genetic disease 2 Flashcards
1
Q
describe Alkaptonuria (ochronosis)
A
- Autosomal recessive
- Deficiency of HOMOGENTISIC ACID OXIDASE
- causes Homogentisic acid accumulates as blue/black pigment which binds to collagen in connective tissue/tendons/cartilage
- Excreted in urine –> urine turns BLACK if allowed to stand and oxidize, or upon adding alkali
2
Q
Describe degenerative arthropathy
A
- HOMOGENTISIC acid deposits in CARTILAGE of ARTICULAR SURFACES which turns to brittle and flakes
- occurs in INTERVERTEBRAL DISCS, and later in knees, hips, shoulders
- small joints are speared
- may be crippling (severe osteoarthritis that occurs earlier in age)
3
Q
Describe lysosomal storage disease
A
- autosomal recessive
- Failure of catabolism of large molecules WITHIN lysosomes due to lack of enzymes (various kinds), mutant inactive enzymes etc
- can be put on enzyme replacement therapy
4
Q
Describe Tay-Sachs disease
A
- Gangliosidase deficiency due to FRAMESHIFT mutation in HexA gene
- LACK of HEXOSAMINIDASE A leading to accumulaation of GM2ganglioside
- often found in Ashkenazi Jew population
- Ballooning of neurons (membranous concentric bodies)
5
Q
what are the features of Tay Sach’s diseaase
A
TAYSACHS
- Testing recommended
- autosomal recessive
- Young death (4 years)
- Spot of Macula (cherry red spots)
- Ashkenazi jews
- CNS degeneration
- Hex A deficiency
- Storage disease
6
Q
describe Cherry red spots
A
- Cherry red spot on the Macula (spot is normal color, but the rest of retina is TOO WHITE due to lipid accumulation)
- produced when ganglion cells (filled with lipid) degenerate, exposing the vascular choroidal tissue
7
Q
Define Amaurotic idiocy
A
- blindness (amaurosis) produced by retinal involvement, together with the mental deterioration produced by destruction of other neurons has given the disease the name amaurotic idiocy
8
Q
describe Gaucher disease
A
- Autosomal recessive
- mutation in gene encoding enzyme Beta-Glucocerebrosidase (GBA) which functions in breaking down glucocerebroside into glucose and a fat called ceramide
9
Q
Mononuclear phagocyte system
A
- defect leads to accumulation of GLUCOSYLCERAMIDE in macrophages of the reticuloendothelial system (RES) and their subsequent enlargements
- Gaucher cells form
10
Q
Define Gaucher cells
A
- Huge macrophages (bloated) with glucocerebroside
- -> accumulates mostly in spleen, liver and bone marrow
- cells appear like “weingkled tissue paper” or “crinkled cigarette paper”
11
Q
describe The types of Guacher Disease
A
- 3 Types:
- -> Type I = adult type, common in ashkenazi jews and is NON-NEURONOPATHIC (compatible with long life)
- -> Type II and III = rare but NEURONOPATHIC (II is most severe)
12
Q
what are the clincial characteristics of Guachers disease
A
- massively enlarged spleen
- large liver and lymph nodes
- Skeletal problems = excruciating bone pain and fractures due to marrow being packed with ever-expanding cells
13
Q
what are the clincial characteristics of Guachers disease
A
- massively enlarged spleen
- large liver and lymph nodes
- Skeletal problems = excruciating bone pain and fractures due to marrow being packed with ever-expanding cells
14
Q
describe Type A niemann-Pick disease
A
- MISSENSE MUTATION with almost total deficiency of the SPHINGOMYELINASE leading to SEVERE accumulation of SPHINGOMYELIN and CHolesterl in lysosome
- -> results in foamy (vacuolated) cytoplasm (engorged lysosomes on EM with concentric lamellated myeling figures known as ZEBRA BODIES)
15
Q
describe Type C niemann-pick disease
A
- deficiency in cholesterol transport
- not an enzyme defect
- NPC1 and NPC2 gene mutations causing a defect in NONenzymatic lipid transport leading to accumulation of GM gangliosides (and free cholesterol) in lysosomes
16
Q
describe the characteristics of Type A niemann-pick disease
A
- severe deficiency of sphingomyelinase
- accumulation of sphingomyelin
- occurs in infants with early death (3 years
- -* Neurologic signs = shrunkin gyri/widened sulci (cell death), retinal cherry red spot (like Tay-sachs)
- Splenomegaly
- hepatomegaly
- enlarged lymph nodes
17
Q
describe the characteristics of Type B niemann-pick disease
A
- sphingomyelinase deficiency
- survive into adulthood
- large livers and spleen
- NO CNS invovlement
18
Q
describe the characteristics of Type C niemann-pick disease
A
- Hydrops fetalis/ still birth
- neonatal hepatitis
- Chronic progressive NEUROLOGICAL DAMAGE
- most common presentation in childhood = ataxia, vertical supranuclear gaze palsy, dystonia, dysarthria, psychomotor deterioration
19
Q
Describe MucoPolySaccharidoses (MPS)
A
- deficient Lysosomal enzymes that degrade MUCOPOLYSACCHARIDES (cleave terminal sugars)
- MPS accumulates in lysosomes of RES and smooth muscles
20
Q
Describe MucoPolySaccharidoses (MPS)
A
- deficient Lysosomal enzymes that degrade GLYCOSAMINOGLYCANS (GAGs) leads to accumulation in tissues
- CLINICAL FEATURES = skeletal abnormalties, corneal clouding, organomegaly, joint stiffness, hermias, short stature, mental retardation
- Vacuolated lymphocytes in peripheral smear and excessive urinary GAGs are typical findings
21
Q
describe Hurler syndrome (MPS IH)
A
- Autosomal recessive
- Deficiency in alpha-L-IDURONIDASE results in accumulation of DERMATAN SULFATE and HEPARAN SULFATE
22
Q
describe the clinical manifestations of HURLER SYNDROME (MPS IH)
A
- affected individual appear normal at birth
- exhibit accelerated growth in first year followed by slowing of growth leading to short stature
- first 2 years, hepatosplenomegaly, corneal clouding, coarse facial features, large tongue, joint stiffness and characteristic skeletal abnormalities develop
- progressive mental retardation, skeletal malformations and cardiopulmonary compromise typically lead to death during the first decade
23
Q
describe Hunter syndrome (MPS II)
A
- deficiency in IDURONOSULFATE SULFATASE
- clinically is similar to MPS IH
- -> NO corneal clouding
- -> symptoms range from severe CNS and visceral involvement with death to normal CNS function and survival into adulthood
24
Q
describe glycogen storage diseases
A
- disorders affecting the synthesis or degradation of glycogen
- characterized by abnormal deposits of glycogen in tissues
- Autosomal recessive
- GSD typically cause fasting hypoglycemia and hepatomegaly
25
Q
describe Type I GSD (Von Gierke disease
A
- Defect in Hepatic Glucose-6-phosphatase or glucose-6-phosphatase translocase which leads to inadequate conversion of glucose-6-phosphate to glucose
- accumulation of glycogen in liver and renal tubules and hypoglycemia
26
Q
describe clinical features of Type I GSD (Von Gierke disease)
A
- enlarged liver, and kidney
- hypoglycemia, lactic acidosis
- hyperlipidemia and hyperuricemia
- LATE COMPLICATIONS = hepatic adenomas and renal failure
- Maintenance of blood glucose concentration with physiologic ranges allows favorable development
27
Q
describe Type V GSD (McArdle disease)
A
- lack of muscle phosphorylase limits ATP generation by glycogenolysis and results in glycogen accumulation
- diagnosis is indicated by ELEVATION in SERUM muscle CREATINE KINASE acivity and failure to increase lactate level with exercise
- confirmed on elevated muscle glycogen and reduced phosphorylase activity
28
Q
describe the clinical features of Type V GSD
A
-
29
Q
describe Type I GSD (Von Gierke disease
A
- Defect in HEPATIC Glucose-6-phosphatase or glucose-6-phosphatase translocase which leads to inadequate conversion of glucose-6-phosphate to glucose
- accumulation of glycogen in liver and renal tubules and hypoglycemia
30
Q
describe Type V GSD (McArdle disease)
A
- lack of MUSCLE phosphorylase limits ATP generation by glycogenolysis and results in glycogen accumulation
- diagnosis is indicated by ELEVATION in SERUM muscle CREATINE KINASE acivity and failure to increase lactate level with exercise
- confirmed on elevated muscle glycogen and reduced phosphorylase activity
31
Q
describe the clinical features of Type V GSD
A
- Excercise intolerance with muscle cramps and myoglobinuria (secondary to rhabdomyolysis)
- develop in late childhood or as an adult
- Intense myoglobinuria may cause ACUTE RENAL FAILURE
32
Q
describe Type II GSD (pompe disease)
A
- deficiency of ACID-ALPHA-1,4-GLUCOSIDASE (acid maltase) results in lysosomal accumulation of glycogen in heart, muscle, liver, and nervous system
- Diagnosis is based on deficient enzyme activity in muscle, fibroblasts, amniotic cells or CVS and identifcation of mutations (SYSTEMIC)
33
Q
describe the clinical features of Pompe disease
A
- infantile-onset form features cardiomegaly, HYPOTONIA and death prior to 2 years of age
- Juvenile form presents as difficult walking in childhood followed by swallowing difficulties and muscle weakness
- -> death from respiratory failure may occur before the end of 2nd decade
- Adult form is slowly progressive muscle weakness with respiratory insufficiency
