Inborn Errors of Metabolism 1 & 2 Flashcards
(71 cards)
1
Q
What are inborn errors of metabolism?
A
- Single gene defects
- Lead to abnormal synthesis or processing of proteins, carbs, or fats
2
Q
Describe the epidemiology of inborn errors of metabolism
- Individually
- Collectively
- Presentation period
A
- Invidually rare
- Collectively common (1/500)
- Many present in newborn peirod (time of substantial catabolism)
- Typical well interval (acute metabolic encephalopathy)
- Acute, life threatening crises requiring immediate intervention (rule out infections first)
3
Q
What are predominant signs/symptoms of IEM?
A
Non-specific signs/symptoms:
- Poor feeding, lethargy, vomiting, hypotonia, respiratory distress, and seizures
4
Q
Describe a high risk IEM patient
A
Full term infant with no risk factors for sepsis who develops lethargy and poor feeding
5
Q
In terms of metabolism, where may problems arise?
A
If enzyme/cofactor:
- are not present
- are present but nonfunctional
- are present and functional but have decreased activity
6
Q
Why might IEM (the enzyme/cofactor issues) cause actual problems/symptoms?
A
- Substance A buildup could lead to toxic byproducts as the body’s way of getting rid of the excess
- There is little/no production of Substance B
7
Q
What are some broad treatment strategies for IEM?
A
• Decrease Substance A
- scavenger medications
- elimination from the diet
- Replace Substance B
- Replace Cofactor
8
Q
What are some inborn errors of metabolism falling under the following categories?
- AA metabolism
- Urea cycle disorders
- Glycogen storage
- Mucopolysaccharidoses
- Lipid storage
A
- AA metabolism: PKU
- Urea cycle disorders: OTCD
- Glycogen storage: Pompe
- Mucopolysaccharidoses: Hunter, Hurler
- Lipid storage: Gaucher
9
Q
What is phenylketonuria?
A
Genetic deficiency of phenylalanine hydroxylase
– PAH converts phenylalanine to tyrosine expressed in liver
Other abnormalities affecting BH4 metabolism
10
Q
What are most mutations causing phenylketonuria?
A
There are >600
- Most are missense with variable effects on protein stability and function
11
Q
Describe the genetics and epidemiology of PKU
A
- # 1 AA disorder
- Autosomal recessive
- US incidence from 1/13.5-19K
- Higher incidence in Europeans and Native Americans
12
Q
Defects in phenylalanine hydroxylase lead to what? How does this lead to the phenotype?
A
Defects in PAH cause:
- Elevated Phenylalanine (Phe)
- Low tyrosine
Cause problems due to:
– Reduced transport of large neutral amino acids to the brain
– Reduced cerebral protein synthesis and hypomyelination
– Inhibition of cholesterol synthesis
– Phenylalanine fibrils
–Decreased synthesis of neurotransmitters/deficiency of tyrosine
13
Q
What are untreated clinical features of phenylketonuria?
A
- Normal at birth
- Developmental delay: first months of life
- Irritability, vomiting, rash, musty odor
- Lighter pigmentation (hair and skin)
- Tyrosine is essential for melanin production
- Poor growth, seizures, microcephaly
- Severe to profound intellectual disability
- Each week left untreated: loss of up to 1 IQ point
50% will have IQ < 35, spasticity, aggressive, autistic, and psychotic behavior
14
Q
How is PKU diagnosed?
A
- Found in newborn screen
- Confirmation by serum phenylalanine level
15
Q
Treatment for PKU? When to start?
A
Treatment is DIETARY; start if phe > 6 mg/dL
– low phenylalanine (low protein, 200 g of natural protein/day)
– Special formula
– Medications
(Don’t cut phe out completely; need some)
Monitor phenylalanine/tyrosine levels
Monitor development
16
Q
Describe Sapropterin (Kuvan) treatment for PKU
A
It is a cofactor for PAH
- By adding additional cofactor, the PAH enzyme may become more active
- Variable results in patients
- Considered effective if Phe reduced by 30%
17
Q
Describe phenylalanine ammonium lyase treatment for PKU
A
“Diversion therapy”; creates alternative pathway
- Not part of standard of care
18
Q
Describe maternal PKU?
- How do Phe levels compare in fetal and maternal blood
A
- In utero effects of Phe
- Microcephaly, dysmorphic features, mental retardation, congenital heart defects
- Preventable with maternal adherence to diet!
- Level of Phe in fetus is 50% higher than in maternal blood
19
Q
T/F: As long as dietary copmliant, people with PKU can live normal life
A
True
20
Q
Describe the standard newborn screening in TX
A
Two screens:
- First within first 72 hrs of age
- Between 7-10 days
(PKU was first to be screened for. Now, more than 30 EIM)
Methods:
- Heel stick on Guthrie bacteriologic assay/agar plate
- Larger circle corresponds to higher Phe levels (bacteria love it)
- Now replaced by tandem mass spectrometry (MS)
- 2 mass spectrometers linked together
- Allows detection fo compounds by separating ions by unique mass (blood spot on filter paper card)
21
Q
Describe the urea cycle
A
Recycles nitrogen compounds and produces urea to be excreted in urine
22
Q
What is the role of ornithine transcarbomylase?
A
(Intra-mitochondrial enzyme)
- Ornithine is combined with carbomyle phosphate by this enzyme (OTC)
- This process forms citrulline, which can diffuse out of mitochondria and continue the cycle
23
Q
Describe urea cycle disorders (specifically OTCD)
- Genetic inheritence
- Epidemiology
- Age of presentation
A
- X-linked (for OTCD; all other urea cycle enzymes are autosomal recessive)
- 1,8000 in US
- Majority present in neonatal period with elevated ammonia and catastrophic illness (except argininemia)
- Patients may have milder, partial defects depending on their genetic mutation
24
Q
What are the gene mutations causing OTC deficiency?
A
Gene mutations are heterogeneous
- Large deletions, insertions, point mutations (usually unique to a given family)
- p.R129H seen in 6% of families
25
OTC enzyme is expressed where?
- Activity depends on what?
Enzyme is expressed in the **liver**
– Activity depends on mutation with 0% (some males) to 97% (some heterozygous females)
26
What are the clinical features of OTCD?
**Catastrophic neonatal presentation**
– Cerebral edema, lethargy, poor suck, vomiting, thermal instability, rapid breathing, respiratory alkalosis (**urea stimulates breathing centers**), seizures, loss of reflexes, coma leading to death
**Males with partial deficiency and OTCD females**
– More subtle: cyclical vomiting, lethargy, dietary self restriction, hallucinations, psychotic episodes
27
What are the biochemical consequences of OTCD?
* **Hyperammonemia** (cannot convert ammonia to urea because of block in the cycle)
* Plasma amino acid analysis: **low citrulline**
* **Glutamine, glycine,** and **alanine** also **elevated**
• **Urine orotic acid is elevated** (excess Carbamoyl Phosphate converted to orotic acid)
(Inhibition of NO synthase)
(Deficiency of creatine)
28
What is responsible for the toxicity of hyperammonemia?
- Elevated glutamine
- Inhibition of TCA cycle
- Inhibition of NO and creatine synthesis
29
Some OTCD females may present also with what?
- Protein avoidance
- Vomiting
- Cognitive delay
Presentation depends on diet, illnesses, X-inactivation, enzyme activity
30
How is OTCD treated?
- Acute
- Outpatient
- Long term
_ACUTE_
– Decrease ammonia level
* **Hemodialysis**
* **Nitrogen scavengers** (**IV** Na **benzoate**/Na **phenylacetate**)
* Benzoate combines w/ glycine to form hippuric acid -\> urine
* Phenylacetate combines w/ glutamine...
– Prevent muscle breakdown (catabolism)
* **Dextrose** infusion and **insulin**
- **IV Arginine** (drive urea cycle forward)
_OUTPATIENT_
– Protein restricted diet
– **Oral** nitrogen scavengers
– Oral citrulline
_LONG TERM_
- Liver transplantation
31
What are the functions of lysosomes?
- Describe their cellular contents
**Recycling centers** that break down small to large molecules
- Contain different **hydrolases** in an acidic environment (**pH 5**)
32
(Broadly) what is the effect of genetic defects of lysosomal enzymes?
**Defective catabolism** of specific substrates, **intralysosomal accumulation** and **functional loss** of cellular systems
33
What are some acid hydrolases (functional in the acidic pH~5 environment) of the lysosome?
- Nucleases
- Proteases
- Glycosidases
- Lipases
- Phosphatases
- Sulfatases
- Phospholipases
All of this depends upon the proton pump (ATPase)
34
How do lysosomal hydrolases get to lysosomes?
Newly synthesized lysosomal hydrolases carry a unique marker in the form of **mannose 6-phosphate (M6P)**
35
What is Gaucher disease?
- Inheritance pattern
Autosomal recessive deficiency of acid-beta glucosidase
- This enzyme typically converts glucosylceramide to B-glucose
36
What is the carrier frequency of Gaucher disease (certain population)?
- 1/18 Ashkenazi Jews are carriers
37
What genes are responsible for Gaucher's disease?
• **Four mutations** (p.N370S, p.L444P, c.84dupG, IVS2+1G\>A) account for **90%** of disease-causing alleles in **Ashkenazi Jewish** population
* In **non-Jewish**, these four alleles account for **50-60%** of disease causing alleles
• Targeted mutation analysis for four common mutations and seven rare mutations available on a clinical basis
Sanger sequencing and deletion/duplication analysis
38
T/F: Gaucher disease is a phenotypic continuum
True
- Asymptomatic all the way to hydrops featlis
- Intermediate include neurologic involvement, Parkinsonian-like, congenital icthyosis, etc.
39
Compare the three types of Gaucher disease in terms of: **whom it strikes**
- **Type 1**: young adults/adults
- **Type 2**: infants
- **Type 3**: children/young adults
40
Compare the three types of Gaucher disease in terms of: **symptoms**
- **Type 1:** no nervous system problems
- **Type 2**: early nervous system problems
- **Type 3**: later onset of nervous system problems
41
Compare the three types of Gaucher disease in terms of: **effects of disease**
- **Type 1**: varies from mild to severe
- **Type 2**: dies in infancy
- **Type 3**: becomes severe
42
Compare the three types of Gaucher disease in terms of: **enzyme activity**
- **Type 1:** some activity but less than normla
- **Type 2**: very little activity
- **Type 3**: little activity
43
The clinical manifestations of Gaucher disease reflect what?
- What cells are involved
Cellular sites of substrate storage
- Liver: Kupffer cells (hepatocytes spared)
- Bone: osteoclasts
- Lung: alveolar macrophages
- Spleen: tissue macrophages
- Bone marrow/monocytes
44
Describe the pathology of the femur in Gaucher's disease
- Hemorrhagic infarction
- Necrosis
- Osteosclerosis
- Severe osteoporosis
- Loss of cortical bone
45
What are other subtypes of Gaucher disease?
- What is involved in each?
– **Perinatal form**: skin abnormalities/non-immune hydrops
– **Cardiovascular form**: calcification of cardiac valves, splenomegaly, corneal opacities, supranuclear ophthalmoplegia
46
What is seen here?
Gaucher cell
47
What is seen here?
Enlarged cells in the spleen of a patient with Gaucher
48
What can be done to treat Gaucher's?
- Recombinant enzyme replacement therapy with glucocerebrosidase
- Substrate reduction therapy
- Chaperones
49
What are GAGs (broadly)?
**Glycosaminoglycans**
- Unbranched polysaccharide chains composed of **repeating disaccharide** units
50
What are the structural components of GAGs?
- How do different GAGs differ?
**Amino sugar**
* N-acetylglucosamine
* N-acetylgalactosamine
Usually a **uronic acid**
* Glucuronic
* Iduronic
GAGs differ in their **sugar residues,** linkage between residues, and the location/number of **sulfate groups**
* Hyaluronan (simplest)
* Chondroitin sulfate and Dermatan sulfate
* Heparan sulfate and Heparan
* Keratan sulfate
51
What is Hurler spectrum?
- Incidence
- Inheritance pattern
- Deficiency in what enzyme/what is this enzyme's function
**Mucopolysaccharidosis I**
* Incidence: 1/100,000
* Autosomal recessive
* Deficiency of **alpha-L-iduronidase**
* Enzyme needed for **degradation of heparan sulfate and dermatan sulfate**
52
Describe the progression of Hurler syndrome
**Appear normal at birth**
_Over first year_
– Coarse facial features
– Wide nasal bridge
– Flattened midface
– Hepatosplenomegaly
– Umbilical or inguinal hernia
– Skeletal abnormalities
_Over 2nd year:_
– Developmental delay
– Respiratory infections (ear, pulmonary)
– Rapidly enlarging head
– Heart failure
– Hernias
– Slowed growth
– Loss of vision and hearing
– Odontoid dysplasia
53
What is the typical lifespan of someone with Hurler's syndrome?
Lifespan **\< 10 years**
54
What is seen here?
Lysosomal storage of GAG
55
What is Hurler-Scheie
- How severe
- When diagnosed
- Symptoms
- Lifespan and COD
* **Intermediate** in severity
* Diagnosed by **2-6 years**
_Symptoms:_
* Joint stiffness
* Recurrent ear, nose, throat symptoms
* Umbilical hernia
* Less coarse facial features
* Small mandible
* Hepatosplenomegaly
* Cardiac disease
* Subluxation of the vertebrae
* Thick meninges, which may lead to weakening or paralysis
* Normal intelligence with some learning disabilities
**Life span usually to mid 20s,** when patients die of **respiratory or cardiac disease.**
56
What is Scheie?
- When diagnosed
- Symptoms
- Lifespan
Least severe form of Mucopolysaccharidosis I
• **Diagnosis** in **teenage** years
_Symptoms/associations:_
* Joint stiffness
* Aortic valve disease
* Blindness
* Cord compression
**Lifespan: middle decades**
57
How is Scheie diagnosed?
• Urinary glucosaminoglycans
* Total and fractionated
* First urine specimen of the day
* Enzyme analysis
* Mutation analysis
58
Describe treatment for Scheie
Enzyme replacement therapy
- **Aldurazyme (Laronidase):** recombinant α-L-iduronidase derived from Chinese Hamster cells
59
What is Hunter syndrome?
- Incidence
- inheritance pattern
- Deficiency in what enzyme
**Mucopolysaccharidosis II**
* Incidence: 1/65-132K males
* **X-linked recessive**
* Deficiency of **iduronate-2-sulfate sulfatase**
* needed for the degradation of **heparan sulfate and dermatan sulfate**
60
For Hunter's syndrome, describe:
- When do onset of symptoms occur
- Clinical presentation
- Lifespan
- Onset of symptoms between **2 - 4 years**.
- The clinical presentation **varies** from patient to patient.
- **Lifespan depends** of the severity of the disease
61
What are symptoms of Hunter syndrome?
- Male v female
* Rarely corneal clouding (Contrast with MPS I)
* Heterozygote female carriers with clinical symptoms are quite rare
62
How is Hunter syndrome diagnosed?
- Urine GAGs
- Enzyme analysis
- Sanger sequencing
63
Treatment for Hunter's syndrome?
Recombinant DNA: **Idursulfase** (Elaprase)
- Human cell line
64
What is Pompe disease?
- Fequency
- Inheritance pattern
- Deficiency in what enzyme (and results in what)
- Overall frequency 1/40K (incidence 1/138K classic infantile and 1/57K late onset)
- **Autosomal recessive** (200+ mutations)
- **Lysosomal acid maltase** (alpha-1-4-glucosidase) deficiency
* Buildup of **glycogen**
65
What are signs/symptoms of Pompe disease?
- Generalized hypotonia
- Myopathic face
- Macroglossia
- Cardiomyopathy
- EKG changes (short PR interval, high amplitude QRS complex)
- Vacuolated lymphocytes
66
How does the enzyme deficiency in Pompe disease contribute to problems?
* Acid maltase deficiency leads to abnormal deposition in skeletal, cardiac, and smooth muscles
* Hypertrophic cardiomyopathy, hypotonia, weakness, respiratory insufficiency
67
Describe features of infantile Pompe disease
- Lifespan
* Severe generalized muscular hypotonia
* Cardiomyopathy
* Enlarged tongue
* Hepatomegaly
* **Usually die within 2 years from cardiac insufficiency**
68
Describe featurs of juvenile Pompe disease
- Lifespan
• Skeletal myopathy
* Leads to respiratory failure
* Delayed gross motor development
* Progressive weakness in limb-girdle fashion
* Involvement of diaphragm
• Usually does not involve the heart
**Death occurs in 2nd-3rd decade**
69
Describe the features of adult Pompe disease
• Progressive proximal weakness in limb-girdle fashion
* Diaphragmatic involvement
* Dilated arteriopathy
* Carotid artery dissection
* Heart and liver are usually not involved
70
What is the treatment for Pompe disease?
**Alglucosidase A** (Myozyme)
- Recombinant DNA, derived from Chinese Hamster Ovary cells
71
Conclusions on IEM
* Collective, IEM are not uncommon
* Expanded newborn screening programs have increased the number of IEM that can be identified
* Early diagnosis and intervention is crucial to prevent neurological sequelae and death
* IEM should always be in the differential diagnosis, particularly in full term infant with no risk factors
* Lysosomal storage disorders are amenable to enzyme replacement therapy, substrate deprivation therapy, and use of chaperones
