ANNOTATION
Genetic Aspects of Cerebral Palsy
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CEREBRAL palsy (CP) is a persistent, but not unchanging, disorder of posture and movement caused by a non-progressive disorder of the brain, first evident from a time of rapid brain development. Since the time of LITTLEand FREUD,debate has continued about the relative contribution of prenatal, perinatal and genetic factors. Deciding whether a child has a permanent movement disorder can be difficult-it is well known that early signs may improve and disappear-but it is clear that parents are keen to receive as much information as possible, and to share unvoiced concerns of attending doctors, sooner rather than later. Parents are often anxious to know about the likelihood of recurrence in future children. The answer to this question may be equally difficult for paediatricians, and this annotation will attempt to outline a pragmatic approach to the problem in the light of current knowledge. CP is not a single entity and the aetiology of similar or different forms is not necessarily the same. In a study', of 1048 low-birthweight infants, 48 were found t o have CP. Intrapartum events were closely related t o the pathogenesis of
hemiplegia, while factors that might influence the rate of fetal development seemed to be important in diplegia. One legacy of LITTLE'Steaching is that for 130 years lay and professional people have put undue emphasis on the causative role of perinatal events in CP. More recent data carry a different emphasis. Matching 183 children with CP with controls, BLAIR and STANLEY3 found birth asphyxia to be the cause of only 6 to 8 per cent. Analysis of data from the Collaborative Perinatal Study of the National Institutes of Neurological2 and Communicative Disorder and Stroke4 suggests that only 14 per cent of the risk of quadriplegia could be attributed to birth asphyxia. This study also indicated that, among children with CP, signs considered characteristic of birth asphyxia-meconiumstained liquor, low 10-minute Apgar scores, apnoea, seizures, persistent neurological abnormalities and slow headgrowth after birth-were more often the result of non-asphyxia1 disorders. A term infant who has sustained birth asphyxia severe enough to cause brain injury will develop signs of hypoxic-ischaemic encephalopathy-notably seizures and abnormalities in tone, degree of alertness, and primitive reflex pattern5. Often there is symptomatic involvement of other organ systems, kidneys, lungs and heart6. If a term infant does not exhibit any signs
of hypoxic-ischaemic encephalopathy, subsequent disability cannot be attributed to birth asphyxia'. It must also be remembered that infants who have sustained o r appear t o have sustained birth asphyxia may have an underlying disorder which predisposes them to respiratory depression in the neonatal period, such as Prader-Willi syndromes, congenital myotonic dystrophy or other muscle disorder. In most, evidence for asphyxia1 damage is lacking and central nervous system infections, including encephalitis and meningitis, in the first year of life account for only 6 per cent of children with c p 4 . The cause in the majority of cases remains unknown. I n a small proportion of cases, approximately 2 per cent, a significant genetic factor will have contributed. In addition, there are inherited disorders which may be slowly progressive and which, particularly in their early stages, may mimic a more static encephalopathy: clearly their recognition is important. Disorders of neuronal migration are likely to account for the movement disorders of many children. In the human fetus, immature neurons guided by radial glial fibres migrate to the cortical plate between seven and 16 weeks of gestational ageg. Neocortex is laid down from within outwards, so that successive waves pass through layers already established. An abnormal pattern of migration will lead to stunting and early death of neuronsg, with effect on the establishment of association pathways: epilepsy, motor, learning and behavioural disorders may all ensue. Although the classification of this group of disorders is based on gross morphological appearance (agyria, pachygyria, microgyria, lissencephaly and so on), detailed neuropathological study of brain tissue obtained at postmortem or at operation has identified localised or lesser degrees of migrational disorderIO. Environmental factors at a critical period may predispose to these disorders. Genetic factors are important in some, for example the short-arm deletion of chromosome 17 in the Miller-Dieker form of lissencephaly". Imaging of the brain with computerised axial tomography or magnetic resonance can define many of these syndromes'*, 1 3 .
Agenesis of the corpus callosum may be seen alongside gyral abnormality or in apparent isolation. Facial appearance may be a diagnostic clue, with hypertelorism, malformed ears and a hypoplastic mandible being frequent association^'^. Recurrence risks in the absence of a family history are small, but recessive and Xlinked dominant forms are known. Although imaging helps us to visualise abnormalities, it does not help to explain them. Identifiable biochemical disorder is present in a small number: fatty acid oxidation in peroxisomes and mitochondria15, cell adhesion molecules and polyamines are all known to have an important influence9. Recessive or Xlinked inheritance may apply to the peroxisomal disorders, whereas different advice would apply for mitochondria1 inheritance. Maternal serum alpha-fetoprotein (AFP) measurement is established as an effective screening method to detect neural-tube defects and as an adjunct to screening for Down syndrome. AFP is normally produced by fetal liver and yolk-sack cells from the third week of intra-uterine life, with serum levels dropping to zero about three weeks after term. It is not only a marker for open neural-tube defects such as anencephaly and spina bifida, but also for closed spina bifida, exomphalos and congenital nephrosis16. It is also a predictor of low birthweight, although sensitivity and specificity is poor. Population data are not yet available to show an association between elevated levels and more subtle neuronal migration problems, although the evaluation of this and other markers would be of value. Neurological examination will allow the identification of specific patterns of movement disorder. Genetic factors in each syndrome must be considered: the following list is by no means exhaustive, but does emphasise the need for an imaginative and detailed approach to the assessment of children with the appearances of a static encephalopathy.
Ataxia, ataxic diplegia and disequilibrium syndrome Although only representative of 15 per cent of children with CPI', it is in this category that there is the highest likelihood
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limitations were remarkably similar. of a genetically determined disorder, or of There was marked heterogeneity between a slowly progressive disorder, likely to be the sibling pairs. mistaken for CP. Much less commonly, ataxia with GUSTAVSON et al.I8 estimate that mental retardation and cerebellar hypobetween one-third and one-half of cases plasia may be transmitted as an x-linked of congenital ataxia with mental retardation are genetically determined. Most of recessive 38. In one report of these are inherited in an autosomal two male siblings and a maternal uncle, recessive manner, but dominant inheritance there was an associated communicating has been found in a few families with hydrocephalus3’. ataxic diplegia18,19. Deterioration of function may be so With improved imaging techniques it slow in some of the progressive disorders with onset in early childhood that one has become apparent that the anatomical may mistakenly consider the child to have basis for many cases of congenital ataxia a static encephalopathy. In ataxia is cerebellar hypoplasia. Often there are other associated abnormalities which may telangiectasia, the gait disorder may be apparent in the second year of life, but help identify a recognised syndrome with telangiectasia is rarely evident before four specific genetic implications. to six years. Cerebellar hypoplasia may be The features of Joubert syndrome are apparent on CT scan. Elevation of serum ataxia, which may be masked by AFP will suggest this diagnosis, which can hypotonia in younger infants, disturbance be confirmed by demonstrating increased of respiratory rhythm with episodes of hyperpnoea and apnoea, abnormal eyechromosomal breakage and sensitivity to movements, mental retardation and hyporadiation in cells cultured from the plasia of the cerebellar vermis20. Other patient40. Metachromatic leukodystrophy (MCL) reported features have been squint, tongue and hexosaminidase A and B deficiency protrusion, polydactyly21, chorioretinal colobomata22!23 and retinal d y ~ p l a s i a ~ ~ . may also cause ataxia in the early stages and can be confirmed by measurement of Inheritance is autosomal recessive2s. the appropriate enzyme in leukocytes. Marinesco-Sjorgren syndrome is characterised by ataxia, mental retardation and MCL may also be the cause of spastic diplegia in the early stages, but dementia cataracts26. Less common features include growth r e t a r d a t i ~ n ~skeletal ~, abnormis usually evident by the time quadrialities26,28, 29, epilepsy, microcephaly and paresis has evolved. pyramidal-tract d y s f ~ n c t i o n ~ Inheritance ~. In Behr syndrome, ataxia is associated with optic atrophy, spasticity, mental is autosomal recessive27. retardation, posterior column sensory Features of Gillespie syndrome are ataxia, aniridia and mental retardation31. loss, and in some cases peripheral Inheritance is suspected to be autosomal neuropathy. The mode of inheritance is recessive. unclear and is either autosomal recessive or autosomal dominant, with variable A non-progressive cerebellar disorder penetrance41. Early-onset ataxia has also with mental retardation and increased tendon reflexes, mainly in the lower been associated with hearing loss, mental limbs, has been reported in H ~ t t e r i t e s ~ ~ . retardation and h y p o g ~ n a d i s m ~and ~, hearing loss, amyotrophy and intellectual Less consistent features are extensor deteri~ration~~. plantar reflexes, short stature, squint, small muscle mass and epilepsy. Cerebellar ataxia and mental retardation Spastic diplegia and quadriplegia have also been reported in association In the presence of a normal perinatal with mild pyramidal-tract signs and short period and without a definite postnatal stature33, congenital h y p e r o s t ~ s i s and ~~ cause, the recurrence risk of these forms of CP is approximately 10 per cent44; the choroidal ~ o l o b o m a t a ~Three ~. sibling risk is greater if the spasticity is sympairs with non-progressive ataxia and metrical4s.47. The recurrence risk is mental retardation have been reported36; similar whether the index case has spastic within each family the onset, clinical course and severity of mental and motor quadriplegia or diplegia and whether or
not microcephaly is present, but there is a slightly increased risk for siblings of patients who have myoclonus or paroxysmal abnormalities on EEG44. Most of the reported familial cases have occurred in offspring of normal parents, many of whom were c o n s a n g u i n e ~ u47. s~~~ Most of these cases had associated mental retardation, but normal intelligence in an individual with spastic diplegia or quadriplegia does not preclude an inherited disorder48. Inheritance is likely to be autosomal recessive in the majority; however, one index case with spastic diplegia gave birth to a similarly affected daughter, raising the possibility of an autosomal dominant mutation49. There have been families with x-linked recessive inheritance. One French-Canadian family had many males, over two generations, affected by a syndrome of mental retardation, myoclonic jerks, microcephaly, mild optic atrophy and spastic diplegiasO. In an Australian family, the gene for an x-linked recessive syndrome of mental retardation, short stature, microcephaly, brachycephaly, spastic diplegia, small testes and possible intra-uterine growthretardation has been mapped to the area near the centromere5'. A sporadic form of spastic diplegia may be mistakenly diagnosed when the patient has a rare familial disorder. In families with familial spastic paraplegia, the inheritance is most often autosomal dominant, so the parents of a child with spastic diplegia and a normal perinatal period warrant examination for increased lower-limb reflexes and extensor plantar responses. In patients with dopa-responsive dystonia, o r Segawa syndrome, a period of normal development, progression, diurnal variation and Parkinsonian features should suggest the diagnosiss2. The movement problem is usually distal rather than proximal, causing the children to walk in bizarre and at times cybernetic fashion. Children with this disorder have CSF concentrations of homovanillic acid, 5-hydroxyindoieacetic acid and biopterin below the normal rangej3. Recognition of this disorder is important, since it is treatable with small doses of dopa^^ and there is a high familial incidence. Although the mode of inheritance is not
known, autosomal dominance with reduced penetrance is likely". Babies with congenital stiffness (hyperekplexia) may be thought to have spastic quadriplegia. Hyperekplexia manifests as permanent hypertonia from birth, which lessens in sleep, is increased by any stimulus, and diminishes during the first year of life. Inheritance is autosomal dominant56. The rarer autosomal recessive disorder of thanatophoric congenital stiffnesss7 has a less benign course, with oesophageal dysmotility and frequent aspiration.
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Athetoid and dystonic CP With the virtual elimination of bilirubin encephalopathy, genetic factors have become relatively more common in the causation of athetoid CP. The recurrence risk is unknown, but is probably of the same order as that for spastic CP. An Xlinked disorder of athetoid CP and myoclonus has been described44,58, so the risk of recurrence is higher for brothers of male cases. Again, inherited disorders may for a time mimic athetoid and dystonic CP. In the first year of life, before self-mutilation begins, boys with Lesch-Nyhan syndrome present with motor delay and dystonia or choreo-athetosis. Elevated serum uric acid and urinary urate:creatine ratio and absence of red-cell hypoxanthine-quanine phosphoribosyl transferase confirm the diagnosis, which is inherited in an Xlinked fashion. Children with glutaricaciduria type 1 may be normal until an encephalopathic state is precipitated by a febrile illness. Choreo-athetosis is a prominent symptom of this disorder, which may be diagnosed by finding glutaric acid and 3-0~-glutaratein urine and confirmed by assay of glutaryl-coA dehydrogenase in fibroblastsS9~ 60. Inheritance is autosomal recessive. Advice to parents should be based on all the information available. Careful attention should be paid to antenatal records, the rate of growth of the fetus as determined by available ultrasound scan reports and the value of the maternal serum AFP. It is often helpful to parents, who in their own minds attribute damage to the labour itself, to go through that
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record with them. Inconclusive pieces of evidence, such as meconium staining of the liquor or low Apgar score, cannot be relied upon to establish important degrees of asphyxia. Only if one can establish the presence of hypoxic-ischaemic encephalopathy can it be said that neuronal i n j u r y is likely to have occurred as a consequence of labour. The baby must be examined for dysmorphic features, signs of a neurocutaneous syndrome or storage disorder. The eyes may carry the choroidoretinitis of a congenital infection, or more rarely the specific retinopathy of an error of metabolism or cerebral dysgenesis. Unless there is clear evidence of a congenital infection-present in only a few children with static encephalopathy-a C T scan looking for evidence of a neuronal migration problem or a pattern of atrophy within arterial territory is indicated, along with a full metabolic screen. In the presence of severe handicap or dysmorphism, karyotyping is also indicated. Where cause can be attributed to the complications of pregnancy, a specific pattern of malformation is recognised or a metabolic disease identified, it is helpful to seek advice from the regional neurometabolic/genetic centre. For the vast majority of children with a static encephalopathy the cause will remain unknown, with no aetiological clue from the history and normal investigations. It is most appropriate t o give these families an empirical risk of recurrence of between 10 and 20 per cent. The lower risk figure may be used when it might be possible to implicate environmental influences such as an influenza-like illness in the early weeks of pregnancy; the higher figure is probably most appropriate for symmetrical problems, and particularly when there are other minor abnormalities outside the nervous system. For children with cerebellar ataxia in the absence of indentifiable conditions, such as ataxia telangiectasia, an empirical risk of one in eight should apply. By providing information on and better understanding of causation, paediatricians are not only giving parents a rational basis for future family planning, but also satisfying their need to understand how what is seen initially as a disaster has occurred,
and to escape feelings of guilt that may well be attendant on their grief. This important task should never be delegated to junior staff and for the best results should be conducted with both parents present, with the information delivered in a simple and straightforward way. The effort will be appreciated. IMELDA HUGHES RICHARDNEWTON* Department of Neurology, Royal Victoria Hospital, Belfast. *Department of Child and Adolescent Neurology, Royal Manchester Children’s Hospital, Pendlebury, Manchester M27 IHA. References 1 . Powell, T. G., Pharoah, P . 0. D., Cooke, R. W. I . . Rosenbloom, L. (1988) ‘Cerebral palsy in low-birthweight infants. I . Spastic hemiplegia: associations with intrapartum stress.’ Developmental Medicine and Child Neurology, 30, I 1- 18. 2. Powell, T. G., Pharoah, P . 0. D., Cooke, R. W. I., Rosenbloom, L. (1988) ‘Cerebral palsy in low-birthweight infants. I I . Spastic diplegia: associations with fetal immaturity.’ Developmental Medicine and Child Neurology,
30, 19-25. 3. Blair, E., Stanley, F. J . (1988) ‘Intrapartum asphyxia: a rare cause of cerebral palsy. Journal of Pediatrics, 112, 515-519. 4. Naeye, R. L., Peters, E. C., Bartholomew, M.: Landis, R. (1989) ‘Origins of cerebral palsy. American Journal of Diseases of Children,
143, 1154-1161. 5. Sarnat, H. B., Sarnat, M. S. (1976) ‘Neonata! encephalopathy following fetal distress. Archives of Neurology, 33, 696-705. 6. Tack, E., Perlman, J . M. (1986) ‘Systemic manifestations of perinatal asphyxia in the newborn.’ Paediatric Research, 20, 362A. (Abstract no. 1212.) 7. Freeman, J . M., Nelson, K. B. (1988) ‘Intra; partum asphyxia and cerebral palsy. Pediatrics, 82, 240-249. 8. Wharton, R., Bresnan, M. J . (1986) ‘PraderLabhart-Willi syndrome and Firth asphyxia: cause versus susceptibility. Annals of Neurology, 20, 438. (Abstract.) 9. Barth, P. G . (1987) ‘Disorders of neuronal migration.’ Canadian Journal of Neurological Sciences, 14, 1-16. 10. Lancet, Editorial (1990) ‘Epilepsy and disorders of neuronal migration.’ Lancet, 2, 1035. 11. Dobyns, W. B., Stratton, R. F., Greenberg, F. (1984) ‘Syndromes with lissencephaly. 1: Miller-Dieker and Norman-Roberts syndromes and isolated lissencephaly.’ American Journal of Medical Genetics, 18, 509-526. 12. Byrd, S. E., Osborn, R. E., Bohan, T. P., Naidich, T. P. (1989) ‘The CT and MR evaluation of migrational disorders of t h t brain. I: Lissencephaly and pachygyria. Pediatric Radiology, 19, 151-156. 13. Byrd, S. E., Osborn, R. E., Bohan, T. P.,
Naidich, T. P . (1989) ‘The C T and MR evaluation of migrational disorders of the brain. 11. Schizencephaly, heterotopia and polymicrogyria.’ Pediatric Radiology, 19, 2 19-222. 14. Parrish, M . L., Roessman, U., Levinsohn, M. W. (1979) ‘Agenesis of the corpus callosum. A study of the frequency of associated malformations.’ Annals of Neurology, 6, 349-354. 15. Brown, G . K . , Haan, E. A., Kirby, D. M., Scholem, R. D., Wraith, J . E., Rogers, J. G., Danks, D. M. (1988) ‘ “Cerebral” lactic acidosis: defects in pyruvate metabolism with profound brain damage and minimal systemic acidosis.’ European Journal of Pediatrics, 147, 10-14. 16. Brock, D. J . H. (1989) ‘Maternal blood markers (alpha-fetoprotein).’ In Reed, G . B., Claireaux, A. E., Bain, A. D. (Eds.) Diseases of the Fetus and Newborn. London: Chapman & Hall. 17. Paneth, N. (1986) ‘Birth and the origins of cerebral palsy.’ New England Journal of Medicine, 315, 125-126. 18. Gustavson, K.-H., Hagberg, B., Sanner, G. (1969) ‘Identical syndromes of cerebral palsy in the same family.’ Acta Paediatrica Scandinavica, 58, 330-340. 19. Ingram, T. T. S. (1962) ‘Congenital ataxic syndromes in cerebral paiy.’ Acta Paediatrica Scandinavica, 51, 209-221. 20. Joubert, M., Eisenring, J. J., Robb, J . P., Andermann, F. (1969) ‘Familial agenesis of the cerebellar vermis.’ Neurology, 19, 813-825. 21. Egger, J., Bellman, M. H., Ross, E. M., Baraitser, M. (1982) ‘Joubert-Boltshauser syndrome with polydactyly in siblings.’ Journal of Neurology, Neurosurgery and Psychiatry, 45, 737-739. 22. Laverda, A. M., Saia, 0. S., Drigo, P., Danieli, E., Clementi, M., Tenconi, R. (1984) ‘Chorioretinal coloboma and Joubert syndrome: a non-random association.’ Journal of Pediatrics, 105, 282-284. 23. Lindhout, D., Barth, P. G., Valk, J., BoenTan, T. B. (1980) ‘The Joubert syndrome associated with bilateral chorioretinal coloboma.’ European Journal of Pediatrics, 134, 173-176. 24. King, M. D., Dudgeon, J . , Stephenson, J. B. P . (1984) ‘Joubert’s syndrome with retinal dysplasia: neonatal tachypnoea as the clue to a genetic brain-eye malformation.’ Archives of Disease in Childhood, 59, 709-7 18. 25. Boltshauser, E., Isler, W. (1977) ‘Joubert syndrome: episodic hyperpnea, abnormal eye movements, retardation and ataxia associated with dysplasia of the cerebellar vermis.’ Neuropadiatrie, 8, 57-66. 26. Marinesco, G., Draganesco, S., Vasiliu, D. (I93 1) ‘Nouvelle maladie familiale caraterisee par une cateracte congenitale et un arret du developpement somato-neuro-psychique.’ Encephale, 26, 97-109. 27. Maloudji, M., Amirhakimi, G. H., Haghighi, P., Khodadoust, A. A. (1972) ‘MarinescoSjogren syndrome: report of an autopsy.’ Brain, 95, 675-680. 28. Sjogren, T. (1950) ‘Hereditary congenital spinocerebellar ataxia accompanied by coneenital cataract and olieoohrenia.’ Confinia keurologica, 10, 293-308u. ’ 29. Alter, M., Talbert, 0. R., Croffead, G . (1962) ‘Cerebellar ataxia, congenital cataracts and retarded somatic and mental maturation.
Report of cases of Marinesco-Sjogren syndrome.’ Neurology, 13, 836-847. 30. Ron, M. A., Pearce, J . (1971) ‘MarinescoSjogren-Garland syndrome with unusual features.’ Journal of the Neurological Sciences, 13, 175-179. 3 1 . Gillespie, F. D. (1965) ‘Aniridia, cerebellar ataxia and oilgophrenia in siblings.’ Archives of Ophthalmology, 73, 338-341. 32. Schurig, V., Van Orman, A , , Bower, P. (1981) “on-progressive cerebellar disorder with mental retardation and autosomal recessive inheritance in Hutterites.’ American Journal of Medical Genetics, 9, 43-53. 33. Kvistov, P . M., Dahl, A,, Skre, H. (1985) ‘Autosomal recessive non-progressive ataxia with an early childhood debut.’ Acta Neurologica Scandinavica, 71, 295-302. 34. Dietrich, F. (1957) ‘Generalisierte Hyperostose und zerebellare Hemmungsmissbildung.’ Schleizerische Archiv f u r Neurologie und Psychiatrie, 80, 100- 134. 35. Pfeiffer, R. A , , Palm, D., Jiinemann, G., Mandl-Kramer, S., Heimann, E. (1974) ‘Nosology of congenital non-progressive cerebellar ataxia. Report of 6 cases in 3 families.’ Neuropadiatrie, 5, 91-102. 36. Wichman, A , , Frank, L. M., Kelly, T. E. (1985) ‘Autosomal recessive congenital cerebellar hypoplasia.’ Clinical Genetics, 27, 373-382. 37. Young, 1. D., Moore, J. R., Tripp, J. H. (1987j ‘Sex-linked recessive congenital ataxia. Journal of Neurology, Neurosurgery and Psychiatry, 50, 1230-1232. 38. Malamud, N., Cohen, P . (1958) ‘Unusual form of cerebellar ataxia with sex-linked inheritance.’ Neurology, 8, 26 1-266. 39. Renier, W. O., Gabreels, F. J. M., Hustinx, T. W. J . , Thijssen, H . 0. M., Ter Haar, B. G . A , , Kroll, E. W . , Beckers, H. (1983) ‘Cerebellar hypoplasia, communicating hydrocephalus and mental retardation in two brothers and a maternal uncle.’ Brain and Development, 5, 41-45. 40. Cox, R., Hosking, G. P., Wilson, J. (1978) ‘Ataxia telangiectasia. Evaluation of radiosensitivity in cultured skin fibroblasts as a diagnostic test.’ Archives of Disease in Childhood, 53, 386-390. 41. Landrigan, P . J., Berenberg, W., Bresnan, M. (1973) ‘Behr’s syndrome: familial optic atrophy, spastic diplegia and ataxia.’ Developmental Medicine and Child Neurology, 15, 41-47. 42. Richards, B. W., Rundle, A. T. (1959) ‘A familiar hormonal disorder associated wit! mental deficiency, deaf mutism and ataxia. Journal of Mental Deficiency Research, 3, 33-55. 43. Berman, W., Haslam, R. H. A., Konigsmark, B. W . , Capute, A . J., Migeon, C. J. (1973) ‘A new familial syndrome with ataxia, hearing loss and mental retardation.’ Archives of Neurology, 29, 258-261. 44. Bundey, S., Griffiths, M. I . (1977) ‘Recurrence risks in families of children with svmmetrical s pastici t y .’ Developmental Medicine and Child Neurology, 19, 179-191. 45. Penrose, L. S. (1938) A Clinical and Genetic Study of I280 Cases of Mental Defect. MRC Special- Report Seriei, No. 229: London: H.M.S.O. 46. Yannot, H. (1949) ‘Infantile cerebral palsy cases with severe mental defect.’ Pediatrics, 3, 820-823. 47. Book, J. A. (1953) ‘A genetic and neuro-
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psychiatric investigation of North Swedish population. Part 11: Mental deficiency and convulsive disorders.’ A c f a Genetica e f StafisficaMedica, 4, 345-414. Wild, N. J . , Rosenbloom, L. (1986) ‘Familial cerebral palsy associated with normal intelligence.’ Postgraduate Medical Journal, 62, 827-830. Bundey, S., Griffiths, M . I., Young, J . A . (1978) ‘Recurrence risk of symmetrical spastic cerebral palsy.’ Developmental Medicine and Child Neurology, 20, 390-391. Seemanova, E., Lesny, I . , Hyanek, J . , Brachfeld, K . , Rossler, M., Proskova, M. (1 973) ‘X-chromosome recessive microcephaly with epilepsy, spastic tetraplegia and absent abdominal reflex. New entity or “Paine syndrome”?’ Humangenefik, 20, 113-1 17. Sutherland, G. R., Gedeon, A. K . , Haan, E. A., Woodroffe, P . , Mulley, J . C . (1988) ‘Linkage studies with the gene for an X-linked syndrome of mental retardation, microcephaly and spastic diplegia.’ American Journal of Medical Genetics, 30, 493-508. Segawa, M., Masaka, A , , Miyagawa, F., Nomura, Y., Imai, H. (1976) ‘Hereditary progressive dystonia with marked diurnal variation.’ Advances in Neurology, 14, 215-233. Fink, J . K . , Barton, N., Cohen, W . , Hallett, M. (1988) ‘Dystonia with marked diurnal variation associated with biopterin deficiency.’
Neurology, 38, 707-7 1 1. 54. Boyd, K., Patterson, V. (1989) ‘Doparesponsive dystonia: a treatable condition misdiagnosed as cerebral palsy.’ British Medical Journal, 298, 1019-1020. 55. Nygaard, T. G., Duvoisin, R. C. (1986) ‘Hereditary dystonic-Parkinsonian syndrome of juvenile onset.’ Neurology, 36, 1424-1428. 56. Tohier, C., Roze, J . C., David, A., Veccierini, M. F., Renaud, P., Mouzard, A. (1991) ‘Hyperekplexia or stiff baby syndrome.’ Archives of Disease in Childhood, 66, 460-46 1. 57. Cantu, J . M., Cuellar, A. (1974) ‘Congenital severe generalised muscle hypertonia during wakefulness: a distinct autosomal recessive disorder.’ Clinical Generics, 6, 32-35. 58. Baar, H. S., Gabriel, A. M. (1966) ‘Sex-linked spastic paraplegia.’ American Journal of Mental Deficiency, 71, 13-18. 59. Leibel, R. L., Shih, V . E., Goodman, S. I . , Baumann, M . L., McCabe, E. R. B., Zwerdling, R. G., Bergman, I . , Costello, C . (1980) ‘Glutaric acidemia: a metabolic disorde; causing progressive choreoathetosis. Neurology, 30, 1 163- 1 168. 60. Gregeresen, N., Brandt, N. J . , Christensen, E., Grtan, I., Rasmussen, K . , Brandt, S. (1977) ‘Glutaric aciduria: clinical and laboratory findings in two brothers.’ Journal of Pediatrics, 90, 740-745.
Further information: AACPDM office, P.O. Box 11086, 1910 Byrd Avenue, # 118, Richmond, Virginia 23230-1086. Tel. (804) 282-0036; Fax (804) 282-0090.
Genetic Aspects of Cerebral Palsy
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CEREBRAL palsy (CP) is a persistent, but not unchanging, disorder of posture and movement caused by a non-progressive disorder of the brain, first evident from a time of rapid brain development. Since the time of LITTLEand FREUD,debate has continued about the relative contribution of prenatal, perinatal and genetic factors. Deciding whether a child has a permanent movement disorder can be difficult-it is well known that early signs may improve and disappear-but it is clear that parents are keen to receive as much information as possible, and to share unvoiced concerns of attending doctors, sooner rather than later. Parents are often anxious to know about the likelihood of recurrence in future children. The answer to this question may be equally difficult for paediatricians, and this annotation will attempt to outline a pragmatic approach to the problem in the light of current knowledge. CP is not a single entity and the aetiology of similar or different forms is not necessarily the same. In a study', of 1048 low-birthweight infants, 48 were found t o have CP. Intrapartum events were closely related t o the pathogenesis of
hemiplegia, while factors that might influence the rate of fetal development seemed to be important in diplegia. One legacy of LITTLE'Steaching is that for 130 years lay and professional people have put undue emphasis on the causative role of perinatal events in CP. More recent data carry a different emphasis. Matching 183 children with CP with controls, BLAIR and STANLEY3 found birth asphyxia to be the cause of only 6 to 8 per cent. Analysis of data from the Collaborative Perinatal Study of the National Institutes of Neurological2 and Communicative Disorder and Stroke4 suggests that only 14 per cent of the risk of quadriplegia could be attributed to birth asphyxia. This study also indicated that, among children with CP, signs considered characteristic of birth asphyxia-meconiumstained liquor, low 10-minute Apgar scores, apnoea, seizures, persistent neurological abnormalities and slow headgrowth after birth-were more often the result of non-asphyxia1 disorders. A term infant who has sustained birth asphyxia severe enough to cause brain injury will develop signs of hypoxic-ischaemic encephalopathy-notably seizures and abnormalities in tone, degree of alertness, and primitive reflex pattern5. Often there is symptomatic involvement of other organ systems, kidneys, lungs and heart6. If a term infant does not exhibit any signs
of hypoxic-ischaemic encephalopathy, subsequent disability cannot be attributed to birth asphyxia'. It must also be remembered that infants who have sustained o r appear t o have sustained birth asphyxia may have an underlying disorder which predisposes them to respiratory depression in the neonatal period, such as Prader-Willi syndromes, congenital myotonic dystrophy or other muscle disorder. In most, evidence for asphyxia1 damage is lacking and central nervous system infections, including encephalitis and meningitis, in the first year of life account for only 6 per cent of children with c p 4 . The cause in the majority of cases remains unknown. I n a small proportion of cases, approximately 2 per cent, a significant genetic factor will have contributed. In addition, there are inherited disorders which may be slowly progressive and which, particularly in their early stages, may mimic a more static encephalopathy: clearly their recognition is important. Disorders of neuronal migration are likely to account for the movement disorders of many children. In the human fetus, immature neurons guided by radial glial fibres migrate to the cortical plate between seven and 16 weeks of gestational ageg. Neocortex is laid down from within outwards, so that successive waves pass through layers already established. An abnormal pattern of migration will lead to stunting and early death of neuronsg, with effect on the establishment of association pathways: epilepsy, motor, learning and behavioural disorders may all ensue. Although the classification of this group of disorders is based on gross morphological appearance (agyria, pachygyria, microgyria, lissencephaly and so on), detailed neuropathological study of brain tissue obtained at postmortem or at operation has identified localised or lesser degrees of migrational disorderIO. Environmental factors at a critical period may predispose to these disorders. Genetic factors are important in some, for example the short-arm deletion of chromosome 17 in the Miller-Dieker form of lissencephaly". Imaging of the brain with computerised axial tomography or magnetic resonance can define many of these syndromes'*, 1 3 .
Agenesis of the corpus callosum may be seen alongside gyral abnormality or in apparent isolation. Facial appearance may be a diagnostic clue, with hypertelorism, malformed ears and a hypoplastic mandible being frequent association^'^. Recurrence risks in the absence of a family history are small, but recessive and Xlinked dominant forms are known. Although imaging helps us to visualise abnormalities, it does not help to explain them. Identifiable biochemical disorder is present in a small number: fatty acid oxidation in peroxisomes and mitochondria15, cell adhesion molecules and polyamines are all known to have an important influence9. Recessive or Xlinked inheritance may apply to the peroxisomal disorders, whereas different advice would apply for mitochondria1 inheritance. Maternal serum alpha-fetoprotein (AFP) measurement is established as an effective screening method to detect neural-tube defects and as an adjunct to screening for Down syndrome. AFP is normally produced by fetal liver and yolk-sack cells from the third week of intra-uterine life, with serum levels dropping to zero about three weeks after term. It is not only a marker for open neural-tube defects such as anencephaly and spina bifida, but also for closed spina bifida, exomphalos and congenital nephrosis16. It is also a predictor of low birthweight, although sensitivity and specificity is poor. Population data are not yet available to show an association between elevated levels and more subtle neuronal migration problems, although the evaluation of this and other markers would be of value. Neurological examination will allow the identification of specific patterns of movement disorder. Genetic factors in each syndrome must be considered: the following list is by no means exhaustive, but does emphasise the need for an imaginative and detailed approach to the assessment of children with the appearances of a static encephalopathy.
Ataxia, ataxic diplegia and disequilibrium syndrome Although only representative of 15 per cent of children with CPI', it is in this category that there is the highest likelihood
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limitations were remarkably similar. of a genetically determined disorder, or of There was marked heterogeneity between a slowly progressive disorder, likely to be the sibling pairs. mistaken for CP. Much less commonly, ataxia with GUSTAVSON et al.I8 estimate that mental retardation and cerebellar hypobetween one-third and one-half of cases plasia may be transmitted as an x-linked of congenital ataxia with mental retardation are genetically determined. Most of recessive 38. In one report of these are inherited in an autosomal two male siblings and a maternal uncle, recessive manner, but dominant inheritance there was an associated communicating has been found in a few families with hydrocephalus3’. ataxic diplegia18,19. Deterioration of function may be so With improved imaging techniques it slow in some of the progressive disorders with onset in early childhood that one has become apparent that the anatomical may mistakenly consider the child to have basis for many cases of congenital ataxia a static encephalopathy. In ataxia is cerebellar hypoplasia. Often there are other associated abnormalities which may telangiectasia, the gait disorder may be apparent in the second year of life, but help identify a recognised syndrome with telangiectasia is rarely evident before four specific genetic implications. to six years. Cerebellar hypoplasia may be The features of Joubert syndrome are apparent on CT scan. Elevation of serum ataxia, which may be masked by AFP will suggest this diagnosis, which can hypotonia in younger infants, disturbance be confirmed by demonstrating increased of respiratory rhythm with episodes of hyperpnoea and apnoea, abnormal eyechromosomal breakage and sensitivity to movements, mental retardation and hyporadiation in cells cultured from the plasia of the cerebellar vermis20. Other patient40. Metachromatic leukodystrophy (MCL) reported features have been squint, tongue and hexosaminidase A and B deficiency protrusion, polydactyly21, chorioretinal colobomata22!23 and retinal d y ~ p l a s i a ~ ~ . may also cause ataxia in the early stages and can be confirmed by measurement of Inheritance is autosomal recessive2s. the appropriate enzyme in leukocytes. Marinesco-Sjorgren syndrome is characterised by ataxia, mental retardation and MCL may also be the cause of spastic diplegia in the early stages, but dementia cataracts26. Less common features include growth r e t a r d a t i ~ n ~skeletal ~, abnormis usually evident by the time quadrialities26,28, 29, epilepsy, microcephaly and paresis has evolved. pyramidal-tract d y s f ~ n c t i o n ~ Inheritance ~. In Behr syndrome, ataxia is associated with optic atrophy, spasticity, mental is autosomal recessive27. retardation, posterior column sensory Features of Gillespie syndrome are ataxia, aniridia and mental retardation31. loss, and in some cases peripheral Inheritance is suspected to be autosomal neuropathy. The mode of inheritance is recessive. unclear and is either autosomal recessive or autosomal dominant, with variable A non-progressive cerebellar disorder penetrance41. Early-onset ataxia has also with mental retardation and increased tendon reflexes, mainly in the lower been associated with hearing loss, mental limbs, has been reported in H ~ t t e r i t e s ~ ~ . retardation and h y p o g ~ n a d i s m ~and ~, hearing loss, amyotrophy and intellectual Less consistent features are extensor deteri~ration~~. plantar reflexes, short stature, squint, small muscle mass and epilepsy. Cerebellar ataxia and mental retardation Spastic diplegia and quadriplegia have also been reported in association In the presence of a normal perinatal with mild pyramidal-tract signs and short period and without a definite postnatal stature33, congenital h y p e r o s t ~ s i s and ~~ cause, the recurrence risk of these forms of CP is approximately 10 per cent44; the choroidal ~ o l o b o m a t a ~Three ~. sibling risk is greater if the spasticity is sympairs with non-progressive ataxia and metrical4s.47. The recurrence risk is mental retardation have been reported36; similar whether the index case has spastic within each family the onset, clinical course and severity of mental and motor quadriplegia or diplegia and whether or
not microcephaly is present, but there is a slightly increased risk for siblings of patients who have myoclonus or paroxysmal abnormalities on EEG44. Most of the reported familial cases have occurred in offspring of normal parents, many of whom were c o n s a n g u i n e ~ u47. s~~~ Most of these cases had associated mental retardation, but normal intelligence in an individual with spastic diplegia or quadriplegia does not preclude an inherited disorder48. Inheritance is likely to be autosomal recessive in the majority; however, one index case with spastic diplegia gave birth to a similarly affected daughter, raising the possibility of an autosomal dominant mutation49. There have been families with x-linked recessive inheritance. One French-Canadian family had many males, over two generations, affected by a syndrome of mental retardation, myoclonic jerks, microcephaly, mild optic atrophy and spastic diplegiasO. In an Australian family, the gene for an x-linked recessive syndrome of mental retardation, short stature, microcephaly, brachycephaly, spastic diplegia, small testes and possible intra-uterine growthretardation has been mapped to the area near the centromere5'. A sporadic form of spastic diplegia may be mistakenly diagnosed when the patient has a rare familial disorder. In families with familial spastic paraplegia, the inheritance is most often autosomal dominant, so the parents of a child with spastic diplegia and a normal perinatal period warrant examination for increased lower-limb reflexes and extensor plantar responses. In patients with dopa-responsive dystonia, o r Segawa syndrome, a period of normal development, progression, diurnal variation and Parkinsonian features should suggest the diagnosiss2. The movement problem is usually distal rather than proximal, causing the children to walk in bizarre and at times cybernetic fashion. Children with this disorder have CSF concentrations of homovanillic acid, 5-hydroxyindoieacetic acid and biopterin below the normal rangej3. Recognition of this disorder is important, since it is treatable with small doses of dopa^^ and there is a high familial incidence. Although the mode of inheritance is not
known, autosomal dominance with reduced penetrance is likely". Babies with congenital stiffness (hyperekplexia) may be thought to have spastic quadriplegia. Hyperekplexia manifests as permanent hypertonia from birth, which lessens in sleep, is increased by any stimulus, and diminishes during the first year of life. Inheritance is autosomal dominant56. The rarer autosomal recessive disorder of thanatophoric congenital stiffnesss7 has a less benign course, with oesophageal dysmotility and frequent aspiration.
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Athetoid and dystonic CP With the virtual elimination of bilirubin encephalopathy, genetic factors have become relatively more common in the causation of athetoid CP. The recurrence risk is unknown, but is probably of the same order as that for spastic CP. An Xlinked disorder of athetoid CP and myoclonus has been described44,58, so the risk of recurrence is higher for brothers of male cases. Again, inherited disorders may for a time mimic athetoid and dystonic CP. In the first year of life, before self-mutilation begins, boys with Lesch-Nyhan syndrome present with motor delay and dystonia or choreo-athetosis. Elevated serum uric acid and urinary urate:creatine ratio and absence of red-cell hypoxanthine-quanine phosphoribosyl transferase confirm the diagnosis, which is inherited in an Xlinked fashion. Children with glutaricaciduria type 1 may be normal until an encephalopathic state is precipitated by a febrile illness. Choreo-athetosis is a prominent symptom of this disorder, which may be diagnosed by finding glutaric acid and 3-0~-glutaratein urine and confirmed by assay of glutaryl-coA dehydrogenase in fibroblastsS9~ 60. Inheritance is autosomal recessive. Advice to parents should be based on all the information available. Careful attention should be paid to antenatal records, the rate of growth of the fetus as determined by available ultrasound scan reports and the value of the maternal serum AFP. It is often helpful to parents, who in their own minds attribute damage to the labour itself, to go through that
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record with them. Inconclusive pieces of evidence, such as meconium staining of the liquor or low Apgar score, cannot be relied upon to establish important degrees of asphyxia. Only if one can establish the presence of hypoxic-ischaemic encephalopathy can it be said that neuronal i n j u r y is likely to have occurred as a consequence of labour. The baby must be examined for dysmorphic features, signs of a neurocutaneous syndrome or storage disorder. The eyes may carry the choroidoretinitis of a congenital infection, or more rarely the specific retinopathy of an error of metabolism or cerebral dysgenesis. Unless there is clear evidence of a congenital infection-present in only a few children with static encephalopathy-a C T scan looking for evidence of a neuronal migration problem or a pattern of atrophy within arterial territory is indicated, along with a full metabolic screen. In the presence of severe handicap or dysmorphism, karyotyping is also indicated. Where cause can be attributed to the complications of pregnancy, a specific pattern of malformation is recognised or a metabolic disease identified, it is helpful to seek advice from the regional neurometabolic/genetic centre. For the vast majority of children with a static encephalopathy the cause will remain unknown, with no aetiological clue from the history and normal investigations. It is most appropriate t o give these families an empirical risk of recurrence of between 10 and 20 per cent. The lower risk figure may be used when it might be possible to implicate environmental influences such as an influenza-like illness in the early weeks of pregnancy; the higher figure is probably most appropriate for symmetrical problems, and particularly when there are other minor abnormalities outside the nervous system. For children with cerebellar ataxia in the absence of indentifiable conditions, such as ataxia telangiectasia, an empirical risk of one in eight should apply. By providing information on and better understanding of causation, paediatricians are not only giving parents a rational basis for future family planning, but also satisfying their need to understand how what is seen initially as a disaster has occurred,
and to escape feelings of guilt that may well be attendant on their grief. This important task should never be delegated to junior staff and for the best results should be conducted with both parents present, with the information delivered in a simple and straightforward way. The effort will be appreciated. IMELDA HUGHES RICHARDNEWTON* Department of Neurology, Royal Victoria Hospital, Belfast. *Department of Child and Adolescent Neurology, Royal Manchester Children’s Hospital, Pendlebury, Manchester M27 IHA. References 1 . Powell, T. G., Pharoah, P . 0. D., Cooke, R. W. I . . Rosenbloom, L. (1988) ‘Cerebral palsy in low-birthweight infants. I . Spastic hemiplegia: associations with intrapartum stress.’ Developmental Medicine and Child Neurology, 30, I 1- 18. 2. Powell, T. G., Pharoah, P . 0. D., Cooke, R. W. I., Rosenbloom, L. (1988) ‘Cerebral palsy in low-birthweight infants. I I . Spastic diplegia: associations with fetal immaturity.’ Developmental Medicine and Child Neurology,
30, 19-25. 3. Blair, E., Stanley, F. J . (1988) ‘Intrapartum asphyxia: a rare cause of cerebral palsy. Journal of Pediatrics, 112, 515-519. 4. Naeye, R. L., Peters, E. C., Bartholomew, M.: Landis, R. (1989) ‘Origins of cerebral palsy. American Journal of Diseases of Children,
143, 1154-1161. 5. Sarnat, H. B., Sarnat, M. S. (1976) ‘Neonata! encephalopathy following fetal distress. Archives of Neurology, 33, 696-705. 6. Tack, E., Perlman, J . M. (1986) ‘Systemic manifestations of perinatal asphyxia in the newborn.’ Paediatric Research, 20, 362A. (Abstract no. 1212.) 7. Freeman, J . M., Nelson, K. B. (1988) ‘Intra; partum asphyxia and cerebral palsy. Pediatrics, 82, 240-249. 8. Wharton, R., Bresnan, M. J . (1986) ‘PraderLabhart-Willi syndrome and Firth asphyxia: cause versus susceptibility. Annals of Neurology, 20, 438. (Abstract.) 9. Barth, P. G . (1987) ‘Disorders of neuronal migration.’ Canadian Journal of Neurological Sciences, 14, 1-16. 10. Lancet, Editorial (1990) ‘Epilepsy and disorders of neuronal migration.’ Lancet, 2, 1035. 11. Dobyns, W. B., Stratton, R. F., Greenberg, F. (1984) ‘Syndromes with lissencephaly. 1: Miller-Dieker and Norman-Roberts syndromes and isolated lissencephaly.’ American Journal of Medical Genetics, 18, 509-526. 12. Byrd, S. E., Osborn, R. E., Bohan, T. P., Naidich, T. P. (1989) ‘The CT and MR evaluation of migrational disorders of t h t brain. I: Lissencephaly and pachygyria. Pediatric Radiology, 19, 151-156. 13. Byrd, S. E., Osborn, R. E., Bohan, T. P.,
Naidich, T. P . (1989) ‘The C T and MR evaluation of migrational disorders of the brain. 11. Schizencephaly, heterotopia and polymicrogyria.’ Pediatric Radiology, 19, 2 19-222. 14. Parrish, M . L., Roessman, U., Levinsohn, M. W. (1979) ‘Agenesis of the corpus callosum. A study of the frequency of associated malformations.’ Annals of Neurology, 6, 349-354. 15. Brown, G . K . , Haan, E. A., Kirby, D. M., Scholem, R. D., Wraith, J . E., Rogers, J. G., Danks, D. M. (1988) ‘ “Cerebral” lactic acidosis: defects in pyruvate metabolism with profound brain damage and minimal systemic acidosis.’ European Journal of Pediatrics, 147, 10-14. 16. Brock, D. J . H. (1989) ‘Maternal blood markers (alpha-fetoprotein).’ In Reed, G . B., Claireaux, A. E., Bain, A. D. (Eds.) Diseases of the Fetus and Newborn. London: Chapman & Hall. 17. Paneth, N. (1986) ‘Birth and the origins of cerebral palsy.’ New England Journal of Medicine, 315, 125-126. 18. Gustavson, K.-H., Hagberg, B., Sanner, G. (1969) ‘Identical syndromes of cerebral palsy in the same family.’ Acta Paediatrica Scandinavica, 58, 330-340. 19. Ingram, T. T. S. (1962) ‘Congenital ataxic syndromes in cerebral paiy.’ Acta Paediatrica Scandinavica, 51, 209-221. 20. Joubert, M., Eisenring, J. J., Robb, J . P., Andermann, F. (1969) ‘Familial agenesis of the cerebellar vermis.’ Neurology, 19, 813-825. 21. Egger, J., Bellman, M. H., Ross, E. M., Baraitser, M. (1982) ‘Joubert-Boltshauser syndrome with polydactyly in siblings.’ Journal of Neurology, Neurosurgery and Psychiatry, 45, 737-739. 22. Laverda, A. M., Saia, 0. S., Drigo, P., Danieli, E., Clementi, M., Tenconi, R. (1984) ‘Chorioretinal coloboma and Joubert syndrome: a non-random association.’ Journal of Pediatrics, 105, 282-284. 23. Lindhout, D., Barth, P. G., Valk, J., BoenTan, T. B. (1980) ‘The Joubert syndrome associated with bilateral chorioretinal coloboma.’ European Journal of Pediatrics, 134, 173-176. 24. King, M. D., Dudgeon, J . , Stephenson, J. B. P . (1984) ‘Joubert’s syndrome with retinal dysplasia: neonatal tachypnoea as the clue to a genetic brain-eye malformation.’ Archives of Disease in Childhood, 59, 709-7 18. 25. Boltshauser, E., Isler, W. (1977) ‘Joubert syndrome: episodic hyperpnea, abnormal eye movements, retardation and ataxia associated with dysplasia of the cerebellar vermis.’ Neuropadiatrie, 8, 57-66. 26. Marinesco, G., Draganesco, S., Vasiliu, D. (I93 1) ‘Nouvelle maladie familiale caraterisee par une cateracte congenitale et un arret du developpement somato-neuro-psychique.’ Encephale, 26, 97-109. 27. Maloudji, M., Amirhakimi, G. H., Haghighi, P., Khodadoust, A. A. (1972) ‘MarinescoSjogren syndrome: report of an autopsy.’ Brain, 95, 675-680. 28. Sjogren, T. (1950) ‘Hereditary congenital spinocerebellar ataxia accompanied by coneenital cataract and olieoohrenia.’ Confinia keurologica, 10, 293-308u. ’ 29. Alter, M., Talbert, 0. R., Croffead, G . (1962) ‘Cerebellar ataxia, congenital cataracts and retarded somatic and mental maturation.
Report of cases of Marinesco-Sjogren syndrome.’ Neurology, 13, 836-847. 30. Ron, M. A., Pearce, J . (1971) ‘MarinescoSjogren-Garland syndrome with unusual features.’ Journal of the Neurological Sciences, 13, 175-179. 3 1 . Gillespie, F. D. (1965) ‘Aniridia, cerebellar ataxia and oilgophrenia in siblings.’ Archives of Ophthalmology, 73, 338-341. 32. Schurig, V., Van Orman, A , , Bower, P. (1981) “on-progressive cerebellar disorder with mental retardation and autosomal recessive inheritance in Hutterites.’ American Journal of Medical Genetics, 9, 43-53. 33. Kvistov, P . M., Dahl, A,, Skre, H. (1985) ‘Autosomal recessive non-progressive ataxia with an early childhood debut.’ Acta Neurologica Scandinavica, 71, 295-302. 34. Dietrich, F. (1957) ‘Generalisierte Hyperostose und zerebellare Hemmungsmissbildung.’ Schleizerische Archiv f u r Neurologie und Psychiatrie, 80, 100- 134. 35. Pfeiffer, R. A , , Palm, D., Jiinemann, G., Mandl-Kramer, S., Heimann, E. (1974) ‘Nosology of congenital non-progressive cerebellar ataxia. Report of 6 cases in 3 families.’ Neuropadiatrie, 5, 91-102. 36. Wichman, A , , Frank, L. M., Kelly, T. E. (1985) ‘Autosomal recessive congenital cerebellar hypoplasia.’ Clinical Genetics, 27, 373-382. 37. Young, 1. D., Moore, J. R., Tripp, J. H. (1987j ‘Sex-linked recessive congenital ataxia. Journal of Neurology, Neurosurgery and Psychiatry, 50, 1230-1232. 38. Malamud, N., Cohen, P . (1958) ‘Unusual form of cerebellar ataxia with sex-linked inheritance.’ Neurology, 8, 26 1-266. 39. Renier, W. O., Gabreels, F. J. M., Hustinx, T. W. J . , Thijssen, H . 0. M., Ter Haar, B. G . A , , Kroll, E. W . , Beckers, H. (1983) ‘Cerebellar hypoplasia, communicating hydrocephalus and mental retardation in two brothers and a maternal uncle.’ Brain and Development, 5, 41-45. 40. Cox, R., Hosking, G. P., Wilson, J. (1978) ‘Ataxia telangiectasia. Evaluation of radiosensitivity in cultured skin fibroblasts as a diagnostic test.’ Archives of Disease in Childhood, 53, 386-390. 41. Landrigan, P . J., Berenberg, W., Bresnan, M. (1973) ‘Behr’s syndrome: familial optic atrophy, spastic diplegia and ataxia.’ Developmental Medicine and Child Neurology, 15, 41-47. 42. Richards, B. W., Rundle, A. T. (1959) ‘A familiar hormonal disorder associated wit! mental deficiency, deaf mutism and ataxia. Journal of Mental Deficiency Research, 3, 33-55. 43. Berman, W., Haslam, R. H. A., Konigsmark, B. W . , Capute, A . J., Migeon, C. J. (1973) ‘A new familial syndrome with ataxia, hearing loss and mental retardation.’ Archives of Neurology, 29, 258-261. 44. Bundey, S., Griffiths, M. I . (1977) ‘Recurrence risks in families of children with svmmetrical s pastici t y .’ Developmental Medicine and Child Neurology, 19, 179-191. 45. Penrose, L. S. (1938) A Clinical and Genetic Study of I280 Cases of Mental Defect. MRC Special- Report Seriei, No. 229: London: H.M.S.O. 46. Yannot, H. (1949) ‘Infantile cerebral palsy cases with severe mental defect.’ Pediatrics, 3, 820-823. 47. Book, J. A. (1953) ‘A genetic and neuro-
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Neurology, 38, 707-7 1 1. 54. Boyd, K., Patterson, V. (1989) ‘Doparesponsive dystonia: a treatable condition misdiagnosed as cerebral palsy.’ British Medical Journal, 298, 1019-1020. 55. Nygaard, T. G., Duvoisin, R. C. (1986) ‘Hereditary dystonic-Parkinsonian syndrome of juvenile onset.’ Neurology, 36, 1424-1428. 56. Tohier, C., Roze, J . C., David, A., Veccierini, M. F., Renaud, P., Mouzard, A. (1991) ‘Hyperekplexia or stiff baby syndrome.’ Archives of Disease in Childhood, 66, 460-46 1. 57. Cantu, J . M., Cuellar, A. (1974) ‘Congenital severe generalised muscle hypertonia during wakefulness: a distinct autosomal recessive disorder.’ Clinical Generics, 6, 32-35. 58. Baar, H. S., Gabriel, A. M. (1966) ‘Sex-linked spastic paraplegia.’ American Journal of Mental Deficiency, 71, 13-18. 59. Leibel, R. L., Shih, V . E., Goodman, S. I . , Baumann, M . L., McCabe, E. R. B., Zwerdling, R. G., Bergman, I . , Costello, C . (1980) ‘Glutaric acidemia: a metabolic disorde; causing progressive choreoathetosis. Neurology, 30, 1 163- 1 168. 60. Gregeresen, N., Brandt, N. J . , Christensen, E., Grtan, I., Rasmussen, K . , Brandt, S. (1977) ‘Glutaric aciduria: clinical and laboratory findings in two brothers.’ Journal of Pediatrics, 90, 740-745.
Further information: AACPDM office, P.O. Box 11086, 1910 Byrd Avenue, # 118, Richmond, Virginia 23230-1086. Tel. (804) 282-0036; Fax (804) 282-0090.
