2. Grasping the Big Picture

One main issue to be faced is the “big picture”.

What is it that you are facing? Whether you really wish to know are not; you need to know. Trust me you need to know. Ask every single question you can imagine and search for as many second opinions as needed until you truly feel you are grounded. It took me years of research to find this spot, but it is worth the effort. There have been regrets for some past decisions but let me be clear when I say that you can not live in the past, you must strive to move forward. So, let’s continue on.

I will now share some currently published information from a Cleveland Clinic article updated 4/11/2022 focused on Genetic research (https://kdp.amazon.com/en_US/help/topic/G200645680).

There are now more than 20 types of lissencephaly. Most of them are separated into two main categories: classic lissencephaly (Type 1) and cobblestone lissencephaly (Type 2). Each category shares similar symptoms but different genetic mutations.

Lissencephaly is indeed rare. Researchers estimate that lissencephaly affects about 1 out of every 100,000 babies.

Symptoms of lissencephaly may include:

  • Seizures (epilepsy develops in the first year of life in 9 out of 10 lissencephaly cases).
  • Difficulty swallowing (dysphagia) and eating.
  • Developmental delays.
  • Mental disability and learning differences.
  • Muscle spasms.
  • Issues with psychomotor functions, such as hand-eye coordination, movement, and dexterity.
  • Failure to thrive (slow physical development in a baby or child).
  • A smaller-than-normal head size (microcephaly).
  • Congenital limb differences involving their hands, fingers, or toes.

What causes lissencephaly? Well, Lissencephaly is caused by both non-genetic and genetic factors and develops in fetuses between the 12th and 24th weeks of pregnancy.

These factors cause impaired neuronal migration of the outer region of the brain during fetal development. Your cerebral cortex, the part of your brain that’s responsible for conscious movement and thought, normally has several deep gyri and sulci (grooves and folds). During fetal development, new cells that’ll later turn into specialized nerve cells normally migrate to the surface of the fetus’s brain. This is called neuronal migration, and it results in the formation of several cell layers. These layers form gyri.

In cases of lissencephaly, the cells don’t migrate to where they’re supposed to, and the fetus doesn’t have enough layers of cells in their cerebral cortex. This causes a lack of or underdevelopment of gyri.

Non-genetic causes of lissencephaly include:

  • Viral infections of the pregnant mother or fetus, especially during the first trimester (the first to twelfth week of pregnancy).
  • A lack of oxygenated blood (ischemia) to the fetus’s brain while they’re developing in the uterus.

Genetic causes of lissencephaly are due to genetic mutations. A genetic mutation is a change in a sequence of your DNA. Your DNA sequence gives your cells the information they need to perform their functions. If part of your DNA sequence isn’t complete or is damaged, you might experience symptoms of a genetic condition. A baby can inherit a genetic mutation from either or both of their biological parents, depending on how the mutation is passed down, but some mutations occur randomly with no previous history of the mutation in your family.

Scientists have discovered several gene mutations that can cause lissencephaly. Some of the affected genes include:

  • LIS1 (PAFAH1B1): A mutation or deletion in the LIS1 gene is associated with both isolated lissencephaly and Miller-Dieker syndrome.
  • DCX: DCX is located on the X chromosome. Since males (AMAB) have one X chromosome and one Y chromosome, they are more likely to be severely affected by this gene mutation that causes lissencephaly. Females (AFAB), who have two X chromosomes, with the same mutation usually have a milder version of the condition.
  • ARX: Infants with an ARX gene mutation have other symptoms along with lissencephaly, such as missing sections of their brain (agenesis of the corpus callosum), abnormal genitalia and severe epilepsy. ARX is also located on the X chromosome, so males are typically more severely affected by this mutation than females.
  • RELN: A mutation of the RELN gene causes Norman-Roberts syndrome, which includes lissencephaly.

And then we come to the question. How is lissencephaly treated? There’s no cure or main treatment for lissencephaly. Instead, healthcare providers target treatment toward the specific symptoms that each child with lissencephaly has. Here Cleveland Clinic is recommending that treatment may require the coordinated efforts of a team of specialists, including:

  • Pediatricians.
  • Neurologists.
  • Gastroenterologists.
  • Nutritionists.
  • Respiratory therapists
  • Occupational and physical therapists.

One important message I wish to convey in this lecture is that, in my experience, there is generally a lack of team collaboration in common practice for Lissencephaly and perhaps other rare disorders. Many specialists treat the secondary diagnosis’ independently from the main diagnosis.

Question – on a related topic.

What is the life expectancy of a child with lissencephaly? The life expectancy of lissencephaly is generally short. Many children with the condition die before they reach 10 years of age. The most common cause of death among people with lissencephaly is aspiration (breathing in a foreign object, such as sucking food into your airway) and respiratory disease.

In a best-case scenario, those with a milder form of Lissencephaly may have a life expectancy up to 20 years.  Joy, our daughter, was placed in an even milder category thought not to affect life expectancy. She was born with the X-linked form of Lissencephaly and with the even rarer condition of Double-Cortex.

With that said, I recently Googled the question: “How long can someone live with Lissencephaly?” The answer set me back: the oldest known person living with Lissencephaly died at the age of 30. Our daughter is now 36 years old.

Oh, let me also state for all individuals with Lissencephaly that the term “smooth brain” from our experience, does not mean the lack of or absence of thought. Their understanding is clearly expressed differently from ours.

Here, I am going to insert what may be considered a Doctoral Thesis wrapped up in a peanut shell.  Classic Lissencephaly, which may theoretically affect up to 200,000 individuals, is found in about 99% of Lissencephaly cases.  These individuals have one Cortex, as do all healthy brains, but the Cortex is unusually smooth and there is a smooth-variance through-out all levels of this condition.

Then we have Double Cortex or Subcortical Band Heterotopia; although still part of the Lissencephaly family, there is one distinct difference which sets it apart.  As you may have already realized, these individuals have not one but two cortexes, slightly separated by white (brain) matter and thus form an unusually thick cortex (we are not sure if the outer cortex is the only cortex which is smooth in nature).  This condition is only shared by about 200 individuals, as I previously mentioned (literally affecting 1 in 39 million individuals). More recent research has uncovered that an individual may have Double Cortex without having Lissencephaly. Think about that for a moment.

Joy has severe difficulties with both gross and fine motor skills (she is unable to bathe or dress herself); she has difficulties with eating and speaking.  Her brain needs a lengthy time to process any response.  In short, this condition greatly impedes the brains’ ability to communicate with its own body.

Although the prior information from Cleveland Clinic shared that in 9 out of 10 cases epilepsy begins by age one, Joy came down with epilepsy as she was turning nine years old. She is now entering her twenty-seventh year of seizure activity. Joy’s cognitive level at age 36 remains stable at about that of an autistic two-year-old and with this said, she is considered to be a genius for her diagnosis; this opinion was shared by Dr William Dobyns who headed up a Genetic Research Team on Lissencephaly (we’ve met on several occasions). The individuals in most of the other levels may only reach a cognitive level of 3 to 5 months of age.

So, actually, what is the reality of Lissencephaly (smooth brain), especially with Double Cortex?  This has been our challenge for 36 years. I’ll expand a little here from my earlier comments. You see, Lissencephaly actually has little to do with the brain lobes (they are generally normal) and everything to do with the cortex in my understanding.

Here is an analogy which I hope creates a clear model for you: Take a piece of aluminum foil and wad it up tightly into a small ball; then gently open it up. Can you visualize this? This would represent a normal Cortex with lots of grooves and folds all over its surface. It is on this type of terrane that all our neurotransmitters and receptors flourish (we don’t have millions of them, but we do have hundreds of thousands of neurotransmitters/receptors). They are the mechanism by which all information is transmitted in and out of our brains.

Now take the same open piece of foil and run it under a warm iron with 2 or 3 passes; you may still see all the same creases, but many of the grooves and folds are gone; this represents smooth brain.  Without the grooves and folds on the Cortex, there is a significant decrease in the number of survivable and operational neurotransmitters with their corresponding receptors.

So how many less?  Your guess is as good as mine.  But here are two questions:

  • 1) How many less neurotransmitters/receptors would it take to reduce the operation of a normal adult brain to that of an autistic two-year-old?
  • 2) How many neurotransmitters/receptors might be found on the Cortex, let’s say, in a severe case of Lissencephaly in which an individual may not live long enough to be discharged from the hospital after birth?

Questions such as these are food for thought.

You see, I’m not simply talking about intelligence or even Epilepsy; the brain, as you know, also sends out messages to the body intended to move your muscles: so, your lungs will expand and contract (We know what would happen if those muscles stopped working). The brain will also let your body know when it is time to use the bathroom, and we know what happens when our body doesn’t clearly get that message.  You may learn more about this as you age.  Trust me on that point.

The brain supports our body’s ability to live.  Do you get my point here?  All treatments for those individuals with rare disorders should only be guided by conventional treatment programs, not “locked” into them (especially for those 90% plus disorders for which there is no FDA approved treatment plan).

There is a world of difference between a patient with Heterotopia (a concussion) and a patient with Lissencephaly/Subcortical Band Heterotopia (smooth brain).  Should the same treatment plan for Epilepsy be used on both groups of patients? I would say, no. Medications are certainly on the table, but should be used to design a unique treatment plan for a unique individual.