Biomedical subjects

Cheryl R Greenberg

Publications and source records attributed to Cheryl R Greenberg.

12 recordsLinked to original sources

PubMed2006

Natural history, outcome, and treatment efficacy in children and adults with glutaryl-CoA dehydrogenase deficiency.

Glutaryl-CoA dehydrogenase (GCDH) deficiency is a rare inborn disorder of L-lysine, L-hydroxylysine, and L-tryptophan metabolism complicated by striatal damage during acute encephalopathic crises. Three decades after its description, the natural history and how to treat this disorder are still incompletely understood. To study which variables influenced the outcome, we conducted an international cross-sectional study in 35 metabolic centers. Our main outcome measures were onset and neurologic sequelae of acute encephalopathic crises. A total of 279 patients (160 male, 119 female) were included who were diagnosed clinically after clinical presentation (n = 218) or presymptomatically by neonatal screening (n = 23), high-risk screening (n = 24), or macrocephaly (n = 14). Most symptomatic patients (n = 185) had encephalopathic crises, characteristically resulting in bilateral striatal damage and dystonia, secondary complications, and reduced life expectancy. First crises usually occurred during infancy (95% by age 2 y); the oldest age at which a repeat crisis was reported was 70 mo. In a few patients, neurologic disease developed without a reported crisis. Differences in the diagnostic criteria and therapeutic protocols for patients with GCDH deficiency resulted in a huge variability in the outcome worldwide. Recursive partitioning demonstrated that timely diagnosis in neurologically asymptomatic patients followed by treatment with L-carnitine and a lysine-restricted diet was the best predictor of good outcome, whereas treatment efficacy was low in patients diagnosed after the onset of neurologic disease. Notably, the biochemical phenotype did not predict the clinical phenotype. Our study proves GCDH deficiency to be a treatable disorder and a good candidate for neonatal screening.

Adult↗

PubMed2005

Quantitative acylcarnitine profiling in peripheral blood mononuclear cells using in vitro loading with palmitic and 2-oxoadipic acids: biochemical confirmation of fatty acid oxidation and organic acid disorders.

Organic acid (OAD) and fatty acid oxidation disorders (FAOD) are inborn errors of metabolism often presenting with life-threatening metabolic decompensation followed by (irreversible) organ failure, and even death during catabolic state. Most of these diseases are considered as treatable, and metabolic decompensations can be avoided by early diagnosis and start of therapy. Confirmation of suspected diagnosis currently relies on enzymatic and mutation analyses and in vitro loading of palmitic acid in human skin fibroblast cultures. Furthermore, in some cases potentially life-threatening in vivo loading or fasting tests are still performed. In this study, we established a standardized in vitro loading test in peripheral blood mononuclear cells (PBMC) that allows reliable biochemical confirmation of a suspected diagnosis within 1 week. Patients with confirmed diagnosis of short-, medium-, very-long-chain, and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiencies, methylmalonic, propionic, isovaleric acidurias, and glutaric aciduria type I were included in the study. PBMC, isolated from heparinized venous blood samples of these individuals were incubated for 5 days with palmitic acid or 2-oxoadipic acid (glutaric aciduria type I), respectively, and quantitative acylcarnitine profiling was subsequently performed in supernatants using electrospray ionization tandem mass spectrometry. All patients were clearly identified, including those with mild biochemical phenotypes who, in particular, are at risk to be missed under balanced metabolic conditions. In glutaric aciduria type I, the same results were also obtained using lymphoblasts. In conclusion, our assay allows biochemical confirmation of a number of FAOD and OAD and could easily be implemented into the confirmatory diagnostic work-up.

Adipates↗

PubMed2005

Neuropathological, biochemical and molecular findings in a glutaric acidemia type 1 cohort.

Glutaric acidemia type 1 (GA-1) is an autosomal recessive disorder characterized by a deficiency of glutaryl-CoA dehydrogenase (GCDH) activity. GA-1 is often associated with an acute encephalopathy between 6 and 18 months of age that causes striatal damage resulting in a severe dystonic movement disorder. Ten autopsy cases have been previously described. Our goal is to understand the disorder better so that treatments can be designed. Therefore, we present the neuropathological features of six additional cases (8 months-40 years), all North American aboriginals with the identical homozygous mutation. This cohort displays similar pathological characteristics to those previously described. Four had macroencephaly. All had striatal atrophy with severe loss of medium-sized neurons. We present several novel findings. This natural time course study allows us to conclude that neuron loss occurs shortly after the encephalopathical crisis and does not progress. In addition, we demonstrate mild loss of large striatal neurons, spongiform changes restricted to brainstem white matter and a mild lymphocytic infiltrate in the early stages. Reverse transcriptase-PCR to detect the GCDH mRNA revealed normal and truncated transcripts similar to those in fibroblasts. All brain regions demonstrated markedly elevated concentrations of GA (3770-21 200 nmol/g protein) and 3-OH-GA (280-740 nmol/g protein), with no evidence of striatal specificity or age dependency. The role of organic acids as toxic agents and as osmolytes is discussed. The pathogenesis of selective neuronal loss cannot be explained on the basis of regional genetic and/or metabolic differences. A suitable animal model for GA-1 is needed.

Adolescent↗

PubMed2005

A locus for Bowen-Conradi syndrome maps to chromosome region 12p13.3.

Bowen-Conradi syndrome (BCS) is a lethal autosomal recessive disorder with an estimated incidence of 1 in 355 live births in the Hutterite population. A few cases have been reported in other populations. Here, we report the results of a genome-wide scan and fine mapping of the BCS locus in Hutterite families. By linkage and haplotype analysis the BCS locus was mapped to a 3.5 cM segment (1.9 Mbp) in chromosome region 12p13.3 bounded by F8VWF and D12S397. When genealogical relationships among the families were taken into account in the linkage analysis, the evidence for linkage was stronger and the number of potentially linked regions was reduced to one. Under the assumption that all the Hutterite patients were identical by descent for a disease-causing mutation, haplotype analysis was used to infer likely historical recombinants and thereby narrow the candidate region to a chromosomal segment shared in common by all the affected children. This study also demonstrates that BCS and cerebro-oculo-facial-skeletal syndrome (COFS) are genetically distinct.

Abnormalities, Multiple↗

PubMed2005

The most common mutation in FKRP causing limb girdle muscular dystrophy type 2I (LGMD2I) may have occurred only once and is present in Hutterites and other populations.

Limb girdle muscular dystrophy (LGMD) is common in the Hutterite population of North America. We previously identified a mutation in the TRIM32 gene in chromosome region 9q32, causing LGMD2H in approximately two-thirds of the 60 Hutterite LGMD patients studied to date. A genomewide scan was undertaken in five families who did not show linkage to the LGMD2H locus on chromosome 9. A second LGMD locus, LGMD2I, was identified in chromosome region 19q13.3, and the causative mutation was identified as c.826C>A (L276I), a missense mutation in the FKRP gene. A comparison of the clinical characteristics of the two LGMD patient groups in this population reveals some differences. LGMD2I patients generally have an earlier age at diagnosis, a more severe course, and higher serum creatine kinase (CK) levels. In addition, some of these patients show calf hypertrophy, cardiac symptoms, and severe reactions to general anesthesia. None of these features are present among LGMD2H patients. A single common haplotype surrounding the FKRP gene was identified in the Hutterite LGMD2I patients. An identical core haplotype was also identified in 19 other non-Hutterite LGMD2I patients from Europe, Canada, and Brazil. The occurrence of this mutation on a common core haplotype suggests that L276I is a founder mutation that is dispersed among populations of European origin.

Chromosome Mapping↗

PubMed2005

Hutterite brothers both affected with two forms of limb girdle muscular dystrophy: LGMD2H and LGMD2I.

Limb girdle muscular dystrophy (LGMD) is very common in the Hutterite population of the North American Prairies. We have recently reported the homozygous c.1459G>A mutation in TRIM32 associated with LGMD2H. We have also identified Hutterite patients with LGMD2I, homozygous for the common c.826C>A mutation in FKRP. To date, all Hutterites with LGMD have been shown to be homozygous for either the TRIM32 or FKRP mutation. We now report a Hutterite family in which both parents and five sons were all found to be homozygous for the TRIM32 mutation. The father had slowly progressive proximal muscle weakness, whereas three sons and their mother, all currently asymptomatic, had normal physical examinations. The remaining two sons (7 and 10 years old), presented with mild decrease in stamina, had normal neuromuscular examinations and were found to be homozygous for the FKRP mutation in addition to the TRIM32 mutation. These two boys do not differ in age at or mode of presentation, physical findings, or serum CK levels compared to age-matched individuals affected with LGMD2I alone. This suggests that the effects of these two mutations are not acting synergistically at this time. It remains to be seen whether there will be signs of interaction between these two mutations as the patients get older.

Adult↗

PubMed2005

Evolutionary comparison provides evidence for pathogenicity of RMRP mutations.

Cartilage-hair hypoplasia (CHH) is a pleiotropic disease caused by recessive mutations in the RMRP gene that result in a wide spectrum of manifestations including short stature, sparse hair, metaphyseal dysplasia, anemia, immune deficiency, and increased incidence of cancer. Molecular diagnosis of CHH has implications for management, prognosis, follow-up, and genetic counseling of affected patients and their families. We report 20 novel mutations in 36 patients with CHH and describe the associated phenotypic spectrum. Given the high mutational heterogeneity (62 mutations reported to date), the high frequency of variations in the region (eight single nucleotide polymorphisms in and around RMRP), and the fact that RMRP is not translated into protein, prediction of mutation pathogenicity is difficult. We addressed this issue by a comparative genomic approach and aligned the genomic sequences of RMRP gene in the entire class of mammals. We found that putative pathogenic mutations are located in highly conserved nucleotides, whereas polymorphisms are located in non-conserved positions. We conclude that the abundance of variations in this small gene is remarkable and at odds with its high conservation through species; it is unclear whether these variations are caused by a high local mutation rate, a failure of repair mechanisms, or a relaxed selective pressure. The marked diversity of mutations in RMRP and the low homozygosity rate in our patient population indicate that CHH is more common than previously estimated, but may go unrecognized because of its variable clinical presentation. Thus, RMRP molecular testing may be indicated in individuals with isolated metaphyseal dysplasia, anemia, or immune dysregulation.

Animals↗

PubMed2004

The C677T methylenetetrahydrofolate reductase variant and third trimester obstetrical complications in women with unexplained elevations of maternal serum alpha-fetoprotein.

INTRODUCTION: The C677T MTHFR variant has been associated with the same third trimester pregnancy complications as seen in women who have elevations of maternal serum alpha-fetoprotein (MSAFP). We hypothesized that these women with third trimester pregnancy complications and MSAFP elevations would have an increased frequency of the variant compared to an abnormal study control group (women with MSAFP elevations without pregnancy complications) as well as to normal population controls. METHODS: Women who had unexplained elevations of MSAFP in pregnancy were ascertained retrospectively. The frequency of the C677T MTHFR variant among those women with unexplained elevations of MSAFP who had experienced later pregnancy complications was compared to that of women with unexplained elevations of MSAFP without complications as well as to that of the previously established Manitoba frequency. RESULTS: Women who had complications of pregnancy and an unexplained MSAFP elevation had a higher allele frequency for the C677T MTHFR variant (q = 0.36,) compared to women with MSAFP elevations and normal pregnancy outcomes (q = 0.25, OR 1.73 95% CI 1.25-2.37, p = 0.03). The frequency was also higher than that of the population controls (q= 0.25, OR 1.70 95% CI 1.11-2.60, p = 0.007). The frequency in women with MSAFP elevations without pregnancy complications was not significantly different from that of the population controls (p = 0.41). CONCLUSION: Women with unexplained elevations of MSAFP and who experience complications in later pregnancy are more likely to have one or two alleles of the C677T MTHFR variant.

Cytosine↗

PubMed2002

Fibular aplasia with ectrodactyly.

Fibular aplasia with split hand/foot or other defects of the central axis is a rare disorder that shares several characteristics with the better known tibial aplasia-ectrodactyly syndrome. They appear to be inherited in an autosomal dominant fashion. In both, however, the phenotype is markedly variable, penetrance is reduced, and apparently sporadic cases are relatively frequent. We report a new case of this disorder and review the clinical and demographic findings in 47 others identified from the literature or other sources. A key observation was that the sex ratio is biased toward males, especially in apparently sporadic cases. This male bias is largely explained by a lower penetrance rate in women. Both affected males and females had affected children, but the risk to offspring was higher when the mother carried the gene, in keeping with a mixed model for genetic susceptibility, i.e., the penetrance of the major predisposing gene is acting against a multifactorially determined level of liability. Given the high degree of nonpenetrance and very variable expressivity, counseling with respect to recurrence risk is problematic and will likely remain so, even when the major predisposing gene is identified.

Abnormalities, Multiple↗

PubMed2002

Expression of X-linked bulbospinal muscular atrophy (Kennedy disease) in two homozygous women.

The authors describe the novel occurrence of homozygosity for the CAG expansion in the androgen receptor gene causing Kennedy disease in two sisters (ages 34 and 42). Symptoms were limited to occasional muscle cramps and twitches. Physical examinations were normal apart from mild hand tremor in both women and rare perioral fasciculations in the older sibling. Electrodiagnostic studies were normal except for evidence of mild motor axonal loss in the sternocleidomastoid muscle of the older sibling.

Adult↗

PubMed2002

Limb-girdle muscular dystrophy type 2H associated with mutation in TRIM32, a putative E3-ubiquitin-ligase gene.

Limb-girdle muscular dystrophy type 2H (LGMD2H) is a mild autosomal recessive myopathy that was first described in the Manitoba Hutterite population. Previous studies in our laboratory mapped the causative gene for this disease to a 6.5-Mb region in chromosomal region 9q31-33, flanked by D9S302 and D9S1850. We have now used additional families and a panel of 26 microsatellite markers to construct haplotypes. Twelve recombination events that reduced the size of the candidate region to 560 kb were identified or inferred. This region is flanked by D9S1126 and D9S737 and contains at least four genes. Exons of these genes were sequenced in one affected individual, and four sequence variations were identified. The families included in our study and 100 control individuals were tested for these variations. On the basis of our results, the mutation in the tripartite-motif-containing gene (TRIM32) that replaces aspartate with asparagine at position 487 appears to be the causative mutation of LGMD2H. All affected individuals were found to be homozygous for D487N, and this mutation was not found in any of the controls. This mutation occurs in an NHL (named after the proteins NCL1, HT2A, and LIN-41) domain at a position that is highly conserved. NHL domains are known to be involved in protein-protein interactions. Although the function of TRIM32 is unknown, current knowledge of the domain structure of this protein suggests that it may be an E3-ubiquitin ligase. If proven, this represents a new pathogenic mechanism leading to muscular dystrophy.

Amino Acid Sequence↗

PubMed2002

Tibial agenesis with radial ray and cardiovascular defects.

The combination of tibial agenesis with radial ray and cardiovascular defects has been observed in patients with Mendelian disorders and in those with multiple congenital anomalies of unknown cause. We report two apparently unrelated children who had unusual combinations of such findings in association with other, predominantly midline, anomalies (imperforate anus, extra ribs, uterus didelphys). Comparison of the anomalies in these infants and similar cases from the literature suggests that they may represent examples of an association of the cardiogenic and limb developmental fields occurring either as manifestations of a previously unrecognized single gene disorder or as an expansion of the VACTERL association.

Abnormalities, Multiple↗