ABGC - Metabolic Genetics

Small Molecule Intoxication Disorders

Disorders causing accumulation of metabolites/toxic conversion that causes toxicity to organs

Reduced Fasting Tolerance Disorders

Disorders that quickly cause a patient to be hypoglycemic, impacting organs that require high glucose levels

Mitochondrial Disorders

Disorders that impact the mitochondria, leading to energy deficiency

Complex Molecule Disorders

Disorders that impact the synthesis/processing/breakdown of complex molecules leading to slowly progressive symptoms

Categories of Metabolic Disorders - Small Molecule Intoxication

• urea cycle disorders

• organic acid disorders

• aminoacidopathies

• carbohydrate disorders

Categories of Metabolic Disorders - Reduced Fasting Intolerance

• fatty acid oxidation disorders

• glycogen storage disorders

Categories of Metabolic Disorders - Mitochondrial Disorders

• Barth

• Leigh

• MELAS

• MERRF

• pyruvate carboxylase

• Pearson

• Kearns-Sayre

Categories of Metabolic Disorders - Complex Molecule Disorders

• Gaucher

• Krabbe

• Smith-Lemli Opitz

• Tay-Sachs

• Mucopolysacchradioses

• Peroxisomal disorders

Most common urea cycle disorder

OTC deficiency

Urea Cycle Disorders - Acute Symptoms

• seizures

• coma

• brain edema

• vomiting, confusion, slurred speech

• death

Urea Cycle Disorders - Long Term Symptoms

• cognitive impairment

• variable ID

• spastic quadriplegia

• ataxia

Urea Cycle Disorders - Acute Treatment

• no protein intake

• IV ammonia scavengers

• hemodialysis

Urea Cycle Disorders - Long Term Treatment

• liver transplant (with severe UCDs)

• protein restricted diet

• potentially gene therapy

Proximal Urea Cycle Disorders

Taking place in mitochondria:

• CPS, NAGS, OTC

• LOW citrulline

Distal Urea Cycle Disorders

Taking place in cytosol:

• ASS1 (citrullinemia), ASL, ARG

• HIGH citrulline

CPS1 Deficiency

• deficient carbamoyl phosphate synthetase 1

• high ammonia, low citrulline

NAGS Deficiency

• deficient N-acetylglutamate synthetase

• high ammonia, low citrulline

OTC Deficiency

• X-linked!

• deficient ornithine transcarbamylase

• high ammonia, high ornithine, high orotic acid, low citrulline

Citrullinemia (ASS1 Deficiency)

• deficient arginosuccinic acid synthetase

• HIGH citrulline levels

ASL Deficiency

• deficient arginosuccinic acid lyase

• high citrulline, high arginosuccinic acid

ARG Deficiency

• deficient arginase

• high arginine, usually no hyperammonemia

Organic Acid Disorders - General Symptoms

• metabolic acidosis

• hyperkalemia

• compensatory hyperventialtion

• changes in consciousness

• flushed skin

• headache

• nausea

• vomiting

Organic Acid Disorders - Biochemical Testing

• urine organic acids

• low pH

• low CO₂

Organic Acid Disorders - Treatment

• low protein diet

• metabolic formula

• carnitine to bind organic acids

Isovaleric Acidemia Gene

IVD

Methylmalonic Acidemia Gene

MUT

Propionic Acidemia Genes

PCCA and PCCB

Isovaleric Acidemia - Clue

smelly feet odor

Galactosemias - General Symptoms

• liver dysfunction

• renal dysfunction

• hypoglycemia

• cataracts

• lactic acidosis

• hyperuricemia

GALT Deficiency

• Gal-1-P deficiency

• speech delay/DD, brain damage, cataracts, hepatomegaly, e-coli sepsis

GALE Deficiency

Psychomotor delays

GALK Deficiency

Cataracts only (maybe ID/FTT with poor diet control)

GALM Deficiency

Cataracts only

Duarte Allele

• p. N314D

• milder manifestation (attenuated protein)

Hereditary Fructose Intolerance - Gene/Protein

• ALDOB

• defective aldolase-B

Hereditary Fructose Intolerance - Symptoms

• liver dysfunction

• FTT

• vomiting

• hypoglycemia

Glutaric Aciduria Type 1 - Gene/Protein

• GCDH

• deficient glutaryl-CoA dehydrogenase enzyme activity

• high lycine = toxic levels of glutaric acid

Glutaric Aciduria Type 1 - Symptoms

• basal ganglia strokes, loss of motor control, encephalopathic crisis

• stroke risk resolves after age 6

Glutaric Aciduria Type 1 - Biochemical Testing

urine organic acids (increased glutaric acid)

Glutaric Aciduria Type 1 - Treatment

• limit protein

• metabolic formula

• toxin clearance with carnitine

Homocystinuria - Gene/Protein

• CBS

• defective cystathionine beta-synthase

• problems with methionine synthesis causing toxic levels of homocysteine

Homocystinuria - Biochemical Testing

• plasma amino acids (high methionine)

• homocysteine levels

Homocystinuria - Symptoms

• marfanoid habitus

• strokes

• ID

• joint contractures

• seizures

Homocystinuria - Treatment

• low protein diet

• metabolic formula

• toxin clearance with betaine/vitamin B6

Non-Ketotic Hyperglycinemia - Gene/Protein

• AMT, GLDC, GCSH

• toxic levels of glycine

Non-Ketotic Hyperglycinemia - Biochemical Testing

plasma amino acids (high glycine levels)

Non-Ketotic Hyperglycinemia - Symptoms

• intractable epilepsy

• profound cognitive disability

• no development of skills

Maple Syrup Urine Disease - Gene/Protein

• BCKDHA, BCKDHB, DBT

• defective branched chain amino acids

• toxic isoleucine, leucine, and valine accumulation (leucine most toxic)

Maple Syrup Urine Disease - Biochemical Testing

• plasma amino acids (isoleucine, leucine, and valine levels)

• NBS (isoleucine/leucine ratios)

Maple Syrup Urine Disease - Symptoms

• maple syrup smell in urine and earwax

• brain swelling

• DD

• poor feeding

• encephalopathy

• seizures, coma, death

Maple Syrup Urine Disease - Treatment

• limit protein

• metabolic formula

Non-Ketotic Hyperglycinemia - Treatment

• can’t limit precursors (most glycine made in body)

• toxin clearance

Phenylketonuria - Gene/Protein

• PAH

• deficient phenylalanine hydroxylase

• high Phe levels and tyrosine build-up

Phenylketonuria - Biochemical Testing

• plasma amino acids (Phe levels)

• NBS (mass spectrometry)

Phenylketonuria - Symptoms

• ID

• microcephaly

• pale hair/skin

• seizures

• psych problems

• mousy odor

Phenylketonuria - Treatment

• limit protein

• metabolic formula

• toxin clearance (Kuvan, Palynziq)

Alkaptonuria - Gene/Protein

• HGD

• defective homogentisic 1,2 dioxygenase

• impacts to tyrosine breakdown, toxic levels of homogentisic acid

Alkaptonuria - Biochemical Testing

urine organic acids (homogentisic acid levels)

Alkaptonuria - Symptoms

• black urine (accumulation in eyes and ears)

• joint inflammation

• bone necrosis

• aortic/mitral valve calcification

Alkaptonuria - Treatment

• can’t limit precursors

• nitisinone to clear toxins

Cystinuria - Gene/Protein

• SLC3A1, SLC7A9

• high cystine levels due to impaired reabsorption of cystine by renal tubules

Cystinuria - Biochemical Testing

urinary cystine excretion

Cystinuria - Symptoms

• kidney stones

• recurrent UTIs

• chronic kidney disease

• hypertension

Cystinosis - Gene/Protein

• CTNS

• defective cystinosin

• cystine accumualtion in lysosomes

Cystinosis - Symptoms

• infantile: renal Fanconi syndrome, poor growth, rickets, photophobia, end stage renal failure (10-12yrs)

• juvenile: renal glomerular failure

• adult/ocular: photophobia from corneal cystine crystal accumulation

Tyrosinemia - Gene/Protein

• Type 1: FAH, defective 4-fumarylacteoacetase

• Type 2: TAT, defective tyrosine transaminase

• Toxic levels of succinylacetone

Tyrosinemia - Biochemical Testing

plasma amino acids (tyrosine and succinylacetone levels)

Tyrosinemia - Symptoms

• Type 1: most severe, hepatosplenomegaly, acute liver failure, liver cancer risk

• Type 2: keratosis palmoplantaris, ID, ocular and cutaneous findings

Tyrosinemia - Treatment

• low protein

• metabolic formula

• toxin clearance with nitisinone (negates cancer risk)

Lesch-Nyhan - Gene/Protein

• X-linked: HPRT1

• deficient hypoxanthine-guanine phosphoribosyltransferase

• overproduction of uric acid

Lesch-Nyhan - Symptoms

• motor dysfunction (cerebral palsy-like)

• ID

• self-injurous behavior

• hyperuricemia

• renal failure

• hyperuricemia only with XX

Fatty Acid Oxidation Disorders

• disorders impacting the converting fatty acids into ketones for energy use in fasting states

• primarily impact liver, muscles, heart, and brain

• ALL present with hypoketotic hypoglycemia

• all autosomal recessive

Fatty Acid Oxidation Disorders - Biochemical Testing

• acylcarnitine profiles in urine/blood

• urine organic acids (detect metabolic byproducts during crisis)

Primary Carnitine/Transporter Deficiency - Gene/Protein

• SLC22A5

• defective carnitine transporter, preventing transport of carnitine into mitochondria to process VLCFA

Primary Carnitine/Transporter Deficiency - Symptoms

• cardiomyopathy

• arrhythmias

• Long QT

• sudden death

• hypoketotic hypoglycemia

Primary Carnitine/Transporter Deficiency - Molecular Testing

20% of PVs in SLC22A5 are intronic (c.-149G>A)

VLCAD Deficiency - Gene/Protein

• ACADVL

• inability to convert VLCFA to medium chain

VLCAD Deficiency - Symptoms

More severe

• cardiomyopathy

• exercise intolerance

• seizures

• chronic weakness

• hepatomegaly

• hypoketotic hypoglycemia

LCHAD/TFP Deficiency - Gene/Protein

• HADHA/HADHB

• part of trifunctional protein that catayzed beta-oxidation

LCHAD/TFP Deficiency - Symptoms

• peripheral neuropathy

• retinitis pigmentosa

• cardiomyopathy

• sudden death

• seizures

• exercise intolerance

• hypoketotic hypoglycemia

MCAD Deficiency - Gene/Protein

• ACADM

• inability to break down medium chain fatty acids

Most common FAOD

MCAD Deficiency

MCAD Deficiency - Symptoms

• actue liver dysfunction

• hypoketotic hypoglycemia

• coma/lethargy/sudden death

• NO cardiomyopathy, rhabdomyolysis, or weakness

SCHAD Deficiency - Gene/Protein

• HADH

• inability to breakdown short chain fatty acids

SCHAD Deficiency - Symptoms

• hyperinsulinism

• hypoketotic hypoglycemia

• acute liver dysfunction

• coma/lethargy/sudden death

Glutaric Acidemia Type 2/MAD Deficiency - Gene/Protein

• ETFA/ETFB/ETFDH

• blocked delivery of electrons into ETC

Glutaric Acidemia Type 2/MAD Deficiency - Symptoms

• MALFORMATIONS: dysmorphic facies, large cystic kidneys, genital anomalies

• cardiomyopathy

• exercise intolerance

• seizures

• encephalopathy

• lethargy/coma/sudden death

• hypoketotic hypoglycemia

Fatty Acid Oxidation Disorders - General Treatment

• frequent feeds (can add cornstarch)

• reduced fat intakes

• use triheptanoin/MCT oil to bypass broken enzyme

Fatty Acid Oxidation Disorders - Acute Treatment

• dextrose infusion

• control hyperammonemia

• diuresis

• dialysis

Fatty Acid Oxidation Disorders - Severity

Most severe: VLCADD, LCHADD, and GA2

No cardiac involvement: MCADD and SCHAD

Glycogen Storage Disorders

• disorders of glucose storage as glycogen in the liver or muscles

• can either manifest with liver, muscle, or liver AND muscle complications

• primarily autosomal recessive

GSD Type I (Von Gierke) - Gene/Protein

• G6PC/SLC37A4

• deficient glucose-6-phosphate

GSD Type I (Von Gierke) - Symptoms

• liver GSD

• hepatomegaly (with normal liver function)

• severe hypoglycemia

• truncal obesity

• doll face

• increased bleeding time

GSD Type Ib (Von Gierke) - Unique Symptoms

• neutropenia

• frequent and severe infections

GSD Type I (Von Gierke) - Treatment

• frequent feeds

• corn starch/glycosade

• restrict to complex carbs

• SGLT2 inhibitors to protect kidneys

• liver transplant if severe

GSD Type II (Pompe Disease) - Gene/Protein

• GAA

• deficient alpha-glucosidase enzyme

• alpha-glucosidase-maltase (adult-onset)

GSD Type II (Pompe Disease) - Symptoms

• muscle GSD

• infantile: cardiomyopathy with arrhythmias

• proximal myopathy

• motor delays

• FTT

• respiratory insufficiency

GSD Type II (Pompe Disease) - Treatment

enzyme replacement therapy available to break down glycogen and restore muscle function

GSD Type V (McArdle Disease) - Gene/Protein

• PYGM

• muscle glycogen phosphorylase deficiency

GSD Type V (McArdle Disease) - Symptoms

• muscle GSD

• hypoglycemia

• exercise intolerance

• rhabdomyolysis

• second wind phenomenon