Unique BICD2 mutation causes severe SMA-LED: Case study
8-year-old girl diagnosed after advanced testing
Researchers reported a unique mutation that supported an 8-year-old girl’s diagnosis of spinal muscle atrophy with lower extremity predominance (SMA-LED). The mutation, mapped to the BICD2 gene, resulted in a severe form of SMA-LED, type 2B, that emerged before birth and was primarily marked by joint contractures in infancy.
The case study, “A Novel De Novo Splice Acceptor Variant in BICD2 Is Associated With Spinal Muscular Atrophy,” was published in the American Journal of Medical Genetics.
SMA is marked by the degeneration of motor neurons, the nerve cells that control muscle movement, which causes symptoms such as muscle weakness and wasting (atrophy).
SMA-LED is a rare form of SMA caused by mutations in the DYNC1H1 gene or BICD2 gene. Such mutations disrupt the dynein-dynactin complex, a group of proteins that facilitate communication between motor neurons. Weakness and atrophy more commonly affect the lower limb muscles, especially the thigh muscles. In some cases, deformities affect the joints of the feet, ankles, and knees, leading to stiff joints (joint contractures).
There are two recognized subtypes of SMA-LED type 2: type 2B, a severe form that starts before birth and is usually fatal in early childhood, and type 2A, which emerges in infancy or early childhood and can be less severe and progress more slowly.
Problems at birth
A team led by researchers in Canada described the diagnostic journey of an 8-year-old girl with a unique mutation in her BICD2 gene.
The girl, of French Canadian and First Nations ancestry, had multiplex arthrogryposis congenita, or multiple joint contractures. While her mother had a history of club feet (inward-turned feet), this was resolved without complications, and she showed no further problems with muscles, nor did the rest of the family.
The girl was born via cesarean section due to a breech position, which was complicated by a fracture of the thigh bone (femur). At birth, she exhibited multiple anomalies, including club feet, contractures on both hands, a slightly curved spine, hip dislocation, and hip acetabular dysplasia, or an abnormally shallow hip bone socket.
She was initially diagnosed with multiplex arthrogryposis congenita and was admitted to the hospital for one month due to feeding difficulties requiring a feeding tube. She also had low muscle tone and weakness, predominantly in the lower extremities, and a lack of reflexes (areflexia). An MRI showed signs of atrophy in the muscles of the hips and upper and lower extremities with fatty displacement.
In her first year, she wore casts for knee and ankle contractures and corrective bracing for scoliosis, a sideways curvature of the spine. She also had surgery for hip problems and experienced recurrent shoulder dislocations.
At age 2, she showed significant spinal curves and underwent further casting. Nerve tests at age 4 indicated severe motor nerve impairment. By age 5, she had received growing rods for scoliosis, but continued to have leg and bone problems and experienced recurrent respiratory tract infections. At nearly 8, she was shorter and heavier than most children her age.
The girl also had delays in gross and fine motor function. Due to contractures, she was unable to use her hands until she was 14 months old. Physiotherapy improved this condition. She started crawling at 16 months, walking when she was about 3, and sat without assistance at almost 4. At the time the study was published, she was unable to walk and had generalized weakness, trunk instability, and hypermobile joints.
mRNA analysis
While initial genetic tests failed to detect a disease-causing mutation, further tests identified a new mutation in the BICD2 gene. Both the mother and father tested negative for this mutation, suggesting it was de novo, meaning not inherited but occurring spontaneously.
At this point, the girl was enrolled in the Care4Rare Canada research program, a collaborative team of clinicians and researchers focused on improving the diagnostic care of people with rare genetic diseases. Using skin cells isolated from a biopsy, doctors performed RNA-seq analysis, a technique that sequences messenger RNA (mRNA), a template for protein production.
Tests showed she carried a unique mutation that affected the splicing, or processing, of mRNA. This variant resulted in either a shortened mRNA, which would be degraded, or a deletion of a small mRNA segment, which allowed the production of an altered protein. In line with these findings, BICD2 protein levels in her skin cells were lower than levels seen in healthy individuals.
Altogether, the data supported a diagnosis of SMA-LED type 2B caused by de novo splice variants in her BICD2 gene.
The researchers called the case an “interesting example” of how some splice variants can have a protective effect by allowing some protein production while also leading to mRNA degradation, lowering protein production, and causing disease.
“This case demonstrates the utility of RNA-seq to clarify the effect of this splice variant in BICD2 and ultimately support the diagnosis of SMALED2B,” the researchers concluded.
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