George H. Thomas

Diagnosis, treatment, and analysis of long-term outcomes in idiopathic normal-pressure hydrocephalus.

OBJECTIVE The response to shunt surgery for idiopathic normal-pressure hydrocephalus (INPH) is variable because INPH is difficult to distinguish from other conditions causing the same symptoms. To date, no clinical picture or diagnostic test can distinguish INPH or predict response to cerebrospinal fluid (CSF) shunt surgery. We reviewed our 10-year experience with INPH to characterize long-term outcome and to identify independent predictors of outcome after shunt surgery. METHODS Patients were classified as having INPH only if they had: 1) ventriculomegaly, 2) two or more INPH clinical features, 3) no risk factor for secondary normal-pressure hydrocephalus, 4) A- or B-waves on CSF pressure monitoring, and 5) clinical improvement during a 3-day CSF drainage trial via a spinal catheter. Independent predictors of outcome were assessed via a multivariate proportional hazards regression analysis. RESULTS One hundred thirty-two patients underwent 179 shunt surgeries. Forty-four (33%), 79 (60%), and 99 (75%) patients demonstrated objective improvement 3, 6, and 24 months after shunt surgery, respectively. Gait improved first in 88 (93%) patients. Dementia and urinary incontinence were twofold less likely to improve. Radiological evidence of corpus callosum distension, gait impairment as the primary symptom, and shorter duration of INPH symptoms predicted improvement. Duration of symptoms and gait as the primary symptom were independent predictors by multivariate analysis. CONCLUSION INPH can be diagnosed accurately with CSF pressure monitoring and CSF drainage via a spinal catheter. CSF shunting is safe and effective for INPH with a long-term shunt response rate of 75%. Independent predictors of improvement are the presence of gait impairment as the dominant symptom and shorter duration of symptoms.

The synthesis of 4-methylumbelliferyl α-ketoside of N-acetylneuraminic acid and its use in a fluorometric assay for neuraminidase

Abstract 4-Methylumbelliferyl α-ketoside of N-acetylneuraminic acid was synthesized by reacting the sodium salt of 4-methylumbelliferone with the 2-chloro-2-deoxy derivative of peracetylated methyl N-acetylneuraminate, followed by preparative silica gel chromatography, deblocking, and purification by gel filtration on Sephadex G-25. The final product was isolated as either the sodium or ammonium salt, and its suitability as a substrate for neuraminidase was evaluated. The optimal pH values for various neuraminidases were 5.6 in acetate buffer (Arthrobacter ureafaciens), 5.0–5.1 in acetate buffer (Clostridium perfringens), and 4.4 in phosphate-citrate buffer (human fibroblasts). Km values for these enzymes at the optimal pH were 6 × 10−4 m (Arthrobacter), 1 × 10−4 m (Clostridium), and 3 × 10−4 m (human fibroblasts).

Recurrent 10q22-q23 deletions : A genomic disorder on 10q associated with cognitive and behavioral abnormalities

Low-copy repeats (LCRs) are genomic features that affect chromosome stability and can produce disease-associated rearrangements. We describe members of three families with deletions in 10q22.3-q23.31, a region harboring a complex set of LCRs, and demonstrate that rearrangements in this region are associated with behavioral and neurodevelopmental abnormalities, including cognitive impairment, autism, hyperactivity, and possibly psychiatric disease. Fine mapping of the deletions in members of all three families by use of a custom 10q oligonucleotide array-based comparative genomic hybridization (NimbleGen) and polymerase chain reaction-based methods demonstrated a different deletion in each family. In one proband, the deletion breakpoints are associated with DNA fragments containing noncontiguous sequences of chromosome 10, whereas, in the other two families, the breakpoints are within paralogous LCRs, removing approximately 7.2 Mb and 32 genes. Our data provide evidence that the 10q22-q23 genomic region harbors one or more genes important for cognitive and behavioral development and that recurrent deletions affecting this interval define a novel genomic disorder.

Hyperpipecolic acidemia associated with hepatomegaly, mental retardation, optic nerve dysplasia and progressive neurological disease.

A male infant with hyperpipecolic acidemia is described. To our knowledge this is only the second report of this disorder. As with the previous case, our patients course was characterized by persistent hepatomegaly, severe mental retardation, progressive loss of developmental milestones and diminished visual acuity associated with nystagmus, abnormal discs and retinal changes. Death occurred at 2 years of age, following a progressive loss of neurological function.

A working group classification of focal prostate atrophy lesions

Focal atrophy is extremely common in prostate specimens. Although there are distinct histologic variants, the terminology is currently nonstandardized and no formal classification has been tested for interobserver reliability. This lack of standardization hampers the ability to study the biologic and clinical significance of these lesions. After informal and formal meetings by a number of the authors, focal atrophy lesions were categorized into 4 distinct subtypes as follows: (i) simple atrophy, (ii) simple atrophy with cyst formation, (iii) postatrophic hyperplasia, and (iv) partial atrophy. In phase 1 of the study, pathologists with varying levels of experience in prostate pathology were invited to view via the Internet a set of “training” images with associated descriptions of lesions considered typical of each subtype. In phase 2 of the study, each participant provided diagnoses on a series of 140 distinct “test” images that were viewed over the Internet. These test images consisted of the 4 subtypes of atrophy and images of normal epithelium, high grade prostatic intraepithelial neoplasia, and carcinoma. The diagnoses for each image from each pathologist were compared with a set of “standard” diagnoses and the κ statistic was computed. Thirty-four pathologists completed both phases of the study. The interobserver reliability (median κ) for classification of lesions as normal, cancer, prostatic intraepithelial neoplasia, or focal atrophy was 0.97. The median κ for the classification of atrophy lesions into the 4 subtypes was 0.80. The median percent agreement with the standard diagnosis for the atrophy subtypes were: simple 60.6%, simple with cyst formation 100%; postatrophic hyperplasia 87.5%; partial atrophy 93.9%. The lower percentage for simple atrophy reflected a propensity to diagnose some of these as simple atrophy with cyst formation. Seven pathologists completed the phase 2 analysis a second time, and their intraobserver reproducibility was excellent. Three of 4 pathologists with low agreement with the standard diagnosis for simple atrophy improved their scores after repeating the analysis after re-examination of the “training set” of images. In conclusion, these criteria for variants of focal prostate atrophy may facilitate studies to examine the relation between various patterns of prostate atrophy and prostate cancer.

Baseline Neuropsychological Profile and Cognitive Response to Cerebrospinal Fluid Shunting for Idiopathic Normal Pressure Hydrocephalus

Objective: To evaluate neurocognitive changes and predict neurocognitive outcome after ventriculoperitoneal shunting for idiopathic normal pressure hydrocephalus (INPH). Background: Reports of neurocognitive response to shunting have been variable and studies that predict cognitive outcomes after shunting are limited. We reviewed our experience with cognitive outcomes for INPH patients who were selected for shunting based on abnormal cerebrospinal fluid (CSF) pressure monitoring and positive response in any of the NPH symptoms following large volume CSF drainage. Methods: Forty-two INPH patients underwent neurocognitive testing and Folstein Mini-Mental State Examination (MMSE) prior to shunting. Neurocognitive testing or MMSEwere performed at least 3 months after shunt insertion. Significant improvement in a neurocognitive subtest was defined as improvement by one standard deviation (1 SD) for the patient’s age, sex and education level. Significant improvement in overall neurocognitive outcome was defined as a 4-point improvement in MMSE or improvement by 1 SD in 50% of the administered neurocognitive subtests. Nonparametric tests were used to assess changes. Predictors of outcome were assessed via logistic regression analysis. Results: Twenty-two patients (52.3%) showed overall neurocognitive improvement, and significant improvement was seen in tests of verbal memory and psychomotor speed. Predictive analysis showed that patients scoring more than 1 SD below mean at baseline on verbal memory immediate recall were fourfold less likely to show overall cognitive improvement, and sixfold less likely if also associated with visuoconstructional deficit or executive dysfunction. Verbal memory scores at baseline were higher in patients who showed overall cognitive improvement. Conclusions: Shunting INPH patients on the basis of CSF pressure monitoring and drainage response shows a significant rate of cognitive improvement, and baseline neurocognitive test scores may distinguish patients likely to respond to shunt surgery from those who will not.

Infantile form of sialic acid storage disorder: Clinical, ultrastructural, and biochemical studies in two siblings

We describe two sibs with coarse facies, hepatosplenomegaly, prominent psychomotor retardation and unexpectedly fair complexion. Ultrastructural studies of conjunctival, skin, bone marrow and liver biopsies from these individuals showed generalized lysosomal storage of polysaccharidelike material, i.e., membrane bound inclusions containing sparse, fibrillo-granular material. Biochemical analyses of urine and cultured fibroblasts from these patients revealed increased levels of free (unbound) sialic acid.The ultrastructural and biochemical findings in these sibs are similar to those previously found in Salla disease, however, the clinical course is much more severe. It is concluded that these children represent a new pathogenetic entity whose basic defect is still to be defined.

Cryptic terminal rearrangement of chromosome 22q13.32 detected by FISH in two unrelated patients.

Two unrelated patients with cryptic subtelomeric deletions of 22q13.3 were identified using FISH with the commercially available Oncor probe, D22S39. Proband 1 was found to have a derivative chromosome 22 resulting from the unbalanced segregation of a t(1;22)(q44;q13.32) in her mother. Additional FISH analysis of proband 1 and her mother placed the breakpoint on chromosome 22 in this family proximal to D22S55 and D22S39 and distal to D22S45. We have mapped D22S39 to within 170 kb of D22S21 using pulsed field gel electrophoresis. D22S21 is genetically mapped between D22S55 and D22S45. These data indicate that the deletion in proband 1 is smaller than in eight of nine reported del(22)(q13.3) patients. Probands 1 and 2 share features of hypotonia, developmental delay, and expressive language delay, also seen in previously reported del(22)(q13.3) patients, although proband 1 appears to be more mildly affected. Proband 1 is also trisomic for the region 1q44-->qter. This very small duplication has been previously reported only once and the patient had idiopathic mental retardation. This is the first report where 22q13.3 terminal deletion patients have been identified through the use of FISH, and the first report of a deletion of this region occurring because of missegregation of a parental balanced cryptic translocation. We feel that investigation of the frequency of del(22)(q13.3) in the idiopathic mentally retarded population is warranted and may be aided by the ability to use a commercially available probe (D22S39), which is already currently in use in a large number of cytogenetic laboratories.

Mucolipidosis III |[lpar]|Pseudo-Hurler Polydystrophy|[rpar]|: Multiple Lysosomal Enzyme Abnormalities in Serum and Cultured Fibroblast Cells

Extract: Four patients with the clinical findings of mucolipidosis III were studied. Cultured skin fibroblast cells from three of these four patients were low in each of the five lysosomal enzyme activities measured. The ranges of the enzyme activities in these three patients were as follows: N-acetyl-β-glucosaminidase (11–19% of normal), β-galactosidase (26–33% of normal), α-fucosidase (31–55% of normal), α-mannosidase (53–62% of normal), and arylsulfatase A (16–21% of normal).In contrast, marked increases in the same enzyme activities were found in serum samples from the same patients. These include N-acetyl-β-glucosaminidase (7–16 times normal), β-galactosidase (8–11 times normal), α-fucosidase (5–10 times normal) and arylsulfatase A (14–24 times normal). Similar increases in the enzyme activities were also found in serum of patient 1; however, the changes were less dramatic.An electrophoretic analysis of one of these enzymes (N-acetyl-β-glucosaminidase) revealed an abnormal pattern in the cultured fibroblast extracts; however, the presence of a normal pattern in the serum samples suggests that this is not due to an alteration in the primary amino acid sequence.Speculation: The lysosomal enzyme activities in serum and fibroblast extracts from the mucolipidosis III patients reported here are very similar to those found previously in mucolipidosis II (I-cell) patients. This suggests that the nature of the defect may be very similar in these two distinct disorders.

Arginine-responsive asymptomatic hyperammonemia in the premature infant

We found that more than 50% of premature infants have elevated plasma ammonium levels during the first 2 months of life. Ammonium levels were twice normal and were unaccompanied by clinical symptoms of vomiting or lethargy. Ten of these infants were given supplements of arginine (1 to 2 mmol/kg/day PO) for 1 to 2 weeks preceded and followed by control periods. In each infant, plasma ammonium levels fell significantly within 2 days of start of arginine supplementation, and increased once arginine was discontinued. We studied 59 additional premature infants, of whom 26 had normal ammonium levels and 33 were hyperammonemic. Plasma arginine and ornithine levels were significantly lower in the hyperammonemic group, but there was no difference in urinary excretion of arginine or ornithine between groups. Half of the hyperammonemic infants received arginine supplementation between 2 and 8 weeks of age. Plasma ammonium levels in the arginine group was 33 + 1 mumol/L., compared to 45 + 2 mumol/L in the untreated group. Follow-up at 18 months of age showed similar IQ scores in all groups, suggesting that significant neurologic deficits do not result from this transient metabolic defect. The mechanism of the hyperammonemia is unclear.