Emergency preparedness for genetics centers, laboratories, and patients: the Southeast Region Genetics Collaborative strategic plan.

Emergencies occur unpredictably and interrupt routine genetic care. The events after hurricanes Katrina and Rita have led to the recognition that a coherent plan is necessary to ensure continuity of operations for genetic centers and laboratories, including newborn screening. No geographic region is protected from the effects of a variety of potential emergencies.

Common leukemia- and lymphoma-associated genetic aberrations in healthy individuals.

Leukemia- and lymphoma-associated (LLA) chromosomal rearrangements are critical in the process of tumorigenesis. These genetic alterations are also important biological markers in the diagnosis, prognosis, and treatment of hematopoietic malignant diseases. To detect the presence or absence of these genetic alterations in healthy individuals, sensitive nested RT-PCR analyses were performed on a large number of peripheral blood samples for selected markers including MLL partial tandem duplications (PTDs), BCR-ABL p190, BCR-ABL p210, MLL-AF4, AML1-ETO, PML-RARA, and CBFB-MYH11.

Cytogenetic and molecular characterization of complex three-way translocations in acute promyelocytic leukemia.

The most frequent chromosomal rearrangement reported in acute promyelocytic leukemia (APL) is t(15; 17) (q22; q21). The t(15; 17) generates the PML/RARA fusion gene that blocks the transcription of genes involved in myeloid cell differentiation. A small number of simple and complex variants of the classical t(15; 17) have been reported.

Eight-year clinical outcomes of long-term enzyme replacement therapy for 884 children with Gaucher disease type 1.

Objective: The goal was to analyze the clinical responses to enzyme replacement therapy with alglucerase or imiglucerase in a large international cohort of children with Gaucher disease type 1.

Methods: Anonymized data from 884 children in the International Collaborative Gaucher Group Gaucher Registry were analyzed to determine the effects of long-term enzyme replacement therapy with alglucerase or imiglucerase on hematologic and visceral manifestations, linear growth, and skeletal disease. The parameters measured were hemoglobin levels, platelet counts, spleen and liver volumes, z scores for height and bone mineral density, and reports of bone pain and bone crises.

Characterization of a cryptic 3.3 Mb deletion in a patient with a "balanced t(15;22) translocation" using high density oligo array CGH and gene expression arrays.

Patients with an apparently balanced translocation and an abnormal phenotype may carry a cryptic deletion/duplication at their translocation breakpoints that may explain their abnormalities. Using microarray CGH (aCGH) and gene expression arrays we studied a child with t(15;22)(q26.1;q11.

Increased apoptosis in cystinotic fibroblasts and renal proximal tubule epithelial cells results from cysteinylation of protein kinase Cdelta.

Cystinosis is a rare genetic disease characterized by defective lysosomal cystine transport and increased lysosomal cystine. How lysosomal cystine causes the lethal nephropathic phenotype is unknown. It was shown recently that cultured fibroblasts and renal proximal tubule epithelial cells whose lysosomes are cystine-loaded display a two-fold or greater increase in apoptosis after both intrinsic and extrinsic stimuli.

9p subtelomere deletion: pathogenic mutation or normal variant?

We report an apparently benign familial 9p subtelomere deletion identified using chromosome-arm-specific subtelomere probes in a patient with multiple congenital anomalies. Our experience demonstrated that the discovery of a subtelomeric deletion and/or duplication does not always guarantee the identification of the etiology for the patients phenotype and a positive finding with subtelomere probes should always be followed by parental study with the same probe in order to distinguish a disease causing alteration from a benign familial polymorphism.

Advanced molecular and cytogenetic technologies in birth defect diagnosis and prevention.

Fluorescence in situ hybridization (FISH) has become an important diagnostic tool as an adjunct to classical cytogenetics. FISH utilizes DNA probes comprised of specific nucleic acid sequences tagged with fluorescent molecules to identify the number and location of specific DNA sequences in human cells. These probes can be used to determine various numerical and structural chromosomal aberrations, in many cases, gene dosage and/or structure alterations.

Lysosomal cystine augments apoptosis and causes the phenotype in cystinosis.

Nephropathic cystinosis is a lethal inborn error of metabolism that destroys kidney function by age 10 years. It is characterized by lysosomal cystine accumulation. How the cystine causes the phenotype is an open question.

Individualization of long-term enzyme replacement therapy for Gaucher disease.

Gaucher disease, the most common lysosomal storage disorder, is a heterogeneous condition affecting multiple organ systems. Patients with nonneuronopathic (type 1) Gaucher disease may suffer from hepatomegaly, splenomegaly, thrombocytopenia, bleeding tendencies, anemia, hypermetabolism, skeletal pathology, growth retardation, pulmonary disease, and decreased quality of life. Enzyme replacement therapy (ERT) with mannose-terminated glucocerebrosidase (imiglucerase, Cerezyme, Genzyme Corporation, Cambridge, MA) reverses or ameliorates many of the manifestations of type 1 Gaucher disease.

High protein diet mimics hypertyrosinemia in newborn infants.

Tyrosinemia resulting from administration of protein-dense infant diets was detected by newborn screening in two infants. Change of formula resulted in rapid resolution of the hypertyrosinemia. These cases identify nonstandard infant diets as a benign and reversible cause of tyrosinemia and a potential cause of positive newborn phenylketonuria screening.

Focal skin defect, limb anomalies and microphthalmia.

We describe two unrelated female patients with congenital single focal skin defects, unilateral microphthalmia and limb anomalies. Growth and psychomotor development were normal and no brain malformation was detected. Although eye and limb anomalies are commonly associated, clinical anophthalmia and limb defects have not been reported with single focal aplasia of the skin.

Desmosterolosis presenting with multiple congenital anomalies and profound developmental delay.

Desmosterol (cholesta-5,24-dien-3beta-ol) is a minor sterol that forms as an intermediate in the cholesterol biosynthetic pathway when the 24-unsaturated sterol bond is reduced as the last step rather than earlier in the conversion of lanosterol to cholesterol. In 1998, FitzPatrick et al. reported a premature infant who died shortly after birth and had marked tissue elevations of desmosterol and a strikingly abnormal phenotype.

Lysosomal cystine storage augments apoptosis in cultured human fibroblasts and renal tubular epithelial cells.

Nephropathic cystinosis is a lethal disorder of lysosomal cystine storage due to defective lysosomal cystine transport. How lysosomal cystine causes this multisystemic disorder culminating in end-stage renal disease is not known, because the cystine is isolated from cellular metabolism by the lysosomal membrane. It is here reported that in both normal and nephropathic cystinotic fibroblasts and cultured renal proximal tubule epithelial cells, increased lysosomal cystine causes an increased rate of apoptosis.

Medical genetic test reporting for cystic fibrosis (deltaF508) and factor V Leiden in North American laboratories.

Purpose: Physicians are ordering an increasing number of genetic tests. Results and additional information provided in the test result report are vital to the physician in making appropriate patient management decisions. Because variability in test result reports can impact patient care, we sought to determine whether variations exist in test reports for cystic fibrosis (CF) and factor V Leiden (fVL) with specific comparison to professional guidelines and recommendations.

Disorders of post-squalene cholesterol biosynthesis leading to human dysmorphogenesis.

Insights in molecular developmental biology in animals and humans are facilitating the understanding of pathophysiologic mechanisms in dysmorphogenesis or abnormalities in normal embryologic structural development. A milestone was recognition of the role of shh in morphogenesis of craniofacial structures, especially the development of holoprosencephaly. The dependence of hedgehog morphogens on cholesterol modification for normal hedgehog signaling function has particular relevance to disorders of cholesterol synthesis which manifest dysmorphogenesis.

Scalp defects, polythelia, microcephaly, and developmental delay: a new syndrome with apparent autosomal dominant inheritance.

We report a family with apparent autosomal dominant inheritance of scalp defects, polythelia, microcephaly, and developmental delay. A review of the literature revealed no previous report of this combination of anomalies. We conclude that these patients have a new autosomal dominant syndrome.

Management dilemmas in patients with hereditary renal adysplasia.

We report a neonatal case of right renal aplasia with left dysplastic kidney and mild pulmonary hypoplasia. The respiratory insufficiency gradually improved on high frequency oscillation and conventional ventilation. Severe hypotension necessitated the use of inotrops.

Long-term outcome in treated combined methylmalonic acidemia and homocystinemia.

Purpose: To describe the clinical and biochemical features and long-term outcome of a cohort of eight patients with methylmalonic acidemia and homocystinuria (cblC).

Methods: Documentation of clinical features at birth and longitudinal follow-up of the biochemical and clinical response to treatment with daily oral carnitine and intramuscular hydroxocobalamin observed during continuous follow-up for an average of 5.7 years.

Phenotypic features in a boy with monosomy 18 mosaicism.

We report on a patient with mosaicism for monosomy 18, a chromosomal abnormality that has been reported only once previously. The patient had cleft lip and palate and mild behavioral and academic problems. His phenotype was milder in comparison with the previously reported patient by Khalifa et al.

Demethylation and expression of methylated plasmid DNA stably transfected into HeLa cells.

In vitro methylation at CG dinucleotides (CpGs) in a transfecting plasmid usually greatly inhibits gene expression in mammalian cells. However, we found that in vitro methylation of all CpGs in episomal or non-episomal plasmids containing the SV40 early promoter/enhancer (SV40 Pr/E) driving expression of an antibiotic-resistance gene decreased the formation of antibiotic-resistant colonies by only approximately 30-45% upon stable transfection of HeLa cells. In contrast, when expression of the antibiotic-resistance gene was driven by the Rous sarcoma virus long terminal repeat or the herpes simplex virus thymidine kinase promoter, this methylation decreased the yield of antibiotic-resistant HeLa transfectant colonies approximately 100-fold.

Adrenal insufficiency in Smith-Lemli-Opitz syndrome.

We describe three unrelated patients with adrenal insufficiency and RSH or Smith-Lemli-Opitz syndrome (SLOS), a disorder due to deficient synthesis of cholesterol. These patients presented with hyponatremia, hyperkalemia, and decreased aldosterone-to-renin ratio, which is a sensitive measure of the renin-aldosterone axis. All patients had profound serum total cholesterol deficiency (14-31 mg/dl) and marked elevation of 7-dehydrocholesterol (10-45 mg/ dl).

Fatal carnitine palmitoyltransferase II deficiency in a newborn: new phenotypic features.

We describe the term male infant of asymptomatic, healthy nonconsanguineous parents presenting on the first day of life with nonketotic hypoglycemia, seizures, hepatomegaly, cardiomegaly with biventricular hypertrophy, and ventricular arrhythmias. Cranial ultrasound revealed cystic dysplasia with several foci of hyperechogenicity within the right basal ganglia. Free carnitine was markedly decreased in the urine and plasma with a pronounced elevation of plasma long-chain acylcarnitines.