A fascination with chromosome rescue in uniparental disomy: Mendelian recessive outlaws and imprinting copyrights infringements

QU's Genetic Discovery Offers New Hope For Treating A Rare Disorder

Dr Michail Nomikos from QU's College of Medicine

A recent research conducted by members of Qatar University's (QU) Health Sector delineated the mechanism that a mutation in a gene encoding for an important protein can lead to homocystinuria, a rare inherited disorder.

This breakthrough discovery holds the potential to pave the way for more effective treatments for those affected by this condition.

In detail, this study revealed how an amino acid change (T236N) in an enzyme called cystathionine-synthase (CBS) causes it to malfunction. CBS is an enzyme that helps break down homocysteine, a substance in the body. When CBS does not work properly due to a mutation, it causes a condition called homocystinuria.

This genetic disorder leads to a harmful buildup of homocysteine, which can cause serious health problems like vision issues, blood clots, and bone deformities. Right now, treatment options are limited for those affected. By understanding how the mutation affects CBS, researchers hope to develop treatments that restore its normal function, offering hope for better care to affected individuals around the world and especially to those in Qatar, where this condition is more common.

This research study was led by Dr Michail Nomikos from QU's College of Medicine, Dr Gheyath Nasrallah from the College of Health Sciences, and PhD graduate Dr Duaa al-Sadeq. Together, this dedicated team combined their expertise in genetics, biochemistry and medical sciences to investigate the impact of the mutation on the CBS enzyme, advancing understanding of this disorder and its potential treatments.

Dr al-Sadeq, who received the Best Dissertation Award in Medical Sciences for her outstanding work on this project, commented: "Our study sheds light on how a single genetic mutation can alter enzyme function in ways that contribute to serious health risks." Dr Nomikos added: "By understanding these molecular changes, we move closer to developing targeted treatments for homocystinuria, offering hope to individuals and families affected by this rare yet impactful disorder in Qatar and across the world." The researchers carefully studied the T236N mutation by using special lab techniques to see how it affects the CBS enzyme's physiological function. To do this, they created two versions of the CBS enzyme, one with the mutation and one without. By comparing how these two versions worked, they were able to observe how the mutation changes the enzyme's structure and how well the mutant enzyme functions.

This research helped them understand exactly how the mutation causes problems in the body, giving important clues about the genetic cause of the disorder. The next step in this exciting research is to find compounds that could potentially recover the function of the mutated enzyme. Through drug screening, researchers hope to find solutions that restore normal enzyme activity, offering a new direction for treating homocystinuria and similar disorders.

2 New US Patients Given Hemophilia B Gene Therapy Hemgenix: Reports

Two new patients in the U.S. Have received Hemgenix (etranacogene dezaparvovec), the first gene therapy to be approved for hemophilia B, per new reports.

The therapy was first administered last year in May to a patient at UC San Diego Health, per a University of California, San Diego, news story. In October, a man who had been on replacement therapies for his hemophilia B for more than four decades was given the gene therapy at Nebraska Medical Center in Omaha.

In both cases, the patients struggled for years with bleeding and severe joint damage. Since the infusion of Hemgenix, the two patients have no longer required replacement therapies.

"It is incredibly rewarding to see just how life-changing this treatment can be for patients who have gone through home infusions, joint pain and bleeding for years," said Annette von Drygalski, MD, director of the Center for Bleeding and Clotting Disorders at UC San Diego Health. "This gene therapy is a truly groundbreaking step forward in quality of life for our patients."

Chad Stevens of Idaho, the patient who received the gene therapy in Omaha, noted in a Nebraska Medicine news story that he had seen his knees and elbows become severely damaged following repeated bleeds over the years. For Stevens, 63, such damage markedly impaired his mobility, even though he had for years been infusing himself with the blood clotting factor his body was missing.

Now, he reported that his knee has been better since receiving the gene therapy, though he doesn't expect the treatment to repair the damage because it was done at an earlier age.

"But if we can keep it from getting any worse … that's the goal," Stevens said.

Hemophilia B gene therapy Hemgenix approved in US in 2022

Hemophilia is a genetic condition characterized by the lack or dysfunction of specific blood clotting factors, which leads to excessive bleeding. Hemophilia B, the second most common form of the disorder, is caused by mutations in the F9 gene, which is responsible for producing a blood clotting protein called factor IX, or FIX.

Before the advent of gene therapy, hemophilia B was primarily managed with prophylactic, or preventive, FIX replacement treatments. These therapies involve supplying the missing clotting factor to restore blood clotting and reduce the risk of bleeds. While effective, they require strict adherence to regular dosing schedules. Further, they do not completely eliminate the risk of unexpected bleeding episodes.

Administered as a single into-the-vein, or intravenous, infusion, Hemgenix is designed to deliver a functional version of the F9 gene, known as FIX-Padua, directly to a patient's cells. It uses a modified, harmless virus to deliver the working gene to liver cells, which are the main producers of clotting factors in the body. The ultimate goal of Hemgenix is to restore the body's natural ability to produce FIX, thereby effectively reducing and preventing bleeding episodes.

In the U.S., Hemgenix has been approved for adults who are on preventive clotting factor treatments, and have or have had life-threatening bleeding episodes, or repeated and severe spontaneous bleeds.

While the therapy offers immense promise, it also comes with hurdles. Treatment is reported to cost $3.5 million, a value that has raised concerns.

However, the cost of clotting factor infusions is also high in the long-term, reaching about $500,000 per year "to keep nothing from happening," according to Alex Nester, MD, a hematologist with Nebraska Medicine.

The successful outcomes of the first patients treated with Hemgenix could mark the beginning of a new era in hemophilia care, according to patient advocates, like Kim Phelan, CEO of The Coalition for Hemophilia B.

"After more than 25 years of anticipation and hope, individuals with hemophilia now have access to a groundbreaking therapy that offers the potential for greater independence and a more normalized life," Phelan said in the Nebraska Medicine story.

UC San Diego Health now IDing eligible candidates for Hemgenix treatment

von Drygalski noted in the UC San Diego story that "recent advancements in gene therapy have revolutionized how we think about hemophilia treatment."

The clinician stressed the improvements seen in quality of life among patients given gene therapy.

"In the last 60 years, we've gone from hemophilia being a serious life-threatening disease to the development of treatment options that provide long-term correction or potentially a cure," von Drygalski said.

Previously, while varying among patients, the average person with hemophilia required treatment about 150 times per year — typically every two to three days. Gene therapy for hemophilia B, meanwhile, is a one-time treatment.

In the last 60 years, we've gone from hemophilia being a serious life-threatening disease to the development of treatment options that provide long-term correction or potentially a cure.

The medical center is in the process of identifying eligible candidates to treat more patients with Hemgenix. To qualify, individuals must be age 18 or older, have moderately severe to severe hemophilia B, and successfully meet liver health and lifestyle screening criteria.

"UC San Diego Health is on the forefront of science and breakthrough treatments for a range of bleeding and clotting disorders, including hemophilia B," von Drygalski said. "We have extensive experience in clinical trials and bringing together multidisciplinary teams to get leading-edge treatments to the patients that need them the most."

Mendelian Genetics: Patterns Of Inheritance And Single-Gene Disorders

Autosomal recessive single-gene diseases occur only in individuals with two mutant alleles of the disease-associated gene. Remember, for any given gene, a person inherits one allele from his or her mother and one allele from his or her father. Therefore, individuals with an autosomal recessive single-gene disease inherit one mutant allele of the disease-associated gene from each of their parents. In pedigrees of families with multiple affected generations, autosomal recessive single-gene diseases often show a clear pattern in which the disease "skips" one or more generations.

Phenylketonuria (PKU) is a prominent example of a single-gene disease with an autosomal recessive inheritance pattern. PKU is associated with mutations in the gene that encodes the enzyme phenylalanine hydroxylase (PAH); when a person has these mutations, he or she cannot properly manufacture PAH, so he or she is subsequently unable to break down the amino acid phenylalanine, which is an essential building block of dietary proteins. As a result, individuals with PKU accumulate high levels of phenylalanine in their urine and blood, and this buildup eventually causes mental retardation and behavioral abnormalities.

The PKU-associated enzyme deficiency was determined biochemically in the 1950s—long before the PAH-encoding gene was mapped to human chromosome 12 and cloned in 1983. Specifically, Dr. Willard Centerwall, whose child was mentally handicapped, developed the first diagnostic test for PKU in 1957. Called the "wet diaper" test, Centerwall's test involved adding a drop of ferric chloride to a wet diaper; if the diaper turned green, the infant was diagnosed with PKU. The wet diaper test was used to reliably test infants at eight weeks after birth; by this time, however, infants who were affected by PKU had already often suffered irreversible brain damage.

Thus, in 1960, Dr. Robert Guthrie, whose niece suffered from PKU and whose son was also mentally handicapped, established a more sensitive method for detecting elevated phenylalanine levels in blood, which permitted a diagnosis of PKU within three days after birth. Guthrie's test used bacteria that were unable to make their own phenylalanine as messengers to report high blood levels of phenylalanine in an infant's blood sample obtained via heel prick. With Guthrie's method, the phenylalanine-deficient bacteria were grown in media together with a paper disk spotted with a drop of the infant's blood. If the phenylalanine levels in the blood were high, the bacteria would grow robustly, and a diagnosis of PKU could be made. Through the ability to discover that their child had PKU at such an early age, parents became able to respond immediately by feeding their child a modified diet low in proteins and phenylalanine, thereby allowing more normal cognitive development. Guthrie's test continues to be used today, and the practice of obtaining an infant's blood sample via heel prick is now used in numerous additional diagnostic tests.

Several other human diseases, including cystic fibrosis, sickle-cell anemia, and oculocutaneous albinism, also exhibit an autosomal recessive inheritance pattern. Cystic fibrosis is associated with recessive mutations in the CFTR gene, whereas sickle-cell anemia is associated with recessive mutations in the beta hemoglobin (HBB) gene. Interestingly, although individuals homozygous for the mutant HBB gene suffer from sickle-cell anemia, heterozygous carriers are resistant to malaria. This fact explains the higher frequency of sickle-cell anemia in today's African Americans, who are descendants of a group that had an advantage against endemic malaria if they carried HBB mutations. Finally, oculocutaneous albinism is associated with autosomal recessive mutations in the OCA2 gene. This gene is involved in biosynthesis of the pigment melanin, which gives color to a person's hair, skin, and eyes.

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