Mucopolysaccharidoses and Peroxisomal Disorders - Biochem Genetics

Mucopolysaccharidoses (MPS): Metabolic Pathways

• Group of diseases caused by mutation in enzymes that are necessary for the breakdown of

  • Heparan Sulfate - Abundant in Brain

  • Keratin Sulfate - Abundant in Skelton

  • Dermatan Sulfate - Abundant in Skeleton

Mucopolysaccharidoses (MPS): Overview

7 Types of MPS

• All are autosomal recessive:

  • Exception MPSII - Hunter syndrome → X-linked Recessive

• All are progressive and Asymptomatic at Birth

  • Exception MPS VII - Sly Syndrome → can present at birth

• All Exhibit Abnormally High Urine MPS (GAG) levels

  • Except GAGs may be only intermittently high in some patients

MPS: Major clinical feaures

“Coarse” Facial Features

• Macrocephaly

• Flat Nasal Bridge

• Large Lips

• Broad Mouth

• Puffiness around eyes

• Coarse “Thatch-Like” Hair

Dysostosis Multiplex: multiple bone deformities

• growth retardation

• Spinal gibus deformity

• “Claw” hand deformity

Mucopolysaccharidoses (MPS): Organ Involvement

Gastroenterologic

• Hepatosplenomegaly: enlarged liver and spleen, but no dysfunction

• Bowels: Umbilical and inguinal hernias

Cardiopulmonary (collection in muscle)

• Cardiomyopathy

• Valvular Heart disease

• HTN

• Coronary Artery disease

Thick Tongue/Airways

• Obstructive airway deiase

• Sever sleep apnea

Mucopolysaccharidoses (MPS): ENT, Hearing, Vision

• Chronic upper respiratory Infections: sometimes first presentation, but nonspecific

• Hearing Loss: conductive and sensorineural

• Ocular Manifestations

  • ***Corneal clouding***: GAG deposition in Cornea

  • Retinal degeneration

  • Glaucoma

  • Optic Nerve Disease

Mucopolysaccharidoses (MPS) Neurological Sequalae

• Neurodegeneration

  • developmental delays and stagnation

  • progressive mental deterioration

• Communicating Hydrocephalus

  • contributes to macrocephaly: shunting alleviates symptoms

• Peripheral nervous System

  • Nerve compression: carpal tunnel, Spinal nerve compression

Mucopolysaccharidoses (MPS I): Overview

• Deficiency of the a-L-Iduronidase enzyme → IDUA Gene

• Spectrum of severity

  • Hurler: Severe affect → neurological deterioration

  • Hurler-Scheie: Moderately affect psychically , but no neurological deterioration (normal intelligence)

  • Scheie: Attenuated affect → neurological deterioration not present

MSP IH (Hurler Disease) classic progression

• Diagnosis made at 15 months of age, at which time he had developmental delay, hepatomegaly, and skeletal dysostosis

• In the photo, at age 4, the patient had short stature, thick tongue, persistent nasal discharge, stiff joints, claw hand & hydrocephalus

• Verbal language skills deteriorated to four or five words. The patient had severe hearing loss and wore hearing aids.

MPS 1 Severe: Outcome without treatment

Features often noted before 1 Year of age → non-specific findings

• Umbilical/Inguinal Hernia

• Frequent Upper Respiratory Infections

Progressive features often noted from 1yo onward

• Coarse facial features and corneal clouding

• Dysostosis Multiplex and Organ involvement

• Developmental delay, Stagnation, Neurodegeneration

Death often by 10 years of age

MPS 1 Severe: Treatment

• Hematopoietic Stem Cell Transplant

  • If started before 2 years of age → increases survival, but does not present neuro, cardiac, and skeletal features

• Recombinant IV Enzyme Replacement Therapy

  • helps NON-NEUROLOGIC complications → but cannot cross the BLOOD-BRAIN barrier (like most lysosomal storage disorders)

MPS 1 Attenuated: Outcome without treatment

• Features usually evident by 3-10 years of age

  • Milder but slow progressive Dysostosis Multiplex, Facial Coarsening

  • Cloudy cornea, Hernia, Heart Valve

  • Normal cognitive outcome to mild learning disability

  • Normal lifespan to death in 2nd/3rd decades

MPS 1 Attenuated: Treatment

• Hematopoietic Stem Cell Transplantation:

  • rarely done because enzyme replacement is so much more effective

• Recombinant Enzyme Replacement Therapy

  • Aldurazyme reduces non-neurologic complications and is most effective for attenuated MPS I

MPS I: Diagnosis

Urine GAG Excretion

• Elevated total GAG levels

• Elevated Heparan and Dermatan Sulfate (also seen in MPS II)

Confirmation: Alpha-L-Iduronidase Enzyme Activity

• WBCs, Plasma, Fibroblasts, Amnio, CVS

IDUA Gene molecular analysis

NBS: only done in Missouri

MPS II (Hunters): Overview

• Iduronate Sulfatase deficiency → mutations in the IDS gene

  • Dermatan and Heparan Sulfate buildup

• ONLY X-Linked

• A Severe and Mild form:

  • Dystosis multiplex

  • Organomegaly

  • Mental retardation → death before 15yo

  • NO CORNEAL CLOUDING

MSP II Severe (Hunter syndrome): Calssic progression

• Diagnosis suspected at 1 year of age because of facial appearance, but urine mucopolysaccharide screen was negative at that time.

• Enzymatic diagnosis then pursued at age 22 months after a family history of a maternal uncle with mental retardation and coarse facial features became known to the parents.

• In the photo, at 6 years of age, the patient shows hepatomegaly, umbilical hernia, joint stiffness, claw-hand, severe hearing loss and severe mental retardation.  There was no corneal clouding.

MPS II Severe: Outcome without treatment

• Features often noted before 1 year of Age

  • Umbilical hernia

  • Frequent upper respiratory infection

• Progressive Features often noted form 1 year of Age onward

  • Coarse facial features WITHOUT CORNEAL CLOUDING

  • Dysostosis Multiplex and Organ Involvement

  • Developmental delay, stagnation, neurodegeneration by 6-8 yo

• Death often by 10-20 yo

MPS II Severe: Treatment

• Hematopoietic Stem Cell Transplantation

  • better if done before 2 yo, but outcome unclear

• Recombinant Enzyme Replacement

  • Elaprase reduced non-neurologic complications (does not cross blood/brain barrier)

MPS II Mild/Attenuated: Outcome without Treatment

• Features usually evident by 10 years of Age

  • Milder but slowly progressive: Facial coarsening, Dysostosis Multiplex

  • Organomegaly, Hernia, Heart valve disease

• Normal cognitive outcome / minimal learning disability

• Range from Normal lifespan to death in 2nd/3rd decades

MPS II Mild/Attenuated: Treatment

• Hematopoietic Stem Cell Transplantation: rarely used b/c enzyme replacement better

• Recombinant Enzyme replacement therapy:

  • reduces non-neurologic complications → most effective for Mild MPS II

MPS II Severe: Diagnosis

Urine GAG Excretion

• Elevated total GAG levels

• Elevated Heparan and Dermatan Sulfate (like MPS I)

Iduronate Sulfatase Enzyme Activity (not useful for carrier screening)

• WBC, Plasma, Amnio, CVS

IDS Gene molecular Analysis

MPS III (SanFallipo Syndrome): Overview

• 4 types → 4 Enzymes → 4 Genes

  • All involved exclusively in Heparan Sulfate

• Main clinical Manifestations are NEUROLOGIC

  • NO COARSENING OF FACIAL FEATURES

  • NO EFFECTIVE TREATMENT (enzyme replacement cannot cross the blood brain barrier)

• Most Common MPS, but VASTLY underdiagnosed

MPS IIIA: Classic Presentation

• The patient had normal developmental skills until about 5 years of age, at which time she was toilet trained, was able to feed and dress herself, and spoke in complete sentences. She was learning to read and write.

• In the photo, at age 7, she had a relatively normal physical appearance with mild hepatomegaly, but now had significant loss of cognitive function.

• At age 11, she was able to feed herself but had lost all verbal skills.

MPS III Sanfilippo: Typical Natural History

Mainly REGRESSIVE

• Early childhood behavior changes (ADHD, aggression)

• Cognitive plateau → Progressive Neurodegeneration

  • ****Little to no Organomegaly, Corneal Clouding ****

• Death often before 20 yo (Cardiopulmonary Effects)

MPS III Sanfilippo Type A-D: Diagnosis

Suspicious if there is REGRESSIVE AUTISM

• Elevated Urine GAGs → HEPARAN SULFATE ONLY

• Need Enzyme/Molecular Analysis to confirm and distinguish Types !-D

MPS IVA (Morquio)

• 2 types of enzymes → 2 types of genes → 2 forms of disease

  • A: more common → Kertan sulfate + Chondroitin 6-Sulfate

  • B: Kertan sulfate only

• Normal Intelligence → No NEUROLGIC EFFECTS

• But very specific Dystosisis and typical Cloudy Cornea

MPS IVA: Skeletal Findings

• Ulnar Deviations of the Wrists

• Shortened forearms

• Pectus Carinatum

• Genu Valgum (Knock-Knees)

MPS IVA (Morquio): Outcome without treatment

Severe form: often leads to death by 30-40yo

• Features often noted between 1-3 yo: skeletal findings

• Progressive features

  • Skeletal short stature, skeletal deformation, spinal stenosis,

  • Non-Skeletal

    • Cornel Clouding, Valvular heart Disease, Mil Hepatomegaly, Hearing impairment, Sleep Apnea, Severe Respiratory Insufficiency

Mild-Form": Mlder, later onset

• ***NO INTELLATUAL DIABLITY WITH ANY FORM OF DIEASE***

MPS IVA (Morquio): Treatment

• Recombinant Enzyme Replacement Therapy: biological and functional improvements → particularly helpful for this condition

• Surgical Procedures

MPS IVA (Morquio): Diagnosis

Urine GAG Excretion

• Elevated Total GAG levels

• Elevated Keratan and Chondroitin 6-Sulfate -

  • ONLY Keratan Sulfate elevate in MPS IVB (B-Galactosidase Gene)

N-Acetylgalactosamine 6-Sulfatase Enzyme Activity

• WBCs, Fibroblasts, Amnio, CVS

• B-Galactosidase measured as well

GALNS Gene molecular analysis

MPS VI (Maroteaux-Lamy): Overview

• Arylsulfatase B deficiency → mutations in ARSB gene

  • Dermatan Sulfate builds up

• Coarsening of features, Skeletal Dysostosis

  • Progressive skeletal weakness

• BUT NO NEUROLGIC AFFECTS → can live normal length lives

****LEAST COMMON MPS***

MPS IV (Marateaux-Lamy): Typical natural history

• Decelerated growth after 1st year → short stature/dwarfism

• Progressive

  • facial coarsening,

  • corneal clouding

  • Cardio-Respiratory disease

  • Organomegaly

  • Dysostosis Multiplex

  • NORMAL INTELLGIENCE

• Death in Teens → SEVERE CASES, longer surival in midl cases

MPS IV (Marateaux-Lamy): Diagnsois

• Elevated GAG → Dermatan Sulfatae

• Enzyme/Molecular Analysis for confirmation

MPS IV (Marateaux-Lamy): Treatment

• IV Recombinant Enzyme Replacement Therapy

  • Biochemical and phenotypic improvement —> VERY EFFECTIVE

MPS VII (Sly Syndrome): Overview

• Rarest MPS:

  • Often starts In-Utero leading to Fetal Demise

  • Evident at Birth Except in Mildest Cases

• Etiology: B-Glucuronidase (GUSB) gene mutation

  • Dermatan, Heparan and Chondroitin 6-Sulfate Accumulate

• Features

  • Dysostosis Multiplex, Organomegaly, Coarse Features, Neurodegeneration, Corneal Clouding

  • Death by 20s even in mild cases

• Treatment

  • Supportive care and Clinical Trials (ERT in Phase III)

Peroxisome Disorders

• Ubiquitous single membrane organelles catalyzing a variety of reactions

  Two Types

  1. Peroxisome biogenesis disorders: faulty construction of peroxisomes → all reaction are faulty (PEX Disorders)

  2. Sing gene enzyme disorder → specific reactions are affected within the peroxisome (only one important: X-linked adrenoleukodystrophy)

X-Linked Adreno Leukodystrophy

Mutations in the ABCD1 Gene → Produces ATP transport protein that transport the very long chain fatty acids into the peroxisomes so they can be degraded via beta oxidation

• Found only on x chromosome → only boys affect: X-Linked Recessive

• Accumulation of very long fatty chains in the body: especially the nervous system + the adrenal gland

3 Major phenotypes

• Childhood leukodystrophy

• Adreno myeloneuropathy

• Addison’s Disease

Untreated X-ALD: Childhood Cereberal Leukodystrophy

The wrost of the 3 pehnotypes

• Males with intial normal devleoment for 4-10 years

• Frist symptoms

  • Behaviour and attention

  • School difficualt, handrwrting issues

  • Visual loss, comerphension difful

• Follwed by rapid neurlogic derion

  • White matter abnormalties

  • adrenocorticol insufficney

• Total disability and death within 2 Year

Untreated X-ALD: Adrenomyeloneuropayh

• Males iwth intially nromal health for 20-40 years

• Then develop

  • leg weakenss, bowle/bladder, and sexual dysfunction

• Followed by adrenocotical insufficney in 70% and progressive cogntive and behavioural impairment in 20% (Can be lethal)

• BRONZING OF THE SKIN

Untreated X-ALD: Isoalted Addisons

10 % of patients

• Primarily Adrenocortical Insufficiency

  • High ACTH → Bronze Skin, Low corticosteroids and Mineralocorticoids → Weakness, Vomiting, Coma

• Wide Range of Age at Onset (2yo-Adult)

  • Late-Onset Mild Myeloneuropathy may also develop

X-Ald: Diagnosis

• Diagnostic Tests: Plasma Very Long Chain Fatty Acid (VLCFA) Levels

  • Abnormal in 99% of affected males, but not as well for affect females or femal carriers

• Genetic Testing: ABCD1 gene mutation

• Prenatal Tests: Molecular, VLCFA levels on Amnio/CVS

• Other routine test

  • Brain MRI

  • Adrenal function testing