French Settlement Disease
and the Hereditary Spastic Paraplegias

Diana Claire Stoute
John P. Doucet, Ph.D.

What is French Settlement Disease?
French Settlement Disease (FSD) is a rare, inherited disease named after the small community where it was first discovered. French Settlement, Louisiana, is located on the Amite River, about 90 miles northwest of New Orleans. The town of about 1000 is part of Livingston Parish, which is the Louisiana equivalent of a county.

For generations, residents of French Settlement have been aware of a rare genetic disease. It was first reported in the medical literature in 1979. FSD is inherited in an autosomal recessive fashion which means that the affected child must inherit the gene from both parents. FSD belongs to the group of genetic diseases called Hereditary Spastic Paraplegias. The underlying genetic cause of FSD is not yet known.

What is Hereditary Spastic Paraplegia?  
Hereditary Spastic Paraplegias (HSPs) are genetic diseases that affect muscles and movements of the lower limbs and torso of the body. There are over twenty different types of HSPs, and the genetic cause for some of these has already been discovered. Doctors estimate that about 20,000 people in the U.S. are affected by one of the HSPs.

The main symptom of an HSP is difficulty walking due to weak and stiff (“spastic”) leg muscles. This weakness and stiffness begins suddenly and slowly gets worse with age, often becoming severe and debilitating. Although symptoms of an HSP are usually confined to the lower extremities, some patients experience upper body problems also, such as problems with the arm or problems with speech or swallowing.

HSPs are difficult to diagnose because the age of onset, the severity, and the rate of worsening vary widely, even within affected members of the same family. The first symptoms of an HSP typically include balance problems, stumbling, or stubbing the toe.

What is Complicated HSP? 
“Complicated” HSP is the diagnosis given to an individual who suffers with lower extremity spasticity along with such neurological problems as peripheral neuropathy, seizures, ataxia, optic neuropathy, retinopathy, dementia, mental retardation, and deafness. Some of these problems associated with Complicated HSP may be life threatening.

An individual diagnosed with lower body spasticity along with one or more less severe symptoms is said to have “uncomplicated” or “pure” HSP. Such symptoms include balance problems, hyperactive reflexes, diminished vibration sensation in the feet, muscle pain and spasms, high arched foot (pes cavus), rapid contraction and relaxation of muscle groups (clonus), and upward extension of the toes when the foot is stroked (Babinski’s sign). 

About 90% of all HSPs are of the uncomplicated type, and the complicated type is seen in only about 10% of cases.

What causes HSP?  
In general, HSPs are caused by degeneration of nerve cells in the brain and spinal cord that control movement of voluntary muscles. Nerve cells that transmit chemical messages to cause muscle movement are commonly called motor neurons. The particular type of nerve cells affected in an HSP are called upper motor neurons because a portion of these cells resides in the brain, specifically in an area called the motor cortex. Upper motor neurons are very long and project from the brain to the brain stem and down the spinal cord, where they send the brain’s messages to lower motor neurons along the way. Lower motor neurons, in turn, carry these messages to the muscles and stimulate or relax them according to the message. When the upper motor neurons degenerate, the circuit between the brain and the muscles is broken, and control of voluntary movements is lost. 

The reason why upper motor neurons degenerate in HSPs is because one or more proteins essential for proper function or maintenance of these cells is missing or improperly formed. When a protein is missing or improperly formed in an HSP or other inherited disease, it is the result of a mutation in one or more genes. Because of the variety of types of the disease, HSPs may be inherited in autosomal dominant, autosomal recessive, or X-linked fashions.

Scientists have identified 21 genes that when mutated can cause one of the types of HSP. For instance, the most common form of uncomplicated autosomal dominant HSP, which accounts for about 45% of uncomplicated cases inherited in this fashion, is caused by mutations in the SPG4 gene, which encodes the protein spastin. Recent work suggests that spastin is responsible for maintenance of the long, internal structure of upper motor neurons, particularly the long, tube-like structures called microtubules. In the absence of properly functioning spastin, microtubules either fail to form properly or fail to be maintained properly, causing the long part of the neuron to shrink and the entire nerve cell to die.

Why is knowing the underlying genetic cause of an HSP important?  
Although the function of spastin is not completely known, identifying the gene that encodes it, the SPG4 gene, is important. Genetic tests based on the SPG4 gene can determine whether an individual will not make properly functioning spastin and develop the spastin-type of HSP. In addition, the same test can determine if children will likely develop HSP later in life.

The most important reason for discovering the genes that cause HSPs is the promise of replacing them or replacing the proteins they encode. This strategy may one day enable the upper motor neurons in a patient with HSP to survive and function normally through adulthood. Replacing genes is a type of treatment called gene therapy, which is a medical strategy based directly on the inherited genetic problem. Currently, gene therapy is proving successful in clinical trials for several different genetic diseases. Gene therapy may not work against all types of genetic disease, and it remains to be seen if any of the HSPs are candidates for this type of treatment. But by discovering genes causing the HSPs, scientists and physicians can envision such direct treatment for the future.

Are all spastic paraplegia inherited?  
Most spastic paraplegias known to doctors are inherited, but several non-inherited forms are also known. Some non-inherited HSPs are caused by viruses and toxic chemicals from plants. Other HSPs are symptoms of other diseases, like primary lateral sclerosis, cerebral palsy, multiple sclerosis (MS), and amyotrophic lateral sclerosis (AML). Still others are caused by spinal cord injuries, tumors, herniated disks in the thoracic region of the spine, and deficiencies of certain vitamins.

Are there genetic tests for HSPs?  There are a number of tests for HSPs. In general, these tests determine from a sample of an individual’s blood if a mutation exists in one or more of the genes known to cause HSP. However, because the genetic cause of French Settlement Disease remains unknown, there is currently no specific test for it.

What are current treatments for HSPs?  
Improving muscle strength, as with most muscular diseases, is key to reducing severity of symptoms and maintaining muscle function for as long as possible. Physical therapy is an important way to increase strength of the lower extremities and improve range of motion. In addition, the cardiovascular conditioning that results from physical therapy can reduce fatigue and improve endurance.

For patients with walking (gait) problems, canes, walkers, and wheelchairs will facilitate mobility and help to prevent falling and subsequent injury.

A number of drugs are available to reduce some of the symptoms of HSP. Baclophen, dantrolene, and tizanidine are sometimes effective at reducing stiffness. A number of drugs are available to reduce urinary urgency.

How did French Settlement Disease originate? 
French Settlement, Louisiana, is a town of about 1000 (2005 estimate) located along the east bank of the Amite River in southwest Livingston Parish. Historically known as “La Côte Francaise” because of the large number of eighteenth century Acadian and French settlers, the village became a settling point for several cultural groups, including Germans, Spanish, Italians, and other American colonials, in addition to the French.

It is through this settlement phenomenon that the origins of French Settlement Disease arose. Genealogy reveals that individuals with FSD share common ancestors, in particular a German couple who immigrated to the French Settlement area in about 1741. At least ten generations now descend from this ancestral couple. 

In the DNA of one of the common ancestors, a mutation (mistake) occurred in an important gene in the DNA of a sperm cell or an egg cell. Each individual has two copies of all genes, but only one copy, selected randomly, is transmitted to each offspring. Therefore, when an individual transmits a gene mutation, there’s a 50% chance that any of his (or her) children will inherit that mutation. Like all diseases inherited in an autosomal recessive fashion, an individual inheriting the FSD-causing mutation is a carrier and is not affected by the disease. 

Several generations after the FSD mutation first occurred, there may be hundreds of carriers of the mutation among the descendants of common ancestors. Eventually, two carriers may conceive children. In this case, the chance of any of their children inheriting the mutation from each parent is combined─which is 50% times 50%, or 25%. Inheriting two copies of the FSD-causing mutation, however, means that there is no mutation-free gene in the child, and a child with two copies of the mutation will develop FSD as an adult.

In general, the chance that two carriers will conceive children is rare. However, during the early settlement of villages, where after several generations there is little outward movement of families from the area, it is more common for carriers to conceive children and thereby contribute to increasing the appearance of a rare genetic disease like FSD.

How was French Settlement Disease discovered?
FSD was discovered through a special collaboration of the community and the clinic, which has proven to be a powerful tool in the discovery and treatment of rare genetic diseases in communities around the world.

With knowledge of a crippling disease affecting a number of adults in their community, Mrs. Mercy Lobell and Mrs. Lucille Cooper of French Settlement met Dr. Henry Rothschild of LSU Medical Center in New Orleans at the 1976 meeting of the Louisiana Genealogical and Historical Society. In 1977, Dr. Rothschild and his colleagues first met with FSD families and examined patients, including six affected persons, in a gathering sponsored by the newly formed French Settlement Historical Society. With genealogical information assembled and analyzed by Mrs. Lobell and Mrs. Mariette Lambert of Metairie, LA, Dr. Rothschild published his findings in the first clinical report of the disease in 1979. 

How is French Settlement Disease different from other HSPs?  
Unfortunately, the differences between HSPs are sometimes hard to distinguish. One way to distinguishing FSD is through its mode of inheritance. FSD is inherited in an autosomal recessive fashion, meaning that an individual must be born with two mutated copies of the disease-causing gene. Autosomal recessive HSPs are more rare than other forms (autosomal dominant, X-linked). Another distinguishing feature of FSD is its age of onset. Whereas the majority of types of autosomal recessive HSP can show symptoms early in life (1-13 years), the average age of onset of FSD patients is 26 years. 

One unambiguous way of distinguishing FSD from other HSPs is through discovery of the gene and gene mutation that causes it. Discovering the genetic cause of FSD would also allow the development of a genetic test to diagnose the disease before the onset of symptoms, enabling an individual to undertake a pre-emptive and limb-strengthening lifestyle. A genetic test would also allow the detection of carriers and prevent extension of the disease. Knowing the causative gene will allow scientists and physicians to find ways to improve therapy and hopefully reverse the effects of the FSD mutation. 

REFERENCES.  The following printed resources were used to prepare this chapter.

Denham L. 1986. French Settlement (La Côte Francaise). In History of Livingston Parish, Louisiana. (History Book Committee of Edward Livingston Historical Association, Eds). Curtis Media Corporation. 

Estes M.D. 1986. French Settlement. In History of Livingston Parish, Louisiana. (History Book Committee of Edward Livingston Historical Association, Eds). Curtis Media Corporation. 

Lobell, M. “The Importance of Genealogy and Local History to the Study of Genetics: French Settlement, a Case Study.” Presented at the 1983 meeting of the Louisiana Historical Association in Hammond, LA. Transcript available from Sims Memorial Library, Southeastern Louisiana University, Hammond, LA.

Rothschild, H. 1976. French Settlement Disease. Pamphlet published by Knights of Columbus Blessed Eugene Council No. 6753. 

Rothschild, H., Happel, L., Rampp, D., Hackett, E. 1979. Autosomal recessive spastic paraplegia: evidence for demyelinization. Clinical Genetics 15: 356-3b60.

Wood, J. et al. 2006. The microtubule-severing protein spastin is essential for axon outgrowth in the zebrafish embryo. Human Molecular Genetics 15: 2763-2771.

HOW TO LEARN MORE

Spastic Paraplegia Foundation, http://www.sp-foundation.org/hsp.htm 

National Institute of Neurological Disorders (NIND) Hereditary Spastic Paraplegia Information Page: http://www.ninds.nih.gov/disorders/hereditary_spastic_paraplegia/hereditary_spastic_paraplegia.htm

ABOUT THE AUTHORS

Diana Claire Stoute is a doctoral candidate in the Department of Genetics at LSU Health Sciences Center in New Orleans.
John P. Doucet, Ph.D., is Associate Professor of Biological Sciences and Director of the University Honors Program at Nicholls State University and Adjunct Associate Professor in Biochemistry and Genetics at LSU Health Sciences Center in New Orleans.

CONTACT THE AUTHORS

Diana Claire Stoute
Department of Genetics
LSU Health Sciences Center
New Orleans , LA 70112
(504) 568-2178
dstou1@lsuhsc.edu

John P. Doucet, Ph.D.
Molecular Genetics Section
Department of Biological Sciences
Nicholls State University
Thibodaux , LA 70310
(985) 448-4721
john.doucet@nicholls.edu


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