What is it?
Imagine you were at war with your body - and
there was nothing you could do about it - the doctors just tell you, “sorry,
it’s genetic”. Well, individuals with hereditary neuralgic amyotrophy (HNA) are
in a lifelong war. The body of someone with HNA is spontaneously recognizing
itself as a villain (and succeeding), eventually leading to its own
destruction, while the mind is sitting there defenseless.
HNA is a rare genetic disorder characterized by
recurring episodes of severe pain and muscle wasting in one or both arms and
shoulders, resulting in paralysis of the affected area. The paralysis is due to
the degradation of the arms and shoulder neurons. This disorder is
characterized as an autosomal dominant disorder. This essentially means that
one copy of the altered gene from a parent is sufficient to cause HNA, and with
each new pregnancy the child has a 50% chance of acquiring the disease (Figure
1). HNA is a rare disease, occurring in about 1 in 10,000 people in the
population (Hannibal et al., 2009).
Triggers and Symptoms
The average age of onset for HNA (when someone
experienced the first episode) is 24 years; however, some people can
experience their first episode as early as 3 years old or as late as 59 years
old (Van Alfen et al. 2000). The attacks may be spontaneous or triggered
by stress such as strenuous exercise, exposure to cold, infections, childbirth,
surgery, or emotional disturbance.
Can you imagine going to go get your wisdom
teeth out one day and that night you wake up to excruciating pain running down
your back and arm? Or can you imagine being a 9-month pregnant woman, with your
first-born baby about to arrive any day? Not only are you worried about all the
challenges you are about to face being a mom, but you are also worried about
giving birth. Not because rumor has it, it hurts, but because giving birth
might trigger an episode which could ultimately lead to you not being able to
properly hold your baby for months or even years. Thankfully, the frequency of
episodes tends to decrease with age; however, affected individuals usually are
left with residual problems such as chronic pain or impaired movement in their
fingers, hands and arms, ultimately handicapping them. So maybe you can
eventually hold your baby, but your fingers might never function well enough to
button your child's jacket.
A typical episode starts with severe pain in
one or both arms or shoulders. The pain is hard to control even with medication
and usually lasts for several weeks. Within weeks the muscles of the affected
area begins to waste away and movement becomes difficult. Partial or full
paralysis of the arms and hands is common. The weakening of the muscle causes
changes in posture and appearance of the hands, arms, shoulders and back. The
most common symptom is from weak shoulder muscles tendency to allow the
shoulder blades to stick out from the back, known as scapular winging (Figure
2). Additional features of HNA include decreased sensation and other abnormal
sensations on the skin such as numbness or tingling.
A recent study characterized two distinct
patterns of HNA. One pattern, the relapsing-remitting course (coined by a group
of researchers), is found in 50% of families affected by HNA. This course
starts with immediate severe pain (indicating the start of an episode) and
lasts several weeks. Following the severe pain, muscle wasting (paresis)
occurs, sometimes completely paralyzing the affected region. Recovery of
strength usually occurs after muscle wasting is complete and progresses slowly
for a period of months to years (Figure 3). Only 28% of these episodes are
followed by complete recovery, with 57% of the recovered episodes being the
first or second attack (Van Alfen et al. 2000).
The second pattern of HNA is called the chronic
undulating course and is found in the remaining 50% of families. In this
course, individuals experience gradually increasing pain over the course of
weeks or even years until the onset of the first attack (Figure 4). Once the
pain subsides, muscle wasting begins. The muscular wasting remains and pain
never completely subsides, leaving the person not only in chronic pain but also
with very little function. Each new attack leads to increased paralysis.
Ultimately, leading to a more permanent loss of function in the affected area
(Van Alfen et al. 2000).
The faulty protein
HNA is caused by a mutation in the Septin 9
gene, SEPT9, which provides the instructions for making the septin-9
protein (apart of a group of proteins called septins). HNA is the first genetic
disorder ever recorded to be associated with septins (Hannibal et al. 2009).
The main job of septins are to bind microtubules together, which is essential
for their function. Microtubules are a part of the cytoskeleton (network of
filaments which provides structure) of a cell, and are incredibly important in
cell division and growth. Essentially, mutated septins will lead to
unfunctional microtubules, ultimately resulting in cells which are growing and
dividing abnormally.
A
recent study looked at the molecular structure of septin-9 and identified two
secondary structures in septin-9 which are involved in forming the microtubule
linkage. They discovered in HNA patients, the mutated septin does not contain
these important secondary structures, preventing the microtubule linkage and
resulting in non-functional microtubules. They demonstrated that when septin-9
was functional in cells, microtubule lengths (Figure 5), thickness, and
stability (Figure 6) all increased. They also showed that a specific septin-9
mutation (R88W) impairs microtubule bundling and resulted in asymmetric neuron
growth (Figure 7) (Bai et al. 2013). This asymmetric neuron growth may lead to
the suit of symptoms, but direct linkages are unknown.
The interplay with the immune system
Autoimmune disorders occur when the immune
system malfunction and attacks the body’s tissues and organs. Researchers
believe that the HNA episodes are an autoimmune attack on the nerves in
shoulders and arms, resulting in the signs and symptoms associated with this
disease. However, the relationship between SEPT9 mutations and the
immune system still remains unclear.
Another recent study looked at mutations in
septin-9 in HNA patients to map regions in SEPT9 gene which are commonly
mutated. They found mutations dramatically enhanced the synthesis of septin-9
proteins, but only when in hypoxic conditions (low oxygen environment). Hypoxic
conditions occur when the body is stressed. This study may be the first to
examine the interplay between the immune system and septin-9 in HNA patients
(McDade, Hall, Russell, 2007).
References:
Bai, X. Bowen, JR. Knox, TK. Zhou, K. Pendziwiat, M. Kuhlenbäumer, G. Sindelar, CV. Spiliotis ET. 2013. Novel septin 9 repeat motifs altered in neuralgic amyotrophy bind and bundle microtubules. The Journal of Cell Biology 203(6): 895–905.
Hannibal, MC. Ruzzo, EK. Miller, LR. Betz, B. Nachan, JG. Knutzen, DM. Barnett, K. Landsverk, ML. Brice, A. LeGuern, E. Bedford, HM. Worrall, BB. Lovitt, S. Appel, SH. Andermann, E. Bird, TD. Chance, PF. 2009. SEPT9 gene sequencing analysis reveals recurrent mutations in hereditary neuralgic amyotrophy. Neurology 72: 1755-1759.
McDade, SS. Hall, PA. Russell, EE. 2009. Translational control of SEPT9 isoforms is perturbed in disease. Hum MOl Genet 16(7): 742-52
Van Alfen, N. Van Engelen, BGM. Reinders, JWC. Kremer, H. Gabreels, FJM. 2000. The natural history of hereditary neuralgic amyotrophy in the Dutch population Two distinct types? Brain 123: 718-723.
Image References:
Autosomal Dominant Inheritance Pattern, photo from Genetic Support Foundation
Patients with HNA and muscular atrophy, photo from Gene Reviews
Autoimmune Disease Meme, created by Curtis Jones
Very interesting topic and well communicated here. The complexity of trigger(s) responsible for an attack of the immune system on the nervous system will be a tough case to crack, but it’s great that HNA is now getting the attention needed in order to facilitate progress toward a better understanding such a painful disorder. Thank you for putting together such a comprehensive article on this topic!
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