Spinocerebellar ataxia type 5 in a family descended from the grandparents of President Lincoln maps to chromosome 11.

Autosomal dominant ataxias are a genetically heterogeneous group of disorders for which spinocerebellar ataxia (SCA) loci on chromosomes 6p, 12q, 14q and 16q have been reported. We have examined 170 individuals (56 of whom were affected) from a previously unreported ten-generation kindred with a dominant ataxia that is clinically and genetically distinct from those previously mapped. The family has two major branches which both descend from the paternal grandparents of President Abraham Lincoln. Among those examined, 56 individuals have a generally non-life threatening cerebellar ataxia. Disease onset varies from 10-68 years and anticipation is evident. We have mapped this gene, spinocerebellar ataxia type 5 (SCA5), to the centromeric region of chromosome 11.

An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8)

Myotonic dystrophy (DM) is the only disease reported to be caused by a CTG expansion. We now report that a non-coding CTG expansion causes a novel form of spinocerebellar ataxia (SCA8). This expansion, located on chromosome 13q21, was isolated directly from the genomic DNA of an ataxia patient by RAPID cloning. SCA8 patients have expansions similar in size (107-127 CTG repeats) to those found among adult-onset DM patients. SCA8 is the first example of a dominant SCA not caused by a CAG expansion translated as a polyglutamine tract.

Brain glyceraldehyde-3-phosphate dehydrogenase activity in human trinucleotide repeat disorders.

BACKGROUND: Although the abnormal gene products responsible for several hereditary neurodegenerative disorders caused by repeat CAG trinucleotides have been identified, the mechanism by which the proteins containing the expanded polyglutamine domains cause cell death is unknown. The observation that several of the mutant proteins interact in vitro with the key glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) suggests that interaction between the different gene products and GAPDH might damage brain neurons. OBJECTIVE: To measure the activity of GAPDH in postmortem brain of patients with CAG repeat disorders. PATIENTS AND METHODS: Activity of GAPDH was measured in morphologically affected and unaffected brain areas of patients with 4 different CAG repeat disorders (Huntington disease, spinocerebellar ataxia 1 [SCA1], SCA2, and SCA3-Machado-Joseph disease), in brains of patients with Friedreich ataxia (a GAA repeat disorder) and Alzheimer disease, and in brains of matched control subjects. RESULTS: Brain GAPDH activity was normal in all groups with the exception of a slight but statistically significant region-specific reduction in the patients with Huntington disease (caudate nucleus, -12%) and Alzheimer disease (temporal cortex, -19%). CONCLUSION: The presence of the polyglutamine-containing proteins in CAG repeat disorders does not result in substantial irreversible inactivation or in increased activity of GAPDH in human brain.

Abnormal ocular motor function predicts clinical diagnosis of familial ataxia.

Ocular motor performance was significantly impaired in familial ataxia patients as compared with normal controls. Ataxic patients showed prolonged saccadic latencies, longer saccadic refixation times, reduced visual tracking performance, and increased hypermetria. Cutoff values were derived and applied to 15 subjects at risk for developing familial ataxia. Three of 15 showed abnormal values in three or more of four categories of ocular motor performance. Within 3 years, all three subjects were diagnosed on clinical grounds as having familial ataxia. We conclude that ocular motor performance is impaired in familial ataxia and may prove useful for earlier diagnosis.

Leptomeningeal dissemination of low-grade gliomas in childhood.

Although leptomeningeal spread (LMS) of primary CNS tumors in children has been well documented in the literature, it has rarely been reported in children with low-grade gliomas. Between 1975 and 1985, 6 of 162 children (3.7%) with low-grade gliomas treated at Children's Hospital of Philadelphia had LMS. LMS was present at diagnosis of the original tumor in one patient, was the first sign of relapse in one patient, occurred simultaneously with local relapse in two patients, and after local relapse in two patients. Pathology of the original tumor was low-grade astrocytoma in five and low-grade oligodendroglioma in one. Primary tumor site was cervical cord in three, chiasm in one, frontal lobe in one, and cerebellum in one. All of the children with LMS had undergone surgical treatment at the time of diagnosis of the primary tumor; four had total resections at some point in their course. Three of the six patients died; three are still alive after treatment with radiation therapy and/or chemotherapy. The longest survival to date has been 3 1/2 years after diagnosis of LMS. We compared clinical characteristics of these six patients with 131 children with low-grade tumors without dissemination treated at our institution during the same time period. LMS, although relatively infrequent, does occur in children with low-grade gliomas, especially spinal cord tumors. LMS may occur at any time during illness and diagnosis may be difficult unless LMS is suspected. Treatment, at times, results in clinical improvement and considerable disease control.

Spinocerebellar ataxia type 8: clinical features in a large family.

OBJECTIVE: To compare the clinical and genetic features of the seven-generation family (MN-A) used to define the spinocerebellar ataxia 8 (SCA8) locus. BACKGROUND: The authors recently described an untranslated CTG expansion that causes a novel form of SCA (SCA8) characterized by reduced penetrance and complex patterns of repeat instability. METHODS: Clinical and molecular features of 82 members of the MN-A family were evaluated by neurologic examination, quantitative dexterity testing, and, in some individuals, MRI and sperm analyses. RESULTS: SCA8 is a slowly progressive, predominantly cerebellar ataxia with marked cerebellar atrophy, affecting gait, swallowing, speech, and limb and eye movements. CTG tracts are longer in affected (mean = 116 CTG repeats) than in unaffected expansion carriers (mean = 90, p < 10-8). Quantitative dexterity testing did not detect even subtle signs of ataxia in unaffected expansion carriers. Surprisingly, all 21 affected MN-A family members inherited an expansion from their mothers. The maternal penetrance bias is consistent with maternal repeat expansions yielding alleles above the pathogenic threshold in the family (>107 CTG) and paternal contractions resulting in shorter alleles. Consistent with the reduced penetrance of paternal transmissions, CTG tracts in all or nearly all sperm (84 to 99) are significantly shorter than in the blood (116) of an affected man. CONCLUSIONS: The biologic relationship between repeat length and ataxia indicates that the CTG repeat is directly involved in SCA8 pathogenesis. Diagnostic testing and genetic counseling are complicated by the reduced penetrance, which often makes the inheritance appear recessive or sporadic, and by interfamilial differences in the length of a stable (CTA)n tract preceding the CTG repeat.

Spinocerebellar ataxia in a large kindred: age at onset, reproduction, and genetic linkage studies.

We studied a large kindred with autosomal dominant spinocerebellar ataxia (SCA) to assess reproductive performance, the impact of genetic counseling, and linkage relationships of the SCA locus. Reproduction was not lower in those with SCA than in unaffected sibs or first cousins. Genetic counseling reduced reproduction during the risk period for development of SCA. Given autosomal dominant transmission of a single gene, we found strong evidence that the locus for SCA in this kindred is linked to the HLA loci.

Brainstem gliomas of childhood: magnetic resonance imaging.

We compared magnetic resonance imaging (MRI) and CT on 16 children with brainstem gliomas. MRI demonstrated masses of decreased signal intensity, which enlarged and distorted brainstems in all patients with active disease and showed brainstem abnormalities in 21 of 23 studies (91%). In one-half of the patients, MRI showed more extensive disease than did CT. Exophytic portions of tumors were shown well on MRI. MRI was more sensitive than CT in demonstrating disease relapse.

Neuropsychological test performance in patients with dominantly inherited spinocerebellar ataxia: relationship to ataxia severity.

To determine whether the cognitive status of patients with dominantly inherited spinocerebellar ataxia (DSCA) might be related to neurologic severity, we administered a comprehensive neuropsychological test battery to 43 patients with DSCA, ranging in ataxia severity from mild to end-stage. As compared with the controls, the mildly ataxic patients scored normally or close to normal as a group on all of the neuropsychological tests. In contrast, approximately one-half of the moderately and all of the severely ataxic patients showed poor performance, independent of age, Hamilton Rating Scale for Depression score, or education, on the Wisconsin Card Sorting Test, suggesting impaired executive system function. In addition, a subgroup of these patients had a neuropsychological profile suggestive of mild generalized cognitive impairment. We conclude that DSCA is not a homogeneous group of disorders with respect to cognitive status and that the neurologic severity of the disorder is a major factor. Impaired executive system function could be explained by damage to olivopontocerebellar system control over cerebral cortical function or to damage to other neuronal systems (especially cholinergic) that degenerate in parallel with the olivopontocerebellar system.

Autosomal dominant spinocerebellar ataxia: locus heterogeneity in a Nebraska kindred.

SCA1 is an adult-onset autosomal dominant ataxia that is genetically linked to loci on chromosome 6p. A highly informative GT-repeat marker, D6S89, has been closely linked to the SCA1 locus in five large kindreds. We have used this marker to perform linkage analysis in a smaller autosomal dominant ataxia family consisting of five generations designated as the Nebraska kindred. This kindred includes 33 affected (12 living) and 40 first-generation at-risk individuals. We examined eight affected individuals; all had gait and limb ataxia. We analyzed the D6S89 locus by the polymerase chain reaction. Based on the analysis of 31 individuals from this kindred, we statistically excluded linkage to D6S89 for moderate-to-tight linkage (less than 11% recombination). These data clearly demonstrate genetic heterogeneity among the autosomal dominant ataxias. In addition, we obtained linkage data for HLA-A and SCA1 in this kindred. Comparison of HLA-A with D6S89 shows the latter marker to be more powerful. Use of D6S89 and other highly polymorphic markers in this region will greatly facilitate genetic classification of ataxias and make presymptomatic diagnosis of SCA1 feasible.

The spectrum of imaging and neuropsychological findings in Pick's disease.

To seek improved methods for the diagnosis of Pick's disease, we reviewed imaging studies of four women and two men (ages 48 to 65 years at onset) and psychometric testing of three of them with autopsy or biopsy-proved Pick's. The presence of Pick bodies was required for the diagnosis. Seven patients with biopsy-proved Alzheimer's disease served as a comparison group. In the Pick's patients, CT in five of six showed marked frontal pole or temporal pole atrophy, which clearly differed from the pattern of cerebral atrophy seen in the Alzheimer's patients. Psychometric testing showed performance patterns that tended to differ from those of the Alzheimer's patients in that recent memory was relatively preserved despite marked impairment of executive functions. The distinctive psychometric pattern in the Pick's patients was evanescent, however. Thus, there were imaging and psychometric findings of potential diagnostic value for Pick's disease, but, for different reasons, they were imperfect.

Striatal monoamine neurotransmitters and metabolites in dominantly inherited olivopontocerebellar atrophy.

We measured the levels of the monoamine neurotransmitters and metabolites in striatum of 14 patients with end-stage dominantly inherited olivopontocerebellar atrophy (OPCA). On average, dopamine levels were reduced in putamen (-53%), caudate (-35%), and nucleus accumbens (-31%). However, individual patient values showed a wide variation, indicating that mild to moderate striatal dopamine loss is a common but not constant feature of OPCA. Seven patients had marked putamen dopamine loss (-62% to -81%) but without evidence of correspondingly severe substantia nigra cell damage; this suggests the possibility of a "dying-back" phenomenon in which nerve terminal loss precedes cell body degeneration. Severe substantia nigra cell loss with almost total (-95% to -99%) putamen and caudate dopamine depletion was present in two patients; however, none of the 14 patients had had a clinical diagnosis of parkinsonism or was receiving antiparkinsonian medication. Mean striatal serotonin levels were normal, whereas concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid were elevated by 47% to 63%; this suggests increased activity of raphe dorsalis serotonin neurons innervating the striatum, which might aggravate the functional consequences of the dopamine deficit.

Incidence of dominant spinocerebellar and Friedreich triplet repeats among 361 ataxia families.

OBJECTIVE: To determine the incidence of spinocerebellar ataxia (SCA) types 1, 2, 3, 6, and 7 and Friedreich's ataxia (FA) among a large panel of ataxia families. BACKGROUND: The ataxias are a clinically and genetically heterogeneous group of neurodegenerative diseases that variably affect the cerebellum, brainstem, and spinocerebellar tracts. Trinucleotide repeat expansions have been shown to be the mutational mechanism for five dominantly inherited SCAs as well as FA. METHODS: We collected DNA samples and clinical data from patients representing 361 families with adult-onset ataxia of unknown etiology. Patients with a clinical diagnosis of FA were specifically excluded from our collection. RESULTS: Among the 178 dominant kindreds, we found SCA1 expansion at a frequency of 5.6%, SCA2 expansion at a frequency of 15.2%, SCA3 expansion at a frequency of 20.8%, SCA6 expansion at a frequency of 15.2%, and SCA7 expansion at a frequency of 4.5%. FA alleles were found in 11.4% of apparently recessive and 5.2% of apparently sporadic patients. Among these patients the repeat sizes for one or both FA alleles were relatively small, with sizes for the smaller allele ranging from 90 to 600 GAA repeats. The clinical presentation for these patients is atypical for FA, with one or more of the following characteristics: adult onset of disease, retained tendon reflexes, normal plantar response, and intact or partially intact sensory perceptions. CONCLUSIONS: Pathogenic trinucleotide repeat expansions were found among 61% of the dominant kindreds. Among patients with apparently recessive or negative family histories of ataxia, 6.8% and 4.4% tested positive for a CAG expansion at one of the dominant loci, and 11.4 and 5.2% of patients with apparently recessive or sporadic forms of ataxia had FA expansions. Because of the significant implications that a dominant versus recessive inheritance pattern has for future generations, it is important to screen patients who do not have a clearly dominant inheritance pattern for expansions at both the FA and the dominant ataxia loci.

Magnetic resonance imaging of cranial radiation lesions.

Fifty-six patients who previously received therapeutic cranial irradiation (CRT) were imaged by a 1.5 Magnetic Resonance (MR) System 0.1-11 years following CRT. Abnormal MR findings within the treatment volume unrelated to tumor, prior to surgery, or coexisting conditions were reviewed for an association with CRT. Twenty-four patients had MR abnormalities considered to be attributable to CRT. These were scored as mild (Grade I) in 6, moderate (Grade II) in 9, and severe (Grade III) in 9. Eight of these 24 patients with CRT findings on MR had CT abnormalities that correlated with the MR. Six lesions seen on computed tomography (CT) were Grade III abnormalities; all were judged as being visualized better by MR. Eight patients had significant neurologic dysfunction attributable to their CRT lesions, and 7 of these had Grade III lesions. Whereas the clinical significance of mild or moderate CRT effects seen on MR is uncertain, Grade III (severe) MR lesions correlate well with important clinical findings.

The role of radiation therapy in the management of childhood craniopharyngioma.

Between 1965 and 1986, 31 children were treated for craniopharyngioma at the Children's Hospital of Philadelphia. Total removal was attempted in all patients. Some patients received radiation therapy following subtotal removal. Of the patients whose first resection was subtotal, five received radiation and seven did not. Four of the 5 patients who were radiated (80%) are stable (median 89 months, range 42-155 months) and one recurred at 42 months, failed salvage with total removal, and subsequently died of disease. Of the seven who were not irradiated, all had recurrences (median 12 months, range 3-192 months) and one died of disease. Nineteen patients initially had total removal and none received adjuvant radiation. One patient died postoperatively. Of the 18 remaining patients, 6 had recurrences (median 24 months, range 7-100 months) and 12 (66%) are stable (median 42 months, range 9-133 months). One of these stable patients died of endocrine complications 24 months after initial surgery. Fourteen of the 31 patients recurred. Two died with recurrence and one required no further treatment. Eleven had second resections following initial surgical removal. Seven of these 11 went on to receive radiation and four did not. All seven who were radiated are stable (median 33 months, range 1-228 months); whereas 1 of the 4 who were not radiated recurred again at 18 months. This patient had a third resection followed by radiation therapy and is now stable at 20 months. After initial surgery (and before radiation, when given) 26 of 31 patients had panhypopituitarism, 4 had partial deficits, and 1 was normal. Severe diencephalic syndrome, loss of visual acuity, and intellectual deficits were no more frequent in patients treated with total removal, subtotal removal, and in patients who received radiation. We conclude that radiation has an important role following subtotal removal and for salvage treatment after initial surgery. Aggressive attempt at total removal does result in prolonged progression-free survival in some patients. Extensive resections may result in significant mortality and endocrine morbidity. This review suggests that subtotal removal and radiation results in outcomes at least as favorable as treatment with total removal alone.

Intracranial ependymomas in children.

Between 1970 and 1988, 51 children with intracranial ependymal tumors (33-infratentorial, 18-supratentorial received initial treatment at the University of Pennsylvania. Therapy consisted of total or near total tumor resection in 15 patients and partial resection or biopsy in 36. Postoperative irradiation alone was given to 18, chemotherapy to 4, and a combination of these two modalities to 26. Patients have been followed for a median period of 7.75 years. The 5-year actuarial survival and progression-free survival (PFS) rates are 46% and 30%, respectively. Of the 30 patients who have progressed, 29 did so locally and one died before the site of failure could be determined. Six patients also had disease outside the primary site at relapse; three of them had received craniospinal irradiation. Local control was significantly better for patients whose tumor dose exceeded 4500 cGy (32% vs. 0%, p = .01) and for Caucasian patients (34% vs. 15%, p =.05). Survival was better for patients who were over 4 years of age at diagnosis (55% vs. 30%, p = .04), for patients who received local radiation doses above 4500 cGy (51% vs. 18%, p = .01), and for Caucasian patients (43% vs. 14%, p = .01). Extent of resection, histology, location, the use of cranial or craniospinal irradiation, and the use of chemotherapy did not significantly impact on survival. We conclude that the inability to control local disease remains the single most important factor leading to treatment failure. Older age, higher local radiation dose, and Caucasian race appear to be the only favorable prognostic factors.

Management of the newborn with myelomeningocele: time for a decision-making process.

The relationship between time of surgical intervention and eventual outcome was examined in 110 newborns with myelomeningocele. Numerous earlier reports have cited a significant increase in mortality and morbidity associated with delay of surgery beyond 48 hours. Within the study population of infants, 52 infants (47%) had "early" surgery within the first 48 hours of life, 32 infants (29%) had "delayed" surgery between 3 and 7 days of age, 12 infants (11%) had "late" surgery between 1 week and 10 months of age, and 14 infants (13%) never had surgery by parental decision. Survival rates were similar between those with early, delayed, or late surgery as 92%, 94%, and 100%, respectively, were alive at age 10 months. Also, no significant association existed between time of surgery and development of ventriculitis, developmental delay, or worsening of paralysis. From these observations, it is concluded that there is no urgency in surgical intervention for the initial management of newborns with myelomeningocele. Rather, there is time for comprehensive discussions, counseling, and emotional support for those parents in need of a decision-making process before establishing consent for or against surgical management of their newborn.

Magnetic resonance imaging of lesions of the posterior fossa and upper cervical cord in childhood.

Magnetic resonance imaging (MRI) promises to be an effective, noninvasive means of visualizing intracranial pathology. It should be especially useful in the evaluation of posterior fossa and cervical spinal cord disease of childhood; computed tomographic (CT) evaluation is frequently suboptimal in this region. MRI results are reported for 46 consecutively seen children with posterior fossa and/or cervical spinal cord disease (28 had brain malignancies; seven had congenital anomalies; three had cerebrovascular accidents). MRI was performed primarily by the partial saturation on a .12 Tesla resistive proton unit. All patients underwent concurrent CT evaluation. MRI demonstrated abnormalities in 96% of scans in patients with structural CNS disease (48 of 50). CNS malignancies were visualized in 100% (28 of 28) of children studied. MRI was especially useful in demonstrating the full extent of infiltrating gliomas and the anatomic location of other mass lesions. MRI frequently demonstrated disease to be more extensive than seen on CT. MRI was more sensitive than CT in documenting response to treatment and disease relapse in patients with infiltrating tumors. Cystic regions within tumors were poorly seen on MRI. Congenital anomalies were demonstrated in all patients evaluated and were better delineated using MRI than CT. MRI is sensitive in the evaluation of posterior fossa and cervical spinal cord disease of childhood and it has obvious advantages over CT; however, its specificity in such evaluations has yet to be proven.

Magnetic resonance imaging of spinal cord disease of childhood.

Correct diagnosis of spinal cord disease in childhood is often delayed, resulting in irreversible neurologic deficits. A major reason for this delay is the lack of a reliable means to noninvasively visualize the spinal cord. Magnetic resonance imaging (MRI) should be useful in the evaluation of diseases of the spinal cord. A 1.5 Tesla MRI unit with a surface coil was used to study 41 children, including eight patients with intrinsic spinal cord lesions, eight patients with masses compressing the cord, 12 patients with congenital anomalies of the cord or surrounding bony structures, three patients with syrinxes, and three patients with vertebral body abnormalities. Intrinsic lesions of the cord were well seen in all cases as intrinsic irregularly widened, abnormally intense cord regions. MRI was helpful in following the course of disease in patients with primary spinal cord tumors. Areas of tumor were separable from syrinx cavities. Extrinsic lesions compressing the cord and vertebral body disease were also well visualized. Congenital anomalies of the spinal cord, including tethering and lipomatous tissue, were better seen on MRI than by any other radiographic technique. MRI is an excellent noninvasive "screening" technique for children with suspected spinal cord disease and may be the only study needed in many patients with congenital spinal cord anomalies. It is also an excellent means to diagnose and follow patients with other forms of intra- and extraspinal pathology.

Head injury in very young children: mechanisms, injury types, and ophthalmologic findings in 100 hospitalized patients younger than 2 years of age.

Head injury in the youngest age group is distinct from that occurring in older children or adults because of differences in mechanisms, injury thresholds, and the frequency with which the question of child abuse is encountered. To analyze some of these characteristics in very young children, the authors prospectively studied 100 consecutively admitted head-injured patients 24 months of age or younger who were drawn from three institutions. Mechanism of injury, injury type, and associated injuries were recorded. All patients underwent ophthalmologic examination to document the presence of retinal hemorrhages. An algorithm incorporating injury type, best history, and associated findings was used to classify each injury as inflicted or accidental. The results confirmed that most head injuries in children younger than 2 years of age occurred from falls, and while different fall heights were associated with different injury types, most household falls were neurologically benign. Using strict criteria, 24% of injuries were presumed inflicted, and an additional 32% were suspicious for abuse, neglect, or social or family problems. Intradural hemorrhage was much more likely to occur from motor vehicle accidents and inflicted injury than from any other mechanism, with the latter being the most common cause of mortality. Retinal hemorrhages were seen in serious accidental head injury but were most commonly encountered in inflicted injury. The presence of more serious injuries associated with particular mechanisms may be related to a predominance of rotational rather than translational forces acting on the head.