MPS and Peroxisomal Disorders Flashcards by Ileana Trujillo

MOI of MPS II/ Hunter syndrome

X-linked

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MPS that can present at birth

MPS VII/ Sly syndrome

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Dysostosis Multiplex

Growth restriction/ short stature

Joint Contractures

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MPS with normal intellect

Scheie (MPS IS), Hunter (MPS II), Morquio (MPS IV), Maroteaux-Larny (MPS VI)

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Hurler syndrome gene

IDUA

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Hurler syndrome clinical manifestations

Corneal clouding; dyostosis multiplex, organomegaly, heart disease, death in childhood

Short stature, thick tongue, persistent nasal discharge, stiff joints, claw hand, hydrocephalus

hearing loss and verbal language detortiation

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Scheie (MPS IS) gene

IDUA

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Clinical features of Scheie

Corneal clouding, stiff joints, normal intelligence, and life span

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Clinical features of Hurler-Scheie

intermediated between IH and IS

case example:
short statue, stiff joints, micrognathia, corneal clouding, umbilical hernia, hepatosplenomegaly, systolic murmur, normal intelligence

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Features often noted prior to 1y in Hurler syndrome

umbilical/inguinal hernia
frequent upper respiratory infections

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Progressive features often noted from one year onward in severe MP1 (Hurler)

coarse facial features & corneal clouding
dysostosis mulitiplex and organ involvement
DD; neurodegeneration

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Treatment options for Hurler

can increase survival and reduce some complications

Hematopoietic stem cell transplantation

Recombinant IV enzyme replacement therapy

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Treatment for Scheie

recombinant IV enzyme replacement therapy

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outcome w/o treatment of Scheie

milder but slowly progressive dysostosis multiplex
milder + progressive facial coarsening
cloudy cornea
hernia
heart valve

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MPS I DX

Elevated total GAG levels
Elevated Heparan and Dermatan Sulfate
Alpha-L Idurondiase Enzyme Activity
IDUA del/dup

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Buzz words for Hunter syndrome

x-linked
no corneal clouding
skin colored ivory with papule and nodules on shoulder blades

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gene for Hunter syndrome

IDS

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Hunter syndrome severe symptoms

dysostosis multiplex
organomegaly
no corneal clouding
ID
death before 15

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Hunter syndrome mild symptoms

normal intelligence
short stature
survival to adulthood+
no corneal clouding

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features often noted prior to 1yo in Hunter syndrome (MPS II)

umbilical/inguinal hernia
frequent upper respiratory infections

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Progressive features often noted 1yo onward in Hunter syndrome

coarse facial features w/o corneal clouding
dysostosis multiplex and organ involvement
developmental delay, stagnation and neurodegeneration by 6-8y
death by 10-20y

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Treatments for Hunter syndrome

Hematopoietic stem cell transplantation

recombinant IV enzyme replacement therapy

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Features noted by 10yo in mild Hunter syndrome

milder/ slowly progressive dysostosis multiplex
milder/ slowly progressive facial coarsening
organomegaly, hernia, heart valve disease

normal cognition
may have normal lifespan

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Treatment for Mild MPS II (Hunter mild)

recombinant IV enzyme replacement therapy

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MPS II DX

Elevated GAG levels elevated heparan and dermatan sulfates Iduronate Sulfatase Enzyme Activity IDS sequencing, del/dup, and southern blot

MPS IIIA (Sanfilippo Syndrome) clinical characteristics

profound mental deterioration hyperactivity relatively mild somatic manifestations milder forms exist

Sanfilippo genes

GNS, HGSNAT, NAGLU, SGSH

Typical natural history of Sanfilippo

mild to no orgnaomegaly little to no corneal clouding no coarsening of facial features no dysostosis multiplex death often by 20 due to cardiopulmonary effects

DX Sanfillippo

Elevated GAGs Need enzyme/ molecular testing to determine subtype

Treatments for Sanfillippo

none

Clinical features for MPS IVA (Morquio A)

Distinctive skeletal abnormalities, corneal clouding, odontoid hypoplasia, milder forms exist, normal intelligence

MPS IV (Morquio) Skeletal findings

short stature Ulnar deviation of the wrists shortened forearms pectus carinatum genu valgum (knock knees) LIGAMENTOUS LAXITY (unusal for MPS)

Features noted by 1y in Morquio syndrome

Kyphoscoliosis, pectus carniatum, knock-knees (genu valgum)

Non-skeletal progressive features of Morquio

Corneal clouding, valvular heart disease, mild hepatomegaly, hearing impairment, sleep apnea, severe respiratory insufficiency little to no cognitive impairment, minimal facial coarsening

Treatments for MPS IV (Morquio)

recombinant IV enzyme replacement therapy orthopedic and other symptomatic surgical procedures

MPS IV (Morquio) dx

GAG levels TYPE A Keratin and Chondroitin 6-Sulfate TYPE B Keratin N-acetylgalactosamine 6 Sulfatase Enzyme Activity GALNS molecular analysis (sequencing, del/dup)

MPS IV (Morquio) gene

GALNS

MPS VI- Maroteaux - Lamy syndrome clinical features

dysostosis multiplex, corneal clouding, normal intelligence, survival to teens in severe form

Typical natural history of MPS VI- Maroteaux - Lamy syndrome

decelerated growth after 1st year progressive facial coarsening, corneal clouding, cardiorespiratory disease, organomegaly, dysostosis multiplex, normal intelligence

DX of MPS VI- Maroteaux - Lamy syndrome

elevated urine GAGs enzyme. molecular testing for ARSB gene

gene for MPS VI- Maroteaux - Lamy syndrome

ARSB

Treatment for MPS VI- Maroteaux - Lamy syndrome

ERT: Naglazyme

MPS VII (Sly syndrome) Clinical features

dysostosis multiplex, hepatosplenomegaly, wide spectrum of severity coarse features neurodegeneration corneal clouding death by 20s includes fetal and neonatal form (often fetal demise)

Important reaction peroxisomes catalyze

very long chain fatty acid beta oxidation

X-Linked Adrenoleukodystrophy (X-ALD) phenotype

childhood leukodystrophy, adrenomyelonueropathy, and Addison's disease

gene in X-ALD

ABCD1

Initial symptoms in X-ALD (childhood cerebral leukodystrophy)

Behavior and attention changes school difficulty, incoordination, handwriting worsens visual loss, comprehension difficulty death often by 2yo

Brain MRI findings in X-ALD (childhood cerebral leukodystrophy)

white matter abnormalities from demyelination

Features of X-ALD (Adrenomyelonueropathy)

males will have normal health for 20-40 years then develop leg weakness, bowel/bladder and sexual dysfunction

Features of X-ALD Addison's disease

primary adrenocortical insufficiency high ACTH = bronze skin, low corticosteroids which leads to weakness, vomitting, coma

DX X-ALD

Plasma VLCFA levels ABCD1 Gene analysis Brain MRI Adrenal function tests

Treatments for X-ALD

Corticosteroid replacement therapy Hematopoietic stem cell transplantation or bone marrow transplant Lorenzo's Oil

Zellewger syndrome also referred to as

cerebrohepatorenal

3 major phenotypes for cerebrohepatorenal

Zellweger syndrome Neonatal adrenoluekodystrophy Infantile refuse disease

cerebrohepatorenal genes

12 PEX genes

Features of Zellweger syndrome (most severe)

neonatal hypotonia, seizure, FTT, liver cysts and dysfunction, chondrodysplasia punctuata, DD death usually by 1y

Dysmorphic features associated with ZSS

flat mid face, high forehead, wide anterior fontanelle, upslanting palpebral fissures, hypotelorism, broad nasal bridge, anteverted nares, micrognathia

Differentials for ZSS

Down syndrome, Prader Willi, Usher syndrome

DX ZSS

biochemical assays showing multiple peroxisomal abnormalities PEX gene analysis

Treating ZSS

Suportive care only