Inborn errors of Metabolism Approach to Diagnosis and management

Inborn errors of Metabolism

Approach to Diagnosis and management

Defining inborn errors of metabolismBroad definition: Any defect related to the inappropriate metabolism of substrates essential for an organism’s survival

1. Defects in energy metabolism

2. Defects in protein synthesis or catabolism leading to intoxication with toxic substrates and/or absence of essential metabolic substrates

3. Synthetic defects – inability to produce an essential structural substrate

4. Defects in transport of essential components – cystic fibrosis, lysinuric protein deficiency

4. Defects in detoxifying specific substances

5. Generalized global tissue dysfunction (mitochondria)

Inborn errors of metabolism:General points

Incidence in heterogeneous population 1:750-1000 However, incidence higher if we include

hyperlipoproteinemias Heterozygote familial hypercholesterolemia has

an incidence of 1:500 Much more common in inbred populations and

consanguineous couples Signs and symptoms of metabolic disease are

usually non-specific Can present at all ages Underdiagnosis of metabolic diseases but improving

with new genetic techniques and improved mass screening

Mortality related to metabolic diseases

120 children aged 0-14 y died in a ten year period of inborn errors of metabolismThis was 3.5% of total child mortality and 9.5% of non-acquired (genetic) mortality

Complexity of inborn errors of metabolism

Diagnosing metabolic disease

Approach to diagnosing metabolic disease Genetic testing for specific at risk

groups Prevention

Screening approach Testing entire population using relatively

inexpensive (price/unit) techniques High throughput (180,000 samples/yr/IL)

Clinical, biochemical, and molecular analysis of symptomatic patients

Populations at risk

Specific population groups are at greater risk for a disease Founder effect Inbreeding

Prevention Premarital testing Prenatal testing Preimplantation genetic diagnosis

Basis for newborn screening

Cost-effective Easy/inexpensive method for detecting IEM

High throughput methods Rapid turnaround High sensitivity (detect most cases) High specificity (low false positive rate) Effective notification system Possibility for intervention Minimal harm to patient

Newborn screening First introduced for PKU (Guthrie) Ames test Extended to several other diseases

including galactosemia, hypothyroidism, sickle cell, thallasemia, congenital adrenal hyperplasia, and homocystinuria

More countries and states including Israel are now using tandem mass spectrometry for more extensive evaluation

WHO criteria for screening

Early methods for screening for inborn errors of

metabolism

Guthrie testPlace blood drop on agar plate

containing B. subtilis and an inhibitor B-2-thienylalanine

High levels of phenylalanine in blood spot overcome inhibition and there is growth

Ames testPaper impregnated with ferric chloride which reacts with phenylalanine

Tandem mass spectrometry (MS/MS)

Approximately .3/1000 detection rate

Phenylketonuria

Phenylalanine hydroxylase

Phenylketonuria In 1934, Folling discovered that children with

mental retardation had high levels of phenylalanine in blood

Classic: deficiency in phenylalanine hydroxylase Abnormalities in tone, myoclonic seizures,

mental retardation, disorders of pigmentation Incidence: 1;10,000-15,000, Turkey: <1:3000 TX: Dietary – reduction in phenylalanine,

provision of tyrosine

CONTROL

PKU

MSUD

Problems with newborn screening

Not all diseases are screened False positive – without disease False negative – disease undetected Some disorders are not disorders Asymptomatic children Unclear treatment recommendations Difficulty in follow-up Privacy issues

Disorders not detected

Disorders of carbohydrate metabolism Mitochondrial disorders Steroid disorders and hyperlipidemias Some urea cycle disorders Tissue specific disorders with no blood

markers

CASE STUDY: Short chain acyl dehydrogenase (SCAD)

deficiency Associated with CNS disease Question of whether this gene should be screened

for US vs. Europe

High prevalence of 319 C>T mutation among Ashkenazic Jews 1:15 carrier rate, 1:900 homozygotes Should be 2700 cases in Israel but only a handful of

symptomatic individuals What type of intervention?

Tay-Sachs

Hexoaminidase A deficiency Cerebral and retinal degeneration Cherry red spot (macular) Hypotonia, motor weakness, developmental

delay Carrier rate 1:30 in Ashkenazic Jews Screening has led to 90% reduction in Jewish

population

Signs of metabolic disease

If the child: Looks bad Smells bad Feels bad Tastes bad Sounds bad

Think Metabolic

Manifestations of metabolic diseases

CNS Neuroanatomic malformations

Leigh’s disease Developmental delay, mental retardations Movement disorders Hypotonia, spasticity Altered mental status Seizures Visual disturbances Pigmented retinopathy Deafness

Cardiac Cardiomegaly (Pompe’s disease) Dilated cardiomyopathy Rhythm Disturbances

Pulmonary Proteinosis (lysinuric protein intolerance) Insufficiency Frequent pneumonia Tachypnea, Kussmaul breathing (acidosis)


GI Dysphagia Pseudo-obstruction, diarrhea Bloating

Liver Insufficiency Inflammation (increased transaminases) Hyperbilirubinemia Cirrhosis Hepatomegaly (glycogen or fats)


Renal Insufficiency Storage disease RTA

Musculoskeletal Malformations Osteopenia/osteoporosis Weakness Myoglobinuria Contractures


Skin Nearly all skin disorders including seborrhea,

ichthyosis Hematological Anemia (all types) Thrombocytopenia/Leukopenia Pancytopenia


Manifestations of mitochondrial disease Cardiomyopathy / myopathy Stroke-like episodes, neuroanatomic changes Lactic acidosis, Leigh syndrome Seizures, myoclonues, dystonia, Parkinsonism Diabetes Deafness Chorea, ataxia, encephalomyelopathy Sudden infant death syndrome Ophalmoplegia, optic neuropathy, pigmented

retinopathy

Nelson, Textbook of Pediatrics, 19th edition, p. 508

Biochemical Hypoglycemia Endocrine disturbances Metabolic acidosis Respiratory acidosis/alkalosis Lactic acidosis Hyperammonemia Hypoalbuminemia Altered coagulation profile Hepatitis profile


Evaluation of infants with suspected metabolic disorders

Primary evaluationArterial blood gasGlucoseCBC and DifferentialLactate/pyruvateUrinary reducing substancesSerum ammoniaLiver function testsPT/PTT

NOTE: Very important at this step to rule out other non-metabolic related causes for clinical manifestations

Secondary evaluation Urine organic acids Serum amino acids Total and free plasma carnitine Very long chain fatty acids Fed and fasting lactate and pyruvate Cardiac echo Opthalmologic exam EEG Head CT and/or MRI


Tertiary evaluation Depends on results of initial evaluation

Specific enzyme assays in lymphocytes, fibroblasts or tissue

Specialized tests, e.g., CSF glycine or lactate, acylcarnitine profile, glycoprotein electrophoresis

Histology, e.g., muscle biopsy, histological staining Mitochondrial studies

Activity O2 Uptake DNA analysis

Challenge tests – fasting, protein loading


Genetic analysis

Mutational analysis When specific defect is known

Reverse genetics Arrays, chips, genomic scanning, SNPs,

Cost effective Excellent coverage Does not always identify correct genetic defect or sole

defect

Advantages over the traditional approach

Treatment of metabolic diseases Enzyme replacement Detoxification

Urea cycle defects Nutritional support Bypass defect

NTBC in tyrosinemia Cofactor treatment Transplantation Genetic therapy

Bone marrow Stem cell

Galactosemia

Classic disease caused by galactose-1-phosphate uridyl transferase

Symptoms after lactose formula or breast feeding

Hepatomegaly and jaundice Gram- sepsis Cataracts if untreated Tx: non-lactose containing formula

Tyrosinemia Type 1 Defect in Fumarylacetoacetate hydrolase Hepatic decompensation, coagulopathy, low

albumin, cirrhosis, RTA DX: elevated tyrosine, characteristic urine

metabolites including succinylacetone Long term – hepatic carcinoma TX: Low tyrosine/phenylalanine diet, treatment

with NTBC, a herbicide, which inhibits hydroxyphenyl-pyruvate hydroxylase

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Inborn errors of Metabolism Approach to Diagnosis and management