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Genetic Causes of CIPA

Peripheral Nerves

Clinical Features

Signal Cascading

CIPA patients appear to have problems unrelated to nerves

Genes=Symptoms?

Could Anhidrosis, poor ossification, nocioception/ thermoception, and wound healing be connected?

SCN9A is also implicated in primary erythermalgia- pain/redness in extremities,

Paroxysmal extreme pain disorder

Direct afferent nervous action

Identified in Israeli Bedouin CIPA patients by J. Cox

DMT-1

Heavy metal accumulation

Neurotrophin Growth Factor (NGFB)

DMT-1 Was isolated as a factor in CIPA in a pair of Han Chinese twins

Heavy metal buildup will inhibit action potential in sensory neurons

Absence causes apoptosis

Binds to TRK family, causing phosphorylation

Role in neuroplasticity

Patients with CIPA lack all NGF dependent neurons, both primary afferent and postganglionic

sympathetic

Dylan Kritter

CIPA Varies in presentation and population

Populations studied include:

  • Kuwaiti
  • Han Chinese
  • Japanese
  • Moroccan Jews
  • Israeli Bedouins
  • South American Natives
  • Turkish
  • Iranian
  • Pakistani
  • Italian
  • Northern European

Five Genes:

SCN9A- Voltage gated sodium channels

DMT-1- Divalent Metal transport channel

NGF- Neurotrophin growth factor

TRKA- NGF receptor, initiates action potential, has immunological role

FAM134B- Immunologic role, survival

of peripheral neurons

TRKA (NRTK1)

Most highly correlated with CIPA

Tropomyosin Related Kinase A (Neurotrophin Receptor Tyrosine Kinase) acts as a receptor for NGF

Autophosphorylates and continues MAPK pathway, important for differentiation of neurons

Roles of TRK

Differentiates and develops

peripheral neurons

NGF activity required for expression of specific heat activated channel

Functions explain CIPA disease process very effectively

Expressed on monocytes, immunologic role

Directs innervation of neurons in postganglionic sympathetic neurons

BGU Department of Clinical Biochemistry and Pharmocology

Principal Investigator Dr. Eli Lewis

Spontaneous injuries, absent nocioception, and inability to recover can be well explained and understood by the genetic abnormalities underlying them

The Cascade effect

Interventions for soft tissue injury stand to improve from further study of CIPA's pathophysiology

Seemingly unrelated functions are tied by one or two genes

FAM134B could be a more integral gene to sensory autonomic function

The "Blot" Thickens

Two novel mutations in two separate Turkish families were identified in FAM134B

FAM134B acts in cellular autophagy by sequestering ER proteins to lysosomes

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