Tag Archive | fatal familial insomnia

The Layperson’s Guide to Neural Disorders That Often Lead to Neurodegeneration and Dementia

Normal brain cellMost dementias – Lewy Body dementia, vascular dementia, early-onset dementias, alcohol-related dementia, and Alzheimer’s Disease among them – appear seemingly suddenly as primary and distinct neurodegenerative processes without definitive causes (except in the case of genetic inheritance, which primarily occurs in rare dementias like Corticobasal Degeneration, Progressive Supranuclear Palsy, and Fatal Familial Insomnia and some of the early-onset dementias).

However, there are a group of neural disorders, which are caused by the same genetic mutation that affects lipid storage in the body, that often have dementia as a secondary symptom as the diseases progress.  

Structure of cell membraneThese neural disorders (all these have sphingolipid metabolism dysfunction in common) – which include Niemann-Pick disease, Tay Sachs disease, and Gaucher disease – are characterized by by increased levels of a particular type of sphingolipid.

There is no cure for these neural disorders and they are all fatal (in many cases, during childhood).

Anatomy of a sphingolipidSpingolipids are the biological product of a chemical process that creates a protective layer on nerve cell membranes and ensures proper – and protective – cell signaling and are critical to optimal brain function.

The genesis of sphingolipids are long-chain – also known as sphingoid – bases that normally have a length of 18 carbons, although they can also have lengths of 16 or 20 carbons. The length of long-chain bases is determined by serine palmitoyltransferase (STP), a multiprotein enzyme.

Chemistry of sphingolipidIn neural disorders like Niemann-Pick disease, Tay Sachs disease, and Gaucher disease, a mutation (known as Stellar) in one of the proteins that makes up STP creates an abnormally high number of 20 carbon long-chain bases, which dramatically interferes with sphingolipid metabolism.

This causes neurodegeneration to occur. In all these neural disorders, much of the neurodegeneration begins soon after birth.

In Tay Sachs disease, neurodegeneration of the brain and spinal cord begins at about six months of age. The average lifespan is four years.

Gaucher disease has three subtypes.

In Type 1 Gaucher disease, symptoms, which include anemia, bone deterioration, and liver and spleen impairment, are non-neurological and do not materialize until middle age. The average life expectancy for Type 1 is 68 years.

Type 2 and Type 3 Gaucher disease are both neuropathic forms of the disease.  Neurodegenerative symptoms include abnormal eye movements, seizures, and systemic brain damage.

In Type 2 Gaucher disease, the onset of symptoms is within three to six months of age. Deterioration is rapid; the average life expectancy is about two years of age.

 Type 3 Gaucher disease is a slower onset and involving version of Type 2. The average onset of neurological involvement is late childhood into adolescence. Life expectancy ranges from the mid-twenties to, in extremely rare cases, the early forties.

Niemann-Pick disease has four types: Type A, Type B, Type C1 and Type C2.

Niemann-Pick disease Type A occurs in infants. Symptoms include enlargement of the liver and spleen (around three months of age) and a failure to thrive during the first year of life. At one year, widespread damage to the lungs occurs, and there is a progressive loss of neurological and motor function.

A cherry red spot on the macula is a common denominator in Tay Sachs Disease and Niemann Pick disease Type 1Along with Tay Sachs disease, Niemann-Pick disease Type A also has a common eye deformity consistent with neurometabolic disease, known as a cherry spot, that occurs within the macula and is often what initially identifies the two neural disorders.

While most children born with Niemann-Pick disease Type A die in infancy, a few may live as long as four years.

Niemann-Pick disease Type B includes most of the same symptoms as Type A (motor skills are not usually affected), but the onset of symptoms is during adolescence. Most people with Niemann-Pick disease Type B survive into adulthood, but mortality rates climb dramatically between twenty and thirty years of age.

Niemann-Pick disease Type C (C1 and C2 are caused by different gene mutations, but the symptoms are the same) is characterized by severe liver disease, severe pulmonary infections, progressive neurodegeneration, and increasing difficulty with speech and swallowing that deteriorates completely over time.

The onset of Niemann-Pick disease Type C can be at any age, but it is most commonly seen by the age of five. The life expectancy with this type is under twenty years of age when symptoms appear in childhood. When symptoms appear later, the life expectancy is ten to twenty years after symptoms begin.



The Rare Dementias: Fatal Familial Insomnia

familial fatal insomnia going gentle into that good nightFatal familial insomnia (FFI) is one of the rarest – the dominant gene that causes this type of dementia has been identified in only 28 families worldwide since its discovery in 1990 – dementias that have been identified so far.

Its first identifiable symptom occurs typically between the ages of 40 and 60 with a sudden increase in trouble falling asleep that quickly progresses to a greater inability to sleep and then just as quickly degenerates into total – and fatal – insomnia. The lifespan of a person once symptoms emerge is very short (around one year).

FFI is in a class of neurological diseases caused by prions ((Creutzfeldt-Jakob disease and its bovine equivalent, Mad Cow disease are other examples). Prions are abnormal pathogens that can be transmitted (in both humans and animals). They cause abnormal folding of prion proteins (normal cellular proteins that are found most abundantly in the brain). Prions are caused by a mutation of the PRNP gene on chromosome 20.

Prion diseases fall into three categories: sporadic, acquired, and genetic.

Sporadic prion diseases are random occurrences of these neurological diseases in people without any known risks or genetic mutations that could cause them. To date, the only prion disease that has sporadic incidences is Creutzfeldt-Jakob disease.

Acquired prion diseases occur because of exposure to the abnormal prion protein. These account for less than 1% of all prion diseases.

Genetic prion diseases are the most common form of prion diseases. FFI, along with Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker Syndrome (GSS), fall into this type of prion disease.

Since the mutated gene that causes FFI is a dominant gene, if only one parent has the mutated gene, the likelihood of his or her children having the mutated gene is 50%. If both parents have the mutated gene, then all their children will have it as well.

familial fatal insomniaThe areas of the brain most severely affected by FFI include the thalamus, the frontal cortex, and the central nervous system.

Because the first symptoms of FFI usually occur at or near the end of childbearing years, parents aren’t even aware that they are passing the defective gene on to their children. However, a diagnostic test has been developed to test for the mutated gene.

FFI has four discrete and degenerative stages.

In the first stage of FFI, the onset of sudden and unexplained persistent insomnia leads to panic attacks and irrational phobias. This stage lasts approximately four months.

During the second stage of FFI, continued sleep deprivation increases the number and severity of panic attacks and hallucinations become pervasive. This stage lasts approximately five months.

In the third stage of FFI, total insomnia occurs, resulting in rapid weight loss and very limited mental functioning. This stage can last for up to three months.

During the fourth and final stage of FFI, dementia and unresponsiveness occur. This stage can last up to six months.

There is no treatment or cure for FFI, and the mortality rate is 100%.

The Atlantic has an very interesting article on FFI that involves a 30-year-old woman whose mother died of FFI at age 52. The daughter is now working and hoping to find a way to intercept and neutralize the genetic mutation before she reaches the age where her symptoms begin. It’s a intriguing story, which I highly recommend.

For an in-depth look at the biology of prions, an excellent reference book is The Family That Couldn’t Sleep.