Welcome to Study of the Week from Patient Worthy. In this segment, we select a study we posted about from the previous week that we think is of particular interest or importance and go more in-depth. In this story we will talk about the details of the study and explain why it’s important, who will be impacted, and more.

If you read our short form research stories and find yourself wanting to learn more, you’ve come to the right place.

This week’s study is…

Autosomal recessive progeroid syndrome due to homozygosity for a TOMM7 variant

We previously published about this research in a story titled “Novel rare form of Progeria Identified in Malaysia” which can be found here. The study was originally published in The Journal of Clinical Investigation. You can read the full text of the study here. 

This research team was affiliated with UT Southwestern.

What Happened?

A team of scientists in Malaysia learned of the case of a Chinese man with unusual clinical features. The man had a head circumference of just 21 in, weighed only 46 lb., and was only 3.8 ft tall. These figures were all under the lowest three percent of the general population. The individual also had some distinctive facial characteristics, such as severe tooth crowding, thin lips, pointed nose, very low body fat, a small lower jaw, and very poor vision. 

The Malaysian researchers suspected that the patient had a rare condition called mandibuloacral dysplasia. In an attempt to confirm these suspicions, the team sent blood samples to Dr. Abhimanyu Garg, Professor, Internal Medicine, UT Southwestern and Section Chief of Nutrition and Metabolic Diseases, Division of Endocrinology, and Director of Metabolic Diseases in the Center for Human Nutrition.

Dr. Garg’s lab found that the patient didn’t have mutations in either of the genes that his research had previously linked to mandibuloacral dysplasia. He wondered if this patient had a syndrome that hadn’t been described before. His team sequenced the genome of the patient and his close relatives for any genetic anomalies. The test brought a gene called TOMM7 to the team’s attention. Prior animal studies had attributed to the function of this gene to the production of a protein that, when mixed with other proteins, helps develop a pore in the outer membranes of mitochondria, a cell organelle responsible for generating energy.

The scientists used skin cells from the patient and started to propagate them in the lab setting; they then compared these cells to the skin cells of unaffected volunteers. The patient’s cells produced fewer proteins responsible for the metabolism of phospholipids. This is an important component in the development of body fat. The mutated skin cells also consumed a lot more oxygen than regular cells and produced more proteins responsible for the metabolism of oxygen. 

The mutated TOMM7 proteins from this patient didn’t work well with the other proteins that played a role in the creation of the mitochondrial pores. These pores, which are responsible for transporting proteins, would presumably be deficient in the patient, and this mechanism is a likely explanation for the man’s unusual features. 

About Progeria

Progeria is an extremely rare genetic disorder which is characterized by accelerated effects of aging. The disorder usually occurs as a new mutation, as its patients rarely survive long enough to transmit the disorder. It is linked to a mutation of the LMNA gene. Symptoms of disease include skin changes, hair loss, poor growth, wrinkled skin, scalp veins, cardiovascular issues, a distinct, small face with a shallow jaw and pinched nose, kidney failure, and vision loss. There is no cure or treatment so far that can slow or halt progression of the disease; most intervention approaches depend on symptoms. Progeria significantly shortens the lifespan of its patients, with most surviving into their mid to late teens. Most patients die from cardiovascular problems. To learn more about progeria, click here.

Why Does it Matter?

This research helped reveal a form of progeria that was previously unknown to science. In addition, the discovery included the identification of the mutation that caused it. The implications of the finding are even further reaching than that, however.

Dr. Garg speculated that perhaps more common variations in the TOMM7 gene could play a role in more typical variations in the exaggerated characteristics in this patient, such as jaw size, height, fat composition, and eyesight. The researchers also learned that the patient had a sister with the same symptoms who passed at age 10.

We don’t know what his life span may be, but based on what we know about his sister, he may be at risk of premature death.” – Dr. Garg

Dr. Garg expressed hope that further research might discover a treatment approach that could prevent this from happening. The discovery might also lead to new treatments for other diseases that share characteristics with this new form of progeria.