Urea Cycle Disorders and Lysosomal Storage Disorders

Metabolism

Series of enzymatic reactions by which an organism converts protein, fats, and carbohydrates into energy

Order of usage: 1. carbs 2. fats 3. protein

When to suspect an inborn error of metabolism?

• Abnormal NBS

• difficulty feeding, FTT

• DD, regression

• FHx: SIDs, early/sudden death, consanguinity

• Multi-organ involvement: seizures, hyper/hypotonia, recurrent URI, valvular disease

Urea Cycle Disorders

Genetic conditions in which the body can’t properly remove the ammonia byproduct produced with protein metabolism, leading to hyperammonemia which can lead to neurological damage.

Most common urea cycle disorder

OTC deficiency

Proximal Urea Cycle Disorders

Disorders affecting the beginning enzymes of the urea cycle (located in mitochondria)

• OTC deficiency

• CPS deficiency

• NAGS deficiency

  • LOW citrulline levels

Distal Urea Cycle Disorders

Disorders affecting the distal enzymes of the urea cycle (located outside the mitchondria)

• ASS1 (Citrullinemia), ASL, and ARG1 deficiency

  • HIGH citrulline levels

UCD Acute Symptoms

• seizures

• coma

• brain edema

• death

UCD Long Term Symptoms

• cognitive impairment

• ID

• spastic quadriplegia

• ataxia

UCD Crisis Treatment

• no protein

• dextrose IV fluid (sugars + fat)

• IV ammonia scavengers

• dialysis

UCD Long Term Treatment

• liver transplant

• protein restricted diet

• oral ammonia scavengers

• gene therapy

Signs and Symptoms of Hyperammonemia

• headache

• personality/behavioral changes

• sleep disorders

• anorexia

• vomiting

• confusion

• psychomotor agitation

• delusions/hallucinations

• slurred speech

NAGS (N-Acetylglutamate Synthetase) Deficiency Genetic Cause

AR: biallelic pathogenic variants in NAGS

• extremely rare, unknown frequency

CPS1 (Carbamyl Phosphate Synthetase I) Deficiency Genetic Cause

AR: biallelic pathogenic variants in CPS1

• Frequency: 1 in 62,000

OTC (Orthinine Transcarbamylase) Deficiency Genetic Cause

X-linked: pathogenic variants in OTC

• most common!

• Frequency: 1 in 14,000

Citrullinemia (Argininosuccinate Synthetase Deficiency) Genetic Cause

AR: biallelic pathogenic variants in ASS1

• frequency: 1 in 57,000

ASL (Argininosuccinate Lyase) Deficiency Genetic Cause

AR: biallelic pathogenic variants in ASL

• frequency: 1 in 70,000 (founder variant in Latin America)

ARG1 (Arginase) Deficiency Genetic Cause

AR: biallelic pathogenic variants in ARG1

• frequency: 1 in 350,000

Lysosome Function and Regulation

Organelle that breaks down and neutralizes waste, regulates expression and signaling, and other pathways (like mTOR)

Lysosomal Storage Disorders

• genetic disorders of the lysosomal enzymes (70+ types)

• all autosomal recessive EXCEPT:

  • Fabry disease

  • MPS II (Hunter syndrome)

  • Danon disease (LAMP2)

Major Lysosomal Storage Disorders

• Fabry disease (GLA)

• Gaucher disease (GBA)

• Tay-Sachs disease (HEXA)

• Krabbe disease (GALC)

• Niemann-Pick (SMPD1)

• Wolman disease and cholesterol ester storage disease (LIPA)

• MPS II/Hunter Syndrome (IDS)

• Danon disease (LAMP2)

• Pompe disease (GAA)

Mucopolysaccharidosis type II (MPS II)/Hunter Syndrome Genetic Cause

X-linked: pathogenic variants in IDS

• Frequency: 1 in 100,000-170,000

MPS II (Hunter Syndrome) Pathophysiology

• I2S enzyme deficiecny

• accumulation of complex sugar molecules (GAGs)

• Direct cellular disease and organ dysfunction

• Cytokine response from GAG accumulation leading to lysosome lysis

MPS II (Hunter Syndrome) Symptoms/Presentation

• CNS: hydrocephalus, myelopathy, seizures, behavioral issues, sleep disturbances, ID

• GI issues: hepatosplenomegaly

• Respiratory difficulties and changes to bone formation

• Appearance: coarse facies

• Ears: SNHL, recurrent otitis media

• Eyes: lack of corneal clouding

MPS II (Hunter Syndrome) Diagnosis

• deficient I2S activity + elevated urine GAGs

• molecular: null variant = severe disease, missense more difficult to predict

MPS II (Hunter Syndrome) Management/Treatment

• enzyme replacement therapy (not great at treating heart, bones, and brain)

• hematopoietic stem cell transplant
• gene therapy

Acid Sphingomyelinase Deficiency (ASD)/Niemann-Pick Disease Genetic Cause

AR: biallelic pathogenic variants in SMPD1

ASD (Niemann-Pick Disease) Pathophysiology

• intracellular accumulation of sphingomyelin in tissues and organs

ASD (Niemann-Pick Disease) Symptoms/Presentation

• hepatosplenomegaly

• feeding/swallowing issues

• respiratory infections

• neurological issues

  • Type A: severe/infantile, neurological involvement

  • Type B: milder, mid-childhood, less neuro

  • Type C: most common, progressive neurological

Pompe Disease Genetic Cause

AR: biallelic pathogenic variants in GAA

Infantile-onset Pompe Disease Symptoms/Presentation

• onset before age 12m with cardiomyopathy

• hypotonia and muscle weakness

• feeding difficulties, FTT

• respiratory distress

• hypertrophic cardiomyopathy

Late-onset Pompe Disease Symptoms/Presentation

• onset before age 12m (without cardiomyopathy)

• onset after age 12m

• proximal muscle weakness

• respiratory insufficiency

Pompe Disease Treatment/Management

• enzyme replacement therapy

• respiratory management

• developmental therapies

• nutritional and feeding

• renal function assessment

• cardiac monitoring and interventions

Pseudodeficiency in LSD

Benign genetic variant that causes low enzyme activity WITHOUT causing substrate accumulation

ASD (Niemann-Pick Disease) Characteristic Feature

Cherry red spot (in retinal cells)