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Renal System > Genetic Heterogeneity of Nephrotic Syndrome > Flashcards

Genetic Heterogeneity of Nephrotic Syndrome Flashcards

1
Q

What are the key major players of nephrotic syndrome? Where do you notice the change in structure?

A

Podocytes (main), foot processes, and slit diaphragms

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2
Q

What is the relationship between genetic mutations and nephrotic syndrome?

A

Multifaceted, involving both monogenic and polygenic factors that contribute to the pathogenesis

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3
Q

In which type of nephrotic syndrome, particularly, do genetic mutations play a crucial role?

A

Steroid-resistant nephrotic syndrome

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4
Q

What are the genes that have been identified to be associated with SRNS?

A

NPHS1
NPHS2
WT1

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5
Q

How do you identify a patient who is suffering from SRNS, especially in children?

A

When ped patients come in, there is no podocyte damage, but there is a genetic mutation. Patients are started on steroids, but proteinuria is still there so SRNS is diagnosed.

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6
Q

How is genetic testing important for nephrotic syndrome?

A

Provides crucial data on the risk associated with nephrotic syndrome

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7
Q

What is the importance of podocyte proteins in nephrotic syndrome?

A

Play an essential role when it comes to glomerular filtration, and pathogenic gene variants in these proteins account for most of the genetic nephrotic syndrome.

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8
Q

What are examples of podocyte proteins?

A

Nephrin,
Podocin,
WT1,
Phospholipase C epsilon,
Laminin beta 2

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9
Q

Why is it important to detect the genetic mutation causing nephrotic syndrome?

A

They have implications for the treatment and prognosis

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10
Q

What is Laminin regulated by?

A

Lam protein

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11
Q

What is the function of Podocin?

A

Essential for the formation of slit diaphragms

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12
Q

What is the gene associated with congenital NS - Finnish type?

A

NPHS1

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13
Q

What is the locus of congenital NS - Finnish type?

A

19q13.1

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14
Q

What is the inheritance of congenital NS-Finnish type like?

A

AR

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15
Q

What is the gene product of congenital NS - Finnish type?

A

Nephrin

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16
Q

What is the age of onset of congenital NS-Finnish type?

A

Infancy

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17
Q

What is the gene associated with SRNS / FSGS?

A

NPHS2

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18
Q

What is the locus of SRNS / FSGS?

A

1q25-31

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19
Q

What is the inheritance of SRNS / FSGS like?

A

AR

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20
Q

What is gene product of SRNS / FSGS?

A

Podocin

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21
Q

What is the age of onset for SRNS / FSGS?

A

3 months to adulthood

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22
Q

What is the gene associated with FSGS/diffuse mesangial sclerosis (DMS)?

A

PLCE1

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23
Q

What is the locus of FSGS/diffuse mesangial sclerosis (DMS)?

A

10q23

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24
Q

What is the mode of inheritance of FSGS/diffuse mesangial sclerosis (DMS)?

A

AR

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25
Q

What is the gene product of FSGS/diffuse mesangial sclerosis (DMS)?

A

Phospholipase C epsilon 1

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26
Q

What is the age of onset of FSGS/diffuse mesangial sclerosis (DMS)?

A

Childhood

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27
Q

What is the gene associated with Denys-Drash syndrome (DDS)?

A

WT1

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28
Q

What is the locus of Denys-Drash syndrome (DDS)?

A

11p13

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29
Q

What is the mode of inheritance of Denys-Drash syndrome (DDS)?

A

AD

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30
Q

What is the gene product of Denys-Drash syndrome (DDS)?

A

WT1

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31
Q

What is the age of onset of Denys-Drash syndrome (DDS)?

A

Infancy

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32
Q

What is the gene associated with Pierson syndrome?

A

LAMB2

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33
Q

What is the locus of the Pierson syndrome?

A

3p21

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34
Q

What is the mode of inheritance of Pierson Syndrome?

A

AR

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35
Q

What is the gene product of Pierson Syndrome?

A

Laminin- β2 chain

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36
Q

What is the age of onset of Pierson Syndrome?

A

Infancy

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37
Q

What is the gene associated with FSGS?

A

ACTN4

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38
Q

What is the locus of FSGS?

A

19q13

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39
Q

What is the mode of inheritance of FSGS?

A

AD

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40
Q

What is the gene product of FSGS?

A

α-actinin-4

41
Q

What is the age of onset of FSGS?

A

Late (adulthood)

42
Q

Does the focal or diffuse presentation determine whether it is monogenic or not?

A

No, it just shows the extent of the mutational change

43
Q

Who should be tested for genetic mutation of nephrotic syndrome? (6)

A
  1. Congenital nephrotic syndrome, onset (0 to 3 months)
  2. Infantile nephrotic syndrome (3 to 12 months)
  3. Childhood nephrotic syndrome > 12 months
  4. A child with a family history of nephrotic syndrome or CKD
  5. No response to steroid or steroid-resistant
  6. An individual with nephrotic syndrome is associated with other congenital malformations
44
Q

What are other congenital malformations that could be associated with nephrotic syndrome?

A

Ambiguous genitalia

45
Q

What is monogenic nephrotic syndrome?

A

A single gene defect, a congenital condition

46
Q

What is the mode of inheritance of monogenic nephrotic syndrome?

A

AR or AD, based on the type

47
Q

What is the incidence of monogenic NS?

A

1 to 3/100000 live births

48
Q

What is the main cause of monogenic nephritic syndrome?

A

Idiopathic (80%)

49
Q

Why can monogenic nephrotic syndrome not be secondary?

A

The injury happens within the podocytes.

50
Q

What are the presentations of monogenic nephrotic syndrome? (6)

A

Heavy proteinuria,
Edema,
Hypoalbuminemia,
Hypoglobulinemia,
Hypercoagulability,
Hyperlipidemia

51
Q

Why is hypercoagulability one of the presentations of NS?

A

Macromolecules, including anticoagulant proteins, also pass through the filtration slits

52
Q

Why is the management of monogenic NS very challenging?

A

Patients are prone to complications like infections, thrombosis and failure to thrive

53
Q

What is the management of monogenic NS?

A

It can progress to end-stage renal disease, which would require dialysis and, eventually, kidney transplantation

54
Q

What are the treatment options availbale for monogenic NS?

A

Immunosuppressive therapy, corticosteroids, or supportive care

55
Q

What is the importance of early detection?

A

Early genetci diagnosis improves management strategies

56
Q

What is genetic testing crucial for? (3)

A
  1. Identifying specific gene mutations
  2. Understanding familial patterns of inheritance
  3. Facilitating appropriate treatment plans tailored to the genetic profile of the patient
57
Q

What is the gene associated with Syndromic NS/Congenital NS?

A

ITGA3

58
Q

What is the locus of Syndromic NS/Congenital NS?

A

17q21

59
Q

What is the mode of inheritance of Syndromic NS/Congenital NS?

A

AR

60
Q

What is the phenotype and mode of inheritance associated with CD2AP gene?

A

FSGS, AD

61
Q

What is the locus of the CD2AP FSGS?

A

6p12.3

62
Q

What is the gene associated with the Nail-patella syndrome?

A

LMX1B

63
Q

What is the mode of inheritance of NAIL-PATELLA syndrome?

A

AD

64
Q

What is the locus of the Nail-Patella syndrome?

A

9p34.1

65
Q

What is the phenotype of the INF2 gene?

A

Syndromic NS FSGS

66
Q

What is the locus of the INF2 gene mutation?

A

14q32

67
Q

What is NPHS1?

A

An adhesion molecule called nephrin protein

68
Q

Where is NPHS1 found?

A

At the slit diaphragm of glomerular podocytes

69
Q

What are the characteristics of the congenital NS - Finnish type?

A

Severe proteinuria, loss of the slit diaphragm and foot processes, and edema

70
Q

What is the prognosis of congenital NS - Finnish type?

A

Rapidly progressive, resulting in ESRD

71
Q

How is the congenital NS-Finnish type detected?

A

Antenatally by elevated alpha-fetoprotein levels

72
Q

What is the most common complication of congenital NS - Finnish type?

A

Failure to thrive and renal failure

73
Q

Which gene is mutated in the SRNS?

A

NPHS2 on chromosome 1

74
Q

What is the mode of inheritance of SRNS?

A

AR

75
Q

What are the different types of SRNS?

A

Familial FSGS, familial/sporadic SRNS

76
Q

What does the NPHS2 gene code for?

A

Podocin

77
Q

What are the clinical manifestations of SRNS?

A

Childhood-onset of proteinuria, hypoalbuminemia, hyperlipidemia, and edema

78
Q

What is the presentation of SRNS under a light microscope?

A

Nonspecific or no histological changes, such as minimal change or FSGS

79
Q

What is diffuse mesangial sclerosis NS?

A

Early onset NS, type 2 NPHS 3

80
Q

What is the alternative name of the NPHS3 gene that causes diffuse mesangial sclerosis?

A

PLCE 1

81
Q

What is the mutation and the mode of inheritance of diffuse mesangial sclerosis NS?

A

Homozygous mutation in the PLCE1 gene on chromosome 10, AR

82
Q

What is the function of the PLCE1 gene?

A

Related to the G-protein signaling pathway and cMYC transcription network

83
Q

What is the main presentation of the PLCE 1 NS?

A

Diffuse mesangial sclerosis - truncated protein

A few cases of homozygous missense show FSGS

84
Q

What is the mutation and mode of inheritance of DDS?

A

AD and caused by a mutation in the tumor suppressor gene WT1 on chromosome 11

85
Q

What is the triad associated with DDS?

A

Ambiguous genitalia
Nephrotic syndrome
Wilm’s tumor

86
Q

What is the management of DDS like?

A

Management is challenging and optimal strategies have yet not been established

87
Q

What are certain indications for prenatal evaluation? (6)

A
  1. Placental weight is below 25% of newborn weight
  2. Enlarged prenatal nucha translucency and fetal edema
  3. Maternal AFP elevated during the 2nd trimester of pregnancy
  4. Pathogenic variant has been previously identified in the family, consanguinity, and history of infantile death
  5. Elevated AFP in proteinuria in utero
  6. US shows hyperechogenic kidneys
88
Q

What do hyperechogenic kidneys look like in the US?

A

Very, very light in color

89
Q

Is it an indication for prenatal evaluation if there is elevated AFP in the first trimester?

A

No, anything prior to the second trimester is not an indication

90
Q

What is the treatment/management of monogenic NS?

A

Control edema and prevent complications
Albumin infusion
Intensity and duration of immunosuppression therapy
ACE inhibitors,
Lipid-lowering agents
Renal transplantation

91
Q

When are albumin infusions given?

A

Only for heavy and constant proteinuria

92
Q

What are ACE inhibitors and lipid-lowering agents added for?

A

To slow disease progression

93
Q

What is the optimal treatment/management method?

A

Renal transplantation as it lowers the relapse rate

94
Q

Are there polygenic NS and steroid-sensitive NS?

A

Yes

95
Q

What contributes to polygenic NS?

A

Genetic variants in HLA-class II with additional genetic mutations like PLCG2 and FOXP3

96
Q

Can someone live asymptomatically with polygenic NS?

A

Yes, if the rest of the triggers (genes) are not activated throughout their life, they can carry on living as asymptomatic

97
Q

What is polygenic NS also known as/

A

Steroid-sensitive NS

98
Q

When does steroid-sensitive NS present?

A

During adulthood, it has weak heritability patterns and modifies through environmental factors

99
Q
A

Renal System (24 decks)

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