As all child neurologists know, cerebral palsy is a devastating disorder that afflicts millions of children worldwide. Most cases of CP are believed to be due to prenatal or perinatal environmental insults and have characteristically abnormal MRI scans, with periventricular leukomalacia, diffuse white matter abnormalities, or encephalomalacia. However, in approximately 20 percent of cases, there is no identifiable etiology, no history of an environmental insult, and no characteristic abnormalities on neuroimaging studies. These cases have left child neurologists puzzled for decades and have suggested that CP may sometimes be heritable.
A major goal of Dr. Michael Kruer’s research is to identify the mechanistic basis of pediatric movement disorders, including juvenile parkinsonism, childhood-onset dystonia, and heritable spastic cerebral palsy (CP). Toward this goal, Dr. Kruer and his colleagues have recently taken an important step, as they have identified a particular gene whose mutation leads to spastic quadriplegic and diplegic CP.
Dr. Kruer conducts his research at the Sanford Children’s Health Research Center in Sioux Falls, South Dakota. He practices pediatric neurology at the Sanford Children’s Specialty Clinic, where he maintains subspecialty clinics focused on neurogenetics and movement disorders. His work identifying a novel CP-inducing gene is currently in press in the Annals of Neurology.
As a first crucial step, Dr. Kruer and his colleagues identified a consanguineous family in which four of the five siblings had spastic cerebral palsy, while the parents, who were second cousins, were unaffected. Through homozygosity mapping and exome sequencing, the investigators identified a homozygous mutation in the gene that encodes gamma adducin.
In mammals, adducin proteins form complexes with actin-spectrin filaments, thus linking cellular membranes to the dynamic cytoskeleton. Adducin exerts an “actin capping” function, thus modulating the fast growing end of actin filaments and controlling actin molecule length. As a result, adducin is involved in all of those cellular processes in which actin-spectrin plays a role, including cellular motility, synaptic vesicle recycling, cell-cell adhesion, cellular proliferation, and neurite extension and retraction.
Utilizing in vitro systems, Dr. Kruer and colleagues studied the pathobiology of the adducin mutation and demonstrated that it impairs actin capping. They found that siRNA knockdown of the adducin transcript led to similar impairment of actin capping, thus suggesting that the mutation causes a loss of function.
The investigators found that the mutation alters cellular migration, a finding which may explain the grey matter heterotopia present in one of the affected patients. In addition, they found that the adducin mutation alters process extension. These results suggest that the mutation impairs functional connectivity and correlate well with the finding that affected patients have abnormalities on diffusion tensor imaging, thus indicating abnormal fiber tracts.
To produce further proof-of-pathogenesis, Dr. Kruer and his colleagues evaluated the effects of the mutation in drosophila. They found that the putative mutation induces brain lesions and impairs locomotion in the flies, strengthening the notion that the adducin mutation underlies the brain dysfunction in the affected individuals.
Thus, Dr. Kruer and his co-workers have identified a gene whose mutation can induce cerebral palsy. The pathogenesis of this heritable form of spasticity involves abnormalities of the dynamic cytoskeleton, ultimately changing process outgrowth, protein trafficking, and cellular migration.
Dr. Kruer completed his undergraduate studies at Arizona State University and obtained his medical degree from the University of Arizona. He performed postdoctoral research at the Translational Genomics Research Institute in Phoenix, AZ and trained in pediatrics at Phoenix Children’s Hospital. He completed a neurodevelopmental disabilities fellowship at Oregon Health & Science University where he also obtained additional postdoctoral training in molecular neurogenetics.
Dr. Kruer has spearheaded the formation of the Cerebral Palsy Genetics Collaborative Network (http://www.sanfordresearch.org/researchcenters/childrenshealth/ kruerlab/cerebralpalsygeneticscollaborativenetwork/). This international multi-institution collaboration seeks to establish the role of single gene mutations in patients with cerebral palsy of unknown cause. The investigators hope to apply next generation sequencing to identify and characterize previously unrecognized forms of single gene CP. These studies will help identify new targets for therapeutic agents. Patients can participate by providing a buccal swab from the comfort of their home. The team welcomes referrals from both physicians and families. Readers of this article who care for families of children with CP of unknown etiology are invited to contact Dr. Kruer’s team at kruerlab@sanfordhealth.org.
Figure Legend
(A) Wild-type fibroblasts (left) show co-localization of ADD1 (red) and ADD3 (green) into functional heteromers (yellow merge) while ADD3 mutant fibroblasts from patients with inherited CP show impaired co-localization (discrete green and red puncta); (B-D) lesions in brains from drosophila lacking functional adducin; (E) flies deficient in adducin can’t walk as well as wild-type flies, recapitulating the human phenotype
