November 11, 2010

Undernutrition

61/2 m/o ex 34 WGA twins with:FTTSevere Global Developmental DelayHypertoniaOculomotor findingsRefluxIntermittent DiarrheaHSMh/o neutropenia and thrombocytopenia

Gaucher Disease

Gaucher DiseaseInborn error of metabolism

Affects recycling of cellular glycolipidsDefect in b-glucocerebrosidase

Accumulation of glucocerebroside in lysosomesMost common lysosomal storage diseaseIncidence 1/75,000 worldwideAutosomal recessive

Clinical PresentationNeurologic dysfunction

Developmental DelayOculomotor dysfunction

Pathologic fracturesHepatosplenomegalyAnemiaNeutropeniaThrombocytopenia

Cardiac and renal symptomstypically absent

Gaucher DiseaseAshkenazi Jews

7% heterozygousFrequency of disease 1:1000

Also common among Swedish

DiagnosisGaucher cells in bone marrow

False negativesGold Standard:

Enzyme assay (b-glucocerebrosidase)Molecular DNA analysis

Carrier testing recommended for close relatives

Clinical featuresThree Clinical Types

Type 1Adult onsetMost commonMost closely tied with Ashkenazi JewsNO CNS findingsVaries from mild to severeEnzyme replacement: near-normal life

expectancy

Type 2Most severe formDeath by age 2Treatment usually not indicatedEarly, severe CNS involvement

Brainstem abnormalities

Type 3Juvenile onset“chronic/subacute form”Most common in SwedishLater onset:

Incoordination, mental deterioration, seizuresSlowly progressive

Becomes severe in later childhood

TreatmentEnzyme replacement therapy

Glucocerebrosidase IVSome improvement within 6 monthsNot effective for CNS symptoms

ResearchOral therapyGene therapy

Storage Diseases

Lysosomal Storage DiseasesMutation in gene coding for production of

lysosomal enzymesAccumulation of substrateImpairment of cell function

>40 different LSD

Start in late infancy or early childhood with slowly progressive symptoms

Lysosomal Storage Diseases

Mucopolysaccharides

Hurler’sHunter’s

SanfilippoMorquio

Glycolipids

GaucherFabry

KrabbeTay Sachs

Lysosomal Storage DiseasesMucopolysaccharidoses

Cannot break down glycosaminoglycans

Clinical effects Coarsening of facial features Skeletal abnormailities

Dysostosis multiplex Joint structure and function Organomegaly +/- Cognitive abilities +/- Corneal clouding

Treatment: enzyme replacement or BMT

Disease Description Inheritance

Hurler’s (MPS I) + corneal clouding+ developmental regression

AR

Hunter’s (MPS II) no corneal clouding+ developmental regression

X-linked

Sanfilippo (MPS III) no corneal clouding+ developmental regression

AR

Morquiro (MPS IV) + corneal clouding* Normal intelligence

AR

Lysosomal Storage DiseasesSphingolipidoses

Developmental regressionOrganomegalyCherry red maculaBone painShort

Disease Description

Gaucher HSM, bone pain, easy bruisibility

Fabry Orange-colored skin lesions, opacities of the eye, vascular disease (heart, brain, kidney)

Krabbe Demyelination and progressive neuro deterioration

Tay Sachs No HSM, cherry red spot, neuro deterioration

Niemann-Pick HSM, cherry red spot, peripheral neuropathy

Glycogen Storage DiseaseVon Gierke Disease (GSD I)

Liver can’t produce glucoseFeatures

Hypoglycemia with prolonged fasting Organomegaly Cherubic face Poor growth Elevated TG and cholesterol

Lab findings Elevated lactic and uric acid

Treatment Frequent snacks and meals

Glycogen Storage DiseasePompe Disease (GSD II)

Cannot use muscle glycogenFeatures

Muscle weakness Muscles are hard

Rhabdomyolysis FTT Macroglossia Cardiomegaly

Treatment Enzyme replacement