1 Lifetime Probability of Cancer by Attained Age in Overall Cancer - - PDF document

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Critical Conversations in Rare & Orphan Diseases: Challenges of Diagnosing and Caring for an Individual with Gaucher Disease

MODULE 1 Epidemiology and Pathophysiology of Gaucher Disease Neal J. Weinreb, MD, FACP

Case 1: 67 y/o Patient with N370S (N409S) Homozygous Gaucher Disease (GD) (Courtesy of Dr. Neal Weinreb)

• 1983, age 37: Asymptomatic; Diagnosed because of uncle and sister with known GD1. Uncle had splenectomy,

but no other treatment. Died age 99 y. Sister on enzyme replacement therapy (ERT).

• 2002, age 56: Evaluated for mild thrombocytopenia and osteopenia; started alendronate (d/ced in 2010), but ERT

deemed not necessary.

• 2013, age 67:

– Bone mineral density (BMD) L-spine normal; Hip T-scores -2.5, -2.4. No bone pain or history of fall or fractures. – Hb 14.1 g/dL; PLT 108,000/µL; WBC and diff normal; No M-spike; Chitotriosidase 1200 (unchanged from 2006); 25-hydroxyvitamin D 40 ng/mL; D-dimer 0.37 (wnl). Spleen volume 1.4 MN; liver volume 0.7 MN. LFTs normal. – Skeletal MRI: Infiltration femoral diaphysis and proximal metaphysis; Erlenmeyer flask deformity; osteonecrosis right knee of unknown age; no lytic lesions or fractures. – Physical findings: No hepatosplenomegaly; tremor of both hands that appears to have worsened; decreased sense of smell; no gait disturbance, but does have an abnormal stare. – Concurrent history: BPH s/p TURP with no bleeding complications; hypothyroidism; hypercholesterolemia. – Started on denosumab and referred to a neurologist who confirmed Parkinson’s disease (PD) by exam and SPECT study showing absent dopaminergic activity in the right and left basal ganglia. 2019, age 72: BMD L-spine normal; L hip: T score -1.6. CBC, chito and organ volumes stable; No changes in bone MRI. On a standard PD regimen, tremor improved; mild bradykinesia; cognitive function normal; total anosmia. No bone pain.

GD: Epidemiology and Pathophysiology

• One of the most common lysosomal storage diseases
• Autosomal recessive inheritance

– Almost always caused by 1q21 GBA1 mutations

• Storage of glucocerebroside, predominantly in the

monocyte/macrophage system

• Prevalence:
• 1 in 40,000-120,000
• 1 in 800 in Ashkenazi Jewish populations
• Variable features

– Age of presentation – Rate of progression – Organ involvement and severity

Gaucher cell: macrophage engorged with lipid-filled lysosomes Named after Dr. Phillipe Gaucher who first described it in 1882

Classification: Major GD Phenotypes

Pan-ethnic (~1:40,000) Prevalent in Ashkenazi Jews (~1:800) Onset in childhood or adulthood Type 1 (Non-neuronopathic) Pan-ethnic (~1:100,000) Onset in infancy, death <2 years Type 2 (Acute Neuronopathic) Pan-ethnic (~1:100,000) Onset in childhood Type 3 (Chronic Neuronopathic)

Glucosylceramide (GL-1) is the Primary Accumulating Lipid in GD

• GL-1 is a component of cell membranes and precursor of complex glycosphingolipids

found in receptors and lipid rafts.

• Lyso-GL1 accumulates via activation of an alternative metabolic pathway,

ceramidase—it is a toxic bioactive lipid.

H

OH H O HO O OH OH CH2OH β‐D‐Glucose Sphingosine GCase β‐D‐Glucose Ceramide β‐D‐Glucose H NH OH H O HO O OH OH CH2OH O Ceramide Sphingosine GL‐1 Lyso‐GL1 GCase

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Lifetime Probability of Cancer by Attained Age in Gaucher Patients

N=2742 Observed Expected RR (95% CI) All cancer* 126 159 0.79 (0.67, 0.94) Multiple myeloma 10 1.7 5.9 (2.82, 10.82) Breast cancer 15 33.2 0.45 (0.25, 0.75) Prostate cancer 10 30.4 0.33 (0.16, 0.60) Colorectal cancer 6 15.5 0.39 (0.14, 0.84) Lung cancer 6 19.9 0.30 (0.11, 0.66) Blood 19 15.6 1.23 (0.73, 1.90) *Includes non-melanoma skin cancers, ovarian cancer, renal carcinoma, bladder cancer, hepatocellular cancer, ganglioneuroma, neurosarcoma, angiosarcoma, thyroid carcinoma pancreatic cancer, testicular rhabdomyosarcoma, carcinoid tumor

Overall Cancer Risk Increased in GD (RR, 1.80; 95% CI, 1.32-2.40)

• Both homozygous N370S and heterozygous N370S mutation had:

– An increased lifetime risk of multiple myeloma (RR, 25; 95% CI, 9.17-54.40) – An increased risk of hematologic malignancies (RR, 3.45; 95% CI, 1.49-6.79)

• 33-fold increased risk of

gammopathy in GD type 1

Accumulating GL-1 and Lyso-GL1 Trigger Lipid-Specific Immune Response and Chronic Inflammation

Gba1 Mutations (Gaucher Carrier or Patient)

A significant risk factor for Parkinson’s disease (PD)

GL-1 Accumulation Leads to Cellular Dysfunction

• Normally, GCase interacts with GL-1 as well as monomers of α-synuclein in lysosomes, facilitating

the breakdown of both at acidic pH.

• Mutated or decreased levels of GCase result in a slowdown of α-synuclein degradation, a gradual

build up of GL-1 and formation of α-synuclein oligomers and fibrils.

• GL-1 stabilizes the α-synuclein oligomers. These oligomers bind to mutated GCase and further

inhibit the enzymatic activity of GCase.

• The GL-1 engorged lysosomes have impaired chaperone-mediated autophagy and

autophagosome fusion.

• This causes increased accumulation of α-synuclein insoluble aggregates in the cytoplasm (Lewy

bodies). These aggregates block trafficking of GCase from the endoplasmic reticulum (ER) to the

• Golgi. Mutant GCase is retained in the ER evoking the ER unfolded protein stress response).

Points to Remember

• GD is one of the most common lysosomal storage diseases world-wide and is

particularly prevalent in Jews whose family origins are traced to northern, eastern and central Europe (Ashkenazim).

• GD is classified as being either neuronopathic (types 2 and 3) or non-

neuronopathic (type 1), but all types can present with severe symptoms early in life.

• GD is caused by trans-biallelic mutations in the GBA1 gene leading to deficient

lysosomal glucocerebrosidase deficiency with storage of glucosylceramide (GL-1) and increases in glucosylsphingosine (lyso-GL1).

• Accumulating GL-1 and lyso-GL1 trigger lipid-specific immune responses and

chronic inflammation that can lead to concurrent malignancies such as MGUS/myeloma, lymphoma and hepatocellular carcinoma.

MGUS, monoclonal gammopathy of unknown significance

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Points to Remember (continued)

• GL-1 accumulation in lysosomes and the presence of mutant

glucocerebrosidase also promote synuclein oligomer aggregation and neuronal death.

• Consequently, despite the label “non-neuronpathic,” patients with GD1

and carrier relatives have an increased risk for Parkinsonism and related synucleopathies.

• Both malignancies and Parkinsonism may occur as late manifestations

even when patients ostensibly have clinically mild GD phenotypes.