Pathophysiology of Mucopolysaccharidosis - Brains for …brains4brain.eu/wp-content/uploads/2015/10/pathophysiology-MPS... · Pathophysiology of Mucopolysaccharidosis ... understanding

Pathophysiology of Mucopolysaccharidosis

Dr. Christina Lampe, MD

The Center for Rare Diseases, Clinics for Pediatric and Adolescent Medicine

Helios Dr. Horst Schmidt Kliniken, Wiesbaden, Germany

Inborn Errors of Metabolism today

- more than 500 diseases (~10 % of the known genetic diseases)

- all areas of metabolism involved

- vast majority are recessive conditions

- individually rare or very rare

- overall frequency around 1:800 (similar to Down syndrome)

LSDs: 1: 5.000 live births MPS: 1: 25.000 live births

5000 genetic diseases

500 metabolic disorders

50 LSD

7 MPS

understanding of pathophysiology and early diagnosis leading to successful therapy for several conditions

The Lysosomal Diseases (LSD)

GAUCHER DIS. 14%

GM1 GANGLIOSIDOSIS 2%

KRABBE DIS. 5%

MPSVI

MPSI

A-MANNOSIDOSIS

METACHROMATIC LEUKOD. 8%

MPSIVA

MPSIIIB

MPSIIIA

MPSII

MPSIII D

MPSIII C

NIEMANN PICK A-B 3%

MULTIPLE SULPH. DEF.

MUCOLIPIDOSIS I-II 2%

MPSVII

NIEMANN PICK C 4%

POMPE 5%

SANDHOFF DIS. 2%

SIALIC ACID DIS.

TAY SACHS DIS. 4%

SIALIDOSIS

WOLMAN DIS.

CYSTINOSIS 4%

FABRY DIS. 7%

ASPARTYLGLUCOSAMINURIA

MPS

34%

Mucopolysaccharidosis

Mucolipidosis

Sphingolipidosis

Oligosaccharidosis

Neuronale Ceroid Lipofuszinois

others

Initial Description of MPS

Charles Hunter, 1917:“A Rare Disease in Two Brothers”

brothers: 10 and 8 yearshearing lossdwarfismmacrocephalycardiomegalyumbilical herniajoint contractures skeletal dysplasia

death at the age of 11 and 16 years

Description of the MPS Types...

M. Hunter - MPS II (1917)

M. Hurler - MPS I (1919)

M. Morquio - MPS IV (1929)

M. Sanfilippo - MPS III (1963)

M. Maroteaux-Lamy - MPS IV (1963)

M. Sly - MPS VII (1969)

M. Scheie - MPS I (MPS V) (1968)

M. Natowicz - MPS IX (1996)

The Lysosome

• ... cell organelles containing digestive enzymes

• ... surrounded by a membrane composed of phospholipids that separate the inside of the

lysosomes from the membrane'sexternal environment

• ... range in size from 0.1 to 1.2 micrometers

• ... like a floating garbage bag that contains enzymescapable of digesting molecules in MPS GAGs

• ... the garbage disposals of the cell

• ... responsible for recyclig or excretion of the disposals(damaged or obsolete cell parts as well as invaderssuch as bacteria)

Lysosomes are...

Deposit Degradation and Recycling

Normal Degradation

Missing Enzyme Accumulation

Enzyme

Degradation

Pathophysiology

Dysfunction of at least 1 lysosomal enzyme

accumulation of glycosaminoglycans

cell dysfunction / cell death

multiorgan-involvement

Proposed Model of Cell Death in LSDs

Accumulation of toxic proteins

Accumulation of dysfunctional mitochondria

Cellular distress

Phagocytosis by Microglia

Chronicinflammation

Cytokine release(LATE STAGE)

Enzyme deficiency

Lysosomalstorage of substrates

Impairmentof autophagy

CELL DEATHSettembre et al. PNAS 2007

Bone and Joint Disease in MPS

Opoka-Winiarska et al. Osteoarthritis Cartilage. 2013.

DS = dermatan sulfate, HS = heparan sulfate, CS = chondroitin sulfate, KS = keratan sulfate, HA= Hyaluronan

Classification of MPSMPS Type

Eponym(s) Enzyme Deficiency GAG Affected

MPS I

Hurler

Hurler-Scheie

Scheie

a-L-iduronidase

DS,HS

DS,HS

DS,HS

MPS IIHunter type AHunter type B

iduronate sulfatase DS,HS

MPS III

Sanfilippo A

Sanfilippo B

Sanfilippo C

Sanfilippo D

heparan N-sulfatase

a-N-acetylglucosaminidase

acetyl CoA:a-glucosaminideacetyltransferase

N-acetylglucosamine-6-sulfatase

HS

HS

HS

HS

MPS IVMorquio A

Morquio B

N-acetyl-galactosamine-6-sulfatase

b-galactosidaseKS,CSKS

MPS VIMaroteaux-

Lamy

N-acetylgalactosamine-4-sulfatase

(arylsulfatase B or ASB)DS

MPS VII Sly b-glucuronidase DS,HS,CS

MPS IXHyaluronidase Def.

Hyaluronoglucosaminindase-1 HA

11 known enzyme deficiencies

Storage of GAGs

7 main MPS types

Introduction to GAGs

Function of GAGs...

Types of GAGs...

Due to the missing enzyme- missing degradation of different GAGs- differnet type of MPS

Where the GAGs are...

DS = dermatan sulfate, HS = heparan sulfate, CS = chondroitin sulfate, KS = keratan sulfate, HA= Hyaluronan

Classification of MPSMPS Type

Eponym(s) Enzyme Deficiency GAG Affected

MPS I

Hurler

Hurler-Scheie

Scheie

a-L-iduronidase

DS,HS

DS,HS

DS,HS

MPS IIHunter type AHunter type B

iduronate sulfatase DS,HS

MPS III

Sanfilippo A

Sanfilippo B

Sanfilippo C

Sanfilippo D

heparan N-sulfatase

a-N-acetylglucosaminidase

acetyl CoA:a-glucosaminideacetyltransferase

N-acetylglucosamine-6-sulfatase

HS

HS

HS

HS

MPS IVMorquio A

Morquio B

N-acetyl-galactosamine-6-sulfatase

b-galactosidaseKS,CSKS

MPS VIMaroteaux-

Lamy

N-acetylgalactosamine-4-sulfatase

(arylsulfatase B or ASB)DS

MPS VII Sly b-glucuronidase DS,HS,CS

MPS IXHyaluronidase Def.

Hyaluronoglucosaminindase-1 HA

11 known enzyme deficiencies

Storage of GAGs

7 main MPS types

MPS II... a typical case Recurrent infections of the upper airways Diarrhoea Hepatosplenomegaly General stiffness Inguinal hernia

MPS II...First Symptoms

Wraith JE, et al. Genet Med. 2008; 10(7):508-16.

Wraith JE, Clarke JTR. The Mucopolysaccharides. In: Blau N, et al, eds. Physician’s Guide to the Treatment and Follow-up of Metabolic Diseases. Heidelburg, Germany: Springer. 2006:195–203.

Cardiac:CardiomyopathyDysplastic valvesHeart murmur

Respiratory:Upper airway obstruction

Obstructive sleep apnea/snoring Restrictive lung disease

Frequent infectionsRestrictive airway disease

Rhinorrhoea

Skeletal:Degenerative hip dysplasia

Kyphosis orKyphoscoliosis

GibbusJoint contractures

Genu valgum deformities

Gastrointestinal: HepatosplenomegalyUmbilical & inguinal herniaSwallowing problemsDiarrhoeaDrooling

Peripheral nervous system: Peripheral nerve entrapment (eg, carpal tunnel syndrome)

Eyes:GlaucomaRetinal dystrophyCorneal clouding

Dental:CariesDental abscessescysts

Ears:Recurrent otitis mediaHearing loss

CNS:Hydrocephalus

atlanto-axial instabilityCervical cord compression

MyelopathySeizures

(Severe behaviour problems)Sleep disturbance

Mental retardationDevelopmental delay

Appearance:Coarse faceShort stature, short neck

Wraith JE, Clarke JTR. The Mucopolysaccharides. In: Blau N, et al, eds. Physician’s Guide to the Treatment and Follow-up of Metabolic Diseases. Heidelburg, Germany: Springer. 2006:195–203.

Disease Progression4 yrs 24 yrs 31 yrs 54 yrs

6 months 9 years5 years 30 years

Appearance of children with MPS is normal at birth

MPS I

MPS II

Disease Progression

M. Hurler M. ScheieM. Hurler-Scheie

Spectrum of Disease Severity MPS I (Scheie, H-S, Hurler)

severe attenuated

• With and without CNS involvement• ERT available

• <2 yrs of age: HSCT or BMT

Spectrum of Disease Severity MPS II (Hunter)

severe attenuated

neuronopathic non-neuronopathic• X-linked• No corneal clouding

• With and without CNS involvement• ERT available

Spectrum of Disease Severity MPS VI (Maroteaux-Lamy)

severe attenuated

fast progressive slowly progressive• No mental retardation

• ERT available

Spectrum of Disease Severity MPS IV (Morquio)

severe attenuated

non classicclassic • Mainly musculoskeletal disease• Hypermobility of joints• Atlanto-axial instability

• ERT available

MPS III (Sanfillippo A-D)

MPS VII (Sly)

• Mainly progressive mental retardation• Neurological problems (seizures)

• Behavioural problems (hyperactivity)• Clinical trial for intrathecal ERT

• Typical: hydrops fetalis• Mental retardation + clinical symptoms

• Clinical trial for ERT

Mucopolysaccharidoses are...

genetic, heterogenous, chronic, progressive, multisystemic, and

life threatening

...but for some MPSs treatment is available !!!

Different MPS - Types

MPS IV:

mainly musculo-skeletal

(hypermobility of joints)

MPS I, II, VI und VII:

Clinical symptoms are very similar

MPS III:

Mainly mental retardation

MPS I MPS II MPS VI

MPS Differential Diagnosis

Mucolipidosis

MSD

Mannosidosis

Diagnosis of MPS Can Be Challenging

Before confirmation with enzyme or genetic testing…

1. Signs and symptoms often not specific to MPS

Not all clinical features will be present or manifest themselves in the same

way in each patient

2. Diagnosis, and therefore treatment, may be delayed –

particularly for those without a known familial history of MPS

3. Delayed treatment leads to irreversible disease

manifestations

DIAGNOSIS

1. Preliminary screening:

Urine testing of GAG excretion (Cave: can be normal in adult and/or attenuated patients!)

Confirmation of Diagnosis:

2. Biochemical analysis: GOLD STANDARD

Enzyme activity testing in leukocytes,

fibroblasts, or plasma (alternatively dry blood spot testing)

3. Genetic analysis:

Mandatory in X-linked disorder! (MPS II)

4.Prenatal diagnostic possible

Therapies

1. Bone Marrow Transplantation / (HSCT) HematopoeticStem Cell Transplantation MPS I

1. Enzyme Replacement Therapy (ERT) MPS I, II, IV, VI

2. Symptom based Therapy (supportive) all MPSs

3. Biotech Based Therapies (in development)

The best therapy is the combination of ERT, regular followups to detect life threatening and quality of life reducingcomplications and an adequate supportive therapy!!!!

Let‘s make a Quizz....

• 18 month old girl height (10.P), weight (3.P)• Consanguineous Turkish parents• Healthy older and healthy younger sister• Normal height (40.P) and weight (60.P) at birth18 months: • No free walking, only standing with support• No speaking, but understanding• Umbilical hernia• thorakolumbar kyphosis, pectus carinatum, hip

dysplasia, craniosynostosis, turricephalus• Muscles hypoton, reflexes normal• Mital insuff I°, tricuspid insuff II°• Snoring, adenoidectomy• No joint stiffness

Quiz Aishe 18 months:

What type of MPS is it????

• 18 month old girl height (10.P), weight (3.P)• Consanguineous Turkish parents• Healthy older and healthy younger sister• Normal height (40.P) and weight (60.P) at birth

18 months: • No free walking, only standing with support• No speaking, but understanding• Umbilical hernia• thorakolumar kyphosis, pectus carinatum, hip


Quizz Aishe 18 Months :

MPS I

MPS II

MPS III

MPS IVMPS VI

MPS VII

MPS IX

• 18 month old girl height (10.P), weight (3.P)• Consanguineous Turkish parents• Healthy older and healthy younger sister• Normal height (40.P) and weight (60.P) at birth

18 months: • No free walking, only standing with support• No speaking, but understanding• Umbilical hernia• thorakolumar kyphosis, pectus carinatum, hip



MPS I

MPS II

MPS III

MPS IVMPS VI

(MPS VII)

MPS IX

´Urinary GAGs: DermatansulfateMPS VI: DSMPS I: DS, HSMPS VII: DS, HS, CS

Enzyme testing in blood: Arysulfatase B deficiencyMPS I: Iduronidase normalMPS VII: β-Glucuronidase normal

Genetics: homocygote ARSB gene


MPS I

MPS II

MPS III

MPS IVMPS VI

(MPS VII)

MPS IX

Diagnostics:

Why is it important to exclude MPS I ?BMT is 1st treatment option up to the age of 2 years in MPS I

Start of ERT at the age of 18 months

Mucopolysaccharidosis are…• rare (1:25.000)

• multisystemic, progressive and extremely heterogeneous

• 70% CNS involvement

• inherited: autosomal-rezessive, (Cave: MPS II x-chromosomal)

• one typial symptom: stiffness and contratures of joints (Cave: MPS IV with

hypermobility)

• typical is a corneal clouding (not in MPS II)

• therapies are available for MPS I, II, IV and VI (trials for III and VII)

ALL PATIENTS NEED SUPPORTIVE THERAPY

Quality of Life !!

Thank you very much for yourattention!!!



MPS I (Scheie, Hurler-Scheie, Hurler Syndrome)

Hurler-Scheie, Hurler Syndrome possible !!



MPS II (Hunter Syndrome)

Hunter syndrome is very unlikely

MPS II is x-linked!



MPS III (Sanfilippo Syndrome)

MPS III (Sanfilippo Syndrome) is unlikely

Coarse face

MPS III hasless clinicalsigns



MPS IV (Morquio Syndrome)

MPS IV (Morquio Syndrome) is unlikely

Coarse face



MPS VI (Maroteaux-Lamy)

MPS VI (Maroteaux-Lamy) is possible!!



MPS VII (Sly Syndrome)

MPS VII (Sly Syndrome) is possible



MPS IX

MPS XI is unlikely

Coarse face

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Pathophysiology of Mucopolysaccharidosis - Brains for …brains4brain.eu/wp-content/uploads/2015/10/pathophysiology-MPS... · Pathophysiology of Mucopolysaccharidosis ... understanding