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Biomedical subjects

R G Boles

Publications and source records attributed to R G Boles.

At least 19 recordsLinked to original sources
PubMed2003

Infantile mitochondrial DNA depletion syndrome associated with methylmalonic aciduria and 3-methylcrotonyl-CoA and propionyl-CoA carboxylase deficiencies in two unrelated patients: a new phenotype of mtDNA depletion syndrome.

Mitochondrial DNA (mtDNA) depletion refers to a quantitative defect in mtDNA and is heterogeneous with regard to causal genotypes and the associated clinical phenotypes. We report two unrelated infants with mtDNA depletion. A diagnosis of methylmalonic aciduria was initially raised in both on the basis of high urine methylmalonic acid and related organic acids and elevated propionylcarnitine and methylmalonylcarnitine. Carboxylase assay with skin fibroblasts revealed low propionyl-CoA and 3-methylcrotonyl-CoA carboxylase and normal pyruvate carboxylase activities. Quantitative Southern blot analysis of mitochondrial and nuclear DNA with muscle tissues revealed the patients' mtDNA to be depleted to 24% and 39% of normal controls. Our two patients showed multiple mitochondrial dysfunction including respiratory chain defects and deficiencies in the two nuclear DNA encoded carboxylases resulting in abnormal urine organic acids. To our knowledge, there is no obvious connection between the defective pathways other than their mitochondrial locations. These two cases may represent a new entity of mitochondrial disease that might be due to a defective common mechanism, such as assembly, maintenance and transport, affecting various mitochondrial enzymes and functions. Mitochondrial depletion should be considered in infants with atypical organic aciduria that may resemblemethylmalonicaciduria, propionicacidaemia, or 3-methylcrotonyl-CoA carboxylase deficiency.

Carbon-Carbon Ligases↗
PubMed2001

LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development.

In humans, low peak bone mass is a significant risk factor for osteoporosis. We report that LRP5, encoding the low-density lipoprotein receptor-related protein 5, affects bone mass accrual during growth. Mutations in LRP5 cause the autosomal recessive disorder osteoporosis-pseudoglioma syndrome (OPPG). We find that OPPG carriers have reduced bone mass when compared to age- and gender-matched controls. We demonstrate LRP5 expression by osteoblasts in situ and show that LRP5 can transduce Wnt signaling in vitro via the canonical pathway. We further show that a mutant-secreted form of LRP5 can reduce bone thickness in mouse calvarial explant cultures. These data indicate that Wnt-mediated signaling via LRP5 affects bone accrual during growth and is important for the establishment of peak bone mass.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Screening for mitochondrial DNA heteroplasmy in children at risk for mitochondrial disease.

Temporal temperature gradient gel electrophoresis was used to screen 70% of the mtDNA, including all 22 tRNA genes, for heteroplasmy in 75 children with neuromuscular and/or multi-system dysfunction and elevated lactate levels, and in 95 controls. Standard PCR/ASO (allele specific oligonucleotide) and Southern analyses were also employed. Excluding common length variants, heteroplasmy was found in 22 patients and two controls (P < 0.001), with four patients demonstrating heteroplasmy in two locations each. Of the 23 heteroplasmic variants sequenced among the patients, 17 were novel point variants in the control region (CR) and only two involved tRNA genes. Heteroplasmy is highly associated with the disease group, and is predominately found in the CR, an area rarely studied in patient populations. These variants may be pathological mutations or disease markers.

Journal Article↗
PubMed2001

Mitochondrial DNA depletion, near-fatal metabolic acidosis, and liver failure in an HIV-infected child treated with combination antiretroviral therapy.

A child with controlled human immunodeficiency virus infection presented with neurologic deterioration, lactic acidosis, and organic aciduria. Muscle biopsy revealed abnormal mitochondrial (mt) morphology, reduced mt enzyme activities, and mtDNA depletion. After adjustment of antiretroviral therapy to a regimen free of nucleoside analogs, marked improvement was seen in clinical status and mt abnormalities.

Acidosis↗
PubMed2000

Brain phenylalanine concentration in the management of adults with phenylketonuria.

Diagnosis by newborn screening and the implementation of a phenylalanine-restricted diet have resulted in normal neurological development in approximately 10,000 persons with phenylketonuria (PKU) in the United States. While it is accepted that a phenylalanine-restricted diet is necessary in childhood, the recommended concentration of phenylalanine in the blood varies. Clinicians now must make recommendations for adults with PKU who probably tolerate higher levels of phenylalanine than children. This factor, quality of life issues, the expense of the diet, and varying genetic and socioeconomic backgrounds, make the choice of dietary recommendations difficult. Molecular analysis of the mutations in PKU has provided insight but has not resulted in clear recommendations for phenylalanine concentration in the blood. Magnetic resonance imaging has provided the recognition that white-matter changes are present in PKU. However, owing to poor correlation of white-matter changes with clinical factors, analysis of white-matter changes has not proved useful. We hypothesize that measurement of brain phenylalanine directly will aid in clinical decision making. Twenty-one subjects with PKU had blood and brain phenylalanine measured simultaneously. Fifteen were randomly selected, 2 were examined for clinical reasons and 4 exceptional patients were chosen because they had maintained high IQs, despite having high historic blood concentrations and having been off the diet for at least 10 years. The correlation of blood and brain phenylalanine is in general poor. However, the four exceptional patients all had relatively low concentrations of phenylalanine in their brains compared to their blood. We suggest that their good clinical status, despite high historic blood levels, is due to their comparatively low brain levels of phenylalanine. We further suggest that measurement of brain phenylalanine concentration is useful in the management of PKU patients.

Adolescent↗
PubMed1999

Glucose transporter type 1 deficiency: a study of two cases with video-EEG.

Glucose transporter type 1 (GLUT1) deficiency is an inborn error of glucose transport. Clinical manifestations are presumed secondary to reduced glucose transport across the blood brain barrier, and include seizures, abnormal tone, developmental delay and hypoglycorrhachia. A high index of suspicion is important as GLUT1 deficiency is a potentially treatable cause of mental retardation. We studied two affected children by continuous video-EEG in order to better understand the cause of the clinical manifestations and improvement on a ketogenic diet. The EEG was characterized by generalized paroxysmal 2-2.5 Hz spike-wave discharges, although normal EEGs were also obtained. Atypical absence seizures were the most prominent clinical seizure. Epileptiform activity and clinical seizures occurred in both children while acutely ketotic and non-ketotic, but were markedly more frequent in one child when non-ketotic. Discharges were not associated with a reduction in substrate for brain metabolism in the blood at that time. Conclusion Atypical absence seizures are common in glucose transporter type 1 deficiency and should alert the clinician to the possibility of this treatable disorder when present in a young child with developmental delay. Our data suggest that the therapeutic mechanism of the ketogenic diet in this disorder is more complicated than simply delivering ketones as an alternative substrate for brain metabolism.

Child↗
PubMed1999

Detection of mitochondrial DNA mutations by temporal temperature gradient gel electrophoresis.

BACKGROUND: A unique requirement for the molecular diagnosis of mitochondrial DNA (mtDNA) disorders is the ability to detect heteroplasmic mtDNA mutations and to distinguish them from homoplasmic sequence variations before further testing (e.g., sequencing) is performed. We evaluated the potential utility of temporal temperature gradient gel electrophoresis (TTGE) for these purposes in patients with suspected mtDNA mutations. METHODS: DNA samples were selected from patients with known mtDNA mutations and patients suspected of mtDNA disorders without detectable mutations by routine analysis. Six regions of mtDNA were PCR amplified and analyzed by TTGE. Electrophoresis was carried out at 145 V with a constant temperature increment of 1.2 degrees C/h. Mutations were identified by direct sequencing of the PCR products and confirmed by PCR/allele-specific oligonucleotide or PCR/restriction fragment length polymorphism analysis. RESULTS: In the experiments using patient samples containing various amounts of mutant mtDNA, TTGE detected as little as 4% mutant heteroplasmy and identified heteroplasmy in the presence of a homoplasmic polymorphism. In 109 specimens with 15 different known mutations, TTGE detected the presence of all mutations and distinguished heteroplasmic mutations from homoplasmic polymorphisms. When 11% of the mtDNA genome was analyzed by TTGE in 104 patients with clinically suspected mitochondrial disorders, 7 cases of heteroplasmy ( approximately 7%) were detected. CONCLUSIONS: TTGE distinguishes heteroplasmic mutation from homoplasmic polymorphisms and appears to be a sensitive tool for detection of sequence variations and heteroplasmy in patients suspected of having mtDNA disorders.

Alleles↗
PubMed1999

Mitochondrial disease and cyclic vomiting syndrome.

Mutations of mitochondrial DNA are being increasingly recognized as a cause of human disease. Six unrelated children have been evaluated with cyclic vomiting syndrome and a strong maternal family history suggesting a mitochondrial DNA mutation. Manifestations suggestive of migraine were present in each child. Additional clinical findings present in all cases include: developmental delay (3/6 cases), seizures (3/6), and poor growth (3/6). The age of onset for vomiting episodes was < or = 1 year in five cases. An elevated body fluid lactate (lactic acid) was found in 5/6 cases. A mitochondrial DNA mutation was confirmed in one child with the finding of a large rearrangement. These cases suggest that mitochondrial DNA mutations can cause cyclic vomiting syndrome. Mitochondrial disease should be considered in cases of cyclic vomiting, especially those with additional pathology or possible maternal inheritance. Initial screening should include plasma lactate and urine organic acids obtained during an episode.

Adolescent↗
PubMed1998

Mitochondrial DNA deletion with Kearns Sayre syndrome in a child with Addison disease.

UNLABELLED: Kearns Sayre syndrome (KSS) is a multisystem disorder with a confounding variety of clinical manifestations, including ocular myopathy, pigmentary retinopathy, heart block and ataxia. Endocrinopathies are common in KSS, including growth hormone deficiency, hypogonadism, diabetes mellitus and hypoparathyroidism. A variety of deletions of mitochondrial DNA (mtDNA) are found in most cases. We report on a 5-year-old boy with Addison disease in whom further investigation revealed a 4.9 kilobase mtDNA deletion and KSS. Later he developed severe lactic acidosis and expired. CONCLUSION: The degree of mutant mtDNA heteroplasmy in various tissues on autopsy did not correlate well with the clinical manifestations, although this may be due at least in part to replacement with other tissue types. Our report is the first of non-autoimmune Addison disease in KSS and patients with KSS should be evaluated for adrenal insufficiency. Early recognition of adrenal insufficiency is crucial to prevent mortality from this cause.

Acidosis, Lactic↗
PubMed1998

Retrospective biochemical screening of fatty acid oxidation disorders in postmortem livers of 418 cases of sudden death in the first year of life.

OBJECTIVE: Fatty acid oxidation (FAO) disorders are frequently reported as the cause of sudden and unexpected death, but their postmortem recognition remains difficult. We have devised a biochemical protocol in which informative findings in liver tissue are microvesicular steatosis, elevated concentrations of C8-C16 fatty acids, glucose depletion, and low carnitine concentration. STUDY DESIGN: We analyzed 27 cases representing five FAO disorders and compared the results with those obtained in a retrospective blinded analysis of 418 cases of sudden infant death (313 SIDS, 45 infections, and 34 accidents and abuse). RESULTS: All cases of accidents and abuse correctly tested negative. Among the others, 25 (6%) showed at least two abnormal findings. Of these, 14 closely matched the biochemical profiles seen in specific FAO disorders. These included 2 cases with medium-chain acyl-CoA dehydrogenase deficiency, 4 cases consistent with glutaric acidemia type 2, 4 cases with either very long-chain acylcoenzyme A dehydrogenase deficiency or long-chain 3-hydroxy-acyl-coenzyme A dehydrogenase deficiency, and 4 cases predicted to be affected with carnitine uptake defect. CONCLUSION: The results of this study support the view that approximately 5% of all cases of sudden infant death are likely caused by an FAO disorder.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1997

Somatic mosaicism for deletion of the entire NF1 gene identified by FISH.

We report a young child with a large congenital cervical plexiform neurofibroma and multiple café-aul-ait spots in a generalized distribution who has mosaicism for complete deletion of the NF1 gene. The deletion was demonstrated with intragenic cosmid probes as well as YACs spanning a 700-kb contig including NF1, by two-color FISH with an NF1 and a control probe. Using different intragenic probes, deletion was found in 77-84% of cultured peripheral blood lymphocytes but not in cultured skin fibroblasts. Neither parent has signs of neurofibromatosis type 1 (NF1) or a gene deletion. This is the first report of mosaicism for complete deletion of the NF1 gene. The child did not have typical NF1 or display segmental features of NF1.

Cells, Cultured↗
PubMed1997

Macular pattern retinal dystrophy, adult-onset diabetes, and deafness: a family study of A3243G mitochondrial heteroplasmy.

PURPOSE: To correlate mitochondrial DNA (mtDNA) mutation with phenotypic expression in three members of a Finnish family with macroreticular pattern dystrophy, non-insulin-dependent diabetes mellitus, and deafness. METHODS: A multiplex polymerase chain reaction/allele-specific oligonucleotide method was used to screen 10 mtDNA point mutations known to cause mitochondrial DNA disorders, often characterized by myopathy, retinopathy, or both. Quantitative analysis of mutant mitochondrial DNA was performed in three tissue types in each of three family members by determining the percentage of mutant mtDNA in blood, buccal cells, and hair follicles. RESULTS: A heteroplasmic A3243G mtDNA point mutation was found in each of the three family members studied. Heteroplasmy refers to the coexistence of normal and mutant mitochondria in the same cell. The average percentage of mutant heteroplasmy ranged from 11% to 25%. The severity of disease symptoms did not appear to correlate with the average degree of mutant heteroplasmy in the three tissues analyzed. CONCLUSIONS: Molecular confirmation in this family emphasizes the importance of mitochondrial DNA mutation analysis in patients with macular pattern retinal dystrophy and other mitochondrial associated nonocular disease, such as non-insulin-dependent diabetes mellitus and deafness. The detection of a disease-associated mitochondrial DNA mutation warrants genetic counseling, appropriate patient follow-up, and possibly the molecular testing of other at-risk family members.

Age of Onset↗