Genetics
Researchers of cerebral palsy continue to ask whether there is a genetic contribution to the development of the disease. Evidence that points to the probability of a genetic aspect can be found among people with siblings affected by cerebral palsy, who are more likely to have the disorder than those with no affected sibling. More convincing evidence of a genetic influence is seen in twin studies which indicate that if one twin is affected with cerebral palsy, the likelihood that the other twin will also have cerebral palsy is greater among monozygotic twins (who share nearly all the same genes) than among dizygotic twins (who share fewer genes in common). The specific genetic factor that appears to cause cerebral palsy is most likely the mutation of a gene, perhaps a polymorphism at the level of a single nucleotide. More than likely, the outcome of any such genetic influence on incurring the disease will vary depending on environment, implicating a gene-environment interaction.
1. Candidate genes and cerebral palsy: A population-based study
OBJECTIVE: The objective of this study was to examine whether selected genetic polymorphisms in the infant are associated with later-diagnosed cerebral palsy. METHODS: A population-based case-control study was conducted of 28 single-nucleotide polymorphisms measured in newborn screening blood spots. A total of 413 children with later-diagnosed cerebral palsy were born to white women in South Australia in 1986-1999, and there were 856 control children. Distributions of genotypic frequencies were examined in total cerebral palsy, in gestational age groups, and by types of cerebral palsy and gender. Genotyping was performed by using a TaqMan assay. RESULTS: For inducible nitric-oxide synthase, possession of the T allele was more common in all children with cerebral palsy and for heterozygotes who were born at term. For lymphotoxin alpha, homozygous variant status was associated with risk for cerebral palsy and with spastic hemiplegic or quadriplegic cerebral palsy. Among term infants, heterozygosity for the endothelial protein C receptor single-nucleotide polymorphism was more frequent in children with cerebral palsy. In preterm infants, the variant A allele of interleukin 8 and heterozygosity for the beta-2 adrenergic receptor were associated with cerebral palsy risk. Interleukin 8 heterozygote status was associated with spastic diplegia. Variants of several genes were associated with cerebral palsy in girls but not in boys. CONCLUSIONS: Two of the 28 single-nucleotide polymorphisms examined were associated with all types of spastic cerebral palsy in both gestational age groups and others with cerebral palsy in gestational age or cerebral palsy subgroups. Some of these associations support previous findings. There may be a genetic contribution to cerebral palsy risk, and additional investigation is warranted of genes and gene-environment interactions in cerebral palsy.
[Gibson, C. S., Maclennan, A. H., Dekker, G. A., Goldwater, P. N., Sullivan, T. R., Munroe, D. J., Tsang, S., Stewart, C. & Nelson, K. B. (2008). Candidate genes and cerebral palsy: A population-based study. Pediatrics, 122(5), 1079-85.]
2. Genetic polymorphisms and cerebral palsy in very preterm infants
In the present study, we examine whether selected genetic polymorphisms contribute to the development of cerebral palsy (CP) in very preterm infants. Subjects were 96 singleton infants with later-diagnosed CP and 119 control children, white non-Hispanic (n for CP=74, controls=88) or white Hispanic (CP=22, controls=31), born <32 wk gestation. Presence of CP was identified through state service agencies, with review of medical records. DNA extracted from archived neonatal blood was genotyped using multi-locus polymerase chain reaction amplification and immobilized sequence-specific oligonucleotide probes. Single nucleotide polymorphisms (SNPs) showing evidence of association with development of CP were endothelial nitric oxide synthase (eNOS) A(-922)G, factor 7 (F7) arg353gln and del(-323)10bp-ins, and lymphotoxin A (LTA) thr26asn. In white non-Hispanic children, beta-2 adrenergic receptor gln27glu was associated with CP risk; in Hispanic children, plasminogen activator inhibitor-1 (PAI-1) 4G(-675)5G and G11053T were associated with risk of CP. In a logistic regression considering these SNPs simultaneously in non-Hispanics, an association with CP was observed for heterozygotes of eNOS -922 (OR 3.0, CI 1.4-6.4), F7 (OR 2.7, CI 1.1-6.5), LTA (OR 2.1, CI 1.0-4.6), and PAI-1 (OR 3.2, CI 1.2-8.7). Factor 5, Factor 2, methylene tetrahydrofolate reductase, tumor necrosis factor-alpha, and other SNPs tested were not significantly associated with CP risk. We conclude that further study of genetic factors that may influence susceptibility to CP in very preterm infants is warranted.
[Nelson, K. B., Dambrosia, J. M., Iovannisci, D. M., Cheng, S., Grether, J. K. & Lammer, E. (2005). Genetic polymorphisms and cerebral palsy in very preterm infants. Pediatric Research, 57(4), 494-9.]
3. High familial risks for cerebral palsy implicate partial heritable aetiology
Cerebral palsy is the commonest cause of severe childhood disability, the aetiology of which is largely unknown. Data on familial aggregation of cerebral palsy are very limited. We defined familial risks for siblings who were hospitalised because of cerebral palsy in Sweden. A nationwide database for neurological diseases was constructed by linking the Multigeneration Register to the Hospital Discharge Register for the years 1987-2001. Standardised hospitalisation ratios (SHRs) were calculated for affected singletons and twins by comparing them with siblings who had no cerebral palsy. A total of 3997 patients were recorded with cerebral palsy. Familial cerebral palsy was uncommon, and it accounted for 1.6% of all cerebral palsy cases. However, for parents who had had one affected child the risk of recurrence in another child was considerably increased. Parents of one affected child had a 4.8-fold risk of having a second affected child, and where the siblings were twins, the risk was 29-fold. These familial risks were particularly high in some clinical subgroups: 17-25 in singletons and 37-155 in twins, including hemiplegia, diplegia and quadriplegia. The remarkably high familial risks are difficult to explain without some contribution of heritable factors. The lack of discordant pairs may suggest that heritable factors are disorder type-specific. Affected concordant sibling pairs should be subjected to molecular studies aiming at identifying the susceptibility gene.
[Hemminki, K., Li, X., Sundquist, K. & Sundquist, J. (2007). High familial risks for cerebral palsy implicate partial heritable aetiology. Paediatric and Perinatal Epidemiology, 21(3), 235-41.]
4. Cerebral palsy in multiple births in Western Australia: Genetic aspects
A study of cerebral palsy in multiple births was undertaken to test genetic involvement and assess the impact of the special conditions of pregnancy and parturition in these cases. Complete ascertainment of cerebral palsy in multiple gestations that occurred in Western Australia between 1956 and 1985 was obtained from the Western Australian Cerebral Palsy Register. There were 74 twins and 5 triplets. Data on sex, birth order, motor handicap, outcome in co-twins and triplets, zygosity, and pedigree information was obtained from the Register, hospital records, and, where possible, by interview of the parent(s) of the propositi. There was a significantly higher (P = 0.0026) concordance rate in MZ than in DZ twin pairs. However, pedigree studies showed no other relatives with a motor handicap similar to that of the propositi. This is consistent with a multifactorial cause in at least some of the cases. The sex ratio of affected twins was found to be 2.1 compared to 1.3 for singletons and all 5 affected triplets were boys. The trend of increasing sex ratio with increasing plurality was significant at the 1% level.
[Petterson, B., Stanley, F. & Henderson, D. (1990). Cerebral palsy in multiple births in Western Australia: Genetic aspects. American Journal of Medical Genetics, 37(3), 346-51.]
5. Study of gene expression profiles and biological mechanism of cerebral palsy using a monozygotic twin pair
The gene expression profile of a normal-suffering monozygotic twin pair is investigated to explore biological mechanisms of spastic type cerebral palsy. Main works include following three aspects: First, a cDNA microarray test is carried out to get the differentially expressed genes of the patient with cerebral palsy compared to her monozygotic twin sister. Second, these differentially expressed genes are searched for their bioinformation within 4 biological databases: FatiGO, FatiGOPlus, KEGG, and SOURCE. Third, a set of special genes and gene families are screened out from the spastic type cerebral palsy patient. These biological analyses reveal that those genes for cell junction are mostly down-regulated, while those genes for metabolism are mostly up-regulated. The individual genes, gene family, and their associated biological functions can reflect the pathological and physiological characteristics of the cerebral palsy.
[Zhang, T., Wang, M., Pan, L., Ding, W., Wang, J. G., Yang, L., Liu, M., Li, W. & Yan, Z. (2007). Study of gene expression profiles and biological mechanism of cerebral palsy using a monozygotic twin pair. Twin Research and Human Genetics, 10(3), 496-507.]
6. Cerebral palsy in twins
Eighty-six children with cerebral palsy (CP) born as a product of twin pregnancies were studied. Data regarding their co-twins were also gathered. The authors' findings suggest that (1) monozygotic twins have a higher risk of CP than dizygotic twins, (2) twin order at birth does not seem to be a relevant factor in the etiology of CP, (3) mothers less than 24 or more than 34 years of age had the highest incidence of children with CP as a product of a twin pregnancy, and (4) the data do not support a genetic basis for the disease.
[Laplaza, F. J., Root, L., Tassanawipas, A. & Cervera, P. (1992). Cerebral palsy in twins. Developmental Medicine and Child Neurology, 34(12), 1053-63.]
7. Cerebral palsy due to chromosomal anomalies and continuous gene syndromes
When cerebral palsy is defined as a disorder of movement and posture that is due to nonprogressive disturbances that occur in the developing fetal and infant brain, a significant proportion-up to 10%—is the consequence of chromosomal anomalies and continuous gene syndromes. Abnormalities of chromosomes are constitutional or acquired. Acquired chromosomal abnormalities develop postnatally, affect only one clone of cells, and are implicated in the evolution of neoplasia. Constitutional abnormalities develop during gametogenesis or early embryogenesis and affect a significant portion of the subject's cells.
[Menkes, J. H. & Flores-Sarnat, L. (2006). Cerebral palsy due to chromosomal anomalies and continuous gene syndromes. Clinics in Perinatology, 33(2), 481-501.]
8. De novo occurrence of novel SPG3A/atlastin mutation presenting as cerebral palsy
BACKGROUND: Mutations in the SPG3A gene (atlastin protein) cause approximately 10% of autosomal-dominant hereditary spastic paraplegia. For many subjects with an SPG3A mutation, spastic gait begins in early childhood and does not significantly worsen even over many years. Such subjects resemble those with spastic diplegic cerebral palsy. To date, only 9 SPG3A mutations have been reported. OBJECTIVE: To analyze the SPG3A coding sequence in an individual with childhood-onset spastic gait, who, prior to the birth of her similarly affected child, had no previous family history of hereditary spastic paraplegia. METHODS: The SPG3A coding sequence was analyzed in DNA samples from the proband, her affected child, her unaffected parents, and control subjects by polymerase-chain-reaction amplification of each exon followed by direct DNA sequencing. Seventeen microsatellite polymorphisms were amplified and analyzed to confirm reported paternity. RESULTS: We identified a novel SPG3A mutation (L157W) in the proband and her affected child. This mutation was absent in the proband's unaffected parents. Results of microsatellite polymorphism analysis were consistent with paternity as reported. These results indicate that this novel SPG3A mutation arose de novo in the proband. CONCLUSIONS: We report the de novo occurrence of a novel SPG3A mutation in a subject with childhood-onset, nonprogressive, spastic diplegia who had no previous family history of hereditary spastic paraplegia until the birth of her similarly affected son. Although rare, the occurrence of a de novo hereditary spastic paraplegia gene mutation must be considered in subjects with spastic diplegic cerebral palsy for whom no other cause is identified. This is extremely important for correct genetic counseling because recurrence risk may be as high as 50% when a mutation is detected.
[Rainier, S., Sher, C., Reish, O., Thomas, D. & Fink, J. K. (2006). De novo occurrence of novel SPG3A/atlastin mutation presenting as cerebral palsy. Archives of Neurology, 63(3), 445-7.]
9. The association between inherited cytokine polymorphisms and cerebral palsy
OBJECTIVE: The purpose of this study was to investigate associations between inherited cytokine polymorphisms and cerebral palsy. STUDY DESIGN: This was a case-control study that used DNA from the newborn infant screening cards of 443 white infants with cerebral palsy and 883 white control infants to test for the following cytokine polymorphisms: tumor necrosis factor-alpha-308, mannose-binding lectin-221, and 3 polymorphisms in exon-1 of the mannose-binding lectin gene at codon-52, -54, and -57. RESULTS: At all gestational ages mannose-binding lectin codon-54 increased the risk of the development of diplegia (homozygous or heterozygous odds ratio, 1.55; 95% CI, 1.03-2.32). For babies who were born at term, the risk of the development of quadriplegia was associated with heterozygous tumor necrosis factor-alpha (odds ratio, 1.82; 95% CI, 1.04-3.15), and mannose-binding lectin codon-54 was associated with diplegia (homozygous or heterozygous odds ratio, 2.12; 95% CI, 1.10-4.05). The presence of any polymorphism in mannose-binding lectin exon-1 at term approximately doubled the risk of the development of diplegia (odds ratio, 1.94; 95% CI, 1.05-3.62). Homozygous or heterozygous tumor necrosis factor-alpha was associated with hemiplegia for babies who were born at <32 weeks of gestation (odds ratio, 2.38; 95% CI, 1.02-5.58). Overall, the presence of any cytokine polymorphism was associated with cerebral palsy (odds ratio, 1.37; 95% CI, 1.02-1.84). CONCLUSION: Carriage of polymorphisms in the tumor necrosis factor-alpha and mannose-binding lectin genes are associated with an increased risk of cerebral palsy.
[Gibson, C. S., MacLennan, A. H., Goldwater, P. N., Haan, E. A., Priest, K., Dekker, G. A. & South Australian Cerebral Palsy Research Group. (2006). The association between inherited cytokine polymorphisms and cerebral palsy. American Journal of Obstetrics and Gynecology, 194(3), 674.e1-11.]
10. Genetics considerations in cerebral palsy
Cerebral palsy refers to a collective of neurologic conditions that share in common disorders of motor function and posture. Traditionally, and still today in many circles, the term is considered almost synonymous with brain injury. Multiple lines of evidence, however, point to the fact that cerebral palsy is rarely caused by problems with perinatal management. In fact, a mounting body of evidence points to strong genetic influences on the occurrence of cerebral palsy. Like most neurogenetic conditions, cerebral palsy exhibits complex inheritance. The best descriptor of the inheritance of cerebral palsy would be that of "multifactorial inheritance." This implies etiologic and genetic heterogeneity with complex interactions with multiple environmental influences. This article reviews known genetic influences on the origin of cerebral palsy. A proposed scheme for the genetic evaluation in identifying the etiology of cerebral palsy is provided.
[Schaefer, G. B. (2008). Genetics considerations in cerebral palsy. Seminars in Pediatric Neurology, 15(1), 21-6.]
11. Genetic factors in athetoid cerebral palsy
Within the cerebral palsy syndromes, athetosis is most commonly causally associated with serious perinatal complications. Genetic factors are thought to play a lesser role, although the risk of recurrence in siblings has been suggested to be as high as 10%. We have conducted a clinical study of 22 subjects with a diagnosis of athetoid cerebral palsy and a review of the literature aiming to identify instances of familial recurrence of athetoid cerebral palsy. The birth history, family history, and previous investigations of subjects with athetoid cerebral palsy were studied and subjects were clinically examined for evidence of an underlying genetic etiology. Factors suggesting a genetic cause were specifically sought, such as advanced paternal age, progression of symptoms, and associated congenital abnormalities. No subjects in the study group had similarly affected relatives, and additional features suggesting a genetic cause were not observed. A literature search identified 16 instances of familial recurrence of athetoid cerebral palsy. Familial cases were typically associated with significant spasticity, microcephaly, intellectual disability, seizures, and a lack of history of birth asphyxia, and most could be explained by either autosomal-recessive or X-linked-recessive inheritance. The genetic contribution to athetoid cerebral palsy is small, with an overall risk of recurrence in siblings of about 1%. This risk is lower than previously suggested in the literature.
[Amor, D. J., Craig, J. E., Delatycki, M. B. & Reddihough, D. (2001). Genetic factors in athetoid cerebral palsy. Journal of Child Neurology, 16(11), 793-7.]