the crampfasciculation syndrome. Arch Neurol 63: 453– 457, 2006 96. Branton MH, Schiffmann R, Sabnis SG, Murray GJ, Quirk JM, Altarescu G, Goldfarb L, Brady RO, Balow JE, Austin HA, Kopp JB: Natural history of Fabry renal disease: Influence of alpha-galactosidase A activity and genetic mutations on clinical course. Medicine 81: 122–138, 2002 97. Flynn DM, Boothby CB, Lake BD, Young, EP: Gut lesions in Fabry’s disease without a rash. Arch Dis Child 47: 26 –33, 1972 98. Ko YH, Kim HJ, Roh YS, Park CK, Kwon CK, Park MH: Atypical Fabry’s disease: An oligosymptomatic variant. Arch Pathol Lab Med 120: 86 – 89, 1996 99. Wang RY, Lelis A, Mirocha J, Wilcox WR: Heterozygous Fabry women are not just carriers, but have a significant burden of disease and impaired quality of life. Genet Med 9: 34 – 45, 2007 100. Nakao S, Kodama C, Takenaka T, Tanaka A, Yasumoto Y, Yoshida A, Kanzaki T, Enriquez ALD, Eng CM, Tanaka H, Tei C, Desnick RJ: Fabry disease: Detection of undiagnosed hemodialysis patients and identification of a “renal variant” phenotype. Kidney Int 64: 801– 807, 2003 101. Nagao Y, Nakashima H, Fukuhara Y, Shimmoto M, Oshima A, Ikari Y, Mori Y, Sakuraba H, Suzuki Y: Hypertrophic cardiomyopathy in late-onset variant of Fabry disease with high residual activity of alpha-galactosidase-A. Clin Genet 39: 233–237, 1991 102. Wozniak MA, Kittner SJ, Tuhrim S, Cole JW, Stern B, Dobbins M, Grace ME, Nazarenko I, Dobrovolny R, McDade E, Desnick RJ: Frequency of unrecognized Fabry disease among young EuropeanAmerican and African-American men with first ischemic stroke. Stroke 41: 78 – 81, 2010 103. Latif F, Tory K, Gnarra J, Yao M, Duh FM, Orcutt ML, Stackhouse T, Kuzmin I, Modi W, Geil L, Schmidt L, Zhou FW, Li H, Wei MH, Chen F, Glenn G, Choyke P, Walther MM, Weng YK, Duan DSR, Dean M, Glavac D, Richards FM, Crossey PA, Fergusonsmith MA, Lepaslier D, Chumakov I, Cohen D, Chinault AC, Maher ER, Linehan WM, Zbar B, Lerman MI: Identification of the von Hippel-Lindau disease tumor-suppressor gene. Science 260: 1317–1320, 1993 104. Chan CC, Vortmeyer AO, Chew EY, Green WR, Matteson DM, Shen DF, Linehan WM, Lubensky IA, Zhuang ZP: VHL gene deletion and enhanced VEGF gene expression detected in the stromal cells of retinal angioma. Arch Ophthalmol 117: 625– 630, 1999


105. Chen F, Kishida T, Yao M, Hustad T, Glavac D, Dean M, Gnarra JR, Orcutt ML, Duh FM, Glenn G, Green J, Hsia YE, Lamiell J, Li H, Wei MH, Schmidt L, Tory K, Kuzmin I, Stackhouse T, Latif F, Linehan WM, Lerman M, Zbar B: Germline mutations in the von Hippel-Lindau disease tumor-suppressor gene: Correlations with phenotype. Hum Mutat 5: 66 –75, 1995 106. Dollfus H, Massin P, Taupin P, Nemeth C, Amara S, Giraud S, Beroud C, Dureau P, Gaudric A, Landais P, Richard S: Retinal hemangioblastoma in von Hippel-Lindau disease: A clinical and molecular study. Invest Ophthalmol Vis Sci 43: 3067–3074, 2002 107. Wittebol-Post D, Hes FJ, Lips CJM: The eye in von Hippel-Lindau disease. Longterm follow-up of screening and treatment: Recommendations. J Intern Med 243: 555– 561, 1998 108. Khan GA, Melman A, Bank N: Renal involvement in neurocutaneous syndromes. J Am Soc Nephrol 5: 1411–1417, 1995 109. Sullivan TJ, Clarke MP, Morin JD: The ocular manifestations of the Sturge-Weber syndrome. J Pediatr Ophthalmol Strabismus 29: 349 –356, 1992 110. Sadda SR, Miller NR, Tamargo R, Wityk R: Bilateral optic neuropathy associated with diffuse cerebral angiomatosis in SturgeWeber syndrome. J Neuro-Ophthalmol 20: 28 –31, 2000 111. Said R, Hamzeh Y, Said S, Tarawneh M, al-Khateeb M: Spectrum of renal involvement in familial mediterranean fever. Kidney Int 41: 414 – 419, 1992 112. Ando E, Ando Y, Maruoka S, Sakai Y, Watanabe S, Yamashita R, Okamura R, Araki S: Ocular microangiopathy in familial amyloidotic polyneuropathy, type 1. Graefes Arch Clin Exp Ophthalmol 230:1–5, 1992 113. Kawaji T, Ando Y, Nakamura M, Yamashita T, Wakita M, Ando E, Hirata A, Tanihara H: Ocular amyloid angiopathy associated with familial amyloidotic polyneuropathy caused by amyloidogenic transthyretin Y114C. Ophthalmology 112: 2212– 2218, 2005 114. Noble KG: Bilateral multifocal retinal arteriolar sheathing as the only ocular finding in hereditary amyloidosis. Am J Ophthalmol 125: 111–113, 1998 115. Frasca GM, Soverini L, Tampieri E, Franceschini G, Calabresi L, Pisciotta L, Preda P, Vangelista A, Stefoni S, Bertolini S: A 33year-old man with nephrotic syndrome and lecithin-cholesterol acyltransferase (LCAT) deficiency. Description of two new mutations in the LCAT gene. Nephrol Dial Transplant 19: 1622–1624, 2004 116. Ayyobi AF, McGladdery SH, Chan S, Mancini GBJ, Hill JS, Frohlich JJ: Lecithin: Cholesterol acyltransferase (LCAT) deficiency and risk of vascular disease: 25 year followup. Atherosclerosis 177: 361–366, 2004

J Am Soc Nephrol 22: ●●●–●●●, 2011

www.jasn.org

117. Hirano K, Kachi S, Ushida C, Naito M: Corneal and macular manifestations in a case of deficient lecithin: cholesterol acyltransferase. Jpn J Ophthalmol 48: 82– 84, 2004 118. Nadim F, Walid H, Adib J: The differential diagnosis of crystals in the retina. Int Ophthalmol 24: 113–121, 2001 119. Kopp N, Leumann E: Changing pattern of primary hyperoxaluria in Switzerland. Nephrol Dial Transplant 10: 2224–2227, 1995 120. Bobrowski AE, Longman CB: The primary hyperoxalurias. Semin Nephrol 28: 152– 162, 2008 121. Blaschke S, Grupp C, Haase J, Kleinoeder T, Hallermann C, Troche I, Grone HJ, Muller, GA: A case of late-onset primary hyperoxaluria type 1. Am J Kidney Dis 39: E11, 2002 122. Wells CG, Johnson RJ, Luo QL, Buntmilam AH, Kalina RE: Retinal oxalosis. A clinicopathologic report. Arch Ophthalmol 107: 1638 –1643, 1989 123. Small KW, Letson R, Scheinman J: Ocular findings in primary hyperoxaluria. Arch Ophthalmol 108: 89 –93, 1990 124. Gahl WA, Thoene JG, Schneider, JA: Cystinosis. N Engl J Med 347: 111–121, 2002 125. Nesterova G, Gahl W: Nephropathic cystinosis: Late complications of a multisystemic disease. Pediatr Nephrol 23: 863– 878, 2008 126. Town M, Jean G, Cherqui S, Attard M, Forestier L, Whitmore SA, Callen DF, Gribouval O, Broyer M, Bates GP, van’t Hoff W, Antignac C: A novel gene encoding an integral membrane protein is mutated in nephropathic cystinosis. Nat Genet 18: 319 –324, 1998 127. Shotelersuk V, Larson D, Anikster Y, McDowell G, Lemons R, Bernardini I, Guo JR, Thoene J, Gahl WA: CTNS mutations in an American-based population of cystinosis patients. Am J Hum Genet 63: 1352–1362, 1998 128. Tsilou ET, Rubin BI, Reed G, Caruso RC, Iwata F, Balog J, Gahl WA, Kaiser-Kupfer MI: Nephropathic cystinosis: Posterior segment manifestations and effects of cysteamine

J Am Soc Nephrol 22: ●●●–●●●, 2011

129.

130.

131.

132.

133.

134.

135.

136.

137.

138.

therapy. Ophthalmology 113: 1002–1009, 2006 Servais A, Moriniere V, Grunfeld JP, Noel LH, Goujon JM, Chadefaux-Vekemans B, Antignac C: Late-onset nephropathic cystinosis: Clinical presentation, outcome, and genotyping. Clin J Am Soc Nephrol 3: 27– 35, 2008 Ji W, Foo JN, O’Roak B, Zhao H, Larson M, Simon D, Newton-Cheh C, State M, Levy D, Lifton R: Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nat Genet 40: 592–599, 2008 Gitelman HJ, Graham JB, Welt LG: A new familial disorder characterized by hypokalemia and hypomagnesemia. Trans Assoc Am Physicians 79: 221–235, 1966 Marchini G, Tosi R, Parolini B, Castagna G, Zarbin M: Choroidal calcification in Bartter syndrome. Am J Ophthalmol 126: 727–729, 1998 Honavar SG, Shields CL, Demirci H, Shields JA: Sclerochoroidal calcification: Clinical manifestations and systemic associations. Arch Ophthalmol 119: 833– 840, 2001 Lemley KV: Kidney disease in nail-patella syndrome. Pediatr Nephrol 24: 2345–2354, 2009 Dreyer SD, Zhou G, Baldini A, Winterpacht A, Zabel B, Cole W, Johnson RL, Lee B: Mutations in LMX1B cause abnormal skeletal patterning and renal dysplasia in nail patella syndrome. Nat Genet 19: 47–50, 1998 Chen H, Lun Y, Ovchinnikov D, Kokubo H, Oberg KC, Pepicelli CV, Gan L, Lee B, Johnson RL: Limb and kidney defects in Lmx1b mutant mice suggest an involvement of LMX1B in human nail patella syndrome. Nat Genet 19: 51–55, 1998 Mimiwati Z, Mackey DA, Craig JE, MacKinnon JR, Rait JL, Liebelt JE, Ayala-Lugo R, Vollrath D, Richards JE: Nail-patella syndrome and its association with glaucoma: A review of eight families. Br J Ophthalmol 90: 1505–1511, 2006 Sweeney E, Fryer A, Mountford R, Green A, McIntosh I: Nail patella syndrome: A review

139.

140.

141.

142.

143.

144.

145.

146.

147.

BRIEF REVIEW

of the phenotype aided by developmental biology. J Med Genet 40: 153–162, 2003 Galloway G, Vivian A: An ophthalmic screening protocol for nail-patella syndrome. J Pediatr Ophthalmol Strabismus 40: 51–53, 2003 Fonck C, Chauveau D, Gagnadoux MF, Pirson Y, Grunfeld JP: Autosomal recessive polycystic kidney disease in adulthood. Nephrol Dial Transplant 16: 1648 –1652, 2001 Bollee G, Fakhouri F, Karras A, Noel LH, Salomon R, Servais A, Lesavre P, Moriniere V, Antignac C, Hummel A: Nephronophthisis related to homozygous NPHP1 gene deletion as a cause of chronic renal failure in adults. Nephrol Dial Transplant 21: 2660 –2663, 2006 Azari AA, Aleman TS, Cideciyan AV, Schwartz SB, Windsor EAM, Sumaroka A, Cheung AY, Steinberg JD, Roman AJ, Stone EM, Sheffield VC, Jacobson SG: Retinal disease expression in Bardet-Biedl syndrome-1 (BBS1) is a spectrum from maculopathy to retina-wide degeneration. Invest Ophthalmol Vis Sci 47: 5004 –5010, 2006 Schonck M, Hoorntje S, vanHooff J: Renal transplantation in Alagille syndrome. Nephrol Dial Transplant 13: 197–199, 1998 Meikle PJ, Hopwood JJ, Clague AE, Carey WF: Prevalence of lysosomal storage disorders. JAMA 281: 249 –254, 1999 Hillsley RE, Hernandez E, Steenbergen C, Bashore TM, Harrison JK: Inherited restrictive cardiomyopathy in a 74-year-old woman: A case of Fabry’s disease. Am Heart J 129: 199 –202, 1995 Devriendt K, Matthijs G, Van Damme B, Van Caesbroeck D, Eccles M, Vanrenterghem Y, Fryns JP, Leys A: Missense mutation and hexanucleotide duplication in the PAX2 gene in two unrelated families with renal-coloboma syndrome (MIM 120330). Hum Genet 103: 149 –153, 1998 Zaffanello M, Taranta A, Palma A, Bettinelli A, Marseglia GL, Emma F: Type IV Bartter syndrome: Report of two new cases. Pediatr Nephrol 21: 766 –770, 2006


13