Week 5: Dr. Knoll IEM Overview + Aminoacidopathies and Organic Acidemias

Basics of Metabolic Disorders

• Metabolism is the sum total of all chemical reactions in the body

• Disorders of metabolism impact enzymes and transporters

• Substrate build-up can be toxic/be converted into a toxic substance

Main Classifications of Metabolic Conditions

• Small molecule intoxication

• Reduced fasting tolerance

• Mitochondrial disorders

• Complex molucules

• Neurotransmitter

General - Small Molecule Intoxication

Small molecule build-up (either normal product or converted product to toxin) - poisons organs

General - Reduced fasting tolerance

Inability to go without food, can cause extreme hypoglycemia with impacts to organs.

General - Mitochondrial Disorders

Disorders in mitochondrial assembly, transcription (nuclear and mitochondrial DNA) that causes energy deficiency impacting high energy organs (ex. brain, liver, eyes)

General - Complex molecules

Slow progressive disorders caused by disruption of synthesis, processing, or breakdown of molecules, commonly impacting bones, joints, spleen, and brain.

General - Neurotransmitter

Problems with the making or breaking down of neurotransmitters (CNS = cognitive issues, PNS = movement)

Clinical Tests for Disorders of Intermediary Metabolism

• Urine organic acids: look at presence of organic acids in urine (more broad)

• Plasma amino acids: determine if there is protein breakdown

• Acylcarnitine profile: determines fat breakdown

Small Molecule Intoxication Disorders

• urea cycle disorders

• organic acid disorders

• aminoacidopathies

• carbohydrate disorders

• metal disorders

Reduced Fasting Tolerance Disorders

• fatty acid oxidation disorders

• glycogen storage disorders

Mitochondrial Disorders

• Barth syndrome

• Leigh disease

• MELAS

• MERRF

• pyruvate carboxylase deficiency

• Pearson

• Kearns-Sayre

Neurotransmitter Disorders

• pyridoxine-dependent epilepsy

• dopa-responsive dystonia

• monoamine oxidase deficiency

• tyrosine hydroxylase deficiency

• sepiapterin reductase deficiency

Complex Molecule Disorders

• Congenital disorders of glycosylation

• Gaucher

• Krabbe

• Smith-Lemli-Opitz

• Tay Sachs

• Mucopolysaccharidoses (MPS)

• Zellweger Spectrum

Most common urea cycle disorders

• OTC

• citrullinemia

• arginosuccinic aciduria

OTC Genetic Cause

X-linked: hemizygous pathogenic variants in OTC

Citrullinemia Genetic Cause

AR: biallelic pathogenic variants in ASS1

Arginosuccinic Aciduria Genetic Cause

AR: biallelic pathogenic variants in ASL

Urea Cycle Disorders Clinical Testing

• plasma amino acids

• ammonia levels

• orotic acid levels

Urea Cycle Disorders Treatment/Management

• low protein diet

• metabolic formula

• ammonul, phenylbutyrate, benzoate to clear toxins

Urea Cycle Disorders Symptoms/Presentation

• hyperammonemia

• acutely - can cause coma and even death

• long term - liver damage

Organic Acid Disorders

• methylmalonic acidemia

• proprionic acidemia

• isovaleric acidemia

Methylmalonic Acidemia Genetic Cause

AR: biallelic pathogenic variants in MUT

Propionic Acidemia Genetic Cause

AR: biallelic pathogenic variants in PCCA or PCCB

Isovaleric Acidemia Genetic Cause

AR: biallelic pathogenic variants in IVD

Organic Acid Disorders Symptoms/Presentation

• when metabolically stable (no excess buildup), no symptoms

• metabolic acidosis:

  • headache

  • decreased BP

  • hyperkalemia

  • muscle twitching

  • vasodilation

  • nausea, vomiting, diarrhea

  • changes in level or consciousness

  • kussmaul respirations (hyperventilation)

Organic Acid Disorders Clinical Test

• urine organic acids

• decreased pH (more acidic)

• decreased CO2 levels

Organic Acid Disorders Treatmnent/Management

• Low protein diet

• metabolic formula

• carnitine to clear toxins

Hallmark of Isovaleric Acidemia

Smell of sweat socks

Aminoacidopathies

• Phenylketonuria (PKU)

• Tyrosinemia Type 1

• Alkaptonuria

• Maple Syrup Urine Disease

• Non-Ketotic Hyperglycinemia

• Homocystinuria

• Glutaric Aciduria Type 1

Phenylketonuria (PKU) Genetic Cause

AR: biallelic pathogenic variants in PAH

PKU Symptoms/Presentation

• inability to break down phenylalanine

• neurocognitive effects with high phenylalanine levels

• intellectual disability

• teratogenic during pregnancy: heart defects, microcephaly, DD

PKU Clinical Testing

Plasma amino acids (phenylalanine)

PKU Treatment/Management

• low protein diet

• metabolic formula

• sapropterin (Kuvan) and palynziq to clear toxin

• early treatment = normal cognition

Hallmark of High Phe Levels

Mousy odor

Tyrosinemia Type 1 Genetic Cause

AR: biallelic pathogenic variants in FAH

Tyrosinemia Type 1 Clinical Testing

• plasma amino acids (for tyrosine)

• succinylacetone levels

Tyrosinemia Type 1 Symptoms/Presentation

• inability to break down tyrosine leading to injury from succinylacetone

• liver damage

• liver cancer can occur from recurrent damage

Tyrosinemia Type 1 Treatment/Management

• low protein diet

• metabolic formula

• nitisinone (reduces liver cancer risk)

Alkaptonuria Genetic Cause

AR: biallelic pathogenic variants in HGD

Alkaptonuria Symptoms/Presentation

• inability to breakdown tyrosine, leading to homogentisic acid build-up

• adult onset (slow progression)

• join inflammation leading to early onset arthritis

• build-up of acid in ears and eyes (blue coloration)

• urine dark when exposed to air

Alkaptonuria Clinical Testing

• urine organic acids (homogentisic acid)

• sometimes can’t be seen in plasma AA

Alkaptonuria Treatment/Management

• difficult to limit precursors

• nitisinone (slightly effective)

Maple Syrup Urine Disease Genetic Cause

AR: biallelic pathogenic variants in BCKDHA, BCKDHB, or DBT

Maple Syrup Urine Disease Symptoms/Presentation

• inability to break down branched chain amino acids

• FTT

• developmental delay

• seizures

• movement problems

• leucine can lead to brain swelling and coma

Hallmark of Maple Syrup Urine Disease

Maple syrup odor in urine and ear wax

Maple Syrup Urine Disease Clinical Testing

Plasma amino acids (leucine, isoleucine, valine)

Maple Syrup Urine Disease Treatment/Management

• low protein diet

• metabolic formula

Non-Ketotic Hyperglycinemia Genetic Cause

AR: biallelic pathogenic variants in AMT, GLDC, or GCSH

Non-Ketotic Hyperglycinemia Clinical Testing

Plasma amino acids (glycine)

Non-Ketotic Hyperglycinemia Symptoms/Presentation

• build-up of glycine

• intractable epilepsy (almost impossible to control)

• profound cognitive disability

Non-Ketotic Hyperglycinemia Treatment/Management

• body makes most glycine (hard to limit intake)

• sodium benzoate, dextromethorphan (clear toxins)

• overall treatment is not super helpful

Homocystinuria Genetic Cause

AR: biallelic pathogenic variants in CBS

Homocystinuria Clinical Testing

• plasma amino acids (methionine)

• homocysteine levels

Homocystinuria Symptoms/Presentation

• can’t breakdown methionine, build-up of homocysteine

• Marfanoid habitus

• strokes (typically in adulthood)

Homocystinuria Treatment/Management

• low protein diet

• metabolic formula

• betaine and vitamin B6 (can get rid of/convert toxin)

Glutaric Aciduria Type 1 Genetic Cause

AR: biallelic pathogenic variants in GCDH

Glutaric Aciduria Type 1 Symptoms/Presentation

• unable to break down lysine, build-up of toxic glutaric acid

• suffen unexpected strokes in basal ganglia

• loss of motor control with basal ganglia stroke

• after age 6, stroke risk resolves

Glutaric Aciduria Type 1 Treatment/Management

• low protein diet

• metabolic formula

• carnitine to clear toxin

Carbohydrate Disorders

• galactosemia

• hereditary fructose intolerance

Galactosemia Genetic Cause

AR: biallelic pathogenic variants in GALT

Galactosemia Symptoms/Presentation

• unable to breakdown galactose

• enlarged liver/liver failure

• brain damage

• cataracts

• jaundice

• kidney damage

• increased risk for e-coli sepsis

• speech delays

Galactosemia Clinical Testing

• GALT enzyme testing

• Gal-1-P levels

• Urine galactitol

Galactosemia Treatment/Management

• no galactose or lactose (no dairy in diet)

• no medications available to clear toxins

Hereditary Fructose Intolerance Genetic Cause

AR: biallelic pathogenic variants in ALDOB

Hereditary Fructose Intolerance Symptoms/Presentation

• accumulation of Fructose-1-phosphate

• hypoglycemia

• nausea/vomiting

• toxic effects (liver, kidney, small intestine)

Hereditary Fructose Intolerance Clinical Testing

• no biochemical testing, enzyme testing previously done with tissue biopsy

• molecular testing only

Hereditary Frucatose Intolerance Treatment/Management

• no fructose or sucrose (fruits and table sugar)

• no medication available to clear toxins

Metal Disorders

• Wilson disease

• Menkes disease

Wilson Disease Genetic Cause

AR: biallelic pathogenic variants in ATP7B

Wilson Disease Symptoms/Presentation

• build up of copper due to mutation in transporter protein

• high copper levels in tissue, low levels in blood

• personality and movement disorders

• liver failure

Hallmark of Wilson Disease

Kayser-Fleischer Rings (copper build-up in eye)

Wilson Disease Clinical Testing

• low serum copper and serum ceruloplasmin

• increased urine copper

Wilson Disease Symptoms/Management

• no high copper foods (ex. nuts, seafood, organ meat)

• chelators (bind and flush copper)

• zinc

Menkes Disease Genetic Cause

X-linked: hemizygous pathogenic variants in ATP7A

Menkes Disease Symptoms/Presentation

• defective copper uptake

• healthy until 2m

• loss of milestones

• hypotonia

• seizures

• FTT

• skin laxity

Hallmarks of Menkes Disease

kinky/tough/wirey hair and cutis laxis

Menkes Disease Clinical Testing

• low serum copper and serum ceruloplasmin

• increased urine copper

Menkes Disease Treatment/Management

copper histidinate (difficult to treat, shortened lifespan)

Peroxisomal Disorders

• Zellweger spectrum

• X-ALD

Zellweger Spectrum Genetic Cause

AR: biallelic pathogenic variants in PEX1, PEX6, PEX12, PEX26

Zellweger Spectrum Symptoms/Presentation

• accumulation of VLCFA due to inability to make peroxisome

• neurologic, liver, skeletal

• neurologic: cognition, SNHL, seizures

• stippling of bones (chondrodysplasia punctata)

• age of presentation: severe (neonatal), mild (childhood)

Zellweger Spectrum Clinical Testing

Very long chain fatty acid levels

Zellweger Spectrum Treatment/Management

• symptomatic

• no curative treatments :(

X-linked adrenoleukodystrophy (X-ALD) Genetic Cause

X-linked: hemizygous pathogenic variants in ABCD1

X-linked adrenoleukodystrophy (X-ALD) Childhood Onset

• Cerebral form - 30%

• Onset 4-8 years

• adrenoleukodystrophy

• neurological regression

X-linked adrenoleukodystrophy (X-ALD) Adult Onset

• Adrenomyeloneuropathy (AMN) form - 45%

• Onset 20-40 years

• adrenoleukodystrophy

• normal cognition

• progressive leg stiffness

• bowel/bladder dysfunction

• can affect some females

X-linked adrenoleukodystrophy (X-ALD) Clinical Testing

Very long chain fatty acid levels

X-linked adrenoleukodystrophy (X-ALD) Treatment/Management

• stem cell transplant can be done with severe form

Sphingolipidoses

• Gaucher

• Fabry

• Pompe

• Niemann Pick C

• Krabbe

• Tay-Sachs / Sandhoff / “GM2”

• Neuronal Ceroid Lipofuscinosis

• Metachromatic Leukodystrophy

Gaucher Type 1 Genetic Cause

AR: biallelic pathogenic variants in GBA

Gaucher Type 1 Symptoms/Presentation

• build-up of glucosal ceramide

• onset in late childhood - young adulthood

• splenomegaly and hepatomegaly

• anemia

• thrombocytopenia

• bone involvement

• normal cognition

Gaucher Type 1 Clinical Testing

• Lyso-Gb1 levels

• GBA enzyme levels

Gaucher Type 1 Treatment/Management

• enzyme replacement

• substrate reduction (pills)

Gaucher Type 1 AJ Founder Variant

p.Asn409Ser - 1 in 15 Ashkenazi Jewish carrier frequency

Fabry Disease Genetic Testing

X-linked: hemizygous pathogenic variants in GLA

Fabry Disease Symptoms/Presentation

• neuropathic pain

• angiokeratomas

• GI issues

• decreased sweating

• normal cognition

• without treatment: kidney and heart complications

Fabry Disease Clinical Testing

• GL3 levels

• GLA enzyme levels

Fabry Disease Treatment/Management

• enzyme replacement therapy (infusions)

• substrate reduction (pills - dependent on enzyme activity)

Pompe Disease Genetic Cause

AR: biallelic pathogenic variants in GAA

Pompe Disease Infantile Form

• Onset in first few months of life

• hypertrophic cardiomyopathy

• skeletal muscle weakness (including diaphragm)

• hypotonia

• normal cognition