A mild form of Alport syndrome: Hereditary nephropathy in the absence of extra-renal features

Yoon H-S, Wilson JC & Eccles MRPathology, University of Otago,

Dunedin, New Zealand

Alport syndrome (AS)• A hereditary disorder resulting from abnormal

type IV collagen • Nephropathy with considerable genetic and

clinical heterogeneity characterized by haematuria, proteinuria and progressive renal failure, first reported by Alport in 1927

• Frequently associated with:– Eye abnormalities– High tone sensorineural deafness

• Rarely associated with:– Mental retardation– Leiomyomatois

Alport syndrome: genetics• 85% of AS patients: X-linked inheritance of

mutations in the COL4A5 gene on Xq22 encoding the 5(IV) collagen chain– COL4A5 is a large gene comprising 51 exons– As many as 609 mutations have been described to

date and are spread throughout the gene without any hot spots (Arup Laboratory 2011)

• 15%: Autosomal inheritance of mutations of the COL4A3 or COL4A4 gene encoding the 3(IV) or 4(IV) on 2q36-37:– 14%: autosomal recessive– 1%: autosomal dominant

Type IV collagen formation

Protomer(VI) chain

Meshwork formation

1

4

23

56

112

345

556

Hudson et al, NEJM 348:2543, 2003

NC1Collagenous7S

Type IV collagen distribution• 1.1.2(IV): Ubiquitously present in basement membrane

(BM) in many tissue• 3.4.5(IV) and 5.5.6(IV): Restricted tissue distribution– In the kidney 1.1.2(IV) network predominates during

early nephrogenesis in GBM.– During the 2nd trimester of foetal development,

3.4.5(IV) network gradually becomes dominant • 3.4.5(IV) is also expressed in the eye, cochlea, lung and

testis while 5.5.6(IV) network is present in skin, oesophagus and smooth muscle.

Initial presentation of the NZ family

• Two sisters (IV6:58 yo and IV8:54 yo) presented to the clinic to be considered as potential live kidney donors for their sons (V29:27 yo and V35:33 yo, respectively) who had ESRF.

• Both women were found to have significant proteinuria (1.8, 1.4g/d, respectively) and hypertension and they proceeded to a renal biopsy (mild mesangial proliferation and hypertensive arteriosclerosis).

• Routine questioning revealed a strong familial history of hypertension and the possibility of a familial form of renal disease.

• Subsequent clinical review of the family identified a number of additional family members with renal disease.

• Negative for hearing loss or eye abnormalities in all individuals tested.

Identif-ication number

Age (yrs old)Gender

Presentation Renal Function and Blood Pressure

Biopsy Inheritance

III2 F   Died on dialysis Not done Affected/ Carrier

IV3 57M

  ESRF. DialysisRenalTransplant at 41

Not done Affected

IV5 46M

ProteinuriaHypertension

Chronic kidney disease

Not done Affected

V24 39M

ProteinuriaHaematuria

Normal renal function

Mild mesangial matrix expansion

Affected

V29 27M

Acute nephritic syndromeHypertension

ESRF. Dialysis2nd renal transplant at 26

Chronic glomerulo-nephritis

Affected

V31 36M

ProteinuriaHypertension

Chronic kidney diseaseBP 136/86

Mesangial cell proliferation

Affected

V35 33M

ProteinuriaHaematuria

ESRF and renal transplant at 28

Chronic glomerulo-nephritis

Affected

IV39 72M

Proteinuria 1.6g/24 hrNo haematuriaHypertension

Mild chronic kidney diseaseBP 144/76

Not done Affected

V42 39M

Proteinuria 1.1g/24 hr

Normal renal functionBP 126/80

Mesangial cell proliferation

Affected

Identif-ication number

Age(yrs old)Gender

Presentation Renal Function and Blood Pressure

Biopsy Inheritance

IV26 58F

Proteinuria 1.8g/24 hr Hypertension

BP 152/76 Mesangial cell proliferationHypertensive arteriosclerosis

Carrier

IV28 54F

Proteinuria1.4g/24 hr Hypertension

Normal renal function

Mesangial cell proliferationHypertensive arteriosclerosis

Carrier

1. Subjects with renal disease identified before DNA tests

Dead:1, ESRF:3, Chronic disease:3

Histology of V42

IHC for 3, 4 and 5(IV)

3 4

5 Abs gift from Dr Sado

Diagnostic dilemma

• Is this Alport syndrome?– No hearing or eye abnormalities– Mild form of kidney disease and late onset• 11 Glomerulonephritis• 4 ESRF (3 males and 1 female) • Low penetrance!!

• A new entity of hereditary kidney disease?

Extended family pedigree

A total of 155 family members for 6 generations examined (81M and 74F).Black symbols: Biopsy confirmed GN (6M).Gray symbols: Clinically GN, biopsy not done (4M & 1F).Black dots: Obligate carriers (21F).White symbols: No clinical disease (71M & 73F).Cross: Confirmed by DNA testing.Predominance of GN in males and lack of male to male transmission consistent with X-linked inheritance

Family pedigree (simplified)

X-chromosomemicrosatellite marker

Two point LOD scores between the GN locus and markers mapping to chromosome Xq21.33-

23

Theta 0 0.01 0.05 0.1 0.2 0.3 0.4

DXS6809 -infinity -0.31 0.88 1.21 1.25 0.99 0.57

DXS6789 3.14 3.08 2.86 2.58 1.98 1.35 0.69

DXS8096 3.59 3.53 3.28 2.96 2.28 1.56 0.8

DXS1210 3.59 3.53 3.28 2.96 2.28 1.56 0.8

DXS6749 -infinity -0.61 -0.01 0.16 0.2 0.13 0.05

The linked region encompassing COL4A5

Nucleotide sequence alteration in COL4A5 in affected family members

Mae III digest of exon50 PCR products

M NC Affected males Affected & carrier females

A allelePresent in all affectedfamily members and not in 192 healthy control

Identif-ication number

Age (yrs old)Gender

Presentation Renal Function and Blood Pressure

Biopsy Inheritance

III2 F   Died on dialysis Not done Affected/ Carrier

IV3 57M

  ESRF. DialysisRenalTransplant at 41

Not done Affected

IV5 46M

ProteinuriaHypertension

Chronic kidney disease

Not done Affected

V24 39M

ProteinuriaHaematuria

Normal renal function

Mild mesangial matrix expansion

Affected

V29 27M

Acute nephritic syndromeHypertension

ESRF. Dialysis2nd renal transplant at 26

Chronic glomerulo-nephritis

Affected

V31 36M

ProteinuriaHypertension

Chronic kidney diseaseBP 136/86

Mesangial cell proliferation

Affected

V35 33M

ProteinuriaHaematuria

ESRF and renal transplant at 28

Chronic glomerulo-nephritis

Affected

IV39 72M

Proteinuria 1.6g/24 hrNo haematuriaHypertension

Mild chronic kidney diseaseBP 144/76

Not done Affected

V42 39M

Proteinuria 1.1g/24 hr

Normal renal functionBP 126/80

Mesangial cell proliferation

Affected

Identif-ication number

Age(yrs old)Gender

Presentation Renal Function and Blood Pressure

Biopsy Inheritance

IV24 69F

Trace microscopic haematuria

Normal renal functionBP 168/86

Not done Carrier

IV26 58F

Proteinuria 1.8g/24 hr Hypertension

BP 152/76 Mesangial cell proliferationHypertensive arteriosclerosis

Carrier

IV28 54F

Proteinuria1.4g/24 hr Hypertension

Normal renal function

Mesangial cell proliferationHypertensive arteriosclerosis

Carrier

IV31 69F

Hypertension Negative urine

Normal renal function

Not done Carrier

IV34 65F

Hypertension Negative urine

Normal renal function

Not done Carrier

IV36 61F

Microscopic haematuria

Normal renal function

Not done Carrier

V40 38F

Haematuria Normal renal functionBP 118/60

Mild mesangial cell proliferation

Carrier

IV47 54F

Negative urine BP 148/70 Not done Carrier

V44 36F

Intermittent microscopic haematuria

Normal renal functionBP 120/76

Not done Carrier

V49 43F

Negative urine Normal renal functionBP 120/70

Not done Carrier

V37 39F

Negative urine Normal renal function

Not done Carrier

1.Renal disease identified before DNA tests 2.Renal disease/carriers identified after DNA tests

Depiction of NC1 domain showing locations of cysteine sequence alterations and clinical details

of patients

Summary

We report a unique cysteine to tyrosine substitution in the NC1 domain of COL4A5 in a New Zealand family who presented with a phenotypically mild form of Alport syndrome, suggesting that in this family substitution of Cys1638Tyr led to late onset renal failure without hearing loss or eye abnormalities.

Histology of female carriers (IV26)

6A 6B

EM (carrier IV26)

150nm

EM (carriers IV26)

Summary

• Thin basement membrane nephropathy could be seen in some carrier women containing COL4A5 mutations.