Skip to main content

Table 2 Example of pathophysiologic maps linking disease cause to final clinical outcomes

From: Recommendations for the development of rare disease drugs using the accelerated approval pathway and for qualifying biomarkers as primary endpoints

Disease Cause (gene or protein level) 1° Pathophys. (cell level) 2° Pathophys. (tissue level) Clinical Physiology (system/organ) Early Clinical (integrated systems) Late Clinical (final major outcome/events)
Mucopolysaccharidosis type 1 (MPS 1) IDUA gene mutations Reduce iduronidase enzymatic activity Accumulation of heparan sulfate and dermatan sulfate GAG in cells and tissues GAG infiltration of upper airway tissue Sleep apnea, ↓O2 Sleep deprivation Right heart failure
GAG infiltration of lungs, liver, rib and spine development Impaired PFT Pulmonary insufficiency Hospitalization/oxygen Increased respiratory infections
Synovial storage Joint ROM defect Nerve compression Difficult hand mobility Unable to do ADL Carpal tunnel syndrome requiring surgery
Thick heart valve Echocardiogram Enlarged heart Congestive heart failure
Abnormal bone/joints formation MR Joint pain, stiffness, contractures Wheelchair bound
Dysostosis multiplex Reduced growth rate Orthopedic interventions
Short stature
Phenylketonuria Defect in PAH gene that expresses PAH that metabolizes Phe ↓Phe destruction leads to ↑Phenylalanine in blood ↑Phenylalanine causes cytotoxic effects White matter abnormalities Mild cognitive impairment Advanced cognitive impairment
Myelin abnormalities Altered neuro function
Myasthenia gravis Antibody to the AchR Inhibition of Ach-based signaling Muscle weakness Drooping eyelids Difficulty keeping eyes open for vision Wheelchair bound Loss of ambulation
Weak legs Difficulty walking
Duchenne muscular dystrophy Genetic defect in dystrophin gene Deficiency of dystrophin protein Rupture of myofibrils Muscle weakness Gower’s sign  
Myopathy Heart abnormality Fatigue Decreased play Heart failure Death
Centrilobular nuclei Decreased FVC Impaired PFT Respiratory insufficiency Ventilatory support
Alpha Dystroglycan related muscular dystrophy Hypo-glycosylation of alpha dystroglycan Defective binding to extracellular matrix, sarcolemmal membrane instability Stem cell regenerative defect Muscle cell death Decreased balance, walking, climbing stairs, rising from chair Muscle weakness, impaired mobility Wheelchair bound
Fabry Disease Mutation α- galactosidase gene Accumulation GL3 in lysosome Multiple cells storage Small vessels storage (cardiomyocytes, podocytes etc.) PNS Acroparesthesia  
CNS Stroke Neurologic deficits
Kidney Proteinuria/injury Renal failure
Heart Arrhythmia Cardiac death
  1. The table outlines 6 diseases as examples for pathophysiologic maps. The first column represents the disease, then the cause, the primary pathophysiologic outcome of the cause through other causes, clinical physiology and clinical outcomes. The table is intended to capture the known steps in a process, from which the location and relevance of a biomarker might be established and compared against. ADL is activities of daily living, CNS is central nervous system, FVC is forced vital capacity during pulmonary function testing, GAG is glycosaminoglycan, GI is gastrointestinal, PAH is phenylalanine hydroxylase, PNS is peripheral nervous system.