Thursday, October 11, 2018

French Settlement Disease

Inspired by a patient

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.
Similarly, a long-term program is the prospect for developing a means to control the condition we have named French Settlement Disease (FSD).  That disease is unique to the descendants of settlers in Livingston Parish of Louisiana.

The disease is one of a group of disorders known collectively by the
medical name, hereditary spastic paraplegia.  Understand each word of that
phrase -- hereditary spastic paraplegia -- and you will understand the basic
concept of this disease.

     1.  Hereditary - received from parents of ancestors
     2.  Spastic - muscles are stiff and the movements awkward
     3.  Paraplegia - slight or incomplete paralysis of the lower part of the body

FSD, therefore, is an inherited defect in which certain chemical reactions
in the body do not proceed normally, resulting in serious disturbances in
the function of the specialized nerves that control not only body movement
but also speech and other processes.

In the past few years, we have focused our efforts on FSD and several
similar diseases.  Strides have already been made in accumulating the know-
ledge needed to control FSD.  But no cure is available yet, and one is not
likely soon.  This leaflet gives an up-to-date report on current progress
and hopes for the future.

What causes the disease?
Until recently that question would have been difficult to answer. However, we now have evidence that FSD occurs when a specific chemical )an enzyme) is missing in the body.  An enzyme is a protein that aids in the body's chemical processes.  Some enzymes convert starch into sugar.
Others help the body get rid of excess sugar.  Still others are necessary for the normal production and utilization of fats (sometimes called lipids.) Literally thousands of different enzymes are necessary for life. Although the search for the specific FSD-related enzyme continues, that
enzyme has not yet been identified.

French Settlement, Louisiana, is an unassuming little town just northwest of New Orleans. It is also the place where a group of genetic disorders known as hereditary spastic paraplegia (HSP), or French Settlement Disease, was first discovered. Unlike the town, the disease is anything but modest: its main features are stiffness and involuntary contractions in the legs. Thirty-five years after the disease’s discovery, a study led by HHMI Investigator Joseph Gleeson at the University of California, San Diego, has almost doubled the number of genes associated with HSP.

Scientists had already linked 22 genes to HSP, but mutations in those genes explained less than 50 percent of the cases. To find more genes, Gleeson and a team of 51 scientists from around the world recruited 55 families with HSP. The scientists sequenced every gene in 93 family members and discovered 18 genes newly linked to the disease. They then created an “HSPome”—a genetic map showing how all the HSP-associated genes interact with each other.

The effort, which took 10 years, allowed the researchers to link HSP to other common neurodegenerative diseases, such as Alzheimer’s. “This told us that common neurodegenerative diseases share similar networks and cellular vulnerabilities,” says Gleeson. “Maybe we need to think about these less as individual diseases and more as collective problems of neuronal susceptibility.”

The findings, reported January 31, 2014, in Science, may help Gleeson and his colleagues develop new treatments for HSP. They’re already pursuing several promising targets.

Novarino G, Fenstermaker AG, Zaki MS, Hofree M, Silhavy JL, Heiberg AD, Abdellateef M, Rosti B, Scott E, Mansour L, Masri A, Kayserili H, Al-Aama JY, Abdel-Salam GMH, Karminejad A, Kara M, Kara B, Bozorgmehri B, Ben-Omran T, Mojahedi F, El Din Mahmoud IG, Bouslam N, Bouhouche A, Benomar A, Hanein S, Raymond L, Forlani S, Mascaro M, Selim L, Shehata N, Al-Allawi N, Bindu PS, Azam M, Gunel M, Caglayan A, Bilguvar K, Tolun A, Issa MY, Schroth J, Spencer EG, Rosti RO, Akizu N, Vaux KK, Johansen A, Koh AA, Megahed H, Durr A, Brice A,
Stevanin G, Gabriel SB, Ideker T, Gleeson JG. Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science. 2014 Jan 31;343(6170):506-511.

Hereditary spastic paraplegias (HSPs) are neurodegenerative motor neuron diseases characterized by progressive age-dependent loss of corticospinal motor tract function. Although the genetic basis is partly understood, only a fraction of cases can receive a genetic diagnosis, and a global view of HSP is lacking. By using whole-exome sequencing in combination with network analysis, we identified 18 previously unknown putative HSP genes and validated nearly all of these genes functionally or genetically. The pathways highlighted by these mutations link HSP to cellular transport, nucleotide metabolism, and synapse and axon development. Network analysis revealed a host of further candidate genes, of which three were mutated in our cohort. Our analysis links HSP to other neurodegenerative disorders and can facilitate gene discovery and mechanistic understanding of disease.

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