Paroxysmal extreme pain disorder
Paroxysmal extreme pain disorder | |
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Other names | PEPD |
Paroxysmal extreme pain disorder originally named familial rectal pain syndrome, is a rare disorder whose most notable features are
Symptoms and signs
The most distinctive feature of PEPD is episodic burning pain of the
During attacks in infants, the child often looks startled or terrified and can scream inconsolably. These attacks can be precipitated by injections, defecation, wiping of the perineum, eating, or the consumption of oral medication. When attacks occur due to such precipitation, pain and flushing are often present in the area of attack precipitation, though symptoms may also be diffuse in nature.[1]
Other symptoms may include hypersalivation when attacks are localized in the mandibular region, or leg weakness after foot trauma. A prominent non-physical symptom are tonic non-epileptic seizures. Such seizures are more common in infancy and childhood than during adulthood. In older children, inconsolable screaming usually precedes such attack, followed by apnea, paleness, and stiffness. Such stiffness can last from seconds to a few minutes.[1]
Attack precipitants are usually physical in nature, such as defecation, eating, or taking medicine. Some less common precipitants are
Patients are largely normal between attacks. The only notable problem is constipation, likely due to apprehension of precipitating an attack. This symptom often decreases with age, likely due to coping mechanisms such as the use of
Cause
The voltage-gated sodium channel NaV1.7 is expressed in nociceptive and sympathetic neurons, where it aids in action potential creation and regulation. The mutations in this gene that have received study all alter the channel's ability to inactivate. Sodium channel inactivation is vital for the proper cessation of action potentials. The decreased inactivation caused by these mutations, then, is expected to cause prolonged action potentials and repetitive firing. Such altered firing will cause increased pain sensation and increased sympathetic nervous system activity, producing the phenotype observed in patients with PEPD.[2]
Pathophysiology
There are a total of 8 mutations that account for the disorder in 8 of 14 studied families. These mutations are clustered in four regions throughout the channel: the linker between domains 2 and 3 (D2-3), the intracellular segment linking segments 4 and 5 in domain 3 (D3S4-5), the linker between domains 3 and 4 (D3-4) and the intracellular segment linking segments 4 and 5 in domain 4 (D4S4-5). The mutations in the D3S4-5 region (I1461T, F1462V and T1461I) are located in or next to an IFM motif that is conserved across all voltage-gated sodium channels. Mutagenesis studies of this region have shown that it acts as part of the inactivation gate, pivoting to block the central pore. Not surprisingly then, the two of these mutations that have received further study show incomplete inactivation. When the IFM motif pivots to block the central pore it interacts with residues in the D3S4-5 region. There are three mutations in this region (V1298F, F1298D and V1299F) that are believed to alter the interaction with the inactivation gate. While this region has been studied by mutagenesis these specific mutations have not all received attention, though they are expected to produce changes similar to the aforementioned IFM region mutations. The M1627K mutation in the D4S4-5 region may also affect a residue involved in interacting with the IFM inactivation motif. This would explain the observed alteration of inactivation and the broadening of a window current. One of the affected families with the R996C mutation, pedigree 12, has a single individual who also has the V1298D mutation. The individual in this family with the compound mutation is the most severely affected, suggesting that the R996C mutation may cause a less severe phenotype. The less severe phenotype of the pedigree 4 family is in concordance with this theory. It is unclear how the R996C mutation affects channel function.[2]
Mutation | Region | Persistent Current? | Physiological Effect | Affected Families by Location |
---|---|---|---|---|
R996C | D2-3 | 4 (UK), 12 (France) | ||
V1298F | D3S4-5 | 15 (UK) | ||
V1298D | D3S4-5 | 12 (France) | ||
V1299F | D3S4-5 | 11 (UK) | ||
I1461T | D3-4 | Yes | Incomplete inactivation due to depolarizing shift of steady-state inactivation curve. | 1 (UK) |
F1462V | D3S4-5 | 9 (UK) | ||
T1464I | D3S4-5 | Yes | Incomplete inactivation due to depolarizing shift of steady-state inactivation curve. | 7 (UK) |
M1627K | D4S4-5 | Yes | Creation of a notable "window current" due to shifting of the inactivation curve. | 8 (France) |
Data from Fertleman 2006[2] and Fertleman 2007[1] |
Diagnosis
Hematological, biochemical and metabolic investigations on blood and urine between attacks are normal, as are
Treatment
Epidemiology
PEPD is an extremely rare disorder with only 15 known affected families.[2] There are some cases, however, of individuals originally diagnosed with epilepsy who are later determined to have PEPD. This suggests that rates of PEPD may be higher than currently believed.[3]
History
PEPD was originally described by Hayden and Grossman in 1959. At that time it was not given a specific name.[4][5] A later report, by Dugan in 1972, labeled this disorder as familial rectal pain syndrome.[6] This name was used for 33 years, until a consortium of patients and clinicians was formed in the hopes of discovering the genetic cause of PEPD. During this process a number of patients expressed dissatisfaction with the name and after considerable discussion between patients and clinicians the name paroxysmal extreme pain disorder was agreed upon in 2005.[5]