Mild orotic aciduria in UMPS heterozygotes: a metabolic finding without clinical consequences.

BACKGROUND: Elevated urinary excretion of orotic acid is associated with treatable disorders of the urea cycle and pyrimidine metabolism. Establishing the correct and timely diagnosis in a patient with orotic aciduria is key to effective treatment. Uridine monophosphate synthase is involved in de novo pyrimidine synthesis. Uridine monophosphate synthase deficiency (or hereditary orotic aciduria), due to biallelic mutations in UMPS, is a rare condition presenting with megaloblastic anemia in the first months of life. If not treated with the pyrimidine precursor uridine, neutropenia, failure to thrive, growth retardation, developmental delay, and intellectual disability may ensue. METHODS AND RESULTS: We identified mild and isolated orotic aciduria in 11 unrelated individuals with diverse clinical signs and symptoms, the most common denominator being intellectual disability/developmental delay. Of note, none had blood count abnormalities, relevant hyperammonemia or altered plasma amino acid profile. All individuals were found to have heterozygous alterations in UMPS. Four of these variants were predicted to be null alleles with complete loss of function. The remaining variants were missense changes and predicted to be damaging to the normal encoded protein. Interestingly, family screening revealed heterozygous UMPS variants in combination with mild orotic aciduria in 19 clinically asymptomatic family members. CONCLUSIONS: We therefore conclude that heterozygous UMPS-mutations can lead to mild and isolated orotic aciduria without clinical consequence. Partial UMPS-deficiency should be included in the differential diagnosis of mild orotic aciduria. The discovery of heterozygotes manifesting clinical symptoms such as hypotonia and developmental delay are likely due to ascertainment bias.

Evaluation of glycogen storage disease as a cause of ketotic hypoglycemia in children.

INTRODUCTION: Ketone formation is a normal response when hypoglycemia occurs. Since the majority of children with recurrent hypoglycemia cannot be diagnosed with a known endocrine or metabolic disorder on a critical sample, ketotic hypoglycemia has been described as the most common cause of low blood glucose concentrations in children. Critical samples, however, will miss the ketotic forms of glycogen storage disease (GSD), which present with elevated ketones, hypoglycemia, and normal hormonal concentrations. RESULTS: A total of 164 children (96 boys, 68 girls) were enrolled in the study. Prediction of pathogenicity of DNA changes using computer modeling confirmed pathology in 20 individuals [four GSD 0, two GSD VI, 12 GSD IX alpha, one GSD IX beta, one GSD IX gamma] (12%). Boys were most likely to have changes in the PHKA2 gene, consistent with GSD IX alpha, an X-linked disorder. CONCLUSIONS: Mutations in genes involved in glycogen synthesis and degradation were commonly found in children with idiopathic ketotic hypoglycemia. GSD IX is likely an unappreciated cause of ketotic hypoglycemia in children, while GSD 0 and VI are relatively uncommon. GSD IX alpha should particularly be considered in boys with unexplained hypoglycemia.

Nasal health in Down syndrome: a cross-sectional study.

OBJECTIVE: To investigate peripheral nasal pathology as a contributor to olfactory impairment in DS. STUDY DESIGN: Twenty DS and 16 non-DS subjects were recruited. Nasal history and symptoms were assessed by self-report or informant. Olfactory threshold, odor identification, and nasal endoscopy were assessed on each subject. RESULTS: DS subjects were impaired on olfactory threshold (P<0.0001) and odor identification (P<0.001). Although DS subjects tended toward upper-respiratory infections, sleep-disordered breathing, and nasal itching, differences were not significant (P=0.07, 0.06, and 0.058, respectively). There were no significant differences on self-reported nasal history or symptoms. Endoscopy showed equivalent health in DS and control subjects. CONCLUSION: This DS population shows olfactory impairment. However, nasal health is comparable in DS subjects and controls. Nasal dysfunction is unlikely to contribute to olfactory impairment in DS. SIGNIFICANCE: Olfactory deficits in DS appear to be secondary to central, rather than rhinologic, pathology. EBM RATING: B-2b.

Presbycusic neuritic degeneration within the osseous spiral lamina.

OBJECTIVE: To describe a neglected anatomic variant occurring with presbycusis. STUDY DESIGN: Retrospective temporal bone histopathology study. METHODS: Quantitative analysis of peripheral hair cells, neurites, neurons, and the stria vascularis in temporal bones from individuals who had presbycusis. Fifty-three patients aged 65 years or older and with a down-sloping audiogram and clinical diagnosis of presbycusis were reviewed. Nine cases had normal hair and ganglion cell populations but reduced peripheral processes (neuritic presbycusis). These were compared with five normal-hearing controls on measurements of anterior middle and basal turn fiber bundle diameter and the ratio of basal to middle diameters. RESULTS: Thresholds at 4 and 8 kHz were significantly poorer in the neuritic presbycusis group than in the control group (p

Scar management: prevention and treatment strategies.

PURPOSE OF REVIEW: Aberrant wound healing results in unsightly scar, hypertrophic scar, and keloid formation, causing functional and cosmetic deformities, discomfort, psychological stress, and patient dissatisfaction. Scar prevention and management, both surgical and nonsurgical, continue to be important issues for the otolaryngologist. RECENT FINDINGS: Both animal and human models continue to point to the integral role of transforming growth factor-beta in aberrant healing. Multiple extracts have promising results as therapies for scarring and are widely marketed but need to be further investigated. Scar prevention advancements include refinements in surgical technique, nutritional supplementation, and optimal wound care. Steroid injections continue to play a major role in the regression of scars and keloids. Dermatography assists in the minimization of scar appearance. Dermatography, laser therapies, intralesional 5-fluorouracil, and adjuvant radiotherapy are emerging therapies. Topical vitamin E utility is revisited. New surgical scar revision techniques include modified excision techniques and skin grafting. SUMMARY: Despite optimal efforts to avoid scar formation, aberrant wound healing may occur. The use of topical agents and intralesional steroid injections can minimize early scar formation. Strategies for prevention and management of keloids and hypertrophic scars continue to develop, as the basic science mechanisms underlying aberrant wound healing are elucidated.

Comparison of TRY and the closely related At1g01380 gene in controlling Arabidopsis trichome patterning.

A screen of activation-tagged Arabidopsis lines resulted in the identification of At1g01380, which encodes a small R3 single repeat MYB gene, as a negative regulator of trichome initiation. Plants that overexpress this gene have fewer trichomes. The gene is closely related to the previously identified negative regulator TRY, and has a similar pattern of expression as TRY in developing leaves. As previously shown for TRY, At1g01380 protein can inhibit the interaction between the positive trichome regulators GL1 and GL3, and likely limits trichome initiation via this inhibition. While TRY and At1g01380 are closely related, they are not completely functionally equivalent. When placed under the transcriptional control of the TRY promoter, At1g01380 can only partially rescue the try mutant. Interestingly, Atg01380 is highly expressed in gl3-sst trichomes, while TRY expression is greatly reduced. The mutation in gl3-sst causes a reduced interaction between the GL1 and GL3 proteins and results in fewer leaf trichomes that develop in clusters. The differential expression of TRY and At1g01380 in this mutant can be used to explain how its altered trichome pattern in gl3-sst [corrected] is generated.