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Pompe disease is a progressive metabolic neuromuscular disorder resulting from deficiency of lysosomal acid α-glucosidase (GAA). Infantile-onset Pompe disease is characterized by cardiomyopathy, respiratory and skeletal muscle weakness, and early death. The safety and efficacy of recombinant human (rh) GAA were evaluated in 18 patients with rapidly progressing infantile-onset Pompe disease.

Over 10 years we performed 103 skin-expansion procedures and placed 207 prostheses on lower limbs, using the same surgical protocol. In 83 cases (80.6%) the expansion was achieved without complications. We recorded 20 complications in all (19.4%). Major complications included sepsis, damage due to undermining, exposure of the prosthesis and necrosis of the flap in 16 cases (15.5%), resulting in complete failure of the method in five cases (4.9%). In all, nine patients had septic complications (8.7% of the patients and 45% of the complications), five had exposure of the prosthesis and two had skin necrosis after expansion. Infection and skin necrosis, which are the main causes of failure of this method, can be prevented by a strict surgical protocolcovering all stages of the procedure. Atraumatic undermining, remote and external valves, suction drains in the cavities, advancement flaps and plaster casts after surgery can help to prevent skin necrosis. A separate and remote approach for each prosthesis can prevent infection of all the prostheses and complete failure of the expansion procedure. Copyright 2001 The British Association of Plastic Surgeons

Glucokinase catalyzes a rate-limiting step in glucose metabolism in hepatocytes and pancreatic beta cells and is considered the "glucose sensor" for regulation of insulin secretion. Patients with maturity-onset diabetes of the young (MODY) have heterozygous point mutations in the glucokinase gene that result in reduced enzymatic activity and decreased insulin secretion. However, it remains unclear whether abnormal liver glucose metabolism contributes to the MODY disease. Here we show that disruption of the glucokinase gene results in a phenotype similar to MODY in heterozygous mice. Reduced islet glucokinase activity causes mildly elevated fasting blood glucose levels. Hyperglycemic clamp studies reveal decreased glucose tolerance and abnormal liver glucose metabolism. These findings demonstrate a key role for glucokinase in glucose homeostasis and implicate both islets and liver in the MODY disease.

Wild-type newborn mice are characterized by the ability of certain liver-specific genes encoding various enzymes and mapping on different chromosomes to respond to glucocorticoid induction. Newborn mice homozygous for deletions at and around the albino locus on chromosome 7 fail to develop this competence for hormone-inducible gene expression even through they do show normal constitutive expression of the same genes. Studies of the glucocorticoid hormone signal transduction pathway reported here show identical expression of glucocorticoid receptor mRNA and protein in deletion homozygotes and normal littermates. Furthermore, the receptor interacts normally with the 90-kDa heat shock protein hsp90. Elevated glucocorticoid hormone levels in newborn deletion homozygotes, most likely resulting from their stressed condition, provide an explanation for the reduced binding activities of receptors reported previously. The elimination of receptors and hormones as direct targets of the chromosomal deletion effects suggests that the failure of inducible gene expression might reside in defective competence of the affected structural genes to respond to the hormonal stimulus.

Several overlapping chromosomal deletions spanning the albino locus in the mouse cause perinatal lethality when homozygous and a block in the transcriptional induction of various unlinked hepatocyte-specific genes. Studies of such lethal albino deletion homozygotes in perinatal stages revealed a deficiency in the transcriptional inducibility of the tyrosine aminotransferase (TAT) gene by glucocorticoids; yet, glucocorticoid receptor and hormone levels were shown to be unaffected. To identify a molecular defect underlying the failure of inducible expression, we examined the chromatin structure of the TAT gene. Whereas in wild-type animals the TAT promoter becomes DNase I hypersensitive at birth, such hypersensitivity fails to develop in lethal albino deletion homozygotes. By contrast, the deletions do not affect the appearance of three DNase I-hypersensitive sites upstream of the TAT promoter in the liver, nor do they affect two hypersensitive sites upstream of the expressed alpha-fetoprotein gene. These findings demonstrate that the abnormality of chromatin structure identified in lethal albino deletion homozygotes occurs on a highly selective basis. Specifically, normal differentiation of the TAT promoter chromatin appears to depend directly or indirectly on the action and product of a gene mapping within the deleted region.

A cluster of unlinked genes encoding gluconeogenic enzymes in the mouse is characterized by the failure of normal hormone-inducible expression in animals homozygous for one of several overlapping deletions mapping on chromosome 7 near the albino locus. Previous investigations have shown hormones and their receptors to be normal in the mutants and therefore not responsible for the abnormalities of inducibility. Instead, these studies have implicated a possible failure of the affected structural enzyme genes themselves to attain during prenatal development the competence for inducible gene expression. The results reported here add serine dehydratase (EC 4.2.1.13) and its structural gene to the affected group of gluconeogenic enzymes and their genes. Even though, in deletion homozygotes, serine dehydratase is expressed normally on the constitutive level, hormone-inducible expression fails to develop. The abnormality appears to reside in a defect of prenatal differentiation of cis-acting regulatory elements of the structural gene essential in the pathway of inducible gene expression.