Lysosomal Storage Disease

rheumatology talk (30 September 2011) MPS

Mucopolysaccharadoses

·         Lysosomal storage diseases

o    Why bother?

§  Rare

§  Nothing you can do

o    Bother now because they can be cured!

Case 1

·         29 yrold repeatedly seen by rheumatologist and ortho for 15 yrs

·         Atypical legg-perthes diseases

·         Finger contractures

·         Elbow contractures

·         Avascular necrosis of pelvis 15/16

·         Thickening of mitral and aortic valves with slight regurge

·         Corneal clouding

Case 2

·         9 yrold boy

·         Pain in the hands

·         Medical history of

o    Birth normal

o    Development normal

o    Trigger fingers at 3 - surgical intervention

o    Post op indurations

·         Worsening contractures of finger joints

o    Cannot form fist

·         No mobility restriction of elbow and knees

·         Progressive Achilles tendon shortening at age 4-5

·         Foot drop with permanent foot deformity

·         Igm-RM negative

·         No ANA

·         No complement abnormalities

·         Arthrosonographhy -

o    No effusion

o    No evidence of acute inflammation

·         no other abnormal lab tests

·         no improvement with NSAIDs

·         visceral changes

o    corneal clouding

o    abdominal US

§  no hepatosplenomegaly

§  kidneys normal

o    echo

§  moderate mitral regurge

§  tricuspid insufficiency

·         family history

o    little brothers have slight clinical presentation of

§  clawing of hands

§  shortening of Achilles tendon

Diagnosis?

Lysosomal storage disease

·         13% of pediatric

·         19% of adult rheumatologists

Has even mentioned lysosomal storage disease

What is the right Dx test should be performed?

·         Only 20% of pediatric

·         No adult rheumatologist

Could answer.

Correct Dx-test is…

·         GAG - 24hr urine (glycosaminoglycans)

o    Determination of total GAG excretion

o    Chromatographic separation of GAGs

·         Determine enzyme activity in plasma, leukocytes, fibroblasts, or blood spots

What are mucoplysaccarigoses (MPS)?

·         Grp of more than 40 genetically inherited diseases known as lysosomal storage diseases (LSDs)

·         Eleven known lysosomal enzyme deficiencies comprise 7 different clinical MPS subtypes

·         Increased tissue storage of GAGs

·         Highly variable clinical presentation

·         Rare (collective MPS incidence in 1/25000 live births)

Pathogenesis

·         Lysosomes become full of undegraded GAGs

Phenotype of severe MPS

·         Broad nose

·         Flat nasal bridge

·         Prominent eyes

·         Enlarged nose and ears

Classification of MPS

·         Classified using eponyms, enzyme deficiency, and GAG involved.

MPS manifestations

·         Neurologic

·         CVS

·         Respi

·         Deafness

·         MSK

o    Dysostosis multiplex

o    Joint contractures

o    Hip dysplasia

o    Atlantoaxial instability

§  MPS 6

o    Vertebral deformity

§  MPS  1

o    Carpal tunnel $

o    Coxa valgra and genu valgum

o    Thickening and shortening of tendons

o    Growth retardations

o    Finger abnormalities

§  Claw hands

§  Thickening of metacarpal, and phalangeal bones

§  MPS 1

·         Vision

o    Glaucoma

o    Corneal clouding

§  Common and early sign

·         GI

o    Hepatomegaly

o    Inguinal hernia

§  Often fail and repeated surgery

·         Infections

o    Pneumonia

o    Otitis media

·         Dental

DD of rheumatic symptoms in MPS

·         Joint contractures

o    Hip dysplasia

o    Epiphysiolysis capitis femoria

o    Post traumatic

o    Osteochondrosis dissecans

o    Inflammatory arthrides

o    Dermatomyositis

o    OA

o    Lysosomal storage diseases (no inflammation)

·         Avascular hip necrosis

o    Legg-perthes disease

o    Corticosteroids

o    Alcoholism, metabolic

o    Vasculitides

o    Sickle cell diseseas

o    Lysosomal storage disease

Case 3

·         10yrold girl

·         Parasthesia of right hand at night and when riding her bicycle

·         History

o    Normal birth

o    Delay of motoric development

o    Bilateral tympanotomy and grommet drain tube done

·         Physical

o    Healthy appearing girl

o    Hoffman - tinnel sign and phalen test right hand positive

§  Carpal tunnel syndrome

·         Hoffmann-tinel sign

·         Phalen test

·         Atrophy of M. abductor policis

·         Can Dx using ultrasound

o    Above flexor tendons

o    Normal <10mm

o    Pathological > 13mm

DD of carpal tunnel syndrome in adults

·         Repetitive strain injury

·         Synovitis and tenosynovitis

o    RA

o    SpA

o    PMR

o    OA

o    Crystal-induced

·         Endocrine and metabolic

o    DM

o    Acromegaly

o    Myxedema

o    MPS

·         Tumor

·         Infections

o    OM

o    Tenosynovitis (mycobacteria)

·         Hormonal

·         Amyloidosis

DD of CTS is rare!

·         66% of children had Lysosomal storage disease

·         57% MPS

Diagnostic algorhythm for MPS

Cimaz. R et al Pediatric Rheumatology 2009, 7.18

What can be achieved with Enzyme-replacement therapy?

·         Decrease of liver spleen size

·         Increase in shoulder mobility

·         Decrease in sleep apnea frequency

·         Better quality of life

Take home message

·         Think of MPS in any patient with…

o    Contractures, tendon alterations without inflammation

o    CTS or hip dysplasia

o    Unexplained corneal clouding

Dx early as possible.