Week 4: MPS & Peroxisomal Disorders AND Inborn Errors of Immunity

All MPS Disorders are autosomal recessive EXCEPT:

MPS II (Hunter Syndrome - XL)

All MPS Disorders are Progressive & Asymptomatic at birth EXCEPT:

MPS VII (Sly Syndrome (seen in utero and can cause death))

The most common MPS Disorder

MPS III (Sanfilippo Syndrome)

The rarest MPS Disorder

MPS VII (Sly Syndrome)

The three types of Glycosaminoglycans (GAGs)

1. Heparan Sulfate

2. Keratin Sulfate

3. Dermatan Sulfate

Heparan Sulfate is abundant in the...

Brain

Both Keratin and Dermatan Sulfate are abundant in the...

Skeleton

For MPS Disorders, list the characteristics of Coarse Facial Features

1. Macrocephaly

2. Saddle Nose

3. Large Lips & Mouth

4. Macroglossia

5. Puffiness around eyes

6. Large Cheeks

7. Thick Eyebrows

8. Coarse, thick, straw hair

9. Hypertrichosis

For MPS, list the characteristics of Dysostosis Multiplex

1. Growth restriction / Short Stature

2. Joint Contractures

Examples of Joint Contractures

1. Claw Hand Deformity

2. Spinal Gibbus Deformity

3. Pelvic & Hip Dysplasia

4. Thick Clavicles & Ribs

5. Short Neck

For MPS Disorders, what systems are being affected?

1. ENT (Respiratory Issues)

2. Hearing (Hearing Loss)

3. Vision (Ocular Manifestations)

For MPS Disorders, describe the organs involved:

1. Hepatosplenomegaly (w/o dysfunction)

2. Bowels: Umbilical/Inguinal Hernias

3. Cardiopulmonary: Cardiomyopathy, Valvular Disease, Systemic & Pulmonary HTN, CAD

4. Macroglossia: OSA & Sleep Apnea

For MPS Disorders, describe the types of Neurological Progression:

1. Neurodegenerations: DD w/ Stagnation & Progressive mental deterioration

2. Communication Hydrocephalus: Contributes to macrocephaly & Affects Peripheral Nervous System (Carpal Tunnel & Nerve Compression)

MPS 1 (Hurler Syndrome) Gene Involved

IDUA

MPS1 Diagnosis

Increased GAGs AND Increased dermatan & heparan sulfate

Types of MPS1

1. Hurler Syndrome (Severe)

2. Hurler-Scheie (alpha-L-iduronidase)

3. Scheie (Attenuated)

Hurler Syndrome (Severe) Symptoms Without Treatment

1. Corneal Clouding

2. Dysostosis Multiplex

3. Organomegaly

4. ID/DD

5. Heart Disease

6. Coarse Facies

7. Death by 10

First Signs of Hurler Syndrome before 1 years old

1. Umbilical/Inguinal Hernias

2. Frequent Upper Respiratory Infections

Hurler-Scheie Syndrome Symptoms

1. Corneal Clouding

2. Joint Stiffness

3. NORMAL INTELLECT

4. NORMAL LIFE SPAN

5. Can have skeletal abnormalities, short stature, hernias, and hepatomegaly

Scheie Syndrome Symptoms without Treatment

1. Less dysmorphic than Hurler (Evident by 3 - 10 years)

2. Milder but slowly progressive dysostosis multiplex & facial coarsening

3. +/- Organomegaly, Corneal Clouding, Hernia, Heart Valve

4. Can have Normal Cognition or Mild ID

5. Can live Normal Life Span or Death by 2nd/3rd decade

ERT For Hurler Syndrome

Aldurazyme

MPS II (Hunter Syndrome) Gene

IDS

MPS II Diagnosis

Increased GAGs AND Increased dermatan & heparan sulfate

Types of Hunter Syndrome

1. Severe

2. Mild

Severe Hunter Syndrome Symptoms without Treatment Before 1 year

Hernias and Frequent Respiratory Infections

Severe Hunter Syndrome Symptoms without Treatment After 1 year

1. NO CORNEAL CLOUDING

2. Coarse Facies

3. Organ Involvement

4. Dysostosis Multiplex

5. ID & DD w/ Stagnation

6. Severe Hearing Loss

6. Neurodegeneration by 6 - 8 years

7. Death prior to 15 years old

Mild Hunter Syndrome Symptoms and Presentation

1. Normal Intelligence & Short Stature

2. By 10 y/o: Milder but slowly progressive dysostosis multiplex & facial coarsening

- +/- organomegaly, hernia, heart valve disease

3. Normal Life Span to 2nd/3rd Decade Death

ERT For Hunter Syndrome

Elaprase

MPS III (Sanfilippo Syndrome) Genes

1. GNA

2. HGSNAT

3. NAGLU

4. SGSH

MPS III Diagnosis

Increased GAGs & Increased Heparan Sulfate

Sanfilippo Syndrome Symptoms

1. Behavior changes (ADHD, aggression) in early childhood

2. Cognitive Plateau -> Neurodegeneration

3. Death by 20 years due to cardiopulmonary involvement

Mild Sanfilippo Symptoms

1. NO organomegaly

2. Little to NO Corneal Clouding

3. NO Coarse Facies

4. NO Dysostosis Multiplex

MPS IV (Morquio Syndrome) Gene

GALNS

MPS IV Diagnosis

Increased GAGs & Increased Keratin & Chondriotin-6-Sulfate

Morquio Syndrome Symptoms and Presentation

1. Skeletal Findings (By 1-3 years old): Ulnar deviation of wrists, Shortened Forearms, Pectus Carinatum, Genu Valgum

2. Nonskeletal Findings: Corneal Clouding, Valvular heart disease, mild hepatomegaly, hearing impairment, sleep apnea, respiratory insufficiency

3. Severe form leads to death by 3rd or 4th decade of life

ERT For Morquio Syndrome

Vimzim

MPS VI (Maroteaux-Lamy Syndrome) Gene

ARSB

Maroteaux-Lamy Syndrome Diagnosis

Increased GAGs & Increased Dermatan Sulfate

Maroteaux-Lamy Syndrome Molecular Testing should be considered in...

Regressive Autism

Maroteaux-Lamy Syndrome Symptoms and Presentation

1. NORMAL INTELLECT

2. Deaccelerated Growth after 1st year -> Short stature/Dwarfism

3. Progressive coarse facies, corneal clouding, cardiopulmonary issues, organomegaly, dysostosis multiplex

4. Death in teens (severe) or later

MPS VII (Sly Syndrome) Gene

GUSB

Sly Syndrome Signs and Symptoms

1. Begins in utero and often leads to death by 20

2. Dysostosis Multiplex, Organomegaly, Coarse Facies, Neurodegeneration, Corneal Clouding

MPS VII Diagnosis

Accumulation of Dermatan, Heparan, and Chondroitin-6-Sulfate

ERT for Sly Syndrome

None are approved

X-Linked Adrenoleukodystrophy (X-ALD) Gene

ABCD1

XALD Diagnosis

Plasma VLCFA Test (Abnormal in 99% males & 85% females)

Can also show in Brain MRI & Adrenal Function Testing

The 3 Phenotypes of X-ALD

1. Childhood Leukodystrophy (35%)

2. Adrenomyeloneuropathy (40-45%)

3. Isolated Addison's (~10%)

Childhood Leukodystrophy Signs and Symptoms

1. Males w/ normal development in first 4-10 years

2. First Symptoms: Behavior and attention changes, School difficulties, incoordination, visual loss, comprehension difficulties

3. Second Set of Symptoms: Rapid neurologic deterioration

- Brain MRI reveals white matter abnormalities from demyelination

- Adrenocortical insufficiency

4. Total disability and death within 2 years

Adrenomyeloneuropathy Signs and Symptoms

1. Males w/ normal development for first 20 - 40 years

2. First Symptoms: Leg weakness, bowel/bladder issues, & sex dysfunction

3. Second Set of Symptoms: Adrenocortical insufficiency (70%) and Behavior impairment (20%)

4. Can be lethal

Isolated Addison's Signs and Symptoms

1. Primary adrenocortical insufficiency

2. High ACTH -> Bronze skin, low corticosteroids & mineral corticoids

3. Wide range of onset (2y - adulthood)

4. Heterozygous Females (20%): Can develop adrenomyeloneuropathy

X-ALD Treatment

1. Preventative: Corticosteroid Replacement Therapy

- HSCT or BMT: Only children w/ cerebral form when MRI showcases leukodystrophy

- Lorenzo's Oil: High in Erucic Acid (normalizes VLCFA levels)

2. Symptomatic: Minimizing and prolonging life

Zellwegger Syndrome Spectrum Genes and Inheritance

12 PEX Genes & AR

Zellweger Syndrome Spectrum Diagnosis

Increased: VLCF, Pipecolic Acid, Bile Acid

Decreased: Plasmalogens

The 3 Phenotypes of Zellweger Syndrome Spectrum

1. Zellweger Syndrome (ZS)

2. Neonatal Adrenoleukodystrophy (NALD)

3. Infantile Refsum Disease (IRD)

Continuum between ZS-NALD-IRD

1. Newborn Period; Hyptonia, FTT, seizures, liver dysfunction, distinctive facies, stippled bone epiphyses

2. Older Children Period: Retinal dystrophy, SNHL, Liver Dysfunction, DD

Characteristic Facies of ZS-NALD-IRD

1. Flat middle face

2. Hypertelorism

3. Wide anterior Fontanelle

ZS (Most severe) Signs and Symptoms

1. Abnormal VLCFA + Large Fontanelles in Newborn

2. Hypotonia, Seizures, FTT, Liver Cysts, Mental Stagnation, Dysmorphic features, macroglossia, high forehead.

3. Death by 1 years old

NALD & IRD (Milder) Symptoms

1. AoO: Childhood or Early Adulthood

2. Slow Progressive DD, hypotonia, hearing loss, visual impairment, adrenocortical insufficiency, liver dysfunction

3. LESS dysmorphism and liver dysfunction

4. Can result in neurodegeneration -> Death

5. Non progressive, some can talk and walk

What is NALD & IRB often mistaken for?

Down Syndrome, Prader-Willi, Usher, & LSDs

Innate Immunity

First Line of Defense (Skin, saliva, and some cells)

Adaptive Immunity

Second Line of Defense (T cells and antibodies)

An increase in neutrophils would indicate...

Period of Infection

Immunodeficiency

Problems w/ IS mounting appropriate defense leading to severe and persistent infections (acquired is more common)

Autoimmune Disease

IS (Adaptive Immunity) attacks the body instead of protecting it.

Allergies

Hypersensitive disorders, IS reacts to harmless foreign substances (releases histamine -> Inflammation + Allergy Symptoms)

Autoinflammatory Disorders

IS (Innate Immunity) attacks the body it is meant to protect.

X-Linked Agammaglobulinemia (Bruton's) Gene

BTK

X-Linked Agammaglobulinemia (Bruton's) Lab Results

Absent B-cells (No B = Bruton's) & Decrease in all immunoglobulins

Agamma = No Antibodies

X-Linked Agammaglobulinemia (Bruton's) Signs and Symptoms

1. AoO: 3-6m

2. Recurrent bacterial infections

3. Conjunctivitis, Otitis Media, Sinopulmonary, Skin manifestations, Meningitis

X-Linked Agammaglobulinemia (Bruton's) Treatment

1. Replacement Immunoglobulins every 2-4wks

2. AVOID Live viral Vaccines

X-Linked Severe Combined Immune Deficiency Gene

IL2RG

SCID on NBS

Blood spot detects T-Cell Lymphopenia via TRECs

Low = Abnormal

X-Linked Severe Combined Immune Deficiency Typical Presentation & Treatment

Detectable on NBS

1. Presentation: Severe Recurrent infections within 3-6m of life, FTT,

2. Treatment: Gene Therapy

X-Linked Severe Combined Immune Deficiency Atypical Presentation & Treatment

NOT Detectable on NBS

1. Presentation: 1st year of life or later-- upper/lower respiratory infections w/ bronchiectasis, Omenn Syndrome, Autoimmunity & EBV lymphoproliferative

2. Treatment: Management based on degree of infections and complications

Wiskott-Aldrich Syndrome Gene & Inheritance

WAS (XL)

Wiskott-Aldrich Syndrome Lab Findings

Increased: IgA/E

Decreased: T Cells

Normal: B cells

Classic Wiskott-Aldrich Syndrome Symptoms and Presentations

Eczema-Thrombocytopenia-Immunodeficiency

Wiskott-Aldrich Syndrome Treatment

1. HCT is the only known curative treatment

2. Topical steroids for eczema and antibiotics for infections

STAT3-related Hyper IgE Syndrome (Job's) Gene & Inheritance

STAT-3 (AD)

STAT3-related Hyper IgE Syndrome (Job's) Clinical Presentation

1. Skin: Boil, Rash, Eczema

2. Immune: Increased IgE

3. Pulmonary: Pneumatocele, Bronchiectasis

4. Musculoskeletal: Scoliosis, pectus joint, hypermobility and teeth retention

5. Other: Facies, Chiari Malformations, Osteopenia, Arterial Tortuosity and Aneurysms

Familial Mediterranean Fever (FMF) Gene & Inheritance

MEFV (AR)

FMF Type 1

1. Recurrent short episodes of inflammation and Serositis

2. Variable Symptoms

3. Amyloidosis is present in most severe cases

FMF Type 2

Amyloidosis is the FIRST complication in an asymptomatic individual

FMF Presentation

1. Inflammation of Pericarditis, Ankle, Connective Tissue

2. Skin Manifestations