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x_NeuroGenetics Review > Inborn Errors of Metabolism 1 & 2 > Flashcards

Inborn Errors of Metabolism 1 & 2 Flashcards

1
Q

What are inborn errors of metabolism?

A
  • Single gene defects
  • Lead to abnormal synthesis or processing of proteins, carbs, or fats
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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)
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3
Q

What are predominant signs/symptoms of IEM?

A

Non-specific signs/symptoms:

  • Poor feeding, lethargy, vomiting, hypotonia, respiratory distress, and seizures
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4
Q

Describe a high risk IEM patient

A

Full term infant with no risk factors for sepsis who develops lethargy and poor feeding

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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
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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
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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
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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
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9
Q

What is phenylketonuria?

A

Genetic deficiency of phenylalanine hydroxylase

– PAH converts phenylalanine to tyrosine expressed in liver

Other abnormalities affecting BH4 metabolism

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10
Q

What are most mutations causing phenylketonuria?

A

There are >600

  • Most are missense with variable effects on protein stability and function
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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
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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

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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

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14
Q

How is PKU diagnosed?

A
  • Found in newborn screen
  • Confirmation by serum phenylalanine level
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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

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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%
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17
Q

Describe phenylalanine ammonium lyase treatment for PKU

A

“Diversion therapy”; creates alternative pathway

  • Not part of standard of care
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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
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19
Q

T/F: As long as dietary copmliant, people with PKU can live normal life

A

True

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20
Q

Describe the standard newborn screening in TX

A

Two screens:

  1. First within first 72 hrs of age
  2. 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)
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21
Q

Describe the urea cycle

A

Recycles nitrogen compounds and produces urea to be excreted in urine

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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
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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
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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
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25
Q

OTC enzyme is expressed where?

  • Activity depends on what?
A

Enzyme is expressed in the liver

– Activity depends on mutation with 0% (some males) to 97% (some heterozygous females)

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26
Q

What are the clinical features of OTCD?

A

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

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27
Q

What are the biochemical consequences of OTCD?

A
  • 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)

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28
Q

What is responsible for the toxicity of hyperammonemia?

A
  • Elevated glutamine
  • Inhibition of TCA cycle
  • Inhibition of NO and creatine synthesis
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29
Q

Some OTCD females may present also with what?

A
  • Protein avoidance
  • Vomiting
  • Cognitive delay

Presentation depends on diet, illnesses, X-inactivation, enzyme activity

30
Q

How is OTCD treated?

  • Acute
  • Outpatient
  • Long term
A

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
Q

What are the functions of lysosomes?

  • Describe their cellular contents
A

Recycling centers that break down small to large molecules

  • Contain different hydrolases in an acidic environment (pH 5)
32
Q

(Broadly) what is the effect of genetic defects of lysosomal enzymes?

A

Defective catabolism of specific substrates, intralysosomal accumulation and functional loss of cellular systems

33
Q

What are some acid hydrolases (functional in the acidic pH~5 environment) of the lysosome?

A
  • Nucleases
  • Proteases
  • Glycosidases
  • Lipases
  • Phosphatases
  • Sulfatases
  • Phospholipases

All of this depends upon the proton pump (ATPase)

34
Q

How do lysosomal hydrolases get to lysosomes?

A

Newly synthesized lysosomal hydrolases carry a unique marker in the form of mannose 6-phosphate (M6P)

35
Q

What is Gaucher disease?

  • Inheritance pattern
A

Autosomal recessive deficiency of acid-beta glucosidase

  • This enzyme typically converts glucosylceramide to B-glucose
36
Q

What is the carrier frequency of Gaucher disease (certain population)?

A
  • 1/18 Ashkenazi Jews are carriers
37
Q

What genes are responsible for Gaucher’s disease?

A

• 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
Q

T/F: Gaucher disease is a phenotypic continuum

A

True

  • Asymptomatic all the way to hydrops featlis
  • Intermediate include neurologic involvement, Parkinsonian-like, congenital icthyosis, etc.
39
Q

Compare the three types of Gaucher disease in terms of: whom it strikes

A
  • Type 1: young adults/adults
  • Type 2: infants
  • Type 3: children/young adults
40
Q

Compare the three types of Gaucher disease in terms of: symptoms

A
  • Type 1: no nervous system problems
  • Type 2: early nervous system problems
  • Type 3: later onset of nervous system problems
41
Q

Compare the three types of Gaucher disease in terms of: effects of disease

A
  • Type 1: varies from mild to severe
  • Type 2: dies in infancy
  • Type 3: becomes severe
42
Q

Compare the three types of Gaucher disease in terms of: enzyme activity

A
  • Type 1: some activity but less than normla
  • Type 2: very little activity
  • Type 3: little activity
43
Q

The clinical manifestations of Gaucher disease reflect what?

  • What cells are involved
A

Cellular sites of substrate storage

  • Liver: Kupffer cells (hepatocytes spared)
  • Bone: osteoclasts
  • Lung: alveolar macrophages
  • Spleen: tissue macrophages
  • Bone marrow/monocytes
44
Q

Describe the pathology of the femur in Gaucher’s disease

A
  • Hemorrhagic infarction
  • Necrosis
  • Osteosclerosis
  • Severe osteoporosis
  • Loss of cortical bone
45
Q

What are other subtypes of Gaucher disease?

  • What is involved in each?
A

– Perinatal form: skin abnormalities/non-immune hydrops

– Cardiovascular form: calcification of cardiac valves, splenomegaly, corneal opacities, supranuclear ophthalmoplegia

46
Q

What is seen here?

A

Gaucher cell

47
Q

What is seen here?

A

Enlarged cells in the spleen of a patient with Gaucher

48
Q

What can be done to treat Gaucher’s?

A
  • Recombinant enzyme replacement therapy with glucocerebrosidase
  • Substrate reduction therapy
  • Chaperones
49
Q

What are GAGs (broadly)?

A

Glycosaminoglycans

  • Unbranched polysaccharide chains composed of repeating disaccharide units
50
Q

What are the structural components of GAGs?

  • How do different GAGs differ?
A

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
Q

What is Hurler spectrum?

  • Incidence
  • Inheritance pattern
  • Deficiency in what enzyme/what is this enzyme’s function
A

Mucopolysaccharidosis I

  • Incidence: 1/100,000
  • Autosomal recessive
  • Deficiency of alpha-L-iduronidase
  • Enzyme needed for degradation of heparan sulfate and dermatan sulfate
52
Q

Describe the progression of Hurler syndrome

A

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
Q

What is the typical lifespan of someone with Hurler’s syndrome?

A

Lifespan < 10 years

54
Q

What is seen here?

A

Lysosomal storage of GAG

55
Q

What is Hurler-Scheie

  • How severe
  • When diagnosed
  • Symptoms
  • Lifespan and COD
A
  • 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
Q

What is Scheie?

  • When diagnosed
  • Symptoms
  • Lifespan
A

Least severe form of Mucopolysaccharidosis I

• Diagnosis in teenage years

Symptoms/associations:

  • Joint stiffness
  • Aortic valve disease
  • Blindness
  • Cord compression

Lifespan: middle decades

57
Q

How is Scheie diagnosed?

A

• Urinary glucosaminoglycans

  • Total and fractionated
  • First urine specimen of the day
  • Enzyme analysis
  • Mutation analysis
58
Q

Describe treatment for Scheie

A

Enzyme replacement therapy

  • Aldurazyme (Laronidase): recombinant α-L-iduronidase derived from Chinese Hamster cells
59
Q

What is Hunter syndrome?

  • Incidence
  • inheritance pattern
  • Deficiency in what enzyme
A

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
Q

For Hunter’s syndrome, describe:

  • When do onset of symptoms occur
  • Clinical presentation
  • Lifespan
A
  • Onset of symptoms between 2 - 4 years.
  • The clinical presentation varies from patient to patient.
  • Lifespan depends of the severity of the disease
61
Q

What are symptoms of Hunter syndrome?

  • Male v female
A
  • Rarely corneal clouding (Contrast with MPS I)
  • Heterozygote female carriers with clinical symptoms are quite rare
62
Q

How is Hunter syndrome diagnosed?

A
  • Urine GAGs
  • Enzyme analysis
  • Sanger sequencing
63
Q

Treatment for Hunter’s syndrome?

A

Recombinant DNA: Idursulfase (Elaprase)

  • Human cell line
64
Q

What is Pompe disease?

  • Fequency
  • Inheritance pattern
  • Deficiency in what enzyme (and results in what)
A
  • 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
Q

What are signs/symptoms of Pompe disease?

A
  • Generalized hypotonia
  • Myopathic face
  • Macroglossia
  • Cardiomyopathy
  • EKG changes (short PR interval, high amplitude QRS complex)
  • Vacuolated lymphocytes
66
Q

How does the enzyme deficiency in Pompe disease contribute to problems?

A
  • Acid maltase deficiency leads to abnormal deposition in skeletal, cardiac, and smooth muscles
  • Hypertrophic cardiomyopathy, hypotonia, weakness, respiratory insufficiency
67
Q

Describe features of infantile Pompe disease

  • Lifespan
A
  • Severe generalized muscular hypotonia
  • Cardiomyopathy
  • Enlarged tongue
  • Hepatomegaly
  • Usually die within 2 years from cardiac insufficiency
68
Q

Describe featurs of juvenile Pompe disease

  • Lifespan
A

• 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
Q

Describe the features of adult Pompe disease

A

• Progressive proximal weakness in limb-girdle fashion

  • Diaphragmatic involvement
  • Dilated arteriopathy
  • Carotid artery dissection
  • Heart and liver are usually not involved
70
Q

What is the treatment for Pompe disease?

A

Alglucosidase A (Myozyme)

  • Recombinant DNA, derived from Chinese Hamster Ovary cells
71
Q

Conclusions on IEM

A
  • 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

x_NeuroGenetics Review (38 decks)

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