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LSD Part 3B Some examples of treatable pediatric and adult onset lysosomal disorders Serge Melançon MD, FRCPC, FCCMG Director, Biochemical Genetics Services February 2010 Gaucher cell 1882 Ernest GAUCHER (1854-1919) Type 1 Gaucher Disease: acid β – glucosidase deficiency The clinical manifestations result from glucosylceramide engorged macrophages causing: enlargement and dysfunction of the liver and spleen, displacement of normal bone marrow by storage cells, and damage to bone leading to infarctions and to fractures rare adult-onset patients have presented early symptoms of Parkinson disease. Type 1 Gaucher Disease: acid β – glucosidase deficiency Some patients with severe visceral (liver and spleen) enlargement have minimal skeletal involvement, Some with severe bone disease have minimal visceral disease. In others, visceral involvement and skeletal involvement are approximately equal in severity. The type of mutation seems to have less influence on the sites of disease involvement, than on overall visceral disease severity. Type 1 Gaucher Disease • Patients may be diagnosed as late as the eighth or ninth decade of life. • Asymptomatic "patients" are ascertained only in the course of family studies or population surveys. • Mildly affected individuals are almost invariably found to have the 1226G/1226G (N370S/N370S) genotype. • Median age of appearance of the first clinical symptoms of patients with this genotype is about 30 years. Emergent concepts in GD • Neurological: Parkingsonism • Skeletal: avascular necrosis, lytic lesions, chronic osteomyelitis (after splenectomy) osteoporotic vertebral crush fractures, osteonecrosis of pelvis • Pulmonary: Fibrosis, emphysema • Neoplastic: hematopoietic malignancies • Immune: polyarthropathy, coeliac and liver diseases • Vitamin B12 deficiency • Co-morbidities: viral or alcoholic hepatitis Diagnosis of Gaucher Disease • Assay of acid β-glucosylceramidase enzyme activity in WBC or skin fibroblasts (unreliable for carrier detection) • Bone marrow examination The changes are nonspecific, and bone marrow examination is not a reliable diagnostic test. • Molecular Genetic Testing sensitivity 11 targeted mutation analysis 98% Gene sequence analysis 99% FD case report • Two males of Italian descent who were identified at ages 38 and 42 years during evaluations for hypercholesterolemia and rheumatoid arthritis, respectively. • The finding of proteinuria in each led to renal biopsies that revealed accumulation of lamellated crystalline structures in the cytoplasm of endothelial cells With podocytes diffusely distended by numerous intracytoplasmic vacuoles Fabry disease • Low levels of α-galactosidase A activity confirmed their diagnoses. • Neither had acroparesthesias, angiokeratoma, anhidrosis, or corneal whorling. Angiokeratomas Cornea verticillata α - Galactosidase A Deficiency: Fabry Disease • • • X-linked recessive Systemic deposition of glycosphingolipids with terminal α-galactosyl moieties (GL3) in body fluids and in the lysosomes of endothelial, perithelial, and smooth-muscle cells of blood vessels. Deposition also occurs in ganglion cells, and in many cell types in the heart, kidneys, eyes, and most other tissues. α - Galactosidase A Deficiency: Fabry Disease • Progression is organ-specific in severity and pace, and does not clearly follow a typical pattern or sequence in individual patients or cohorts of patients • Multi-organ assessment and monitoring are required to determine disease severity • Early involvement leads to early symptoms involving the peripheral and autonomic nervous system • Late complications involve the heart, kidneys, and cerebrovascular system α - Galactosidase A Deficiency: Fabry Disease • Among adults, the age at diagnosis and age at initiation of ERT were reported to occur 10 and 8 years later in females than males, respectively. • Women develop renal, cardiac, and cerebrovascular manifestations of Fabry disease and a greater effort must be made to diagnose and monitor these patients. • Nearly half of the 138 Fabry Registry patients who reported strokes, experienced them prior to being diagnosed with Fabry disease. • This highlights the need for earlier diagnosis, so patients can be monitored for risk factors associated with stroke. α - Galactosidase A Deficiency: Fabry Disease • Children were reported to be diagnosed at a median age of 9 years for both genders. • They experienced substantial symptoms, and few were treated with ERT or received pain management. • Children with Fabry disease should be monitored for signs/symptoms and their neuropathic pain should be treated appropriately. Diagnosis of Fabry Disease Fabry disease should be considered in males and females with the following signs: 1. Periodic crises of severe pain in the extremities (acroparesthesias) 2. Vascular cutaneous lesions (angiokeratomas) 3. Hypohidrosis 4. Characteristic corneal and lenticular opacities 5. Stroke 6. Left ventricular hypertrophy 7. Renal insufficiency of unknown etiology Diagnosis of Fabry Disease • Alpha-galactosidase A (α-Gal A) enzyme activity (Unreliable for carrier detection) • Molecular Genetic Testing sensitivity • Sequence analysis/mutation scanning ~ 100% in males, unknown in females • Determination of urinary GL3 appears to be a reliable screening test in affected individuals (Auray-Blais C et al. Molecular Genetics and Metabolism 93 (2008) 331–340) PD case report • 32 years-old female with back pain • Progressive proximal muscle weakness • Exercise-induced urinary incontinence • Disproportionate atrophy of the paraspinal muscles seen on CT scanning PD case report • No signs of cardiomyopathy on heart US • Somnolence, morning headache, orthopnea, and exertional dyspnea • Obstructive sleep apnea • Pulmonary function revealed diminished vital capacity Pompe is a familial, pan-ethnic Disease Estimated prevalence <10,000 patients worldwide Higher frequency in individuals of following descent: -African American -Dutch -Chinese Clinical Manifestations Pompe disease is a metabolic myopathy (cardiac, skeletal and smooth muscle) with a continuum of clinical manifestations From early onset + rapid progression to death To later onset + slower progression (longer survival with marked morbidity) • Clinical spectrum determined by: GAA mutations: fully deleterious partially deleterious GAA activity: total deficiency partial deficiency Glycogen accumulation and muscle damage: rapid slower A spectrum of GAA Gene Mutations Exists In Pompe Disease GAA mutations Genzyme data; Clinicals n=340 alleles (Genzyme n=340 alleles) c.-32-13T>G (22%) c.525delT (6%) Del Ex18 (6%) R854X 5% R854X (5%) As of November 2005, 230 cases genotyped at Genzyme; 59 novel mutations Patients with Pompe Disease Share a Common Pathophysiology GAA Mutations GAA Deficiency Muscle Pathology Total deficiency OR Rapid glycogen accumulation Age at symptoms: <1 year Partial deficiency Less rapid glycogen accumulation Age at symptoms: adulthood Pompe Disease: Progression Rate of Clinical Deterioration Rapid Slower [Early symptom onset] [Later symptom onset] PLUS From Nyhan and Ozand Atlas of Metab Dis Disease Duration Short (death in 1st year of life) Picture from IPA website Longer (with significant morbidity) Pompe Disease: Onset in Infancy Quadriceps Myopathy Baseline, age 8 mos. Heart Cardiomyopathy Courtesy Dr. B. Byrne Pompe Disease: Late Onset Loss of ambulation Respiratory Failure Pictures from the IPA Website Progressive Muscle Weakness Leads to Loss of Independent Ambulation and Respiratory Failure (IPA Dutch Cohort; n=54) 1st symptoms Progressive muscle weakness Use of ambulatory devices (48%) Use of ventilator support (37%) Hagemans et al. Brain 2005 Diagnosis of Pompe Disease Specific tests Acid alpha-glucosidase (GAA) enzyme activity. In cultured fibroblasts (6 weeks) or in peripheral blood (blood spots) Complete deficiency (activity <1% of normal controls) of GAA enzyme activity in classic infantile-onset PD. Partial deficiency (activity that is 2%-40% of normal controls) of GAA enzyme activity non-classic infantile-onset and late-onset forms Muscle biopsy. 20%-30% of individuals with late-onset Pompe disease with documented partial enzyme deficiency may not show any musclespecific changes Diagnosis of Pompe Disease Molecular Genetic Testing • Sequence analysis/mutation scanning sensitivity p.Arg854X p.Asp645Glu IVS1 -13T>G Other GAA sequence variants ~ 50%-60% ~ 40%-80% ~ 50%-85% 83%-93% Overall Survival at 18 Months of Age 18/18 trial patients [100%] 1/61 untreated controls [2%; 95% CI: 0% - 6%] Clinical Trial Patients Untreated Historical Cohort 95% Confidence Intervals Survival Free of Invasive Ventilation at 18 Months of Age (Primary End Point) 15/18 trial patients [83%; 95% CI: 66% - 100%] 1/61 untreated controls [2%; 95% CI: 0% - 6%] Clinical Trial Patients Untreated Historical Cohort 95% Confidence Intervals Changes in LV Mass (by cardiac echo) All patients with data showed reduction in LV mass: 58% after 1 year of Myozyme, in average +7.1 Z-score 9 8 Meqn LVM Z-score 7 6 +3.2 Z-score 5 4 3 2 Upper Limit of Normal 1 0 -1 Baseline Week 26 Week 52 Challenges: Treat Early Functional Status Worsens with Longer Disease Duration Percent of Muscle Glycogen Increases with Age % 70 60 50 47% 40 30 28% 20 10 0 < 6 months 6 months – 3 years Late onset PD Trials Forced Vital Capacity (FVC) Study 2704, ‘LOTS’: Design • 90 patients enrolled at 8 sites in US and EU – 10 to 70 years (Mean = 44.5 years) – 0 to 45.4 years symptoms duration (Mean = 15.7 years) • Randomized, double-blind, placebo-controlled 12 month study with 2:1 drug to placebo assignment – US – 58 patients (2 pediatric, 56 adults) – EU – 32 patients (2 pediatric, 30 adults) • All patients were ambulatory and not invasively ventilated • Pulmonary and muscle strength and function were assessed every 12 weeks – Primary Endpoints • Distance walked in 6 minutes • Forced Vital Capacity (FVC) • Results – Clinical benefits were seen for respiratory and motor function Jessica, MPS I MPS I • Progressive, inherited • Lysosomal storage disorder – deficiency of -L- iduronidase enzyme – progressive accumulation of glycosaminoglycans (GAGs) Multisystemic Manifestations • • • • • • • Brain Ears, nose, throat Lungs Heart Liver Spleen Bones and joints MPS I Major Manifestations Facial dysmorphism Communicating hydrocephalus Developmental delay Hearing loss Corneal clouding Skeletal abnormalities Obstructive airway disease Cardiac complications Hepatomegaly Joint stiffness MPS I Spectrum of Disease Severity Severe Less severe -L-iduronidase deficiency Hurler Hurler-Scheie Scheie Disease Progression: Severe MPS I 10 months 12 months 39 months 22 months 34 months Disease Progression: Moderate MPS I 6 years Disease Progression: mild MPS I 3 years 4 years 11 years 6 years 8 years Diagnosis of MPS I • Patients see several specialists before diagnosis • Presumptive diagnosis – observation of symptoms and laboratory findings • coarse facial features • hepatosplenomegaly • skeletal, joint, or ocular findings characteristic of MPS I • Family history/medical pedigree • Analysis of urinary GAGs Enzyme Assay: Definitive Diagnosis • Assay for a-L-iduronidase activity – measure in leukocytes, cultured skin fibroblasts, serum, plasma • Markedly deficient in affected patients – less than 1% normal • Enzyme activity does not correlate with disease severity THE END OF LYSOSOMAL DISORDERS