Molecular confirmation of nine cases of Cornelia de Lange syndrome diagnosed prenatally.

OBJECTIVES: Cornelia de Lange syndrome (CdLS) is characterized by distinct facial features, growth retardation, upper limb reduction defects, hirsutism, and intellectual disability. NIPBL mutations have been identified in approximately 60% of patients with CdLS diagnosed postnatally. Prenatal ultrasound findings include upper limb reduction defects, intrauterine growth restriction, and micrognathia. CdLS has also been associated with decreased PAPP-A and increased nuchal translucency (NT). We reviewed NIPBL sequence analysis results for 12 prenatal samples in our laboratory to determine the frequency of mutations in our cohort. METHODS: This retrospective study analyzed data from all 12 prenatal cases with suspected CdLS, which were received by The University of Chicago Genetic Services Laboratories. Diagnostic NIPBL sequencing was performed for all samples. Clinical information was collected from referring physicians. RESULTS: NIPBL mutations were identified in 9 out of the 12 cases prenatally (75%). Amongst the NIPBL mutation-positive cases with clinical information available, the most common findings were upper limb malformations and micrognathia. Five patients had NT measurements in the first trimester, of which four were noted to be increased. CONCLUSION: We demonstrate that prenatally-detected phenotypes of CdLS, particularly severe micrognathia and bilateral upper limb defects, are associated with an increased frequency of NIPBL mutations.

Camptocormia (bent spine) in patients with Parkinson's disease--characterization and possible pathogenesis of an unusual phenomenon.

Camptocormia is characterized by severe forward flexion of the thoracolumbar spine which increases while walking and disappears in the recumbent position. We describe for the first time eight patients with presumed idiopathic Parkinson's disease (mean age 66+/-5 yrs; mean symptom duration 13.1+/-5.1 yrs) who developed camptocormia. This impressive abnormal posture emerged 4-14 years from disease onset, and in some patients stooped posture was the prominent symptom at diagnosis. There was no clear correlation between camptocormia and levodopa treatment. In some patients the camptocormic posture improved, and in others it was unchanged or even aggravated following levodopa administration. Three patients reported worsening of this symptom during "off" periods and also with fatigue. The pathogenesis of this phenomenon is unknown but might represent either a rare type of dystonia or an extreme form of rigidity.

Primary progressive freezing gait.

Freezing gait is an incapacitating symptom often observed in patients with Parkinson's disease. It has been less frequently described in association with multi-infarct state, multisystem atrophies, and normotensive hydrocephalus. In our movement disorder clinic, we have diagnosed (and followed up to 3 years; median, 16 months), 18 patients in whom progressive freezing gait was the sole neurological dysfunction. These 15 men and 3 women (aged 60-82 years; 74 +/- 6) were subjected to an extensive neurological workup that included clinical evaluation, videotaping for grading of gait disability, comprehensive blood and cerebrospinal fluid (CSF) analysis, and brain computed tomography (CT) and magnetic resonance imaging (MRI). Mean disease duration was 2.5 +/- 1.9 years (range, 0.5-6). Neurological examination disclosed freezing gait, often associated with varying degrees of postural instability. The degree of freezing gait ranged from sudden motor blocks only when confronted with obstacles to severe disability with total inability to start walking requiring a walker, massive assistance, or a wheelchair. However, patients could mimic gait movements with absolutely no freezing when seated or lying prone, and most of them could overcome arrests by the "walking-over-lines" maneuver. Otherwise, neurological examination was normal with no signs of bradykinesia, rigidity, or tremor. Blood chemistry and CSF analysis were normal. Brain CT and MRI were normal or showed mild cortical atrophy in 12 and putative lacunes in 6 patients. Therapy with levodopa or dopamine agonists was ineffective. During the follow-up period, a gradual progression of the freezing gait was observed. However, it remained unaccompanied by any other neurological findings.(ABSTRACT TRUNCATED AT 250 WORDS)

Monosomy 3 and isochromosome 8q in a uveal melanoma.

Chromosome analysis of a locally invasive uveal melanoma revealed monosomy 3 and i(8q). Sublines with multiple copies of the i(8q) were also present. Loss of heterozygosity for genes on chromosome 3 and duplication of genes on 8q may play an important role in progression of uveal melanoma.

Dementia in idiopathic Parkinson's disease. Variables associated with its occurrence in 203 patients.

A series of 203 patients with primary Parkinson's disease treated with L-DOPA, with adequate neurological documentation of mental status at serial intervals during their illness, constitutes the study population. Based on the results of the latest neurological examination, slightly less than one-third (29%) had mental impairment assessed as neurologically significant. Of the eleven clinical variables analysed (Cox regression analysis) for potential influence on the occurrence of an organic mental syndrome, four had a statistically significant effect: (1) the stage of disease at initial neurological examination; (2) the occurrence of acute confusional states; (3) the years of Parkinson's prior to L-DOPA; and (4) the total duration of L-DOPA therapy. The pathogenesis of dementia in this subgroup of Parkinson's disease is discussed.

Does unilateral dopamine deficit contribute to depression?

A system of emotional control of behavior is believed to be lateralized to the right hemisphere. Given that dopaminergic pathways are involved in affective behavior, depression, which is recognized as an integral part of Parkinson's disease, may be associated with a dopamine imbalance. The present study examined this hypothesis in patients with unilateral symptomatology indicating either left hemisphere parkinsonism (LHP) or right hemisphere parkinsonism (RHP). Sixteen patients were tested on a battery of neuropsychological tests and several scales for evaluating mood. The two groups did not differ significantly on either cognitive or emotional measures. However, RHP patients rated themselves higher on the Present Scale of Cantril, and showed some neglect of the left visual field, as compared to LHP patients.

Length of the Y chromosome and chromosomal variants in inpatient children with psychiatric disorders: two studies.

In a study of 41 inpatient boys with psychiatric disorders, it was found that this group had significantly increased length of the long arm of the Y chromosome (Yq+) as compared to a normal control group. The length of the Y chromosome in the inpatient group correlated with psychiatric symptom severity, hyperactivity, parental psychopathology and paternal alcoholism. A further study of minor chromosomal variants in 56 inpatient boys and girls revealed no differences in individual or pooled variants in the patient group, as compared to the control group. However, those in the patient group with one or more variants showed more severe psychiatric and other psychosocial symptoms than those in the group without variants. Those who had both longer Y chromosomes and a minor chromosomal variant had more severe psychiatric symptom severity.

Organic mental syndrome and confusional states in Parkinson's disease. Relationship to computerized tomographic signs of cerebral atrophy.

Ninety-three patients with a diagnosis of Parkinson's disease, otherwise unselected, were specifically evaluated for organic mental syndrome (OMS) and other neurologic motor signs other than those referrable to extrapyramidal dysfunction; in addition, they had cranial computerized tomography (CT) to measure any structural changes in brain parenchyma. Cortical (sulci) atrophy and ventricular enlargement as CT signs of cerebral atrophy were correlated with different clinical patterns of the disease. An age-adjusted control population, with intact mentation, was similarly studied. The presence of classic OMS in a sizable segment of the usual parkinsonian population was invariably associated with CT signs of cerebral atrophy. Atrophic changes on CT scans, however, were not necessarily correlated with any intellectual dysfunction, or only weakly so, independent of age. The "typical" parkinsonian patients without evidence of OMS were indistinguishable from an age-adjusted control group with regard to structural changes in their scans. However, the parkinsonian patients with definite, permanent OMS and other focal neurologic deficit probably constitute a separate or distinct subset of the parkinsonian population, with a pathologic substrate more likely to be similar to that of the so-called Alzheimer-type dementias. Duration of the parkinsonian syndrome was not predictive of either mental status or scan findings, after adjustment for age as a factor.

Chromosomal variants in mentally retarded and normal men.

The possible phenotypic effect of chromosomal variants is as yet an unsolved problem. QM- and C-banded chromosomes of 100 male patients with idiopathic mental retardation were compared with chromosomes of 100 Royal Military College cadets, as controls. Increased size of 9qh seems to be a factor with possible negative effects. 9qh- was found to be more common in the control sample. Another variant found more often in the retarded subjects was 16qh-. Increased frequencies of Yq+ or small inversions in chromosomes 3 and 9 were not found in the retarded.

Inversion of 'flourescent' segment in chromosome 3: a polymorphic trait.

The frequency of the 'inversion' of flourescent constitutive heterochromatin in chromosome 3 was the same in a sample of 370 retarded persons as in a sample of 222 mentally normal men. It can be concluded that this 'inversion' is not associated with mental retardation. This variant is more common (4%) in the Canadian population we studied than in samples reported by most other authors (0-1.7%). Possibly the founder effect could play a role in the differences. Two cases of homozygotes for this 'inversion' were identified.

C-bands in seven cases of accessory small chromosomes.

The C-bands of two cases of familial, genetically inactive, accessory small chromosomes and five cases of genetically active chromosomes were examined. Inactive chromosomes consist of constitutive heterochromatin and satellites only. In active chromosomes, euchromatin was present. These chromosomes contained two, one or no C-bands, although all these chromosomes were morphologically monocentric. C-banding is more informative than other banding methods for this category of chromosomes.

Ultrastructure of the syndrome of continuous muscle fibre activity.

The ultrastructure of muscle and the myoneural junction of a man of 60 suffering from the syndrome of continuous muscle fibre activity was studied. This syndrome is manifested by disturbances of walking, muscle weakness, permanent muscle contractions and involuntary movements. The myoneural junction was hypertrophied and showed ramifications of the secondary clefts. The presynaptic nerve ending contained no synaptic vesicles. The relationship of these findings to the disease is discussed.