Trisomy 13 - Patau Syndrome

I'm continuing my look at Trisomy disorders by profiling Patau Syndrome, Trisomy 13. Though discovered in 1657, the genetic cause was determined by Dr. Klaus Patau in 1960. As with all instances of trisomy, Patau Syndrome occurs when three copies of chromosome 13 are in some or all of an individual's cells. There are three forms of Trisomy 13:

1. Partial trisomy involves the presence of part of an extra copy of chromosome 13 in the cells.
2. Trisomy 13 mosaicism occurs when some of the cells have an extra chromosome 13.
3. Trisomy 13 has a full extra copy of chromosome 13 in all of the cells.

In some rare cases the extra genetic material may translocate and attach to a different chromosome. Trisomy 13 is fairly uncommon, occurring in approximately 1 in 10,000-21,700 newborns. Due to the severity of genetic damage (remember the lower the number of the chromosome the more genetic information it contains) the condition sometimes results in miscarriage or stillbirth (around 8% of prenatal diagnoses). Further, 80% of babies born with Trisomy 13 will not survive beyond their first year. However, those who do survive birth and early infancy can live to adulthood. Children with partial or mosaic Patau have an even more hopeful outlook. Therefore it saddens me to know that up to 64% of babies diagnosed prenatally with Trisomy 13 are eliminated by elective abortion.

Each child with Trisomy 13 will have different needs depending on what symptoms are evident. Some common issues include:

• Cleft lip or palate
• Close set eyes - may even fuse into one structure
• Extra fingers or toes
• Seizures
• Limb abnormalities
• Small head
• Small lower jaw
• Congenital heart defects - placement toward right side of chest, septal or ductal defects
• Holoprosencephaly - the forebrain doesn't divide properly

Often these physical challenges are detected first by ultrasound. MRI or CT scans may also be used. Chromosome studies are used to specify the type (Patau) and sub-type (partial, mosaic, or full) of Trisomy.

Caring for an infant with Trisomy 13 often involves addressing breathing issues like apnea, feeding problems, heart failure, seizures, and challenges with seeing and hearing. It is essential for families to find support as they walk through caring for a child with Trisomy 13. One well-known organization to contact is SOFT. Another is Hope for Trisomy 13 and 18.

How fitting that March is Trisomy Awareness month!

Trisomy 9

Several months ago I started a series about Trisomy genetic disorders. I'm just getting back to that series after taking a brief break. You may want to refresh your memory on what Trisomy is and how it occurs. I've also written about Trisomy 8.

There are three forms of Trisomy 9:

1. Full Trisomy 9 is the most severe form in which every cell has three copies of chromosome 9. In most cases the developing embryo is not viable and the pregnancy will end in the first trimester by miscarriage. Some babies with full Trisomy 9 survive until birth, but only live for a short period of time.
2. Partial Trisomy 9 involves an extra portion of chromosome 9 is included in each cell. You can get an idea of what that might look like here (scroll down to diagnosis). Life expectancy with this form of Trisomy 9 varies widely. This form is generally more rare than full and mosaic forms.
3. Similar to Trisomy 8, Trisomy 9 often occurs in a mosaic form in which some, but not all, of an individual's cells have three copies of chromosome 9. Depending on the severity of medical challenges the life span of individuals with Mosaic Trisomy 9 can be shortened dramatically.

 Statistically, individuals with Trisomy 9 share several characteristics including medical issues, physical challenges, and behavioral traits. Each affected individual is unique and should not be "expected" to fit a certain developmental profile, but some common challenges include: low birth weight, congenital heart defects, global developmental delays, cognitive challenges, cranio-facial differences, and low muscle tone.
For more information on Trisomy 9, check out the following links:

• a fairly personal view from one family is here
• links to several other resources are here
• a more clinical view
• break out the tissue for this video about some girl scouts reaching out to one little girl with trisomy 9 mosaic syndrome.

Trisomy 8 - Warkany Syndrome

Trisomy 8 is a genetic disorder where three copies of chromosome 8 exist in every cell of an individual. You can review my earlier general trisomy post to refresh your memory on how that can occur. Recall that the chromosomes are numbered from largest (chromosome 1) to smallest. The larger a chromosome is, the more genetic information - instructions for cell development and function - it contains. Chromosome 8 is not the largest, but still contains a significant amount of DNA. Generally with three copies of chromosome 8 in each cell, too much damage is present for viability beyond early fetal development. Statistically Trisomy 8 is responsible for about 0.7% of miscarriages.

Some individuals have a different form of Trisomy 8 called mosaic syndrome, or T8mS. In T8mS only some of the person's cells have three copies of chromosome 8. The person may have cells in one type of tissue (e.g. blood or muscle) that have two copies of chromosome 8 and cells in another tissue (e.g. skin or eye) that have three copies. T8mS results from non-disjunction occurring during the process of mitosis (cell-division) rather than during meiosis (fertilization). Depending on when the mitosis goes awry there may be only a few effects, or several. However, the percentage of cells affected does not apparently correlate with the severity or which symptoms will appear.

Several distinct physical features are potential indicators of T8mS, including: low-set or abnormal ear shape, bulbed nose, strabismus (eye turns in), structural heart problems, palate abnormalities, and deep hand and feet creases. T8mS can also cause cognitive impairment and delays that may be mild or moderate. Treatment depends greatly on the symptoms of each individual. Heart problems can usually be corrected with surgery as can cleft palate. Strabismus can be treated with an eye-patch therapy or surgery.

More information on Trisomy 8 can be found here. During my research for this post, I also ran across the website for a support group called Unique. They distribute detailed information and provide support for individuals with T8mS and other genetic disorders.

Trisomy

Trisomy is an umbrella term for several genetic conditions in which three copies of one or more chromosomes is present in the cells of an individual rather than two copies of each chromosome. Usually human cells have 23 pairs of chromosomes for a total of 46. During the process of producing eggs and sperm (Meiosis - scroll down to "Making New Cells and Cell Types" in this link for detailed description and diagrams) the parent's chromosomes (2n) are divided in half among "daughter" cells. Usually each daughter cell gets half (n) of each chromosome pair. Trisomy occurs when one daughter cell gets an extra copy of a chromosome (n+1) due to nondisjunction (the chromosomes do not separate). The other daughter cell loses a copy (n-1), which results in monosomy. Upon mating an n+1 gamete combining with an n cell from the other parent produces an offspring with 2n+1 chromosomes (trisomy). An n-1 gamete combining with an n cell from the other parent produces an offspring 2n-1 chromosomes (monosomy) -- these zygotes are generally not viable.

In the process of researching this post I drew myself a diagram to consolidate some of the information I was gathering, to illustrate the formation of a 2n+1 zygote. I'm sharing it here with a couple of disclaimers. Please note that this is only one sequence that could lead to trisomy. Also, I am not a molecular biologist, so my diagram may be overly simplified, but hopefully is clear enough to explain the basic steps. Click on the picture to see a larger version...

Trisomy may result in conditions that are life-threatening to the offspring. In some cases the child will have severe physical or cognitive challenges. In other cases the issues can be so mild as to go undiagnosed. The latter is particularly true of  some sex chromosome trisomies.The degree of severity appears to be related to the amount of genetic information that is affected. Because the chromosomes are numbered according to size, with 1 being the largest chromosome, the lower numbered chromosomes are responsible for more DNA or genetic information than the higher numbered chromosomes. Trisomy 21 (Down Syndrome) affects one of the smaller chromosomes, fewer genes are affected, and so fewer challenges affect the developing child relative to trisomy of lower numbered chromosomes.

There are several kinds of trisomy that affect the autosomes (the non-sex determining chromosomes):
Trisomy 8 - Warkany Syndrome
Trisomy 9
Trisomy 13 - Patau Syndrome
Trisomy 16
Trisomy 18  - Edwards Syndrome
Trisomy 21  - Down Syndrome
Trisomy 22  - Cat eye Syndrome

There are also several kinds of trisomy affecting the sex chromosomes:
XXX - Triple X Syndrome
XXY - Klinefelter's Syndrome
XYY - XYY Syndrome

I hope to explore each trisomy in more detail in future posts. For now I hope understanding more about how these conditions arise has been helpful. I also wanted to share a link for SOFT (Support Organization For Trisomy 18, 13, and Related Disorders), an organization that supports families affected particularly by Trisomy 18 and 13. Besides Down Syndrome, these are the most common forms of trisomy, and finding support is a critical step.

Phelan-McDermid Syndrome Primer

I first heard about Phelan-McDermid Syndrome (also called PMS, but not to be confused with the female monthly cycle issues) after reading this recent blog post on Autism Speaks. PMS is related to autism due to behavioral symptoms (poor eye contact, social anxiety, and perseverative actions) but some question whether the genetic deletion is a cause of autism or if it separates these individuals from other spectrum disorders. Because many of the symptoms overlap, children with PMS may be diagnosed with autism or ADHD or dystonic CP or some combination of these unless a specific genetic test is performed.

PMS is cause by the absence or loss of genes at the tip of Chromosome 22 (a 22q13 deletion). The loss of Shank3/ProSAP2 gene is suspected to be the primary cause of the symptoms associated with PMS. The Shank3 gene plays a role in the formation of the nervous system during fetal development. As in many spectrum disorders, invididuals with PMS may have mild or more severe challenges in several areas, including:

• delayed or absent speech and communication
• low muscle tone (hypotonia) - delayed sitting up, rolling over, crawling, walking
• challenges with eating (sometimes beginning with bottle/breast feeding as a newborn)
• sleep disturbances
• emotional instability

There are also some physical characteristics that may be present:

• may be tall for their age
• subtle facial features: long head shape, puffiness around the eyes, long eyelashes, droopy eyelids, puffy cheeks, large ears
• large fleshy hands, underdeveloped toenails, lack of perspiration - easily overheat.

Both the autism speaks blog above and an article at the Phelan-McDermind Syndrome Foundation website note that as individuals with PMS get older and more skills are expected they fall further behind and their challenges become more apparent. There is also some evidence that individuals with PMS may lose one skill while they make progress in another area.

PMS and Fragile X Syndrome both present strong arguments for the benefits of genetic testing - basically to receive a more specific diagnosis that will allow more focused efforts in intervention, support, and treatment. Some of the comments from the autism speaks blog article seemed to imply that this level of specificity is not necessary if the child is "accepted" and supported in their education and development. What do you think about these issues? We have not pursued any genetic testing for our daughter (yet) mostly due to financial considerations and insurance concerns. Certian phrases in this article made me wonder if we should, though. For instance similar to the little girl highlighted by Autism Speaks, several people have noted that our daughter is "too social" to be autistic, though that is her official diagnosis. I maintain that though she enjoys being with people she does not understand social constructs...her desire to be with people is a great motivator for helping her learn some of the obvious rules of social behavior, but some of the more subtle interactions still seem to be beyond her reach. I am more curious than ever whether we should consider genetic testing and whether it would clear up some of the mysteries we continue to face, but given our excellent progress to date I wonder how much we would gain. I welcome your input...just click on comments below.

If you are interested in learning more about Pheland-McDermid Syndrome I suggest you begin here.

Fragile X Syndrome

Over the last year or so I've written some short pieces about Fragile X Syndrome, but I've never written a primer about it. It is timely to do so now for a couple of reasons. First, a group of Fragile X advocates - parents, doctors, therapists and researchers - recently completed an annual trip to Washington, D.C. to meet with various congressional leaders to encourage them to increase funding for research into Fragile X Syndrome, and to sponsor legislation to benefit individuals with Fragile X and other special needs. Second, in just a few short days Autism Awareness Month (April) will begin.

Are you aware that for 2-6% of all individuals diagnosed with autism, the Fragile X gene mutation is the cause? That may not sound like much, but it is the largest known, single-gene mutation cause of autism. You can learn more about the distinction between the two disorders and the link between them by reading here. Suffice it to say that anyone diagnosed with autism should be tested for the Fragile X mutation and that any strides toward understanding and treating Fragile X may help us learn more about autism, too.

Fragile X is also the most common inherited form of cognitive disability. It begins as a mutation on a gene (FMR1) found on the X chromosome. This mutation affects the structure of the X-chromosome such that under magnification it actually looks "broken", hence the name of the disorder. The FMR1 gene is responsible for instructing cells how to make the protein FMRP. The role of FMRP is not known, but clearly has some role in brain development. In the simplest scenario, because FMR1 is located on the X-chromosome, Fragile-X is carried by females. Since females have two X-chromosomes one can still generate FMRP if the other bears the FMR1 mutation; they have the mutation, but not the disorder. Males with a fragile X cannot make FMRP and will develop the characteristics of Fragile X Syndrome. However, both males and females can be carriers and both males and females can have Fragile X, so it's complicated.

In addition to behavioral characteristics that are similar to autism (language delays, motor delays, sensory disorder, poor eye contact, etc.) often individuals with Fragile X have some physical characteristics in common (large ears, long face, soft skin, flexible joints, and flat feet). Usually there are cognitive issues ranging from mild learning differences to severe cognitive disabilities.

To learn more about Fragile X, I recommend starting at the National Fragile X Foundation website. In particular, this video, which I have linked to before is very powerful.

Dyslexia

After profiling several rare disorders I thought I should look at something that is quite common. According to some sources Dyslexia is the most common learning disability among children - it affects an individual's ability to read, write, spell and sometimes speak even though their cognitive abilities are average and there is no hearing or vision impairment to explain the difficulty. Dyslexia can be mild or severe and is a life-long condition with no cure. However, the symptoms may change over time, and many strategies and coping skills can be learned to overcome the challenges. I was told some time ago that children with speech and language delays are more likely to have challenges later with reading, so I've been on the look out for dyslexia in my daughter for quite a while. She is now almost seven, and she is reading, but still struggling somewhat. Her teacher assures me that she's on track and progressing. I decided I should educate myself a little and learn what exactly I should be watching for.

When I started researching for this post all I knew about dyslexia is the symptom of writing letters and numbers backward or mixing up the sequence of letters or digits when reading or writing. Reversing letters and numbers apparently is quite common until age seven or eight and then should diminish. Some other symptoms of dyslexia include:

• disorganized writing
• challenges remembering story elements even from favorites
• difficulty with spatial relationships - both academic and athletic
• confusion of left and right; may not use one hand dominantly
• difficulty moving in rhythm with music
• may not remember or understand oral instructions
• following more than one command at a time is challenging
• may struggle with verbal expression, at a loss for words even if they know what they want to say.
• emotional difficulties may arise - withdrawal, depression, poor self-esteem
• behavioral issues - social challenges, acting out, may appear lazy

Some of these symptoms of course overlap with other disorders, so it is important to pursue appropriate assessments in order to reach an accurate diagnosis. Evidently there is a whole list of tests and assessments that can be used to pinpoint the exact area of difficulty a student is having with their reading. Appropriate strategies and coping skills can then be taught to overcome that challenge.

There are actually three main causes of dyslexia:
1) Trauma induced dyslexia occurs after some accident or other injury affects the area of the brain that controls reading and writing. This is increasingly rare in our populations, probably thanks to the now widespread use of car seats and seat belts in vehicles, and helmets for bicycling, etc.

2) Primary dyslexia occurs from the congenital dysfunction of the cerebral cortex (left hemisphere) and is an inherited disorder that most commonly affects boys. This form does not change over time and often limits reading abilities to a fourth grade level.

3) Developmental dyslexia is thought to be caused by hormonal effects during early fetal development. This form is also more common in boys, but also diminishes as the individual matures.

Parents should consult with school staff if they suspect dyslexia is affecting their child's ability to learn. If the child already has an IEP their plan can be modified to specifically address this concern. If the student does not already have an IEP the school will likely begin by assembling a Student Study Team which includes relevant school staff and the parents. Within this team a strategy to assess and support the student's learning can be developed.

For more information about dyslexia:


MedicineNet article and discussion
Learning Disabilities Online

I also thought I would mention that a friend of mine, Janet Ann Collins, recently published a children's book where some of the main characters are affected by dyslexia. It's called Signs of Trouble. She posted the cover art on Facebook today, and I'm sure that influenced my choice of topic for this post!

Batten Disease

You may remember in my post about Ralph's World I mentioned a benefit concert Ralph was doing to support Jasper Against Batten. I wanted to follow up on that post by learning a little more about Batten Disease, and thought I'd share what I learned with you. Batten Disease is named for Dr. Frederick Batten who first described the juvenile form of this disease in 1903, formally known as Neuronal Ceroid Lipofuscinosis (NCL). There are actually four types of Batten Disease, differentiated primarily by the age of onset. In all cases NCL or Batten Disease has a root cause in a genetic mutation that leads to inefficient waste removal from neurons (nerve cells) in the brain. As the waste builds up the neurons begin to fail leading to seizures and progressive loss of sight, motor skills, and cognitive abilities. Eventually all forms of the disease are fatal. The earlier degeneration begins the shorter the expected life span. So in Infantile NCL which begins between ages six months to two years, the child will usually not survive beyond early childhood. Meanwhile, adult onset NCL, which is extremely rare, begins before age 40 and results in a somewhat shortened lifespan. Late Infantile Batten begins between ages 2-4 years; Juvenile Batten begins between the ages of 5-8. All forms of the disease are rare because in order to contract the disease a child must inherit two recessive genes, one from each parent. Each offspring of such a couple has a 1:4 chance of contracting the disease and a 1:2 chance of becoming a carrier (having one copy of the recessive gene).

In short, this is one of those devastating diseases that is hidden in the maze of our DNA, is not evident prenatally, is degenerative, fatal, and rare. The intersection of these characteristics results in an "orphan" disease, meaning there is little research into the cause, possible treatments or final cure. Big pharmaceutical companies, sadly but understandably, put their efforts toward diseases that have big markets: diabetes, cholesterol, cancer, and the like. That leaves smaller laboratories, usually government agencies or academic institutions to pursue evils like Batten.

The family that started Jasper Against Batten are real heroes in this fight. Their son, Jasper, has Late Infantile Batten, and aside from the energy they have put into their own personal fight, they started a foundation to raise money to support research of treatments for all forms of NCL. Their story reminds me of the Lorenzo's Oil story and again why we should advocate and that each life is sacred and powerful.

Sunday Digest 23

Time to share a few links that I've found over the last few weeks that seem especially important or inspirational to me.

1) I have really been enjoying Reports from a Resident Alien. This blog is written by a young woman who is on the autism spectrum and studies biomedical engineering in college. Perhaps it is my science background that connects here, but there is also a piece of me that sees a role model for my own daughter. At any rate, I am always interested to hear from individuals on the spectrum as I think they can teach us so much about how to best support others on the spectrum. Lisa's recent post about "stimming" is an excellent example of this. There are a lot of misconceptions out there about what stimming is and how it should be addressed by neurotypical individuals. I especially appreciated Lisa pointing out that neurotypicals use stimming too (ever find yourself fiddling with something in your hand while you are waiting for someone or having a challenging conversation?) and that there are ways to replace one activity that is too distracting or dangerous with another that is more socially acceptable or safer. This is a long post, but it is well worth the read.

2) And here's more from another favorite Lisa, at Lisa Leonard Online. She shared this story of her two sons interacting at school and how her younger son helped explain her older son's differences to some peers. We have not hit this milestone of sibling interaction yet. It may come sooner than I am ready. It is good to see that it can be a really positive interaction for all concerned.

3) I found this article about new genetic research on autism through OUR Journey Thru Autism (OJTA). The article gives some support to an idea I've been considering for a while: that there may be more than one (several even) root causes of autism that we currently lump into one disorder because the symptoms are similar. These root causes may be copy number variants (please forgive the typos in this link - it is the best layman's explanation of CNVs I could find) which I admit I do not fully understand. I have not formally studied biology since high school (um...) more years ago than I want to admit. CNVs apparently relate to the number of gene copies that an individual inherits. Usually you get two, one from mom and one from dad. Apparently sometimes in the copying process some mistakes happen - sometimes a gene is deleted and sometimes it gets stuck on the copier and you get three or four copies instead of two. Generally these mistakes are harmless and the resultant individual is not affected in any appreciable way by their genetic alteration. However, if, for example, key genes involved in neurology are affected then neurological disorders, like autism, may result. Please note this does not rule out the involvement of some environmental factor - perhaps there is something influencing the copying mechanism, or perhaps the genetic damage is "turned on" by some environmental influence. However, from my perspective as a person who studied how chemicals interact with biological systems, understanding the genetic processes involved in autism is key to identifying any environmental factors...otherwise we can chase multiple false leads and still not get to the right answers. There are simply too many chemicals out there that might be the trigger. Please don't say we should just get rid of all the chemicals. They are all around you...everything you touch, breathe, see, and eat is a chemical. I don't think you can understand the environmental factors without the genetic basis and vice versa...it is not an either or game, it is both and.

Still two links to go, and I think this is my longest "digest" yet...better find some breezy ones. :-)

4) Okay - I don't know about you, but I'm always looking for ideas of what to pack in my kid's snack AND lunch bags that have to go to school every day. She's a little picky about what she eats, but mostly she just doesn't care about eating as much as she cares about getting attention from other people, protecting her ears from the din of the lunchroom, and getting outside with time to PLAY! So lunch better be yummy, nutritious and INTERESTING! Tall order. I'll be checking out this list of snack ideas (and any others I come across) in more detail.

5) How about some music to lift your spirits? This arrangement of Crown Him with Many Crowns (1995) by Michael W. Smith gets me DANCING (and I don't dance...) every time I hear it. Enjoy!