‘Blend’ of PWS, Spastic Paraplegia in Boy Due to Mother’s Double Chromosome Copy
Condition underscores importance of genetic testing with recessive disorders, researchers said
A boy was found to manifest “blended” symptoms of both Prader-Willi syndrome (PWS) and a form of hereditary spastic paraplegia caused by a double copy of a faulty chromosome he inherited from his mother, according to a report from the U.S.
The report, “Blended Phenotype of Prader-Willi Syndrome and HSP-SPG11 Caused by Maternal Uniparental Isodisomy,” was published in Neurology: Genetics.
PWS occurs as a result of genetic information that’s either missing or faulty in the PWS locus, a region of chromosome 15 that’s turned on, or active, only on the copy that comes from the father. This is called genetic imprinting.
Less often, it happens that two equal copies of chromosome 15 come from the person’s mother and none come from the father. This is called maternal uniparental isodisomy. When this happens, the PWS locus is inactive, or turned off.
The PWS locus contains genes that provide instructions for making proteins needed to control growth, appetite, and sleep. When these genes are missing or inactive, symptoms of PWS occur.
They can range from a delay in development and growth in early infancy to learning difficulties and uncontrollable appetite that leads to rapid weight gain and obesity during childhood.
Researchers have reported the case of a 12-year-old boy who presented a “blend” of symptoms of PWS and hereditary spastic paraplegia type 11.
Symptoms of PWS, spastic paraplegia result in weakness, spasticity
This form of hereditary spastic paraplegia (paralysis) results from two faulty copies of the SPG11 gene that provides instructions for making spatacsin, a protein present throughout the nervous system. Its absence causes weakness and stiffness (spasticity) in the leg muscles, which get worse over time.
As an infant, the boy had hypotonia, or low muscle tone and reached motor milestones late. He sat unassisted at 11 months, stood up at 18 months, and began to walk at 25 months. He also had a speech delays, but eventually made steady progress.
At 7 months, he had focal seizures that resulted in loss of awareness. Focal seizures may include uncontrolled body movements and temporary confusion that occur because of abnormal electrical activity in one area of the brain. The symptoms were treated with oxcarbazepine and later with topiramate, both anti-seizure medications.
Around age 2, the boy began eating in excess (hyperphagia) and gained 13 pounds in five months.
These combined symptoms led doctors to consider PWS and genetic testing confirmed maternal uniparental isodisomy of chromosome 15.
At age 8, the boy developed weakness and spasticity in his legs, and later began having difficulty with gait, dysarthria (difficulty speaking), slowness of movement — known as bradykinesia — and loss of cognitive skills.
An MRI revealed thinning of the anterior corpus callosum, a region in the brain that connects its two sides, and of the white matter around the brain’s cavities (ventricles). It also revealed “ears of the lynx,” a sign of hereditary spastic paraplegia that looks like the tufts of hair on the tips of a lynx’s ears.
Mutations in both copies of SPG11 gene
To look for a genetic basis for the boy’s new symptoms, the researchers used exome sequencing to “read” the information carried in the DNA bits that contain information to make proteins. They identified a mutation in both copies of the SPG11 gene.
The mutation, called c.733_734del (p.Met245fs), has been reported previously as a cause of hereditary spastic paraplegia type 11. The SPG11 gene sits in chromosome 15 and the boy had inherited the two faulty copies from his mother.
At age 12, he continued having spasticity and moderate to severe dysarthria. He also had difficulty swallowing, or dysphagia, and lost control of his bladder. He was able to walk short distances with help, but required a wheelchair outside his home.
There also were some symptoms of parkinsonism similar to Parkinson’s disease. They included an abnormally weak voice (hypophonia), loss of facial expressions, called hypomimia, bradykinesia, and a hand tremor.
The boy scored 41 points on the Spastic Paraplegia Rating Scale, a measure of disease severity that ranges from zero to 52, the higher score being more severe.
His neurological function appeared to worsen at a faster rate than usual for hereditary spastic paraplegia, “which may be part of this unique blended phenotype [set of disease manifestations],” the researchers wrote.
Treatment with baclofen, a medication used to treat muscle spasticity, and levodopa plus carbidopa, a mainstay of treatment for Parkinson’s, helped ease his symptoms to some extent.
“These clinical observations highlight the importance of pursuing additional genetic testing for recessive diseases in patients with imprinting disorders when presenting with features outside of well-described syndromes,” the researchers said.