Friday, October 24, 2014

Transplant Decision

We found out that Laya is not a carrier of GM1 (Yay!) and she is a perfect match for Evan. Knowing this, it did make the decision a little harder. But, we have decided not to go with a Bone Marrow transplant for Evan.

Please note: I am not a scientist or doctor! The following is what I I've learned based on info from the doctors and case studies on the internet. We had to learn as much as we could about a whole different field, that's why it was hard to make the decision, we didn't feel we knew enough about it. 

We have a few main reasons for not doing the transplant
  1. We couldn't find any real evidence that doing a BMT would change the course of GM1. No guarantees, it would have been a gamble. We were initially hopeful about it, because of the success Bone Marrow transplants have had with Hurler's patients (MPS type I, a very similar diseases to ours has been able to maintain IQ over time!). But we also knew it didn't have much success, if any, with Tay Sachs disease, (GM2 Gangliosidosis). The studies we've found haven't changed the course of the disease and sometimes make the disease progress quicker. One article we found explained that GM1 Gangliosidosis works much more similarly to GM2 Gangliosidosis in the way it destroys brain cells.  MPS I seems to kill brain cells in a more round about way. (At least that's how I understand it) Once we came to that conclusion, we immediately decided not to do a BMT. We knew going into it, that everything would have to align perfectly for us to go through with a transplant. 
  2. It would have been very hard on Evan. He is at the height of his life right now. He is able to play, climb, get into everything :) and live a pretty normal life. As the course of the disease takes him, he will lose skills from here on out. It would not have been fun and he would have regressed quicker through the process and possibly would not be able to gain those skills back even if the transplant was "successful." 
  3. 10% chance he would die from the process or from complications by it. 
  4. Another 10% chance the transplant would not be successful and he would have do get another transplant. (At least I believe that's what they told me)
Note: If Evan had Hurler Syndrome, we probably would have done a Bone Marrow transplant, since Laya was such a perfect donor for him and he has not had much mental regression (if any) from the disease. There would be a strong hope of prolonging much better mental stability and learning ability. 

Clinical Trial offers some hope for us: 
We are hoping to be involved (Evan and Eli) in the clinical trial called Syner-G using the drug Zavesca along with the Ketogenic diet. There is the theoretical possibility that it will slow down the progression of the disease and possibly halt it for a time. None of that has been proven yet, so up to this point, it is still all speculative. 

Jeanine Utz at UMN has been working with our insurance. First they tried to just put the drug through, it didn't work and they wanted a prior authorization. The insurance then denied the prior-auth, so now the team is working on an appeal. She said they would have the appeal done by 10/28/14. So we'll see what happens. She indicated that this was completely normal and frankly it usually happens this way. We shall wait and see. 

As we were trying to decide about transplant, I looked around the internet to find some data on some of these BMTs. Here are some links we found. 

My conclusion: Overall success of BMT in Hurler Syndrome - MPS I

BMT in Hunter syndrome - MPS II My conclusion: it hasn't shown much success Neurologically

Little Bone Marrow success in Tay-Sachs, Sandhoff and GM-1

Three kids journey with TaySachs and BMT: This story can really freak you out if you are considering a transplant. I think the story is spun a certain direction, but the events are accurate.  - Overview of the story
Article from a parent of Dakota
Dakota at age 8 with her parents  - (Dakota lived to age 15, she died spring 2014, I believe.)

Animal Model
O'Brien et al. (1990) performed allogeneic bone marrow transplantation early in life in a case of canine GM1-gangliosidosis. Despite successful engraftment, no benefit was found. 

Substrate reduction therapy.


The therapeutic options for lysosomal storage diseases (LSDs) have expanded greatly over the past decade, although for many disorders there is still no effective treatment. Given that the majority of LSDs involve pathological changes in both the brain and peripheral tissues, effective treatment of central nervous system (CNS) and peripheral manifestations still remains a considerable technical challenge. Type 1 Gaucher disease has two approved treatment modalities - enzyme replacement therapy (ERT) and substrate reduction therapy (SRT) - which have unique, independent and potentially complementary mechanisms of action. The availability of these two therapies has greatly increased the options for the effective clinical management of type 1 Gaucher disease. ERT involves the intravenous administration of fully functional enzyme that is taken up by cells and delivered to the lysosome, where it can compensate for the underlying enzyme deficiency. SRT uses an orally available, small molecule drug that inhibits the first committed step in glycosphingolipid biosynthesis. The aim is to reduce the rate of biosynthesis of glycosphingolipids to offset the catabolic defect, restoring the balance between the rate of biosynthesis and the rate of catabolism. SRT also has the potential to treat LSDs with CNS pathology, as the drug in clinical use (miglustat, Zavesca; Actelion Pharmaceuticals Ltd, Allschwil, Switzerland) crosses the blood-brain barrier. In this review, the current status of SRT for the treatment of Gaucher disease and other LSDs will be discussed, based upon preclinical and clinical studies.


SRT is an oral alternative treatment option for patients with type 1 Gaucher disease unwilling or unable to receive ERT. With the recent reports of clinical improvement/stabilization of CNS manifestations following SRT in patients with Niemann-Pick disease type C, miglustat may also have a role to play in the management of patients with glycosphingolipid storage in the brain. Furthermore, as SRT synergises with other therapeutic modalities, it may also prove to be a key component of combination therapies in the future.
Status at Minoryx

Through its proprietary technological platform (SEE-Tx), Minoryx has identified a novel series of non-competitive pharmacological chaperones which are able to stabilize GLB1 and restore its enzymatic activity.

These compounds are binding on a novel site identified through SEE-Tx and contrary to pharmacological chaperones targeting the active site, they do not inhibit GLB1. Also, Minoryx has established collaborations with many of the academic groups leading research on this field.
Currently the project is at lead optimization and a development candidate is expected in the following months. Such compound would be a first-in-class drug for the treatment of GM1-glangliosidosis and/or Morquio B diseases.

Thursday, October 2, 2014

Exhaustive list of GM1 Symptoms

 I tried to make this list as comprehensive with regards to possible symptoms as I could. I combined any of the information I have been able to find. 

Eli and Evan Leishman were diagnosed with GM1 Gangliosidosis Type II in August 2014

There is no established cure at this point, although treatment and study is being developed to possibly slow or arrest the progression of the disease.  

What is GM1 gangliosidosis? A type of Lysosomal Storage Disorder which also falls under the categories of Genetic Brain Disorders, Inborn Errors of Metabolism and Metabolic Disorder  
It is a beta-galactosidase-1 (GLB1) enzyme deficiency.  GM1 Gangliosidosis is an inherited disorder that progressively destroys nerve cells (neurons) in the brain and spinal cord. It is an inherited disease in which one or more enzymes in the lysosomes are defective. Lysosomes are cell's recycling centers, where proteins, fats and other molecules are broken down into their basic building blocks, which are then reused to make new molecules. Lysosomal storage diseases occur when lysosomes lack the enzymes they need to perform their recycling tasks, leading to abnormal accumulation of the molecules the lysosome is supposed to break down. 

Eli and Evan have been diagnosed with GM1 type 2, the late-infantile or juvenile type. There are 3 types of GM1 presented below, but the features can overlap significantly. Some believe GM1 to be a continuous disease spectrum instead of three distinct types. 

Symptoms of GM1 
*I starred the symptoms I've seen in my own children.

Neurologic findings  
*developmental delay, arrest and regression 
*Exaggerated startle reaction to loud noises
*Tonic-Clonic Seizure - generalized seizure that affects the entire brain.  
*Dementia – a loss of brain function that affects memory, thinking, language, judgment and behavior.  
*Speech delay then speech disturbance and speech loss (Type I - Infantile Types usually don't develop speech at all)
*profound intellectual disability 
*Severe psychomotor retardation -involves a slowing-down of thought and a reduction of physical movements in an individual. 
Muscular System (Often Neurologic in source)
Joint contractures - stiffness or constriction in the joints that restricts normal movement. It develops when your normally pliable connective tissues become less flexible. 
*Generalized Hypotonia (low muscle tone) initially, developing into spasticity.   
*Spasticity is stiff or rigid muscles. It may also be called unusual tightness or increased muscle tone. Reflexes (for example, a knee-jerk reflex) are stronger or exaggerated. The condition can interfere with walking, movement, or speech. 
*Muscle Weakness 
Hyperreflexia – Is defined as overactive or over-responsive reflexes. Examples of this can include twitching or spastic tendencies.
Generalized dystonia – painful muscle contractions resulting in uncontrollable distortions. It causes twisting and repetitive movements or abnormal postures.  
*Ataxia – a balance disorder, consisting of lack of voluntary coordination of  muscle movements. (Type I infantile cases are usually unable to develop the ability to sit or walk in the first place)
*Decerebrate rigidity (decerebrate response, extensor posturing) - it describes the involuntary extension of the upper extremeties in response to external stimuli. In decerebrate posturing, the head is arched back, the arms are extended by the sides, and the legs are extended.[6] A hallmark of decerebrate posturing is extended elbows.[12] The arms and legs are extended and rotated internally. 
*Growth Retardation 
Ophthalmologic findings
*Clouding of the clear outer covering of the eye (the cornea)
Loss of vision as the light sensing tissue at the back of the eye (the retina) gradually deteriorates  
cherry-red spot - about %50 develop it 
*StrabismusStrabismus is a disorder in which the two eyes do not line up in the same direction, and therefore do not look at the same object at the same time. (Eli has had three eye surgeries to correct this, before his diagnosis)
Optic atrophy - the optic nerve, which carries impulses from the eye to the brain begins to waste away or deteriorate 
Retinal hemorrhage is a disorder of the eye in which bleeding occurs into the light sensitive tissue on the back wall of the eye. 
*Nystagmus is a term to describe fast, uncontrollable movements of the eyes. 
Dysmorphic features
(These features display in some infantile cases, but are usually not present with juvenile or adult)
Frontal bossing a prominent, protruding forehead.
Depressed nasal bridge and broad nasal tip 
Large low-set ears  
Long philtrum - the skin between the nose and mouth 
Course skin, thick skin 
Gingival hypertrophy  - enlarged gums 
Macroglossia – unusually large tongue 
Hirsutism – excessive amounts of hair, broad hands and feet 
Brachydactyly - shortness of the fingers and toes. 
Facial Edema - or facial swelling  
Cardiovascular findings
Dilated and/or hypertrophic cardiomyopathy  is a condition in which the heart becomes weakened and enlarged and cannot pump blood efficiently.  (common in Infantile Cases)
Atrial tachycardia is a type of atrial arrhythmia (faster heart rate) 
Skeletal abnormalities
*Lumbar Gibbus deformity is a form of structural kyphosis, where one or more adjacent vertebrae become wedged, producing a hump outward curviture in the lumbar region. (Eli's kyphosis in his lumbar spine was noticed by his mother a few months before he turned 3. He was prescribed a stiff body brace to wear 23 hours per day. He wore that for more than a year)
Dorso Lumbar Kyphoscoliosis - describes an abnormal curvature of the spine in both a coronal and sagittal plane. It is a combination of kyphosis and scoliosis. 
Digestive, Lymphatic and Respiratory System
Poor appetite, poor sucking in infants 
Hepatosplenomegaly (HSM) enlarged liver and spleen 
Inguinal hernia – protrusion of abdominal cavity contents through the inguinal canal 
Umbilical Hernia - An umbilical hernia is an outward bulging (protrusion) of the abdominal lining or part of the abdominal organ(s) through the area around the belly button. 
*Swallowing disturbance,*spitting/throwing up and thicker mucous production (Started with spitting up after meals probably at least twice a day and coughing while drinking water or eating. At the beginning Eli was sent home multiple times from school because of throwing up, but he never turned out to be sick. (age 5) Then he had trouble swallowing water and would spit out at least half of the water out of the corner of his mouth while drinking. Got a feeding tube at age 6. As of 1/20/18 Eli's swallowing disturbance is including terrible choking episodes, even though he is tube fed only at this point (age 8). He has choking episodes from choking on spit up or thick saliva or secretions.)
Recurrent bronchopneumonia -  is the acute inflammation of the walls of the bronchioles 
Reproductive System 
Swelling of the scrotum 
Other Rare symptoms
Angiokeratoma corporis diffusum (reported infrequently) also called Fabry disease 
Hydrops fetalis (has been reported) - is a serious condition in which abnormal amounts of fluid build up in two or more body areas of a fetus or newborn. 
*Prominent dermal melanocytosis (Mongolian spots) (Has been reported) - Mongolian  spots are flat, blue, or blue-gray skin markings near the buttocks that appear at birth or shortly thereafter. (I've seen mongolian spots on Evan's body much more than Eli's) 

Prognosis/Life Expectancy for GM1 Gangliosidosis
Prognosis will vary based on how aggressively parents choose to uphold life, but most sources say the following:

Type I Infantile Form
Type I is the most common form of the disease and usually becomes apparent by 6 months and can have most, if not all, of the symptoms listed above. 
Life Expectancy - Individuals with GM1 gangliosidosis Type I usually do not survive past early childhood, often succumbing during the second year of life because of infection and cardiopulmonary failure. 

*Type II Late infantile and juvenile forms
Age of Onset - Some sources I've found say age of onset for late-infantile is around 18 months of age and the age of onset for juvenile closer to 5 years. Other sources combine the two forms, late-infantile/juvenile form as having onset between 7 months and 3 years. Another source I've found completely takes out the juvenile type and describes the late infantile as having an onset typically between ages 1 and 3 years with the adult striking between ages 3 and 30. 

Type II can have all the same symptoms as Type I, but at a later onset (and with slower progression), with the exception of dysmorphic features, cherry red spots and enlarged organs which are not usually found with late-infantile and juvenile children. Common neurological symptoms include ataxia, seizures, dementia, and difficulties with speech.
Life Expectancy - Type II progresses more slowly than type I, but still causes a shortened life expectancy. People with the late infantile form typically survive into mid-childhood, (around 6-12 years) while those with the juvenile form may live into early adulthood. 

Type III or Adult onset
The third type of GM1 Gangliosidosis is known as the adult or chronic form, and it represents the mildest end of the disease spectrum. The age at which symptoms first appear varies in GM1 Gangliosidosis type III, onset generally during childhood or adolescence and by cerebellar dysfunction. 
Symptoms: The characteristic features of this type include involuntary tensing of various muscles (dystonia), abnormalities of the spinal bones (vertebrae), slowly progressive dementia, dysathria, dystonia, corneal clouding in some patients, short stature, mild vertebral anomalies and ataxia. Eye movements are normal. Angiokeratomas may develop on the lower part of the trunk of the body. Most patients have a normal size liver and spleen.  

Life expectancy varies among people with GM1 gangliosidosis type III, but a shortened life expectancy is likely.

Aspiration pneumonia - patients with G M1 gangliosidosis are at risk for aspiration pneumonia and recurrent respiratory infections resulting from neurologic compromise. 
Congestive heart failure may result secondary to cardiomyopathy.
Atlantoaxial instability Atlantoaxial instability (AAI) is characterized by excessive movement at the junction between the atlas (C1) and axis (C2) as a result of either a bony or ligamentous abnormality. Neurologic symptoms occur when the spinal cord is involved. This can develop because of abnormally shaped cervical vertebrae. If this occurs, patients should be monitored, and they eventually should undergo surgical stabilization to avoid the risk of spinal cord injury.