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CMM 625: Genetic Disorders II > MPS & Peroxisomal Disorders > Flashcards

MPS & Peroxisomal Disorders Flashcards

1
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A
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2
Q

What is the combined incidence of MPS?

A

Approximately 1/20,000

MPS stands for Mucopolysaccharidoses, a group of inherited lysosomal storage disorders.

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3
Q

Are MPS disorders autosomal dominant or autosomal recessive?

A

All are autosomal recessive except Hunter Syndrome (X-Linked)

The only exception is MPS II, which is X-linked.

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4
Q

Which MPS disorder is an exception to being asymptomatic at birth?

A

MPS VII – Sly Syndrome

All other MPS disorders are progressive and asymptomatic at birth.

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5
Q

What is a common laboratory finding in MPS disorders?

A

Abnormally high urine MPS (GAG) levels

GAGs may be only intermittently high in some patients.

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6
Q

Name three types of Glycosaminoglycans (GAGs) associated with MPS.

A
  • Heparan sulfate
  • Keratan sulfate
  • Dermatan sulfate

These GAGs play various roles in the body, including structural components.

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7
Q

Where is heparan sulfate abundant in the body?

A

In the brain

Heparan sulfate is a critical component of the extracellular matrix.

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8
Q

Where are keratan sulfate and dermatan sulfate abundant?

A

In the skeleton

These GAGs contribute to the structural integrity of bones and cartilage.

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9
Q

What are the characteristic facial features of MPS?

A

Course facial features

Includes distinct changes in appearance, often noted in patients.

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10
Q

What is macrocephaly?

A

Abnormal enlargement of the head

Often associated with various medical conditions, including MPS.

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11
Q

What does a saddle nose look like?

A

Flat nasal bridge and broad nasal tip

A common feature in patients with MPS.

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12
Q

What are the characteristics of lips in MPS?

A

Large lips and broad mouth

Contributes to the overall coarse facial features.

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13
Q

What does macroglossia refer to?

A

Enlarged tongue

This can affect speech and eating in affected individuals.

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14
Q

What is puffiness around the eyes indicative of?

A

Swelling or edema around the eyes

A common physical manifestation in MPS patients.

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15
Q

What are the facial characteristics associated with large cheeks in MPS?

A

Prominent and rounded cheeks

Contributes to the overall appearance of the face.

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16
Q

What is the significance of thick eyebrows in MPS?

A

Prominent and bushy eyebrows

A distinguishing feature in the facial characteristics of MPS.

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17
Q

How is coarse, thick hair described in individuals with MPS?

A

Thatch-like hair

This type of hair texture is often noted in MPS patients.

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18
Q

What does hypertrichosis refer to?

A

Excessive hair growth

This can occur in various areas of the body in MPS patients.

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19
Q

What are the musculoskeletal features of MPS?

A
  • Dysostosis Multiplex** key feature
  • Growth restriction/short stature
  • Joint contractures
  • “claw” hand deformity
  • Spinal gibbus deformity
  • Pelvic and hip dysplasia
  • Thick clavicles and ribs
  • Short neck
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20
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21
Q

What is a common gastrointestinal manifestation of MPS?

A

Hepatosplenomegaly

Hepatosplenomegaly refers to the enlargement of both the liver and spleen.

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22
Q

Name two gastrointestinal issues associated with MPS.

A
  • Umbilical hernias
  • Inguinal hernias

Hernias can occur due to increased intra-abdominal pressure.

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23
Q

What are common bowel symptoms in MPS patients?

A
  • Loose stools
  • Diarrhea

These symptoms can be a result of gastrointestinal dysmotility.

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24
Q

What cardiovascular condition is associated with MPS?

A

Cardiomyopathy

Cardiomyopathy is a disease of the heart muscle that affects its size, shape, and ability to pump blood.

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25
What type of heart disease is associated with MPS?
Valvular Heart Disease ## Footnote Valvular heart disease involves damage to one or more of the heart's valves.
26
What systemic condition can develop in MPS patients?
Systemic and Pulmonary Hypertension ## Footnote Hypertension refers to high blood pressure in the systemic or pulmonary arteries.
27
What type of coronary condition is linked to MPS?
Coronary Artery Disease ## Footnote This condition involves the narrowing of the coronary arteries due to plaque buildup.
28
What respiratory condition is associated with MPS?
Obstructive airway disease ## Footnote This includes conditions that block airflow, such as asthma or chronic bronchitis.
29
What anatomical feature can contribute to obstructive airway disease in MPS?
Thick, large tongue ## Footnote A large tongue can obstruct the airway, particularly during sleep.
30
What sleep condition is common among MPS patients?
Severe sleep apnea ## Footnote Sleep apnea is a serious sleep disorder where breathing repeatedly stops and starts.
31
What are common ENT concerns in MPS?
Rhinitis, Sinusitis, Otitis, Chronic Upper Respiratory Infections ## Footnote MPS refers to Mucopolysaccharidoses, a group of inherited disorders caused by the absence of specific enzymes involved in the breakdown of glycosaminoglycans (GAGs).
32
What types of hearing loss are associated with MPS?
Progressive, conductive or sensorineural, related to recurrent infections and inner ear GAG deposition ## Footnote Hearing loss in MPS is often due to a combination of factors, including chronic infections and the accumulation of GAGs in the ear.
33
Which condition is an exception to corneal clouding in MPS?
Hunter Syndrome ## Footnote In Hunter Syndrome, GAG deposition occurs in the cornea but does not lead to corneal clouding as seen in other types of MPS.
34
What ocular manifestations can occur in MPS?
Corneal clouding, Retinal degeneration, Glaucoma, Optic nerve disease ## Footnote These ocular issues are related to the accumulation of GAGs and can lead to significant vision problems.
35
True or False: Corneal clouding occurs in all types of MPS.
False ## Footnote Hunter Syndrome is the notable exception where corneal clouding does not occur despite GAG deposition in the cornea.
36
What is communicating hydrocephalus?
A condition where cerebrospinal fluid (CSF) can flow between the ventricles, which remain open.
37
How does communicating hydrocephalus contribute to macrocephaly?
It leads to an increase in head size due to fluid accumulation.
38
What treatment can alleviate symptoms of communicating hydrocephalus?
Shunting can alleviate symptoms.
39
What is carpal tunnel syndrome?
A condition caused by compression of the median nerve in the wrist.
40
What are nerve compressions?
Conditions where nerves are pinched or compressed, leading to pain or dysfunction.
41
Fill in the blank: _______ refers to the fact that CSF can still flow between the ventricles.
Communicating
42
What is the severe form of MPS I?
Hurler Syndrome ## Footnote MPS I is classified into two forms based on severity.
43
What is the attenuated form of MPS I?
Scheie ## Footnote Attenuated forms of MPS I present with milder symptoms.
44
What deficiency is associated with MPS I?
L-iduronidase deficiency ## Footnote This enzyme deficiency leads to the accumulation of glycosaminoglycans.
45
Which gene is associated with MPS I?
IDUA gene ## Footnote Mutations in this gene cause MPS I.
46
Is MPS I included in the Arizona Newborn Screening (NBS)?
Yes ## Footnote Early detection through NBS can lead to better management of the disease.
47
What is the outcome of untreated Attenuated MPS I (Scheie)?
Features usually evident by 3-10 years of age ## Footnote Symptoms include milder but slowly progressive dysostosis multiplex, facial coarsening, and various organ complications.
48
What percentage of Attenuated MPS I patients exhibit dysostosis multiplex?
85% ## Footnote Indicates common skeletal abnormalities seen in the condition.
49
List some features associated with Attenuated MPS I.
* Milder but slowly progressive dysostosis multiplex * Milder but slowly progressive facial coarsening * +/- organomegaly * Cloudy cornea (82%) * Hernia (60%) * Heart valve (88%) ## Footnote These features can vary in presentation and severity among individuals.
50
What is the cognitive outcome for individuals with Attenuated MPS I?
Normal cognitive outcome to mildly learning disabled ## Footnote Cognitive impairment is not common but can occur.
51
What is the typical lifespan of individuals with Attenuated MPS I?
Normal lifespan to death in 2nd or 3rd decades ## Footnote Life expectancy can be significantly affected by complications.
52
What is the primary treatment for Attenuated MPS I?
Recombinant IV enzyme replacement therapy (ERT) ## Footnote Aldurazyme is specifically mentioned as an effective treatment.
53
How does Aldurazyme benefit patients with Attenuated MPS I?
Reduces non-neurologic complications ## Footnote It is most effective for managing the condition.
54
What is the role of hematopoietic stem cell transplantation (HSCT) in treating Attenuated MPS I?
Rarely used due to high risk of complications and effectiveness of ERT ## Footnote HSCT may not provide significant benefits compared to ERT.
55
What is the primary method for diagnosing MPS I?
Urine GAG Excretion ## Footnote GAG stands for glycosaminoglycans.
56
What levels are elevated in the diagnosis of MPS I?
Elevated total GAG levels ## Footnote This includes specific types of GAGs.
57
Which specific GAGs are elevated in MPS I?
Elevated Heparan and Dermatan Sulfate ## Footnote These are types of glycosaminoglycans.
58
What enzyme activity is measured for MPS I diagnosis?
Alpha-L-Iduronidase Enzyme Activity ## Footnote This enzyme is crucial for breaking down specific GAGs.
59
What types of biological samples can be analyzed for MPS I diagnosis?
WBCs, plasma, fibroblasts, amnio, CVS ## Footnote CVS refers to chorionic villus sampling.
60
What is the correlation of enzyme activity with the severity or carrier status in MPS I?
Poor correlation with severity or carrier status ## Footnote This means enzyme levels do not reliably indicate disease severity.
61
Which gene is analyzed for MPS I diagnosis?
IDUA gene molecular analysis ## Footnote IDUA stands for iduronidase alpha gene.
62
What type of genetic analysis is performed on the IDUA gene?
Sequencing with del/dup positive in ~100% ## Footnote Del/dup refers to deletions and duplications in the gene.
63
Is there a correlation between genotype and phenotype in MPS I?
Some genotype/phenotype correlation ## Footnote This indicates that certain genetic variants can predict clinical features.
64
What are pseudodeficiency alleles in the context of MPS I?
Alleles that do not cause disease but may show reduced enzyme activity ## Footnote These can complicate diagnosis.
65
What is one of the screening methods available for MPS I?
Newborn Screening ## Footnote This screening is crucial for early detection and management.
66
Is MPS I on NBS in Arizona?
Yes ## Footnote AZ refers to Arizona.
67
What is the outcome of severe form treatment without intervention by 10 years of age?
Death by 10 years of age ## Footnote This highlights the critical importance of timely treatment.
68
What is the expected lifespan for individuals with the attenuated form of the condition?
Normal lifespan to death in 2nd or 3rd decades ## Footnote The attenuated form allows for a longer life compared to the severe form.
69
What is the role of hematopoietic stem cell transplantation (HSCT) in treatment?
Can increase survival and reduce complications if started before 2 years of age ## Footnote However, it does not prevent all neuro, cardiac, or skeletal features.
70
Is HSCT commonly used in attenuated form of the condition?
Rarely used in attenuated form ## Footnote The application of HSCT is more critical in severe cases.
71
What is recombinant IV enzyme replacement therapy (ERT) used for?
Reduces non-neurologic complications ## Footnote Aldurazyme is a specific treatment that falls under this category.
72
What is MPS II commonly known as?
Hunter Syndrome
73
What are the forms of MPS II?
Severe and mild forms
74
What type of genetic inheritance pattern does MPS II follow?
X-Linked Recessive
75
Which gene is associated with MPS II?
IDS gene
76
Is Hunter Syndrome on NBS in Arizona?
No
77
What is a key diagnostic test for MPS II?
Urine GAG excretion ## Footnote GAG stands for glycosaminoglycans, which are important for diagnosing mucopolysaccharidoses.
78
What elevated levels are indicative of MPS II?
Elevated total GAG levels ## Footnote This includes specific GAGs such as Heparan and Dermatan Sulfates.
79
What enzyme activity is measured for MPS II diagnosis?
Iduronate Sulfatase Enzyme Activity ## Footnote This enzyme is crucial for the breakdown of specific glycosaminoglycans.
80
Which biological samples can be used for MPS II diagnosis?
WBCs, plasma, fibroblasts, amnio, CVS ## Footnote These samples help assess enzyme activity and genetic status.
81
Is there a strong correlation between severity of MPS II and carrier status?
Poor correlation ## Footnote This indicates that severity may not predict carrier status effectively.
82
What must be normal in other sulfatases for MPS II diagnosis?
Normal activity ## Footnote This ensures that the test results are specific to Iduronate Sulfatase.
83
What type of genetic analysis is performed for MPS II?
IDS gene molecular analysis ## Footnote IDS stands for Iduronate Sulfatase, and its analysis is critical for diagnosis.
84
What methods are used in IDS gene molecular analysis?
Sequencing, del/dup, and southern blot ## Footnote These methods are positive in approximately 100% of cases.
85
What must be excluded when analyzing the IDS gene?
Rearrangement with neighboring pseudogene ## Footnote This is essential to obtain accurate results.
86
Is there a correlation between genotype and phenotype in MPS II?
Some correlation ## Footnote This suggests that certain genetic variations may affect clinical presentation.
87
What are pseudodeficiency alleles in the context of MPS II?
Genetic variants that do not cause disease but show reduced enzyme activity ## Footnote These can complicate diagnosis by mimicking MPS II without causing symptoms.
88
What are the outcomes without treatment for MPS II?
Features often noted before 1 year of age include: * Umbilical/inguinal hernia * Frequent upper respiratory infections ## Footnote Progressive features often noted from 1 year of age onward.
89
What progressive features are noted from 1 year of age in MPS II?
Progressive features include: * Coarse facial features without corneal clouding * Dysostosis multiplex and organ involvement * Developmental delay, stagnation, and neurodegeneration by 6-8 years old * Death by 10-20 years of age
90
True or False: Death typically occurs by 10-20 years of age in untreated MPS II.
True
91
What is the questionable benefit treatment option for MPS II?
Hematopoietic stem cell transplantation
92
What is the name of the recombinant IV enzyme replacement therapy for MPS II?
Elaprase
93
What does Elaprase reduce in patients with MPS II?
Non-neurologic complications
94
Fill in the blank: Features often noted before 1 year of age include _______.
umbilical/inguinal hernia and frequent upper respiratory infections
95
What are the key features of MPS II noted after 1 year of age?
Coarse facial features without corneal clouding, dysostosis multiplex, organ involvement
96
What is the incidence rate of MPS III (Sanfilippo syndrome)?
Approximately 1 in 70,000 ## Footnote MPS III is the most common type of Mucopolysaccharidosis.
97
How many genes are involved in the metabolism of Heparan Sulfate in MPS III?
Four genes ## Footnote The genes are GNS, HGSNAT, NAGLU, and SGSH.
98
What are some early behavioral changes associated with MPS III?
* ADHD * Aggression ## Footnote These changes typically appear in early childhood.
99
What is the typical natural history of MPS III?
Cognitive plateau followed by progressive neurodegeneration ## Footnote Milder cases can occur.
100
What are the common physical findings in patients with MPS III?
* Mild to no organomegaly * Little or no corneal clouding * No coarsening of facial features * No dysostosis multiplex ## Footnote These findings are typical in MPS III patients.
101
What is the typical age of death for individuals with MPS III?
Often before 20 years of age ## Footnote Death is usually due to cardiopulmonary effects.
102
What laboratory finding is indicative of MPS III?
Elevated urine GAGs (Heparan Sulfate) ## Footnote This is a key diagnostic marker.
103
What is needed to confirm and distinguish between types A-D of MPS III?
Enzyme/molecular analysis ## Footnote Diagnosis requires specific testing beyond urine GAGs.
104
True or False: There are currently available treatments for MPS III.
False ## Footnote No treatments are currently available for this condition.
105
What is another name for MPS IV?
Morquio Syndrome
106
What are skeletal findings in MPS IV?
* Ulnar deviation of the wrists * Shortened forearms * Pectus carinatum * Genu valgum (knock-knees)
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108
What is the outcome of untreated MPS IV?
Often leads to death by ~30-40 years of age ## Footnote MPS IV is a severe form of mucopolysaccharidosis.
109
What is a treatment option for MPS IV?
Recombinant IV enzyme replacement therapy ## Footnote This therapy aims to provide the missing enzyme that patients with MPS IV lack.
110
What is Vimizim used for in the treatment of MPS IV?
For biochemical and functional improvements ## Footnote Vimizim is a specific medication used in enzyme replacement therapy.
111
What types of procedures may be included in the treatment of MPS IV?
Orthopedic and other symptomatic surgical procedures ## Footnote These procedures are aimed at managing symptoms and improving quality of life.
112
True or False: MPS IV can lead to death in early childhood if untreated.
False ## Footnote While MPS IV is severe, death typically occurs by the age of 30-40 years.
113
Fill in the blank: The severe form of MPS IV often leads to death by _______ years of age.
30-40
114
What is a key diagnostic test for MPS IV?
Urine GAG excretion ## Footnote GAG stands for glycosaminoglycans, which are important for diagnosing mucopolysaccharidoses.
115
What are the elevated GAG levels associated with MPS IV?
Elevated total GAG levels, Elevated Keratan and Chondroitin 6-Sulfate ## Footnote Elevated Keratan Sulfate is specifically noted in MPS IVB.
116
What is the specific enzyme activity measured in MPS IV?
N-Acetylgalactosamine 6-Sulfatase Enzyme Activity ## Footnote This enzyme activity can be measured in various cell types including WBCs and fibroblasts.
117
In which biological samples can N-Acetylgalactosamine 6-Sulfatase Enzyme Activity be measured?
WBCs, fibroblasts, amnio, CVS ## Footnote CVS refers to chorionic villus sampling.
118
What is the correlation of N-Acetylgalactosamine 6-Sulfatase Enzyme Activity with the severity of MPS IV?
Poor correlation with severity/carrier status ## Footnote This indicates that enzyme activity does not consistently predict disease severity.
119
What additional tests should be performed alongside measuring N-Acetylgalactosamine 6-Sulfatase?
Measure other sulfatases, B-Galactosidase ## Footnote This is important for comprehensive assessment and diagnosis.
120
What gene is associated with MPS IV and what type of analysis is performed?
GALNS gene molecular analysis ## Footnote This analysis includes sequencing and deletion/duplication testing.
121
What percentage of cases show positive results for deletions or duplications in GALNS gene analysis?
~86% ## Footnote This high percentage indicates a strong likelihood of detecting genetic abnormalities in MPS IV.
122
Is there a genotype/phenotype correlation in MPS IV?
Some genotype/phenotype correlation but many uncharacterized mutations ## Footnote This suggests that while there are some known correlations, many mutations remain unexplored.
123
Fill in the blank: Only _______ is elevated in MPS IVB.
Keratan Sulfate ## Footnote This differentiates MPS IVB from other types of MPS IV.
124
What is another name for MPS VI?
Maroteaux-Lamy
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126
What is the incidence of MPS VI?
~1/250-400,000 ## Footnote MPS VI is one of the least common mucopolysaccharidoses.
127
What deficiency is associated with MPS VI?
Arylsulfatase B Deficiency ## Footnote This deficiency leads to dermatan sulfate accumulation.
128
What is a typical natural history of MPS VI?
Decelerated growth after 1st year, short stature/dwarfism ## Footnote Milder cases may present differently.
129
List some clinical features of MPS VI.
* Progressive facial coarsening * Corneal clouding * Cardiorespiratory disease * Organomegaly * Dysostosis multiplex * Normal intelligence
130
What is the prognosis for severe cases of MPS VI?
Death in teens ## Footnote Milder cases may have longer survival.
131
What is a key diagnostic marker for MPS VI?
Elevated urine GAGs (dermatan sulfate) ## Footnote Testing may also be considered in cases of regressive Autism.
132
What genetic analysis is used for confirmation of MPS VI?
Enzyme/molecular analysis for ARSB gene
133
What is the treatment for MPS VI?
IV Recombinant ERT ## Footnote The specific treatment is called Naglazyme.
134
What improvements does Naglazyme provide?
Biochemical and phenotypic improvement

CMM 625: Genetic Disorders II (9 decks)

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