Muscular dystrophy is a group of rare muscle-wasting diseases with a wide range of biological features, symptoms, and genetic origins. To obtain a precise diagnosis and offer appropriate genetic counseling, doctors must carry out clinical, biochemical, and genetic tests. Now, a new study finds that mutations in the INPP5K gene gives rise to a new type of congenital muscular dystrophy that presents with short stature, intellectual disability, and cataracts.
The study – led by George Washington University in Washington, DC, and St. George’s University of London in the United Kingdom – is published in the American Journal of Human Genetics.
Muscular dystrophy is a group of rare disorders caused by gene mutations that disrupt the production of proteins important for generating and maintaining healthy muscles. Some of the mutations can also affect proteins in the eyes or brain.
There are several different types of muscular dystrophy, according to the particular genes that are involved. Examples include: Duchenne, Becker, myotonic, congenital, facioscapulohumeral, limb-girdle, and oculopharyngeal.
Different types of muscular dystrophy affect different muscle groups, the severity of impairment, and the age at which signs and symptoms first appear.
The new study concerns congenital muscular dystrophy, a type that becomes apparent at or near birth. Babies born with the disease are weak at birth and may have difficulties swallowing or breathing.
Congenital muscular dystrophy – of which there are several subtypes – causes overall muscle weakness and may also give rise to stiff or loose joints.
- Muscular dystrophy can run in families
- It can also arise in an individual with no family history of the disease
- Over time, the disease diminishes mobility and makes it harder to carry out daily tasks.
Depending on the subtype, the disease may involve intellectual disability, learning disability, spinal curvature, respiratory insufficiency, eye defects, or seizures.
Prof. Chiara Manzini, one of the senior authors of the new study and assistant professor in pharmacology and physiology at George Washington University, heads a group that specializes in finding genes that cause neurodevelopmental diseases. She describes the challenges and needs involved in diagnosing patients with rare conditions:
“The average pediatrician may only see one child with a rare disorder in his or her entire career. Even working with a team of specialists, it can sometimes take years for a child to be diagnosed with a specific rare disease.”
“With a correct diagnosis, families have access to the best care and what to expect as far as the progression of the disease. From a research standpoint, we can develop new, targeted therapies to help these patients,” she adds.
Prof. Manzini and colleagues studied five individuals from four families who presented with a range of different clinical features, including muscular dystrophy, intellectual disability, short stature, and cataracts.
Although these features overlap with other known and related syndromes, the researchers found that the individuals concerned all shared a unique mutation in a gene called INPP5K, which they note “encodes the inositol polyphosphate-5-phosphatase K, also known as SKIP (skeletal muscle and kidney enriched inositol phosphatase), which is highly expressed in the brain and muscle.”
The team believes that the discovery reveals that the five patients share a new type of congenital muscular dystrophy.
Most genes that give rise to congenital muscular dystrophy are responsible for maintaining links between muscle fibers.
INPP5K is different, in that it is active inside cells where it helps to control protein trafficking and signal responses to insulin and other factors.
“Now that we’ve identified the genetic mutation, we want to know why the disruption in the gene causes this disorder. The unique mechanism of this gene could help us develop therapies we have not thought about before, and may move research in a different direction.”
Prof. Chiara Manzini