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Pathology of Phenylketonuria

Deficiency of Phenylalanine Hydroxylase which converts Phenylalanine to Tyrosine. Build up of phenylalanine in the blood which disrupts brain development in an unknown manner.

Clinical Findings in Phenylketonuria

Newborn screening is now done.

If not detected early, will have mental retardation. If treatment is discontinued after age 6 will have more subtle mental problems later (disrupted executive planning, concentration and memory problems).

High levels of phenylalanine and its metabolites (phenylacetate and phenyllactate) in urine

Genetics of Phenylketonuria

Autosomal recessive

Treatment of Phenylketonuria

Restrict phenylalanine in diet (all natural protein) to minimize flux through pathway. Treatment continues for life.

Provide high levels of tetrahydrobiotrin (BH4) cofactor to enhance function of residual enzyme.

Supplement with Tyrosine

Experimentation with replacement by bacterial enzyme.

Organic Acidemia

Metabolic disorder which causes a build-up in non-amino organic acid intermediates on an amino acid metabolic pathway.

Pathology in Propionic Acidemia

Deficiency in propionyl-CoA carboxylase which causes a build up in propionic acid.

Propionyl CoA precursers include:
- VOMIT: Valine, Odd-chain FAs, Methionine, Isoleucine, Threonine
- Cholesterol, Thiamine, Uracil
- Normal GI Flora

Clinical Findings in Propionic Acidemia

Normally identified in newborn screening.

Mental Retardation
Recurrant metabolic decompensation
End organ failure
Short lifespan even with careful treatment.

Child presenting with vomiting.
Acidotic with anion gap.
High levels of organic acid in urine.
High Plasma Ammonia

Treatment of Propionic Acidemia

VOMIT free dietary formulation and Antibiotics to reduce GI bacteria.

Supplement with Biotin cofactor

Carnitidine is given to help elimination of propionic acid.

Treat hyperammonemia and give bicarbonate to buffer pH.

BH4 deficiency / Malignant PKU

Deficiency of tetrahydrobioptrin cofactor essential for phenylalanine hydroxlase AND other enzymes.

Presents the same as PKU but must rule out BH4 deficiency because PKU treatment will not address additional enzymatic disorders.

Pathology of Ornathene Transcarboxylase Deficiency (OTC)

Urea cycle defect prevents metabolism of ammonia in the liver and leads to hyperammonemia.

Also blocks the production of citruline.

Clinical Findings in Ornathene Transcarboxylase Deficiency


Can cause seizures, cereberal edema, hyperventilation and alkalosis,

Atypical cases (some female carriers) can present during times of stress, such as pregnancy, or after high protein load.

Treatment of OTC

Restrict all protein intake, minimal levels of essential amino acids.

Supplement with Citrulline

Liver Transplant is recommended and is currently the only enzyme replacement for ornathene decarboxylate.

Dialysis to remove ammonia, ammnoia scavenging medications

Genetics of Ornathene Transcarboxylase Deficiency

X-linked recessive.

Pathology of Galactosemia

Deficiency of any of the key enzymes required to catabolize galactose (from lactose)

Clinical Presentation of Galactosemia

E. Coli Sepsis
Newborn Coagulopathy
Liver disfunction / failure
Primary ovarian failure
Learning disabilities

Treatment of Galactosemia

Lactose and galactose free diet (no breast milk or standard formula)

Treat secondary effects (sepsis, coagulopathy)

Genetics of Galactosemia

Autosomal recessive

Pathology of Glycogen Storage Disease 1a

Deficiency in Glucose-6-phosphatase prevents the liver from converting glycogen into glucose that can be transported to the blood.

Alternative pathways for G6P are increased:
1. G6P -> Pyruvate -> lactate
2. G6P -> Pyruvate -> AcCoA -> Triglycerides
3. G6P -> (Phosphate pentose shunt) -> Uric Acid

Clinical Presentation of Glycogen Storage Disease 1a

Severe Hypoglycemia (can induce seizures)
Elevated blood lactate
Elevated blood triglycerides
Elevated blood uric acid

Cannot tolerate 2 hour fast.

Long Term:
- Hepatomegly from hepatic steatosis
- Lactic acidosis - growth restriction - osteopenia
- Pancreatitis
- Gout and Kidney Stones from hyperuricemia
- Hepatic adenomas, Nephromegly

Treatment of GSD1a

Provide constant supply of glucose - cornstarch, frequent feeding, gastrostomy tubes

Treat secondary effects - uric acid, acid/base maintenance, anti-lipid meds.

Genetics of Glycogen Storage Disease 1a

Autosomal recessive

MCAD Deficiency

Medium Chain Acetyl-CoA Dehydrogenase Deficiency

Pathology of MCAD

Inability to process medium-chain fatty acids due to enzyme deficiency. Most common fatty acid oxidative defect.

Clinical Findings in MCAD

Hypoglycemia with hypoketonemia (low ketone levels in urine during fasting).

Hyperammonemia that can lead to liver disease.

Sudden death is first sign in ~18% of cases.

Neurologic (lethargy, coma, siezure)

Treatment of MCAD

Restrict flux through fatty acid oxidative pathway by avoiding fasting, go to ER when have diarrhea.

Low fat, high carbohydrate diet.

Treat 2' effects - hyperammonemia, hypoglycemia, liver failure.

Pathology of Gaucher Disease

Sphingolipidoses due to enzyme deficiency.

Macrophages filled with lipids, "Gaucher Cells", accumulate in the spleen, liver, bone marrow, and other tissue. Chronic inflammation leads to tissue damage.

Clinical finding of Gaucher Disease

Signs and symptoms are a consequence of accumulation of storage material in tissue and in macrophages.

Skeletal disease
- Erlenmeyer Flask deformity of femur
- Bone infarct, osteoporosis, factures

Genetics of Gaucher Disease

Autosomal recessive

Treatment of Gaucher Disease

Enzyme replacement (biweekly IV)

Restrict substrate by pharmacologially blocking upstream enzyme (when enzyme replacement doesn't work)

Treat 2' effects
- Bisphosphate for osteopenia
- Pain management

Pathology of Hurler's Disease (MPS1)

Disorder of Mucopolysaccaride (GAG) Metabolism. Accumulation of dermatan and heparin sulfate.

Clinical findings of Hurler's Disease (MPS1)

Dysostosis Multiplex
Heart Disease
Mental Retardation
Death in Childhood

Treatment of Hurler's Disease (MPS1)

Enzyme replacement via recombinant OR bone marrow transplant

Treatment of 2' effects

Pathology of Mitochondrial Diseases

Caused by mutations in mitochondrial OR nuclear DNA impacting mitochondrial enzymes in the respiratory chain.

When cause is mitochondrial DNA, presentation can vary over time with changes in mitochondrial inheritance.

Common Manifestations in Mitochondrial Diseases

Impact in high-energy organs
- Lactic Acidosis
- Myopathies
- Cardiomyopathy
- Hepatopathy
- Developmental Delay
- Deafness and Blindness
- Stroke-like episodes
- Diabetes


Mitochondrial Encephalopathy with Lactic Acidosis and Stroke-like Episodes.

- "Normal" at first, then present with blindness parallysis
- Degenerative and fatal


Myoclonic Epilepsy with Ragged Red Fibers

Leigh's Disease

Progressive, neurometabolic mitochonidrial disease

Key finding is bilateral, symmetric stroke rarely seen in other conditions.

Which IEM diseases are X-Linked

OTC Deficiency

Which IEM diseases have enzyme replacement therapy?

PKU (trial)
Gaucher's Disease
Hurler's Disease

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