The demographic impact of Partition in the Punjab in 1947.

We use data from the 1931, 1941, and 1951 censuses of India and the 1951 census of Pakistan to examine the demographic consequences of Partition in the Punjab in 1947. Had growth rates for the period 1931-41 for the Punjab as a whole continued to 1951, the population of the Punjab would have been 2.9 million larger than that recorded in 1951. Population losses from migration and mortality above age 20 were approximately 2.7 million greater between 1941 and 1951 than would have been predicted by loss rates between 1931 and 1941. We estimate a net Partition-related population movement out of the combined Punjab of about 400,000. We conclude from several lines of analysis that Partition-related population losses in the Punjab, either from deaths or unrecorded migration, were in the range 2.3-3.2 million. Partition was also marked by a dramatic religious homogenization at the district level.

Complementary DNA probes for the Duchenne muscular dystrophy locus demonstrate a previously undetectable deletion in a patient with dystrophic myopathy, glycerol kinase deficiency, and congenital adrenal hypoplasia.

Genomic DNA from a patient with dystrophic myopathy, glycerol kinase deficiency, and congenital adrenal hypoplasia was investigated using cDNA probes for the Duchenne muscular dystrophy (DMD) locus. Genomic probes had not detected a deletion in this patient. Southern analysis of Hind III-digested genomic DNA from this patient identified a deletion when the three distal Hinc II DMD cDNA fragments were used as probes. The deletion began in the genomic region corresponding to the 1.05-kb Hinc II cDNA fragment and extended through the 3' end of the DMD gene. This represents a centromeric breakpoint that corresponds to a position approximately 10.2-10.6 kb from the 5' end of the 14-kb DMD cDNA. These investigations demonstrate the value of the DMD cDNA probes for improved diagnoses in patients with molecular lesions involving the DMD locus. Furthermore, this novel deletion involving the coding portion of the 3' end of the DMD gene assists in the ordering of exons in this region and will provide insight into the functional role of the carboxy terminus of the DMD gene product, dystrophin.

Rare myelin protein zero sequence variant in late onset CMT1B.

Myelin protein zero (MPZ) mutations cause demyelinating neuropathies that range from severe neonatal to milder adult forms. We report a 65-year-old woman with slowly progressive leg weakness starting at 47. Examination revealed distal weakness and atrophy in all extremities, impaired light touch in both feet and pin perception to proximal calves, absent leg reflexes, and unsteady gait. Electrodiagnostic studies revealed a severe sensorimotor polyneuropathy with conduction velocities of 25 m/s - to normal. The conduction velocities in the upper 20's were seen in lower extremities with severe reduction of the corresponding compound muscle action potential amplitudes. She had a MPZ mutation with A-C transversion (nucleotide: 116, codon: 10, histidine-to-proline). Her sister has an identical mutation, with high arches, distal leg weakness, decreased vibration sensation in toes and ankle areflexia. Nerve conduction studies revealed a moderate-severe sensorimotor polyneuropathy with nerve conduction velocities of 36 m/s - to normal. Their mother had an abnormal gait and conduction velocities of 29-30 m/s. A third sister is clinically and genetically unaffected. One report has previously described four patients with this mutation with similar clinical and electrodiagnostic features. In patients tested for possible CMT, the frequency of MPZ His-Pro codon 10 substitutions was 0.11% (27 of 24,076 alleles).

Proton spectroscopy in myotonic dystrophy: correlations with CTG repeats.

OBJECTIVES: To seek cerebral metabolite abnormalities in patients with myotonic dystrophy and to determine whether the degree of cerebral abnormalities (measured by proton magnetic resonance spectroscopy) correlates with severity of the genetic defect (measured by trinucleotide repeats). DESIGN: Fourteen patients with myotonic dystrophy were compared with 24 healthy control subjects. SETTING: A university-affiliated medical center. RESULTS: Compared with healthy subjects, patients with myotonic dystrophy had elevated levels of myoinositol (+19% in the occipital region and +12.9% in the temporoparietal region), total creatine (+7.6% and +6.8%), and choline-containing compounds (+21% and +7.7%). Furthermore, the creatine and myoinositol peak areas correlated with the number of trinucleotide cytosine-thymine-guanine(n) (CTG)n repeats from leukocytes, especially in the temporoparietal brain region (r=0.76; P=.004). CONCLUSIONS: Neurochemical alterations observed with proton magnetic resonance spectroscopy are proportional to the cytosine-thymine-guanine repeat size. Increases in myoinositol and creatine concentrations may be caused by increased glial content, while elevated levels of choline-containing compounds are most likely caused by increased glial content and cell membrane abnormalities. Proton magnetic resonance spectroscopy is a powerful noninvasive tool to study brain biochemistry, which may reflect the extent of neuropathological involvement in patients with myotonic dystrophy.

Relative stability of a minimal CTG repeat expansion in a large kindred with myotonic dystrophy.

The genetic basis for myotonic dystrophy (DM) is a CTG trinucleotide repeat expansion. The number of CTG repeats commonly increases in affected individuals of successive generations, in association with anticipation. We identified a large DM family in which multiple members had minimal CTG repeat expansions, and in which the number of CTG repeats remained in the minimally expanded range through at least three, and possibly four, generations. This relative stability of minimal CTG repeat expansions may help to maintain the DM mutation in the population.

Effects of the sex of myotonic dystrophy patients on the unstable triplet repeat in their affected offspring.

The mutation responsible for myotonic dystrophy (DM) is an unstable expansion of the CTG repeat within the myotonin protein kinase gene. To examine whether the parental origin of the expanded repeat influences the repeat size in offspring, we studied 51 father-child and 59 mother-child pairs with DM. Small expansions in fathers resulted in larger size expansions in their offspring, while large paternal expansions resulted in less size change in their offspring. However, there was no correlation between maternal size expansion and size increase in offspring for either congenital or noncongenital DM. These data suggest that the sex of the affected parent influences the unstable expansion of the repeat in DM offspring. While some evidence suggests that DNA methylation status cannot explain this observation, the mechanism for differential maternal/paternal transmission expansion is currently unknown.

Spinocerebellar ataxia type 2 with parkinsonism in ethnic Chinese.

OBJECTIVE: To describe the clinical and molecular genetic analysis of a large family of northern Chinese descent with a mutation at the SCA2 locus causing carbidopa-levodopa-responsive parkinsonism. BACKGROUND: Most causes of parkinsonism remain unknown. However, molecular genetic analysis of families with parkinsonism has recently identified five distinct loci and pathogenic mutations in four of those. Additionally, some of the spinocerebellar ataxia syndromes (SCA), particularly Machado-Joseph syndrome (SCA3), are known to cause parkinsonism. Spinocerebellar ataxia type 2 (SCA2) has not previously been described as causing a typical dopamine-responsive asymmetric PD phenotype. METHODS: A large family was evaluated clinically and molecularly for apparent autosomal dominant parkinsonism. RESULTS: The phenotype includes presentation consistent with typical dopamine-responsive parkinsonism. Other presentations in this family include a parkinsonism/ataxia phenotype, which is classic for SCA2 and parkinsonism, resembling progressive supranuclear palsy. CONCLUSIONS: Patients presenting with a family history of parkinsonism, including familial progressive supranuclear palsy and PD, should be tested for the spinocerebellar ataxia type 2 expansion.

Demyelinating neuropathy in a patient with multiple sclerosis and genotypical HMSN-1.

Patients with multiple sclerosis (MS) may develop a peripheral neuropathy, sometimes attributed to nutritional deficiency. Other patients present with a demyelinating neuropathy which is presumed to be the result of an autoimmune process that affects both the central and peripheral nervous systems. We report a case of concurring MS and demyelinating neuropathy, without a positive family history, in whom genetic testing proved the neuropathy to be hereditary and not autoimmune. Hereditary neuropathy should be a consideration in sporadic cases of peripheral neuropathy and MS.

Charcot-Marie-Tooth neuropathy: clinical phenotypes of four novel mutations in the MPZ and Cx 32 genes.

Charcot-Marie-Tooth Hereditary Neuropathy is a heterogeneous syndrome associated with mutations in several different genes including peripheral myelin protein 22, myelin P0, connexin 32, and early growth response 2. There is considerable variability in the phenotypic expression of this syndrome and the relationship of this variability to mutation genotypes requires extensive analysis. Here we describe the phenotypes and genotypes of four new mutations underlying the Charcot-Marie-Tooth syndrome and document segregation with disease. Four families with Charcot-Marie-Tooth were ascertained, examined, and evaluated electrophysiologically. Each family had peripheral blood DNA screened for mutations in myelin protein 22, myelin P0, and connexin 32. Two families were found with new mutations in the myelin P0 gene: S140T in the extracellular domain and K236del in the cytoplasmic domain. All families showed segregation of the mutations with the Charcot-Marie-Tooth phenotype as did a new family with the rare G163R mutation in the membrane domain. A 49-year-old man with the S140T mutation demonstrated conduction block on electrophysiological testing. A family with a novel S49P mutation in the connexin 32 gene had a neuropathy with very slow nerve conduction. These new mutations in the myelin P0 and connexin 32 genes help to clarify the pathophysiology of the clinical Charcot-Marie-Tooth syndrome. The S140T mutation in myelin P0 can be associated with conduction block and Charcot-Marie-Tooth should be part of the differential diagnosis of that phenomenon. Mutations in the cytoplasmic domain of myelin P0 can cause clinical neuropathy. The S49P mutation in the connexin 32 gene can produce aspects of a demyelinating type of X-linked hereditary neuropathy.

Mental retardation locus in Xp21 chromosome microdeletion.

Xp21 microdeletion syndrome is associated with variable size Xp21 deletions that usually include the glycerol kinase locus. The clinical phenotypes we studied in this chromosome region include: Xpter - Aland Island eye disease (AIED) -adrenal hypoplasia (AH) -glycerol kinase (GKD) -Duchenne muscular dystrophy (DMD) -retinitis pigmentosa (RP) -ornithine transcarbamylase (OTC) -centromere. In a compilation of 18 individuals in 14 families with the AH, GKD, and DMD loci deleted, 17 were male and all were developmentally delayed. In contrast, we report mentally retarded female carriers in two Xp21 deletion syndrome families with DMD, GKD, and AH in affected males. In the first family with normal karyotypes, a submicroscopic deletion was associated with DMD in the retarded male and with retardation in carrier females. In the second family an X chromosome with a cytogenetically deleted Xp21 distal to the OTC and RP genes segregated in the affected male and retarded female carriers. DNA analysis at the DMD locus verified the cytogenetic findings. This report of mental retardation in otherwise asymptomatic female carriers of Xp21 deletion classifies one form of mental retardation in females.

Congenital adrenal hypoplasia and selective absence of pituitary luteinizing hormone: a new autosomal recessive syndrome.

Congenital hypoplasia of the adrenal glands (CHA) is a rare condition, particularly in the absence of a central nervous system (CNS) anomaly. Two major types of CHA have been described in the setting of an apparently normal CNS and pituitary: a cytomegalic type usually with X-linked recessive inheritance and a miniature adult type that, when hereditary, is an autosomal recessive trait. Glycerol kinase deficiency (GKD) is an X-linked recessive trait, and it may be associated with CHA and adrenal insufficiency, presumably because of deletion of adjacent X-linked loci. We report on three sibling infants, one male and two females, with normal CNS and lethal CHA of the miniature adult type, selective absence of pituitary LH; two of the infants also had glycerol kinase (GK) activity that was decreased but not in the GKD range. Restriction fragment length polymorphism (RFLP) analysis of X chromosome markers located at Xp21-p22 was carried out on the maternal grandfather, both parents, two of three affected infants, and a living normal brother. The results excluded the X-linked type of this disorder associated with GKD in this family. Autosomal recessive inheritance is most likely.

Negative-configuration electroretinogram in Oregon eye disease. Consistent phenotype in Xp21 deletion syndrome.

OBJECTIVE: To determine whether abnormal configurations on electroretinogram were a consistent finding in patients with Xp21 deletion and to characterize the associated ophthalmologic phenotype. DESIGN: Case series. SETTING: University hospitals and eye institutes. PATIENTS: Five patients with complex glycerol kinase deficiency (Duchenne-type or Becker's muscular dystrophy, glycerol kinase deficiency, and congenital adrenal hypoplasia) and demonstrated chromosomal deletions at Xp21. Control patients were matched by age. MAIN OUTCOME MEASURES: Clinical information was obtained from medical records. Complete ophthalmologic examinations were performed. Electroretinography was performed using a Ganzfeld technique and chloral hydrate sedation. RESULTS: We report the clinical features and abnormal configurations on electroretinograms of five patients with complex glycerol kinase deficiency, including follow-up studies on a previously described patient. The original patient had ocular hypopigmentation; four, strabismus; two, myopia; three, astigmatism; and one, symptomatic night blindness. All had negative configurations on scotopic electroretinograms showing a reduced-amplitude B wave in the dark-adapted state. CONCLUSIONS: Our original report suggested a diagnosis of Aland Island eye disease, which appears to be an incomplete form of congenital stationary night blindness. Linkage data place Aland Island eye disease and congenital stationary night blindness at Xp11, whereas our patients had deletions at Xp21. The phenotype reported here may represent the effects of a single gene defect or the compound effects of the Xp21 contiguous gene syndrome (complex glycerol kinase deficiency). The phenotype is referred to as Oregon eye disease.

1-Thioglycerol: inhibitor of glycerol kinase activity in vitro and in situ.

The infantile form of glycerol kinase (GK) deficiency (McKusick No. 30703) (1) is characterized by adrenal cortical insufficiency, adrenal hypoplasia and developmental delay. The underlying biochemical mechanism(s) responsible for the observed clinical presentations are undetermined. Pursuant to our examination of the molecular pathogenesis of this enzyme deficiency, we have endeavored to develop a model for this disorder. 1-thioglycerol (1-TG) was investigated as a potential GK inhibitor in adrenal gland, an organ consistently affected, and in cultured fibroblasts, available from affected individuals. In 105,000 g bovine adrenal supernatant the Ki for 1-TG was 1.9 mM. In human fibroblast 105,000 g supernatant, the Ki for 1-TG was 3.4 mM. In both tissues the inhibition was purely competitive with respect to glycerol. Using incorporation of [14C(U)]-glycerol into protein as an index of GK activity in situ in human skin fibroblasts, GK deficient fibroblasts incorporate less than 10% of that observed in normal fibroblasts. Addition of 1-TG to normal fibroblasts resulted in inhibited incorporation rates. The specificity of these effects in situ was examined. Our findings indicate that 1-TG may be a suitable inhibitor of GK activity for the development of a model for glycerol kinase deficiency.

Human glycerol kinase: comparison of properties from fibroblasts and liver.

Kinetic differences in the glycerol kinase activities from human liver and fibroblasts have been previously demonstrated by this laboratory. The present study was undertaken to characterize these enzymatic activities more completely. The pH profiles were similar for the hepatic and fibroblast activities, but the stability of hepatic glycerol kinase varied much more markedly with pH than the fibroblast activity. Subcellular distribution of this enzymatic activity was quite different for liver and fibroblasts, as was the electrophoretic mobility of these activities on polyacrylamide gels. While these data do not distinguish between tissue specific isozymic forms or post-transcriptional modification, hepatic and fibroblast activities are altered similarly in patients with an inherited deficiency of glycerol kinase.

Fatal infantile X-linked neuropathy.

We report a pedigree with severe X-linked neuropathy that occurs in male infants and results in death, typically by 2 years of age. The proband of our report was weak with preserved mentation. He underwent extensive evaluation, which revealed abnormal nerve conduction studies, neurogenic changes on muscle biopsy, a decreased number of large myelinated fibers and rare onion bulb formations on nerve biopsy, negative gene testing for spinal muscular atrophy, CMT1a, and CMTX1 and a normal brain magnetic resonance image. The proband's mother, an obligate carrier, had normal nerve conduction studies. Male infants with a spinal muscular atrophy phenotype but normal genetic studies should be evaluated for this fatal X-linked neuropathy.

Genotypic variations of type III collagen in patients with cerebral aneurysms.

It has been hypothesized that either qualitative or quantitative abnormalities in type III collagen may be involved in the pathogenesis of cerebral aneurysms. The current study investigated allele frequencies for the type III collagen gene in patients with cerebral aneurysms. A diallelic Ava II polymorphism defined the type III collagen gene. The smaller of the two alleles was found in 11 of 19 aneurysm patients (58%) versus two of 15 controls (13%) (p = .006). The overall frequency of this allele was 0.34 in aneurysm patients versus 0.10 in controls (p = .011). This significant difference in allele frequency suggests that genotypic variations in the type III collagen gene may be etiologically related to aneurysm formation.

Occupational status and mobility among undocumented immigrants by gender.

PIP: Immigration has long been a national and state concern. The 1989 Legalized Population Survey (LPS-1) collected data on illegal immigrants to the US who subsequently became legalized aliens under the provisions of the 1986 Immigration Reform and Control Act. These data are used in a study assessing whether undocumented male and female immigrants improve their earnings and occupational status over time and the extent of variation in occupational status and mobility by gender and region. The data indicate that both undocumented men and women, on average, improved their earnings and occupational status between their first jobs in the US and their jobs just before applying for legalization under the 1986 Immigration Reform and Control Act. However, the earnings, occupational status, and occupational mobility of men were greater than for women.^ieng

Gender differences in the occupational status of undocumented immigrants in the United States: experience before and after legalization.

"This article examines the incorporation of a national sample of undocumented immigrants both before and after they applied to legalize their status under the provisions of the [U.S.] Immigration Reform and Control Act of 1986 (IRCA). Data from the 1989 and 1992 Legalized Population Surveys (LPS-1 and LPS-2) are used. These surveys provide labor force and occupational data for three critical reference periods: as newly arrived undocumented immigrants, as experienced undocumented immigrants, and as documented immigrants.... The overall upward mobility of both men and women between first job and the occupation held at time of application for legalization continued after legalization. On average, men also continued to report higher status jobs than women, although women did somewhat better after their status was legalized." This is a revised version of a paper originally presented at the 1997 Annual Meeting of the Population Association of America.