A familial syndrome of infantile optic atrophy, movement disorder, and spastic paraplegia.

We describe 19 cases of a familial syndrome consisting of infantile optic atrophy and an early movement disorder in which chorea predominated. About one-half the patients developed spastic paraparesis during the second decade of life. Ataxia and cognitive deficits were common, usually of mild degree. Seventeen of the patients were females. Sixteen had similarly affected siblings, but none had affected parents. All but one belonged to the Iraqi Jewish community in Israel, giving a minimal prevalence rate in this ethnic group of about 1:10,000.

Covariance analysis of laboratory variance in steady-state serum phenytoin concentrations.

Inpatients (n = 57) on long term prophylaxis with 2 oral phenytoin preparations were followed up via monthly checks of serum drug concentrations. Duplicate serum aliquots were submitted to 2 laboratories, and covariance analysis was used to estimate laboratory error. The laboratory-associated variance of examinations using the 'EMIT' or 'TDX' systems was 7.1 to 10 (mg/L)2, while that of chromatographic assays was 37.1 (mg/L)2. Laboratory errors were distributed in a non-normal fashion. The ratio of the maximum rate of metabolism (Vmax) and the Michaelis-Menten constant (Km) tended to remain constant between individuals. A linear analytical model showed little more residual variance than one based on Michaelis-Menten pharmacokinetics.

Motor abnormalities during sleep in patients with childhood hereditary progressive dystonia, and their unaffected family members.

The structure of sleep and number of body movements (BMS) and periodic leg movements during sleep (PMS), were studied in three unrelated girls suffering from L-DOPA responsive hereditary dystonia with marked diurnal fluctuation and in their 11 healthy, close relatives. All three girls had an increased number of BMS during rapid eye movement (REM) sleep. Five of the six parents and three siblings had abnormal PMS. One pair of parents had BMS similar to those of their affected daughter. The occurrence of BMS and PMS in the families studied may indicate a common mechanism for both. Because familial PMS is quite rare in its pure form, and this type of dystonia is also rarely encountered, the occurrence of BMS and PMS in members of these families may imply a causative relation between these two sleep-related motor phenomena.

The risk of having a second retarded child.

We have studied segregation ratios in 282 Israeli families with normal, nonconsanguineous parents and retarded offspring without specific etiologic diagnosis. Severity of retardation and nature of medical history significantly affected recurrence risk, while sex of propositus and sibs and presence or absence of epilepsy, cerebral palsy, microcephaly, and short stature did not. Segregation rations were 0.095 in cases of severe retardation with normal medical history, 0.216 for mild retardation with normal medical history, 0.230 in cases of all retardation with maternal reproductive inefficiency, and 0.110 for all retardation with other reported prenatal, perinatal, or infantile complications. Estimated recurrence risks in most simplex families dropped sharply with each additional normal child. The recurrence risks are higher than some previously published estimates. Different ascertainment criteria may be responsible for this variation. The criteria used here were compatible with a 3.2% population prevalence of mental retardation with a 0.223 segregation ratio in multiplex sibships. It is recommended that future studies of recurrence risks include similar data permitting evaluation of sensitivity of ascertainment criteria.

Auditory perception in early lateralized brain damage.

In a study of hemispheric dominance for the perception of speech the performance of 28 young children with congenital or infantile hemiplegia was compared with that of their normal peers and recently brain damage nonaphasic adults. Our results confirm Goodglass's findings that in children with early left hemisphere damage the transfer of dominance for speech processing is completed in childhood, and they show that this process of hemispheric transfer can be completed by 3 years of age. Comparison with results on adults with CVA provides additional evidence that in early lateralized brain cognitive functions normally dominant in one cerebral hemisphere are developed in the alternative hemisphere in a way that apparently does not happen later in life.

Long-term follow-up review of 31 children with severe closed head trauma.

Thirty-one children aged 3 to 15 years were followed for 5 to 11 years after suffering severe closed head trauma which caused coma for 1 week or more (median duration of coma 3 weeks). One patient remained in a persistent vegetative state until his death 9 years later. The other 30 recovered consciousness and were discharged. All suffered diminution of their abilities, and 24 of them had major permanent disability. The most common motor disabilities were pure spastic hemiparesis (seven cases), basal ganglia syndromes (four cases), ataxia (three cases), and a combination of hemiparesis and ataxia (five cases). Of the 30 patients, 26 regained independent ambulation, seven were epileptic, and 14 were dysarthric in various degrees. Only 10 had the cognitive ability to profit from the normal educational system, and none had attempted postsecondary education. Social problems were common. The worst outcomes were associated with intracranial bleeding and/or brain contusion seen on computerized tomography (CT) scans at the acute stage; the best were associated with normal CT scans. The degree of residual disability in these children seems no less than that of adults with trauma of similar severity.

Ineffectiveness of oral coenzyme Q10 supplementation in 3-methylglutaconic aciduria, type 3.

Coenzyme Q10 was administered under placebo controlled blinded crossover conditions to six subjects suffering from type 3 3-methylglutaconic aciduria ('optic atrophy plus'), following a report of benefit. Despite attainment of high plasma levels of coenzyme Q10, no clinical benefit was observed and there was no diminution of urinary excretion of 3-methylglutaconic acid.

Late neuropsychologic status after childhood head trauma.

A neurologic and neuropsychologic test battery was administered to a sample of 35 children drawn from all those in a defined geographic area who had been hospitalized for head trauma before age 7 during the years 1970-1976. Examination was performed 3 1/2 to 10 years after injury, at age 6-15. Twelve subjects had been diagnosed at the time of injury as suffering moderate insult and had been referred to the metropolitan neurosurgical center, while twenty-three with only mild injury had been retained for observation in a local pediatric ward. The twelve with more severe insult were significantly inferior to the other subjects on the Block Design and Coding subtests of the revised Wechsler Intelligence Scale for Children. The Koppitz score of the Bender Test, the WISC-R scatter, the Benton Visual Retention Test, the GATB Motor Speed Test and the Bourdon-Wiersma Vigilance Test showed less diagnostic power and failed to distinguish between the group with more severe injury and that with less. A detailed and carefully scored neurologic examination also failed to distinguish between the two groups. The findings suggest that relatively common traumatic injury may be associated with detectable late cognitive deficit, and that some WISC-R subtests may be among the best measures for detecting such deficit.

Multiple syndromes of 3-methylglutaconic aciduria.

The most common clinical syndromes associated with 3-methylglutaconic aciduria are presented. In some patients these syndromes are multisystemic, progressive disorders of unknown etiology. Tissues deriving significant energy through oxidative metabolism (notably brain and cardiac muscle) are most often affected and in some the primary defect may reside within the mitochondrial respiratory chain. Although increasing biochemical evidence suggests that 3-methylglutaconic aciduria may correlate with deranged mitochondrial energy metabolism, the biochemical origin of 3-methylglutaconic acid and the significance of its increased excretion remain unknown. This review describes these syndromes and illustrates the necessity of urinary organic acid analysis to assist in the differential diagnosis.

Consanguinity analysis in heterogeneous populations.

Consanguinity analysis can be performed in populations comprising collections of genetic isolates, and the resulting estimates can be valid and useful in phenotypes caused by numerous recessive genes, such as mental retardation and congenital nerve deafness. Maximum likelihood methods are presented for estimating gene frequency and proportions of homozygous cases of morbid phenotypes in such populations.

Estimated frequency of genetic and nongenetic causes of congenital idiopathic cerebral palsy in west Sweden.

Mathematical analysis of prenatal and perinatal risk factors was performed on the first 681 published cases of idiopathic congenital cerebral palsy (born 1959-1970) in the west Swedish population-based cerebral palsy (CP) study. Analysis indicates that an estimated 40% of etiologically undiagnosed cases of CP in the community (48% of those born at term and 24% of those born prematurely) are genetically caused. These proportions of genetic causation are no less in CP than in idiopathic mental retardation. Genetic causes account for 60% of maturely born hemiplegics, 45% of maturely born spastic diplegics, 32% of premature spastic diplegics and virtually all cases of pure ataxia. About 23% of CP cases in the community have suffered nongenetic brain damage in accordance with the two-stage model. The residue of 37% is characterized by a single risk factor, usually perinatal.

Consanguinity analysis of congenital deafness in Northern Israel.

Consanguinity analysis of heterogeneous populations was performed on a group of 82 Israeli Jewish families with congenitally deaf probands, including 37 multiplex families with normal parents, 10 multiplex families with deaf parents, and 35 simplex families with deafness of unknown cause. Representative gene frequency was estimated as .0198, with two to four major gene loci per ethnic group. In both the simplex families and those with deaf parents, the only significant etiology found was homozygosity for pathologic recessive genes. Comparison of these findings in Israeli isolates with those in panmictic populations seems to imply that the genetic loci are not identical in the various isolates.

Reported seizures in early childhood: a 14-year follow-up.

A detailed medical history is commonly regarded as a reliable means of classifying unexplained childhood losses of consciousness into diagnostic groups such as febrile seizures, epileptic attacks and breath-holding spells. The authors have tested this assumption by comparing adolescent follow-up status with the initial medical history in 56 individuals who suffered sudden losses of consciousness before age five. Only three of these 56 were epileptic when followed-up in adolescence and only two had received anticonvulsants at any time. The prognosis for 26 individuals with afebrile seizures without evidence of breath-holding syncope was not significantly worse than that for another 16 with febrile seizures. These findings indicate a good prognosis for untreated childhood seizures of a type often classified as epileptic.

Prognosis for recovery from prolonged posttraumatic unawareness: logistic analysis.

This study reviews the course and outcome of 130 patients who remained in a state of prolonged unawareness 30 days after severe cranio-cerebral trauma. Prognostic indicators and outcome were fitted by a logistic model. The significant prognostic factors observable in the first week after trauma were found to be ventilatory status, motor reactivity and significant extraneural trauma. The significant prognostic factors after the first month of unawareness were early ventilatory status, early motor reactivity, late epilepsy and hydrocephalus. The estimated probability of recovery of awareness (that is, consciousness) ranged from 0.94 in patients with early decorticate posturing in the absence of both extraneural trauma and ventilatory disturbance to 0.06 in patients with flaccidity, extraneural trauma and ventilatory disturbance in the first week after injury.

Survivors of severe traumatic brain injury in childhood. I. Incidence, background and hospital course.

Survivors of severe craniocerebral injury in childhood require prolonged rehabilitation care. We have surveyed the incidence, social characteristics and early hospital course of such patients in Israel. Yearly incidence was 1:100,000. Thirty-six patients were surveyed. Thirteen of these patients (36%) were described as suffering from cognitive deficits prior to injury and in 11 families (30%), the parent pair showed disturbed function before the injury. Thirty-three of the patients (92%) were victims of road accidents, the child being a pedestrian in 70% of these. Duration of coma was over 1 week in all the children but one, and only a minority of the children underwent neurosurgical interventions. The data on premorbid disturbed function are highly suggestive but not conclusive in the absence of a relevant control group. However, the findings are in accord with findings in adult craniocerebral injured patients in whom recognizable social factors seem clearly associated with craniocerebral injury.

Rehabilitation outcome after anoxic brain damage.

Outcome was analyzed in a group of 31 patients who were comatose for more than 24 hours after cardiopulmonary arrest and were thereafter referred for inpatient rehabilitation. Seventeen regained functional ambulation, 20 regained oral communication, and 13 regained full independence in activities of daily living. Two regained their approximate previous cognitive level, and one regained his previous level of employment. These outcomes are strikingly inferior to those of patients with prolonged coma after craniocerebral trauma who were hospitalized in the same center during the same period. Both age and coma duration were correlated with outcome. The relatively better outcomes were seen in patients who were 25 years or younger at the time of anoxic injury, and whose coma lasted less than 24 hours.

Practice of prophylactic anticonvulsant treatment in head injury.

The policy of patient selection for prophylactic anticonvulsant treatment has been evaluated retrospectively in 124 head-injured patients admitted consecutively for rehabilitation after primary neurosurgical treatment. Prophylaxis had been instituted in about 60% (51/83) of high risk patients and in about 30% (12/41) of the patients who did not belong to the high risk categories. The use of existing risk data as guidelines for decisions about anticonvulsant prophylaxis is discussed.

Epidemiological findings in traumatic post-comatose unawareness.

We have examined the epidemiological background of 134 consecutive patients admitted to our centre who suffered from post-traumatic unconsciousness of over 1 month's duration. The incidence of such unconsciousness in Israel is estimated as 4 per 1,000,000, or one case in 410 hospitalizations for head trauma. The cause of trauma was a road accident in 69% of cases. Among victims, pedestrians and cyclists were more likely than four-wheeled vehicle drivers and their passengers to suffer from prolonged unconsciousness, from which they were less likely to recover.