Inborn+Errors+of+Metabolism

=**Objectives**=


 * 1. Define IEM and understand what causes them.** (p.505)

Inherited genetic mutation occuring within a gene coding for an enzyme that is required in a metabolic pathway. Faulty gene may result in enyzme with decreased functionality (mutations in AA sequences critical for function), decreased availability (reduced expression), or absence (no expression). IEMs can also arise secondary to defects in transport proteins.


 * 2. General features and categories of IEMs.** (p.506, 507)

__Mode of inheritance__ Predominantly autosomal recessive or x-linked recessive, but IEMs can have different forms with different modes of inheritance

__Frequency__
 * Individual IEM frequency is very rare but shear number of different types of IEMs makes up a significant incidence
 * Indivence varries based on gender and age
 * Early age of manifestation are typically more severe and rapidily progressing copared to later manifestations which are usually due to challenge by environmental factors.

__Categorgies__ Metabolism of:
 * Carbohydrates
 * Amino Acids
 * Organic Acids
 * Fatty Acids
 * Porphyrin
 * Purine/Pyrimidine
 * Steroid
 * Mitochondrial
 * Peroxisomal
 * Lysosomal


 * 3. Typical clinical presentation.** (p.508)

Because of variety of IEMs, nearly any presenting complaint can be caused by IEM, especially in childhood.


 * Failure to thrive/grow, delayed development
 * ambiguous genitalia, delayed puberty, precocious puberty
 * Seizures, dementia, encephalopathy

Consider IEM in any critically ill neonate See page 508 for complete details.


 * 4. Newborn screening and appropriate diagnositic testing.** (p.509)

Newborn screening for routine IEMs can allow for early detection/intervention through dietary modification/supplementation, etc. Screening typically for relatively common IEMs where analytical methodology is available for mass screening and for which effective therapy exists. Tandem mass spectometry is currently the prefered method for screending because it is fast and sensitive, able to process amny different compounds from a small blood sample.


 * 5a. Understand hyperphenylalaninemia.** (p.514-519)

__Mode of Inheritance__ Autosomal recessive

__Underlying metabolic defect and altered metabolites__ phenylalanine-4-hydroxylase deficiency in classical presentation; can also be caused by defect in tetrahydrobiopterin (BH4) co-factor. Inability to convert phe to tyr, resulting in accumulating phe and phe metabolites.

__Clinical Presentation__ Irritability, eczema, musty odor from phenylalanine metabolites, increased muscle tone, active muscle tendon reflexes, mental retardation, seizures, microcephaly, decreased body growth

__Treatment options or prevention__ Dietary restriction of phenylalanine with possible BH4 and tyrosine supplements. Goal is to maintian phenylalanine at 2-10 mg/dL. Less severely affected patients can be challenged to determine if life-long dietary restriction is necessary.


 * 5b. Understand homocysteinuria.** (p.514-519)

__Mode of Inheritance__ Autosomal recessive

__Underlying metabolic defect and altered metabolites__ Classical form with defect in cystathionine synthase; can be caused by errors with methionine synthase and vitamin B12 or folate deficency. Inability to get rid of homocysteine by making cysteine or methionine.

__Clinical Presentation__ Delayed development, psychiatric symptoms, muscle weakness, mental retardation, osteoporosos, severe myopia and ectopia lentis (lens dislocation), thromboembolic complciations of CNS and pulmonary emboli.

__Treatment options or prevention__ Methionine-restricted, cysteine supplemented diet. Vitamin B6, Folate, betaine, or vitamin B12 at high doeses, depending on specific defect.


 * 6a. Understand Galactosemias.**

__Mode of Inheritance__ Autosomal recessive

__Underlying metabolic defect and altered metabolites__ Defect in ability to metabolize glucose: (1) Galactose-1P uridyltransferase (most common) (2) galactokinase (3) uridine diphospho hexose 4-epimerase

Defect results in accumulation of glaactose which is converted to galactitol, a toxic metabolite.

__Clinical Presentation__ Onset during breast feeding with hypotonia, jaundice, lethargy, seizures, enlarged liver, hypoglycemia, and cataracts from galactitol buildup.

__Treatment options or prevention__ Prescribe glactose free diet, restrict milk intake throughout life.


 * 6b. Understand Medium Chain Acyl CoA Dehydrogenase Deficiency.**

__Mode of Inheritance__ Autosomal recessive

__Underlying metabolic defect and altered metabolites__ Defect in metabolizing medium chain fatty acids cused by errors anywhere in the fatty acid metabolism pathway:
 * carnitine uptake (carnitine transporter defect)
 * acylcarnitine shuttling (carnitine palmitoyltransferase 1 defect)
 * acylcarnitine translocation (acylcarnitine translocase defect)
 * acylcarnitine processing (carnitine palmitoyltransferase 2 defect)
 * acyl-CoA processing (defect in acyl-CoA dehydrogensase, enoyl-CoA hydratise, beta-hydroxylacyl-CoA dehydrogenase, and beta-ketoacyl-CoA transferase

__Clinical Presentation__ Present hypoglycemia due to continued glucose consumption during fasting because of inability to switch to fat resources to make ketone bodies. Excretion of carnitine in urine in effort to conserve CoA by substituting carnitine for CoA. Monocarboxylic fatty acids and dicarboxylic organic caids fromed by omega-oxidation since beta-oxidation not working. Hyperammonemia accounting for lethargy and coma, cumulating to cerebral edema.

Symptoms may not be present in frequently fed infant because of decreased reliance on secondary fuel sources during fasting -- typically symptoms occur when feeding is reduced and less frequent.

__Treatment options or prevention__ Avoid fasting, increase carbohydrates and amino acids in diet and reduce fat intake.


 * 6c. Understand Inherited hyperammonemia.**

__Mode of Inheritance__ Autosomal recessive

__Underlying metabolic defect and altered metabolites__ Defect in urea cycle caused most commonly by argininosuccinate lyase which converts argininosuccinate to arginine and fumurate. can also be caused by problems with argininosuccinate synthetase, glutamate synthase, ornithine transcarbamylase, and carbamyl phosphate synthase I. Errors in di-basic amino acid transport can also result in disruption.

__Clinical Presentation__ Hyperammonemia, poor growth, anorexia, hypothermia, papilledema (swelling optic disc), hepatomegaly, disdiadochokinesia (can't do repetative motions), etc. (see p.530)

__Treatment options or prevention__ Cessation of protein intake, increase non-protein caloric intake. Hemodialysis, i.v. sodium phenylbutyrate/benzoate. Supplement with arginine for patients with arginosuccinic aciduria (mild form of hyperammonemia).


 * 6d. Understand Mucopolysaccharidoses.**

__Mode of Inheritance__ Autosomal recessive except Hunter's syndrome which is x-linked recessive

__Underlying metabolic defect and altered metabolites__ Mucopolysaccharides not degraded by defective lysosomal enzymes (iduronidase, etc.) resulting in accumulation of heparan, dermatan, and keratan sulfates.

__Clinical Presentation__ Multiple organ systems may be involved depending on which disease.

CNS - hydorcephalus (defect in CSF reabsorption), mental retardation Cardiovascular disease - angina-type symptoms secondary to arteriosclerosis and ischemia Pulminary disease - obstructive airway disease Ophthalmologic disease - corneal clouding, glaucoma Muscularskeletal disease - short stature, joint stiffness

(see p. 533)

__Treatment options or prevention__ Bone marrow transplantation has some positive effects ni reducing hepatosplenomegaly, airway obstruction, and cardiopulmonary disease to allow survival past first decade of life. Most patients die in infancy.