Overview of Inherited Metabolic Disorders

Pediatric Resident Academic Half Day

Outline

1. Overview of genetic / metabolic diseases2. Overview of cell metabolism

Amino acids Glucose homeostasis Fatty acids Complex molecule biosynthesis & degradation Energy metabolism

3. Approaches to treatment4. Example case histories for discussion

What Are Genetic Metabolic Disorders?

Genetic disorders of the body’s biochemistry that can cause:▫ Death▫ disability

Our goal is:▫ prevention of these

outcomes by early diagnoses and treatment

▫ Primary, secondary & tertiary prevention

How expensive is this?

Inborn Errors of Metabolism(Genetic / Metabolic Disorders)

Genetic deficiencies in production of proteins:

Enzymes Transport proteins Receptor proteins Sub-cellular organelles:

▫ structural, assembly & chaperone proteins

Overview of Inherited Metabolic Disease

over 700 separate IEM described most present early:

in utero 8 %birth - 1 yr 55 %1 yr-puberty 32 %adulthood 5 %

for many, early detection prior to irreversible pathology may permit intervention with diet or medical therapy to prevent long-term death or disability

approaches to early detection: symptomatic presentation screening

IEM affect about about 1/1000 to 1/2000 persons

Classification by Pathogenic Mechanism

IEM that lead to an acute or progressive intoxication from accumulation of toxic compounds proximal to the metabolic block ( PKU,UCD,MMA,IVA, galactosemia etc.)

IEM with symptoms due to partial deficiency in energy production ( GSD’s, B-oxidation defects, mitochondrial disorders, congenital lactic acidosis etc.)

IEM that have: disturbed biosynthesis of complex molecules( CDGS) disturbed degradation of complex molecules (MPS, GM1

gangliosidosis, Tay-Sach’s/Sandhoff)

Sandhoff Disease

Hurler-Scheie Syndrome

Untreated Phenylketonuria

Overview of Intermediary Metabolism as It Relates to

Inherited Metabolic Diseases

Key Metabolic Functions That Our Bodies Must Do:

Accept dietary nutrients and supply them to appropriate body tissues in sufficient but non-toxic amounts

maintain appropriate biosynthetic mechanisms to convert dietary nutrients into required metabolites

maintain metabolic homeostatic mechanisms to ensure that critical nutrients are available as necessary

ensure optimum levels of nutrients by controlling absorption, degradative metabolism and elimination (renal, GI, biliary etc.)

provide mechanisms to support tissue turnover / growth

Genetic Metabolic Disorders Can Cause Disruption of any of these Essential

Processes

The particular process disrupted determines the clinical outcome in a particular patient

Mechanisms of Disruption Include:

toxicity due to excessive metabolite levels (PKU) inadequate essential precursors (SLOS) inadequate energy production (mitochondrial disorders) abnormal biosynthesis of macromolecules (CDGS) abnormal macromolecule degradation (LSD / peroxisomes) abnormal transport (cystinuria, cystinosis)

The Cellular Basis of Metabolism

Overview of Metabolism

Amino Acid Metabolism

Dietary BodyProtein Protein

Free amino acid

“Overflow” “Biosynthesis”

NH3Gluconeogenesis OtherKetogenesis Bioactive

metabolites

Branched Chain Amino Acid Metabolism:Leucine & Isovaleric Acidemia

Isovaleryl-CoA Dehydrogenase

Deficiency

“Isovaleric Acidemia”

Maintainence of Euglycemia during Fed & Fasting States

Maintenance of blood and tissue glucose levels is critical for function

CNS function (except in the infant, CNS is almost completely dependent on glucose from the blood for energy

other tissues also require glucose but can utilize other energy sources as well ie fatty acids and amino acids, glycerol and lactate

Requirements to Maintain Euglycemia Under “Fasting” Conditions

Functioning hepatic gluconeogenic & glycogenolytic enzyme systems

adequate endogenous gluconeogenic substrates (amino acids, glycerol, lactate)

adequate B-oxidation of fatty acids to synthesize glucose & ketones

functional endocrine system to modulate & integrate the above system components

Homeostatic Processes Maintaining Euglycemia(insulin & glucagon in response to glucose levels)

FED STATE High GI absorption High Glycogen

biosynthesis High triglyceride

biosynthesis Low gluconeogenesis Low lipolysis

FASTING STATE Low GI absorption High Glycogenolysis High Lipolysis with

mobilization of fatty acids & ketones

High Gluconeogenesis

Phases of Glucose Homeostasis

1.Glucose absorptive phase: 3 - 4 hrs after glucose ingestion (high insulin)

2.Post absorptive/early starvation: 3-12 hrsglucose (from hepatic glycogen) to brain, RBC, renal medulla

3. Early / Intermediate Starvation: 14+ hrsgluconeogenesis & (later) lipolysis

GSD-0

GSD-IV

GSD-1a&b

GSD-V, GSD-VI, GSD-IX

GSD-II ( lysosomal)

GSD-III

GSD-VII

GSD-X, GSD-XII, GSD-XIII

GSD-XI (LDH)

LIVER

MUSCLE

Trifunctional protein

VLCAD,MCAD, SCAD

Biosynthesis & Degradation of Complex Molecules

Considerable energy and substrates are used in cells for the synthesis and degradation of macromolecules that:

Perform biological functions Become components of sub-cellular

structures

Endoplasmic Reticulum: Synthesis of Glycoproteins

N-Glycosylation & the Mannose Pathway

Abnormal glycopeptide Biosynthesis Disorders of N-Glycosylation

Abnormal Glycopeptide BiosynthesisO-Glycosylation and its Disorders

Lysosomes: Degradation ofMacromolecules

Metabolic Role of Lysosomes

Degradation of endogenous and exogenous macromolecules

Acidic hydrolysis: Molecules include:mucopolysaccharides sphingolipids

peptidesoligosaccharides glycopeptides lipids

S-acetylated proteins monosaccharides/aminoacids/monomers

Typical Lysosomal Storage Disease History

Initially “clinically normal” Slow onset of symptoms usually involving

multiple organs / systems Progressive deterioration Usually premature death Typical features often include:

neurodegeneration, organ enlargement, connective tissue involvement, cardiac & pulmonary involvement, other organs (vascular endothelium, muscle, kidney)

40+ Lysosomal Storage Diseases Identified

Sphingolipidoses: Tay-Sach’s, Sandhoff, GM1 gangliosidosis, MLD,Krabbes, Fabry, Gaucher, Farber, Niemann-Pick

Mucopolysaccharidoses:Hurler/ Hurler-Scheie/Scheie, Hunter, San Filippo, Morquio,Maroteau-Lamy, Sly

GlycogenosesPompe disease

Lipid Storage diseasesWolman, cholesterol ester, NP”C”

Oligosaccharide/glycopeptidoses

Mannosidoses, fucosidosis, Schindlers, sialidoses,

aspartylglycosaminuria

Multiple enzyme deficiencies

I-cell & MLIII, multiple sulfatase deficiency, galactosialidosis

Transport deficienciesCystinosis, Salla disease, ISS

Peptide Storage DiseasesPycnodysostoses, infantile NClF

Salla Disease FibroblastsDistended Lysosomes

Mitochondria: Abnormal Energy Production

Amino acid metabolism Urea cycle ( removal of ammonia) Steroid biosynthesis

Fatty acid oxidation ( carnitine, B-oxidation) Ketone body metabolism Carbohydrate metabolism (PDH)

Aerobic energy product’n

Metabolic Jobs of Mitochondria

Respiratory chain (inner compartment)(Five multimeric complexes + two electron carriers)

Complex I: 46 subunits ( 7 mDNA + 39 nDNA) Complex II: 4 subunits ( 4 nDNA) Coenzyme Q10 (ubiquinone) - carrier to complex III) Complex III: ( 11 subunits (1 mDNA – 10nDNA) Cytochrome C - mobile carrier to complex IV Complex IV: 13 subunits (3 mDNA – 10 nDNA)

Protons extruded by Cplx’s I,II, III, & IV Complex V: ATP synthase – “Couples” proton

reintake which is coupled to ATP synthesis

Mitochondria: Electron Transport Chain Enzyme Complexes ATP produced in using the respiratory chain

TCA Cycle & Respiratory Chain

Energy Production in Mitochondria

Cplx I

Cplx II

Cplx III

Cplx IV

Cplx V

FAD-H2

NAD-H2

NAD

FAD

Glycolysis, pyruvate, aconitate, Malate + other dehydrogen’n

Rx’s

Succinate, Isol, Val, Met, Thr, SCFA’s

ETF / ETF-QO

Fatty .Acid B-oxid’n, dimethylglycine, sarcosine

(CoQ10)

(CoQ10)

(Cyt-C)

H+

O2

H20

H+

H+

H+ADP

ATPInner Mitoch. Membrane

Mitochondria

Only organelle other then nucleus that has: DNA (circular / double stranded) - 16,569

bases Can synthesize own RNA & proteins

mDNA – 37 genes 24 for translation (2 rRNA / 22 tRNA) 13 for proteins of Respiratory Chain subunits

nDNA – many genes code for 1000+ mitochondrial proteins

(structural, transport, chaparone & enzyme)

Any significant defect can lead to deficient function and result in clinical abnormality

Based on physiological function(s) affected Based on organ(s) affected Based on severity of mutation and resulting

deficiency of protein-mediated biochemical function

Recognition often difficult clinically and usually requires laboratory support for screeening, diagnosis and treament.

Approaches to treatment

Common Treatment Examples

Restriction / supplements / medications PKU & other aminoacidopathies Urea cycle disorders Organic acidopathies (MMA,PA, IVA etc.)

Ensure nutrient availability Glycogen storage disorders B-oxidation disorders

Enhancement of organelle function mitochondrial disorders

Cell / organ replacement lysosomal storage disorders

More Recent Approaches to Therapy

End organ protection: large chain neutal amino acids in PKU

Stabilization of “mis-folded” proteins: otherwise that would be recognized as having defective “folding” and removed via proteosome mechanism

Improved correction of biochemical milieu in cells of patient with the metabolic defect:

End Organ Protection in PKUCNS

High plasma phenylalanine

BBB

High plasma phenylalanine

CNS

BBB

Isol

Leu

Val

Tyr

Trypt

Met

Low PHE Diet PreKunil

High PHE Lower PHE

PKU: Extra tyrosine for protein synthesis, neurotransmitter biosynthesis, pigment biosynthesis

Urea Cycle Disorders: Extra arginine to maintain adequate levels of urea cycle intermediates

“ Many IEM Diets require Further Modification”

Indirect Therapy: Replacement of Essential Metabolites

Urea Cycle DisordersMay need increased leucine, isoleucine & valine to compensate for loss of “N” as phenylacetyl-glutamine

Organ Transplantation (to provide metabolic capability)

Liver Familial Hypercholesterolemia (LDL-cholesterol receptor deficiency) Tyrosinemia Glycogen Storage Disease (Type I) Primary hyperoxaluria *

Kidney Fabry Disease Cystinosis Primary hyperoxaluria *

Bone Marrow Various lysosomal storage diseases ie. Hurler syndrome (MPSI)

Cornea Cystinosis, Fabry disease

Biopterin-responsive PKU (PAH Deficiency)

Not due to a biopterin biosynthesis disorder

Up to 1/3 of PKU patients (usually milder variants)

Will have higher tolerance for PHE in diet when on BH4

OR Be able to avoid low-PHE diet

Clinical trials now in process

Lysosomal Storage Disorders:Treatment options

Supportive care Enzyme replacement therapy Substrate depletion (biosynthesis inhibitors) Hematopoeitic stem cell transplant Chaperone Therapy (research only) End organ protection therapy (research

only) Gene therapy

LYSOSOME

Glucosylceramide

Glucosylceramide

BiosynthesisDegradation

ERT

Biosynthesis

Inhibitor

Cellular Damage

Enzyme Replacement Therapy vrs.

Substate Biosynthesis Inhibition

Endoplasmic

Endoplasmic protein modification & folding

Misfolded Properly folded

“Chaperone” Therapy

Protein Biosynthesis in RER

Degradation via Ubiquitin plus proteosome

system

Transport from trans-GOLGI to lysosme with activation at acidic pH

Case Histories

1. Case 1 – Positive Newborn Metabolic Screen2. Case 2 – Hepatomegaly with abnormal liver

pathology3. Case 3 – 18 month boy with hepatomegaly

and obtundation4. Case 4 – 5 year girl with hearing loss &

macrocephaly5. Case 5 – 10 month boy with developmental

delay & dysmorphic facies