Hearing Loss Not Inevitable for GGPS1-linked Congenital MD

Hearing loss and ovarian insufficiency not a certain outcome of rare disease type

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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congenital muscular dystrophy | Muscular Dystrophy News | Case Report | illustration of children holding hands

A form of congenital muscular dystrophy caused by mutations in a gene called GGPS1 may not always lead to hearing loss, contrary to what has been described previously, according to a recent study.

The report, “GGPS1-associated muscular dystrophy with and without hearing loss,” was published as a brief communication in the Annals of Clinical and Translational Neurology.

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Muscular dystrophy causes muscles to slowly weaken and waste over time. When symptoms are present at birth (or shortly thereafter), the disease is said to be congenital.

There are many forms of congenital muscular dystrophy, each with its own genetic cause. Recently, researchers have identified a form of the disease that is marked by low muscle tone, hearing loss, and primary ovarian insufficiency, which occurs when the ovaries stop working as they should at an early age. It’s caused by mutations in the GGPS1 gene.

This gene provides the instructions to make GGPP, a protein that helps other proteins interact with cellular membranes which subsequently promotes vesicular trafficking in cells.

Study included 13 people with congenital disease due to rare GGPS1 mutations

In the report, an international team of researchers describe the cases of 13 patients (six male and seven female) with this form of congenital muscular dystrophy. All but two of the patients were born from consanguineous (related by blood) parents.

Eleven of the patients came from four never-reported British, Iranian, Egyptian, and Brazilian families carrying very rare missense mutations in the two copies of the GGPS1 gene. A missense mutation is a change in a DNA sequence that results in one of the protein’s building blocks (amino acids) being swapped for another one. The two other patients, from Pakistan, continued to be followed up after they were first described in 2020.

The disease manifested at a mean age of 16 months, ranging from prenatal to preschooler age. The first symptoms were a delay in motor milestones in 10 (76.9%) patients, a weak cry in three (23.1%), and muscle weakness in another three (23.1%).

The babies were able to sit up at a mean of 9.7 months and walk at a mean of 1.7 years, which was later than the normal range of ages for these motor milestones.

The most common symptom occurring throughout the course of the disease was muscle weakness in 12 (92.3%) patients; its onset was at a mean age of 2.7 years. The second most common symptom was respiratory insufficiency. This required non-invasive ventilation to push air into the lungs in six (46.2%) patients and tracheostomy, which is an opening in the windpipe that provides an airway for breathing, in two (15.4%) patients.

Hearing loss, whether present at birth or shortly thereafter, occurred in six (46.2%) patients. The remaining patients did not experience hearing loss, as confirmed by a physical examination and hearing (audiometric) tests.

One female patient reached puberty at the time of the study, and at 30, she did not have clinical signs of primary ovarian insufficiency.

This is in contrast to previous reports in which most patients experienced hearing loss, and all female patients who had reached puberty also had primary ovarian insufficiency.

“Hearing loss and ovarian insufficiency might be variable features of the GGPS1-associated muscular dystrophy,” the researchers wrote.

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To determine whether the gene is normally turned on in the muscles, the inner ear, and the ovaries, the researchers checked its levels in cells from these tissues in mice. They found that the gene was expressed in all these tissues, albeit at lower levels in neonatal skeletal muscle cells. Gene expression is the process by which information in a gene is synthesized to create a working product, such as a protein.

Six patients lost the ability to walk at a mean age of 8.1  years. While the disease progressed slowly in most patients (92.3%), “older individuals … tended to have a more severe phenotype reflecting the progressive nature of the disease in most instances,” the researchers wrote.

To find out which mutations could be causing the disease, the researchers used a technique called exome sequencing that looks at the DNA sequence of all genes encoding the instructions for making proteins. They found that all patients had very rare mutations in the GGPS1 gene.

Some of the mutations (variants) had not been reported before but were considered to be likely disease-causing based on how they were passed down through families with the disease as well as on computer analysis predictions.

“Although it is difficult to determine the exact molecular cause of the observed clinical variability, we can hypothesize a possible link with localisation of the GGPS1 variants within the gene,” the researchers wrote.