Taste and smell perception and quality of life during and after systemic therapy for breast cancer.

PURPOSE: The purpose of the study was to assess self-reported taste and smell perception after chemotherapy in breast cancer patients compared with women without cancer, and to assess whether taste and smell perception is associated with quality of life after the end of chemotherapy. METHODS: We included 135 newly diagnosed breast cancer patients who completed chemotherapy and 114 women without cancer. Questionnaires on taste, smell, and quality of life were completed shortly after and 6 months after chemotherapy (patients) or at two moments with 6 months' time window in between (comparisons). RESULTS: Self-reported taste and smell perception were significantly lower in patients shortly after chemotherapy compared to the comparison group. Most patients recovered 6 months after chemotherapy, although patients who were still receiving trastuzumab then reported a lower taste and smell perception compared to patients who were not. A lower self-reported taste and smell were statistically significantly associated with a worse quality of life, social, emotional, and role functioning shortly after chemotherapy. Six months after chemotherapy, taste and smell were statistically significantly associated with quality of life, social and role functioning, but only in patients receiving trastuzumab. CONCLUSIONS: Most taste and smell alterations recovered within 6 months after the end of chemotherapy for breast cancer, but not for patients receiving trastuzumab. These results highlight the importance of monitoring taste and smell alterations during and after treatment with chemotherapy and trastuzumab, as they may impact quality of life.

Differences in dietary intake during chemotherapy in breast cancer patients compared to women without cancer.

PURPOSE: Breast cancer patients receiving chemotherapy often experience symptoms such as nausea, vomiting and loss of appetite that potentially affect dietary habits. This study assessed the intake of energy, macronutrients and food groups before and during chemotherapy in breast cancer patients compared with women without cancer, and determined the association between symptoms and energy and macronutrient intake. METHODS: This study included 117 newly diagnosed breast cancer patients scheduled for chemotherapy and 88 women without cancer. Habitual intake before chemotherapy was assessed with a food frequency questionnaire. Two 24-h dietary recalls were completed on random days for each participant during the whole chemotherapy treatment for patients and within 6 months after recruitment for women without cancer. Shortly, after the dietary recall, participants filled out questionnaires on symptoms. RESULTS: Before chemotherapy, habitual energy and macronutrient intake was similar for breast cancer patients and women without cancer. During chemotherapy, breast cancer patients reported a significantly lower total energy, fat, protein and alcohol intake than women without cancer, as shown by a lower intake of pastry and biscuits, cheese, legumes and meat products. A decline in subjective taste perception, appetite and hunger and experiencing a dry mouth, difficulty chewing, lack of energy and nausea were associated with a lower energy intake. CONCLUSIONS: Symptoms induced by chemotherapy are associated with lower dietary intake and manifested by a lower intake of specific food groups. To ensure an optimal dietary intake during chemotherapy, it is important to monitor nutritional status and symptom burden during chemotherapy in breast cancer patients.

A microdeletion in cytochrome c oxidase (COX) subunit III associated with COX deficiency and recurrent myoglobinuria.

We have identified a 15-bp microdeletion in a highly conserved region of the mitochondrially encoded gene for cytochrome c oxidase (COX) subunit III in a patient with severe isolated COX deficiency and recurrent myoglobinuria. The mutant mitochondrial DNA (mtDNA) comprised 92% of the mtDNA in muscle and 0.7% in leukocytes. Immunoblots and immunocytochemistry suggested a lack of assembly or instability of the complex. Microdissected muscle fibres revealed significantly higher portions of mutant mtDNA in COX-negative than in COX-positive fibres. This represents the first case of isolated COX deficiency to be defined at the molecular level.

X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy.

To determine whether human X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome (IPEX; MIM 304930) is the genetic equivalent of the scurfy (sf) mouse, we sequenced the human ortholog (FOXP3) of the gene mutated in scurfy mice (Foxp3), in IPEX patients. We found four non-polymorphic mutations. Each mutation affects the forkhead/winged-helix domain of the scurfin protein, indicating that the mutations may disrupt critical DNA interactions.

Carbohydrate-deficient glycoprotein syndrome: not an N-linked oligosaccharide processing defect, but an abnormality in lipid-linked oligosaccharide biosynthesis?

The carbohydrate-deficient glycoprotein syndrome (CDGS) is a developmental disease associated with an abnormally high isoelectric point of serum transferrin. Carbohydrate analyses of this glycoprotein initially suggested a defect in N-linked oligosaccharide processing, although more recent studies indicate a defect in the attachment of these sugar chains to the protein. We studied both serum glycoproteins and fibroblast-derived [2-3H]mannose-labeled oligosaccharides from CDGS patients and normal controls. While there was a decrease in the glycosylation of serum glycoproteins of affected individuals, differences were not seen in either monosaccharide composition or oligosaccharide structures. The lectin-binding profiles of glycopeptides from [2-3H]-mannose-labeled fibroblasts were likewise indistinguishable. However, the incorporation of [2-3H]mannose into both glycoproteins and the dolichol-linked oligosaccharide precursor was significantly reduced. Thus, at least in some patients, CDGS is not due to a defect in processing of N-linked oligosaccharides, but rather to defective synthesis and transfer of nascent dolichol-linked oligosaccharide precursors. This abnormality could result in both a failure to glycosylate some sites on some proteins, as well as secondary abnormalities in overall glycoprotein processing and/or function.

Mutations in the liver glycogen synthase gene in children with hypoglycemia due to glycogen storage disease type 0.

Glycogen storage disease type 0 (GSD-0) is a rare form of fasting hypoglycemia presenting in infancy or early childhood and accompanied by high blood ketones and low alanine and lactate concentrations. Although feeding relieves symptoms, it often results in postprandial hyperglycemia and hyperlactatemia. The glycogen synthase (GS) activity has been low or immeasurable in liver biopsies, whereas the liver glycogen content has been only moderately decreased. To investigate whether mutations in the liver GS gene (GYS2) on chromosome 12p12.2 were involved in GSD-0, we determined the exon-intron structure of the GYS2 gene and examined nine affected children from five families for linkage of GSD-0 to the GYS2 gene. Mutation screening of the 16 GYS2 exons was done by single-strand conformational polymorphism (SSCP) and direct sequencing. Liver GS deficiency was diagnosed from liver biopsies (GS activity and glycogen content). GS activity in the liver of the affected children was extremely low or nil, resulting in subnormal glycogen content. After suggestive linkage to the GYS2 gene had been established (LOD score = 2.9; P < 0.01), mutation screening revealed several different mutations in these families, including a premature stop codon in exon 5 (Arg246X), a 5'-donor splice site mutation in intron 6 (G+1T--> CT), and missense mutations Asn39Ser, Ala339Pro, His446Asp, Pro479Gln, Ser483Pro, and Met491Arg. Seven of the affected children carried mutations on both alleles. The mutations could not be found in 200 healthy persons. Expression of the mutated enzymes in COS7 cells indicated severely impaired GS activity. In conclusion, the results demonstrate that GSD-0 is caused by different mutations in the GYS2 gene.

S-adenosylhomocysteine hydrolase deficiency in a 26-year-old man.

This paper reports the third proven human case of deficient S-adenosylhomocysteine (AdoHcy) hydrolase activity. The patient is similar to the only two previously reported cases with this disorder in having severe myopathy, developmental delay, elevated serum creatine kinase (CK) concentrations, and hypermethioninaemia. Although he has been followed from infancy, the basic enzyme deficiency was established only at age 26 years. The diagnosis was based on markedly elevated plasma concentrations of both AdoHcy and S-adenosylmethionine, some 20% of the mean control activity of AdoHcy hydrolase activity in haemolysates of his red-blood cells, and two missense mutations in his gene encoding AdoHcy hydrolase. He had low values of erythrocyte phosphatidylcholine and plasma free choline and marginally elevated excretion of guanidinoacetate, suggesting that the elevated AdoHcy may have been inhibiting methylation of phosphatidylethanolamine and guanidinoacetate. His leukocyte DNA was globally more methylated than the DNA's of his parents or the mean extent of methylation measured in age-matched control subjects.

Clustered inactivating mutations and benign polymorphisms of the calcium receptor gene in familial benign hypocalciuric hypercalcemia suggest receptor functional domains.

The predominant variety of familial benign hypocalciuric hypercalcemia (FBHH) is FBHH(3q), which is associated with presumed inactivating mutations of the cell surface calcium receptor (CaR) gene on chromosome 3q13.3-q21. We sought mutations of the CaR gene in FBHH by direct sequencing of PCR-amplified genomic DNA from 14 affected families: 8 mapped to 3q13, 1 mapped to chromosome 19p, and 5 unmapped. We sequenced the entire coding region of the gene (exons 2-7) in one or two affected members of each family and found six point mutations that altered one amino acid, cosegregated with hypercalcemia, and were absent in more than 100 unaffected persons. Four mutations were unique (S53P, D215G, S657Y, and P748R), and two had been reported previously (P55L and R185Q). Of four mutant CaR proteins expressed in Xenopus oocytes, three were deficient in extracellular Ca2+-induced signaling. No CaR mutations were found in eight families, including the one mapped to chromosome 19p. Three benign polymorphisms occurred in the COOH-terminal region of the CaR protein in 10%, 15%, and 30% of more than 100 unaffected persons. Thus, FBHH-causing CaR mutations were clustered in the NH2-terminal extracellular and membrane-spanning regions of the receptor protein. We suggest that these are important functional domains, probably for calcium binding and signal transduction, respectively. Finally, mutations in regulatory or intronic regions of the CaR gene may also underlie many cases of FBHH.

Mannosidosis in three brothers--a review of the literature.

Three brothers with mannosidosis were studied, and their clinical and biochemical manifestations are compared with those of 41 cases in the literature. All three boys have psychomotor and growth retardation, characteristic facies, recurrent respiratory infections, sensorineural deafness, craniosynostosis, protuberant abdomens, and thin limbs. Roentgenographic findings of mild dysostosis multiplex, thick calvaria, abnormally contoured vertebrae, coarse trabeculi and thin cortices are consistent with those of reported cases. The lymphocytes of peripheral blood and bone marrow are vacuolated. Alpha-mannosidase deficiency in leukocytes and cultured skin fibroblasts and glycoproteinuria have been documented. The biochemistry of this glycoproteinosis and the pitfalls in diagnosis, such as improper assay conditions of pH and substrate concentration, are discussed. Extrapolation of in vitro and animal model studies suggest that trace metal therapy may be more effective than attempts at enzyme replacement to treat this hereditary storage disease.

Metabolic myopathies: evaluation by graded exercise testing.

Exertional muscle pain and fatigue are common complaints; some patients with these symptoms have a metabolic myopathy. We have performed graded exercise testing with analysis of expired ventilation on 13 individuals with various kinds of metabolic myopathies. Their results differed from normal and reflected the underlying biochemical abnormality. Patients with disorders of the mitochondrial electron transport chain demonstrated marked limitations in aerobic metabolism and a greatly reduced maximum oxygen consumption. During intense exertion, normal individuals increase carbon dioxide generation due to buffering of lactic acid. This did not occur in patients with McArdle disease, in whom the respiratory exchange ratio (carbon dioxide production/oxygen consumption) did not rise above 1.0 at maximum exercise. These results indicated a deficit in anaerobic metabolism. Pyruvate dehydrogenase complex allows pyruvate produced from carbohydrate metabolism to enter the citric acid cycle. Patients with this enzyme deficiency showed an initially normal pattern followed by an abrupt cessation in carbohydrate dependent aerobic metabolism at higher work loads. During high-intensity exercise, progressive anaerobic metabolism was not accompanied by additional oxygen consumption. Finally, results from a patient with carnitine palmitoyl transferase deficiency revealed an early dependence on carbohydrate metabolism. The ventilatory threshold occurred at a low percentage of maximal oxygen consumption, reflecting the limited availability of lipid substrates for aerobic metabolism. Detection of some muscle metabolic abnormalities can be made on small biopsy specimens. However, definitive diagnosis of the defect nearly always requires studies on fresh or frozen muscle tissue obtained by an open biopsy. The decision on how the tissue should be processed and which metabolic studies should be performed frequently needs to be made before the biopsy is obtained. Thus, a noninvasive method to initially characterize patients with potential metabolic disorders is useful. Exercise testing with expired gas analysis can indicate the presence of a metabolic myopathy and results can then be used to direct the appropriate biochemical evaluations.

Absorption of individual fatty acids from long chain or medium chain triglycerides in very small infants.

Using stool samples previously obtained for a nutritional balance study of very small infants, the intake, excretion, and percent absorption (%A) of individual fatty acids were quantitated by gas-liquid chromatography in two groups of patients; one receiving a formula providing fat as long chain triglycerides (LCT), the other providing 40% fat as medium chain triglyceride (MCT). The total fat intake for each group was 7.22 g/kg/day (MCT group), 6.02 g/kg/day (LCT group) and the absorption was 6.79 g/kg/day (MCT group) and 5.41 g/kg/day (LCT group). The %A of individual acids was comparable in both groups being greater than 99% for MCT and being lowest (62%) for C18:0 FA. As a consequence, infants in the MCT-fed group had a better total %A of fat, 95.2 vs 89.9% and absorbed more fat than the LCT group.

A rippling muscle disease gene is localized to 1q41: evidence for multiple genes.

Rippling muscle disease (RMD) is an inherited disorder of skeletal muscle in which mechanical stimuli provoke electrically silent contractions. Patient symptoms are muscle cramps, pain, and stiffness, particularly during or following exercise. Clinical signs are balling of muscle following percussion and a characteristic lateral rolling movement of muscle occurring after contraction followed by stretching. We report a new 44-member pedigree segregating RMD as an autosomal dominant trait. A genetic linkage study in this family, using a novel approach of testing closely spaced highly polymorphic markers in affected individuals, localized the responsible gene to the distal end of the long arm of chromosome 1 with a maximum multipoint lod score of 3.56 (theta = 0). In this family, RMD is localized to a 12-cM region near D1S235. We studied two previously reported German families for linkage to the same locus, and this same area did not cosegregate with the disease, a finding that shows that different genetic defects can cause a similar clinical phenotype (genetic heterogeneity). An understanding of the defect in contraction control within the muscle fibers in this disease may lead to a better understanding of muscle force transduction, intracellular calcium homeostasis, or both.

Juvenile multiple sclerosis-like episodes associated with a defect of mitochondrial beta oxidation.

We describe a young girl who presented with recurrent episodes of central nervous system (CNS) demyelination mimicking multiple sclerosis. Metabolic evaluations and decreased oxidation of [9,10(n)-3H] palmitate demonstrated defective mitochondrial beta oxidation, but complementation studies of the patient's cells, fused with cell lines with known defects of beta oxidation, failed to identify a known disorder. While progressive CNS demyelination has occurred in patients with defective peroxisomal very long-chain fatty acid oxidation, this is the 1st time it has occurred with defective mitochondrial beta oxidation. This patient appears to represent a novel disorder of beta oxidation producing intermittent demyelination with profound CNS symptoms. Recognition of the defect led to appropriate therapy, which caused marked clinical improvement.

Outcome of pyruvate dehydrogenase deficiency treated with ketogenic diets. Studies in patients with identical mutations.

Inborn errors of the pyruvate dehydrogenase complex (PDC) are associated with lactic acidosis, neuroanatomic defects, developmental delay, and early death. PDC deficiency is a clinically heterogeneous disorder, with most mutations located in the coding region of the X-linked alpha subunit of the first catalytic component, pyruvate dehydrogenase (E1). Treatment of E1 deficiency hs included cofactor replacement, activation of PDC with dichloroacetate, and ketogenic diets. In this report, we describe the outcome of ketogenic diet treatment in seven boys with E1 deficiency. These patients were divided into two groups based on their mutations (R349H, three patients; and R234G, four patients, two sibling pairs). All seven patients received ketogenic diets with varying degrees of carbohydrate restriction. Clinical outcome was compared within each group and between siblings as related to the intensity and duration of dietary intervention. Subjects who either had the diet initiated earlier in life or who were placed on greater carbohydrate restriction had increased longevity and improved mental development. Based on the improved outcomes of patients with identical mutations, it appears that a nearly carbohydrate-free diet initiated shortly after birth may be useful in the treatment of E1 deficiency.

Nutrient and mineral retention and vitamin D absorption in low-birth-weight infants: effect of medium-chain triglycerides.

A randomized prospective study of the effect of medium-chain triglycerides (MCT) upon the absorption and retention of major minerals and nutrients, as well as upon 25-hydroxy vitamin D levels, was performed in low-birth-weight infants. Ten infants received a high-calcium and vitamin D-containing formula, which contained 50% of its fat as MCT, while ten other infants received a similar formula in which all the fat was in long-chain triglycerides. There was a five-day delay in reaching full oral feeding volumes, and therefore there was a delay in the onset of the balance study in the MCT group, primarily due to gastrointestinal symptoms. There was a significant improvement in the percent of fat absorption (P less than .05) with MCT, but no difference in the percent of absorption or retention of calcium, phosphorus, sodium, or nitrogen. 25-Hydroxy vitamin D levels decreased in both groups after full oral feeding volumes had been established, but all values were within normal ranges. At the high intake levels of calcium and vitamin D given to the infants, MCT did not increase major mineral or nutrient absorption.

Amino acids as substrates in children with growth hormone deficiency and hypoglycemia.

In order to investigate the role of amino acid (AA) substrates in the hypoglycemia associated with human growth hormone (hGH) deficiency, we measured 12-hour fasting blood glucose and total quantitative AA concentrations in 11 children with hGH deficiency during three study periods: (1) before hGH replacement; (2) after 12 months of hGH treatment; and (3) after discontinuation of hGH for three months. The results were compared to studies in 16 control subjects. Fasting blood glucose concentrations were significantly (P less than .05) lower in the hGH-deficient children prior to hGH treatment as compared to the control subjects (67.0 +/- 5.3 vs 80.7 +/- 5.3 mg/100 ml, mean +/- SE). Fasting total serum AA concentrations were similar in the patients and in the control subjects; however, after 12 months of hGH replacement, there was a significant (P less than .01) elevation of serum AA (2,750 +/- 170 vs 2,283 micromoles/liter). Fasting serum concentrations of alanine, glycine, arginine, and tryptophan were also significantly elevated (P less than .01) with hGH treatment; ornithine, tyrosine, lysine, methionine, and phenylalanine showed lesser elevations (P less than 0.5), whereas threonine decreased significantly (P less than 0.01). The fasting hypoglycemia seen with isolated hGH deficiency is not an AA substrate-limited disorder. The finding of increased concentrations of AA with hGH replacement suggests increased retention of nitrogen and synthesis of AA for gluconeogenesis due to availability of other substrates.

Verbal dyspraxia in treated galactosemia.

Galactosemia is an inborn error of metabolism that causes life-threatening illness a few days after galactose-containing milk is fed to a newborn. Early treatment with a strict lactose-free diet results in rapid improvement, and, until recently, it was thought that the long-term prognosis in such infants was usually good. The speech characteristics of 24 patients treated for galactosemia were examined. Fifty-four percent had the specific speech disorder, verbal dyspraxia. This finding was not related to age at diagnosis, severity of symptoms in the newborn period, or to biochemical control. There may be, however, a relation between dyspraxia and diminished IQ scores observed in the group of patients with dyspraxia judged as "severe." The findings indicate the association of a specific and unusual speech defect with a specific and rare metabolic disorder.

Neonatal hypothyroidism detected by the Northwest Regional Screening Program.

The Northwest Regional Screening Program to detect congenital hypothyroidism in infants born in Oregon, Montana, Alaska, and Idaho (combined birthrate of 69,000/ yr) was added to our ongoing screening program in 1975. The program utilizes dried blood filter paper specimens collected routinely in the first few days of life in all four states and again at about 6 weeks of age in Oregon only. The screening test consist of an initial thyroxine (T4) measurement; a thyroid-stimulating hormore (TSH) determination is performed on those specimens with T4 concentrations in the lowest 3% group. Serum samples obtained by venipuncture are requested for confirmation of the diagnosis. In the first two years of the program, 25 infants with primary hypothyroidism were detected amont 110,667 infants screened, a frequency of 1:4,430. Fourteen cases of thyroxine-binding globulin deficiency were also detected, a frequency of 1:7,900. Using the T4 followed by TSH testing approach, the frequency of request for repeat specimens was 0.4% in Oregon and 0.05% in the other states. The cost per specimen was $1.96. The majority of infants lacked clinical signs or symptoms of hypothyroidism; only one infant was clinically suspected of having hypothyroidism prior to detection. The most common neonatal symptoms were constipation, lethargy, and prolonged jaundice, while the most common physical signs were hypotonia, umbilical hernia, and large fontanels. Thyroid scans showed the most common etiology to be thyroid aplasia, followed by an ectopic gland, hypoplasia, and goiter. Serum T4 concentrations were lowest in those infants with aplasia, intermediate in infants with an ectopic gland or hypoplasia, and normal in the infant with the goiter. Neonatal hypothyroidism varies in degree and has several different causes; the capacity to secrete thyroid hormone, the duration before hypothyroidism becomes clinically manifest, and possibly the eventual prognosis for intellectual function depend on the nature of the underlying cause. While the mean age at treatment was 59 days, the goal of diagnosing congenital hypothyroidism and treating affected infants by 1 month of age seems realistic.

Aland Island eye disease (Forsius-Eriksson ocular albinism) and an Xp21 deletion in a patient with Duchenne muscular dystrophy, glycerol kinase deficiency, and congenital adrenal hypoplasia.

Glycerol kinase deficiency (GKD) has been described in isolation and in complex phenotypes including either congenital adrenal hypoplasia, Duchenne muscular dystrophy, or both. Cytogenetic and molecular studies have localized these defects to a deletion involving the X chromosome at band Xp21, consistent with its X-linked recessive pattern of inheritance. Other clinical findings in the complex glycerol kinase deficiency (CGKD) patients are mental retardation, short stature, and hypogonadotropic hypogonadism. We report on a 6-year-old boy who, in addition to the CGKD phenotype described above, had ocular hypopigmentation consistent with Forsius-Eriksson ocular albinism, also known as type 2 ocular albinism or Aland Island eye disease. Cytogenetic analysis shows an interstitial deletion in the short arm of the X-chromosome at Xp21.

Magnetic resonance spectroscopy of normal and diseased muscles.

Phosphorus magnetic resonance spectroscopy (P MRS) affords and innovative approach to the study of the oxidative enzyme content of normal and diseased muscles. Examples of the evaluation of the enzyme content of normal muscles by an exercise protocol are provided. The protocol affords a hyperbolic work/cost profile, the Vmax of which is calculated by the reciprocal plots giving the enzyme content and the "effective Michaelis constant" with an evaluation of the resting metabolism. This steady state protocol clearly illustrates enzyme adaptation, on the one hand, and tissue atrophy particularly in the case of tissue injury, Duchenne's dystrophy, and genetic deletion of specific enzymes, on the other hand. The method is rapid, safe, and affords a quantitative evaluation of the disease process and possibilities for following appropriate therapies. So far, approx 1000 examinations of normal and diseased human limbs have been carried out in our laboratory in over the past four years.