November 11, 2010

Undernutrition

61/2 m/o ex 34 WGA twins with: FTT Severe Global Developmental Delay Hypertonia Oculomotor findings Reflux Intermittent Diarrhea HSM h/o neutropenia and thrombocytopenia

Gaucher Disease Inborn error of metabolism Affects recycling of cellular glycolipids Defect in  -glucocerebrosidase Accumulation of glucocerebroside in lysosomes Most common lysosomal storage disease Incidence 1/75,000 worldwide Autosomal recessive

Clinical Presentation Neurologic dysfunction Developmental Delay Oculomotor dysfunction Pathologic fractures Hepatosplenomegaly Anemia Neutropenia Thrombocytopenia Cardiac and renal symptoms typically absent

Gaucher Disease Ashkenazi Jews 7% heterozygous Frequency of disease 1:1000 Also common among Swedish

Diagnosis Gaucher cells in bone marrow False negatives Gold Standard: Enzyme assay (  -glucocerebrosidase) Molecular DNA analysis Carrier testing recommended for close relatives

Three Clinical Types

Type 1 Adult onset Most common Most closely tied with Ashkenazi Jews NO CNS findings Varies from mild to severe Enzyme replacement: near-normal life expectancy

Type 2 Most severe form Death by age 2 Treatment usually not indicated Early, severe CNS involvement Brainstem abnormalities

Type 3 Juvenile onset “chronic/subacute form” Most common in Swedish Later onset: Incoordination, mental deterioration, seizures Slowly progressive Becomes severe in later childhood

Treatment Enzyme replacement therapy Glucocerebrosidase IV Some improvement within 6 months Not effective for CNS symptoms Research Oral therapy Gene therapy

Lysosomal Storage Diseases Mutation in gene coding for production of lysosomal enzymes Accumulation of substrate Impairment of cell function >40 different LSD Start in late infancy or early childhood with slowly progressive symptoms

Lysosomal Storage Diseases Mucopolysaccharides Hurler’s Hunter’s Sanfilippo Morquio Glycolipids Gaucher Fabry Krabbe Tay Sachs

Lysosomal Storage Diseases Mucopolysaccharidoses 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

DiseaseDescriptionInheritance 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 Diseases Sphingolipidoses Developmental regression Organomegaly Cherry red macula Bone pain Short

DiseaseDescription GaucherHSM, bone pain, easy bruisibility FabryOrange-colored skin lesions, opacities of the eye, vascular disease (heart, brain, kidney) KrabbeDemyelination and progressive neuro deterioration Tay SachsNo HSM, cherry red spot, neuro deterioration Niemann-PickHSM, cherry red spot, peripheral neuropathy

Glycogen Storage Disease Von Gierke Disease (GSD I) Liver can’t produce glucose Features 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 Disease Pompe Disease (GSD II) Cannot use muscle glycogen Features Muscle weakness Muscles are hard Rhabdomyolysis FTT Macroglossia Cardiomegaly Treatment Enzyme replacement