Inborn Errors of Metab

8/6/2019 Inborn Errors of Metab

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Inborn Errors of Metabolismand Genetic Disorders

Inherited as autosomal recessive or x-

linked

Phenylketonuria

Galactosemia

Cystic Fibrosis


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Phenylketonuria (PKU)

Autosomal recessive disorder

Severe deficiency of phenylalanine

hydroxylase Inability to convert phenylalanine to

tyrosine


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Clinical Manifestation

Normal at birthNormal at birth

by 6 months of life: severe MRby 6 months of life: severe MR

Seizures, neurologic abnormalities,Seizures, neurologic abnormalities,

decreased pigmentation of hair and skindecreased pigmentation of hair and skin

Maternal PKU:Maternal PKU:

Between 75% and 90% of children bornBetween 75% and 90% of children born

to such women are mentally retardedto such women are mentally retardedandand microcephalicmicrocephalic

15% have congenital heart disease15% have congenital heart disease


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Hepatic Phenylalanine HydoxylaseSystem

Minor shunt pathways: yield

phenylpyruvic acid

phenyllactic acid

phenylacetic acid (STRONG MUSTY OR MOUSYODOR

in urine)

o-hydroxyphenylacetic acid


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Types of PKU

1. Benign hyperphenylalaninemia/Mild PKU

2. Type I: Classic PKU (most common)

Deficient PAH

Common in Scandinavian descent,uncommon in African American/Jewish

3. Type II:

Deficient dihypropteridine reductase

BH4 cannot be regenerated

4. Type III:

Deficient dihydrobiopterin synthetase


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Management

Dietary restriction of phenylalanine

Somatic gene therapy

Maternal dietary restriction of

phenylalanine before conception andthroughout pregnancy


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Galactosemia

A

utosomal recessive disorder of galactosemetabolism

Lactose

Major carbohydrate of mammalian milk

Split into glucose and galactose by

lactase in intestinal microvilli


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Galactose Metabolism


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Variants of Galactosemia

1. Total lack of galactose 1 phosphateuridyl transferase (GALT)

More common

Leads to deposition of galactose 1phosphate in the liver, spleen, lens of

the eyes, kidneys, heart muscle,

cerebral cortex and erythrocytes

2. Galactokinase deficiency Rare variant

Milder form of the disease


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Clinical Manifestation Failure to thrive at birth

Vomiting and diarrhea after few days of milk

ingestion

Jaundice and hepatomegaly

fatty change, widespread scarringresembling cirrhosis of alcohol abuse

Opacification of lens

Galactitol accumulation in lens

Aminoaciduria due to impaired amino acid

transport in the kidney


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Diagnosis

(+) reducing sugar other than glucose in

the urine

Transferase deficiency in WBC and RBC Assay of GALT activity in cultured amniotic

fluid


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Management

early removal of galactose from the diet for

at least the first 2 years of life


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Cystic Fibrosis

most common lethal genetic disease thataffects Caucasian populations

Autosomal recessive transmission

disorder in epithelial transport

affects fluid secretion

exocrine glands

epithelial lining of the respiratory,

gastrointestinal, and reproductive tracts


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Clinical Manifestation

Meconium Ileus

Exocrine pancreatic insufficiency

Protein and fat malabsorption

Deficiency of fat soluble vitamins

Cardiorespiratory complications

Liver disease

Infertility (CBAVD)

Elevated sweat electrolyte concentration


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Diagnosis

1.Chronic sinopulmonary disease manifested bya. Persistent colonization/infection with typical cystic

fibrosis pathogens, including Staphylococcus aureus,

nontypeable Hemophilus influenzae, mucoid and

nonmucoid Pseudomonas aeruginosa, Burkholderia

cepacia

b. Chronic cough and sputum production

c. Persistent chest radiograph abnormalities (e.g.,

bronchiectasis, atelectasis, infiltrates, hyperinflation)

d. Airway obstruction manifested by wheezing and airtrapping

e. Nasal polyps; radiographic or computed tomographic

abnormalities of paranasal sinuses

f.Digital clubbing

Clinical Features and Diagnostic Criteria forCystic Fibrosis


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DiagnosisClinical Features and Diagnostic Criteria forCystic Fibrosis

2.Gastrointestinal and nutritional abnormalities, includinga. Intestinal: meconium ileus, distal intestinal obstruction

syndrome, rectal prolapse

b. Pancreatic: pancreatic insufficiency, recurrent pancreatitis

c. Hepatic: chronic hepatic disease manifested by clinical or

histologic evidence of focal biliary cirrhosis, or multilobular cirrhosis

d. Nutritional: failure to thrive (protein-calorie malnutrition),

hypoproteinemia, edema, complications secondary to fat-soluble

vitamin deficiency

3.Salt-loss syndromes: acute salt depletion, chronic metabolicacidosis

4.Male urogenital abnormalities resulting in obstructive

azoospermia (congenital bilateral absence of vas deferens)


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Diagnosis

Criteria for Diagnosis of Cystic FibrosisOne or more characteristic phenotypic features,

OR a history of cystic fibrosis in a sibling,

OR a positive newborn screening test result

AND

An increased sweat chloride concentration on two or more

occasions

OR identification of two cystic fibrosis mutations,

OR demonstration of abnormal epithelial nasal ion

transport

GOLD STANDARD:

CFTR gene sequencing


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CFTR gene found on chromosome band

7q31.2

Protein encoded has:

2 transmembrane domains

2 cytoplasmic nucleotide-binding domain

Regulatory domain with protein kinase A

and C phosphorylation sites

Cystic Fibrosis TransmembraneConductance Regulator


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Cystic Fibrosis TransmembraneConductance Regulator

In cystic fibrosis

abnormal function of an epithelialchloride channel protein


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CFTR


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CFTR Function

CFTR regulates multiple additional ionchannels and cellular processes

Functions of CFTR are tissue specific

CFTR mediates transport of bicarbonate ions


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CFTR Protein MutationClassification

Class I: Defective protein synthesis

Class II: Abnormal protein folding,

processing and trafficking

Class III: Defective regulation Class IV: Decreased conductance

Class V: Reduced abundance

Class VI: Altered regulation of separate ion

channels


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Genetic Modifiers

Cystic fibrosis modifier locus

Mapped to chromosome 19q13

Influences incidence of meconium ileus

Mannose binding lectin

Key effector of innate immunity

(opsonization and phagocytosis)

Increase of end stage lung disease


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LUNGS

extensive mucus plugging

and dilation of the

tracheobronchial tree.

PANCREAS

ducts are dilated and plugged

with eosinophilic mucin, and theparenchymal glands are atrophic

and replaced by fibrous tissue


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Management

Improved control of infection

Bilateral lung, heart-lung, liver, pancreas,

or liver-pancreas transplant

Gene therapy


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Sudden Infant DeathSyndrome

Disease of unknown cause

Diagnosis of exclusion

sudden death of an infant under 1 year ofage which remains unexplained after a

thorough case investigation, including

performance of a complete autopsy,

examination of the death scene, andreview of the clinical history

Crib death or Cot death


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Epidemiology

Leading cause of death between age 1 mo

and 1 yr

90% occur during the 1st

6 months; mostbetween 2 and 4 months

Apparent life threatening event (ALTE)

resuscitation after such an episode


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Pathogenesis

Multifactorial condition

Triple risk model

Vulnerable infant: delayeddevelopment of arousal and

cardiorespiratory control

Critical development period

Exogenous stressor


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Other Risk Factors

Prematureor LBW infants

Male gender

SIDS in a prior sibling Prior history of mild respiratory infection

Prone position when sleeping, sleeping on

soft surfaces, thermal stress

Maternal smoking, young maternal age,

inadequate prenatal care, frequent

childbirth


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Morphology

Multiple petechiae on the thymus, pleura

and epicardium

Congestion and vascular engorgement oflungs

Astrogliosis of brainstem

Extramedullary hematopoiesis


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Inborn Errors of Metab

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