A patient with a rare metabolic disease and myo-inositol administration leading to a new treatment for epilepsy.
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Congenital disorders of glycosylation↗
Biomedical subjects
Gerard T Berry
Publications and source records attributed to Gerard T Berry.
Liver transplantation is not curative for methylmalonic acidopathy caused by methylmalonyl-CoA mutase deficiency.
Methylmalonic acidopathy resulting from severe methylmalonyl-CoA mutase deficiency causes acute, potentially lethal ketoacidotic episodes, renal failure, and acute and chronic neurologic disease. As dietary and alkali therapy is suboptimal, liver transplantation during infancy has been touted as a potential cure. However, reports in liver transplant recipients about new onset neurologic disease, in the absence of ketoacidosis, and progressive renal insufficiency have cast doubt about its effectiveness. We report the long-term (9 years) outcome for the first patient with severe methylmalonic acidopathy transplanted in the USA and provide new biochemical data that indicate why transplanted patients are still susceptible to "metabolic strokes". In our 10-year-old male patient, there is clear evidence that the de novo synthesis of propionyl-CoA within the CNS leads to brain methylmalonate (MMA) accumulation that is largely unaffected by transplantation. Liver replacement is not a cure for methylmalonic acidopathy.
Amino Acid Metabolism, Inborn Errors↗
SMIT1 haploinsufficiency causes brain inositol deficiency without affecting lithium-sensitive behavior.
Two leading hypotheses to explain lithium action in bipolar disorder propose either inositol depletion or inhibition of GSK-3 as mechanisms of action. Behavioral effects of lithium are mimicked in Gsk-3beta+/- mice, but the contribution of inositol depletion to these behaviors has not been tested. According to the inositol depletion hypothesis, lithium-sensitive behavior is secondary to impaired phosphatidylinositol synthesis caused by inositol deficiency. By disrupting the sodium myo-inositol transporter1 gene, SMIT1, we show that depletion of brain myo-inositol in SMIT1+/- mice has no effect on lithium-sensitive behavior. These findings, taken together with our previous work showing that SMIT-/- mice have an even greater depletion of inositol in brain with no reduction in phosphatidylinositol levels, are difficult to reconcile with the current formulation of the inositol depletion hypothesis.
Animals↗
Epimerase-deficiency galactosemia is not a binary condition.
Epimerase-deficiency galactosemia results from the impairment of UDP-galactose 4'-epimerase (GALE), the third enzyme in the Leloir pathway of galactose metabolism. Originally identified as a clinically benign "peripheral" condition with enzyme impairment restricted to circulating blood cells, GALE deficiency was later demonstrated also to exist in a rare but clinically severe "generalized" form, with enzyme impairment affecting a range of tissues. Isolated cases of clinically and/or biochemically intermediate cases of epimerase deficiency have also been reported. We report here studies of 10 patients who, in the neonatal period, received the diagnosis of hemolysate epimerase deficiency. We have characterized these patients with regard to three parameters: (1) GALE activity in transformed lymphoblasts, representing a "nonperipheral" tissue, (2) metabolic sensitivity of those lymphoblasts to galactose challenge in culture, and (3) evidence of normal versus abnormal galactose metabolism in the patients themselves. Our results demonstrate two important points. First, whereas some of the patients studied exhibited near-normal levels of GALE activity in lymphoblasts, consistent with a diagnosis of peripheral epimerase deficiency, many did not. We detected a spectrum of GALE activity levels ranging from 15%-64% of control levels, demonstrating that epimerase deficiency is not a binary condition; it is a continuum disorder. Second, lymphoblasts demonstrating the most severe reduction in GALE activity also demonstrated abnormal metabolite levels in the presence of external galactose and, in some cases, also in the absence of galactose. These abnormalities included elevated galactose-1P, elevated UDP-galactose, and deficient UDP-glucose. Moreover, some of the patients themselves also demonstrated metabolic abnormalities, both on and off galactose-restricted diet. Long-term follow-up studies of these and other patients will be required to elucidate the clinical significance of these biochemical abnormalities and the potential impact of dietary intervention on outcome.
Base Sequence↗
Elements of diabetic nephropathy in a patient with GLUT 2 deficiency.
The Fanconi-Bickel syndrome is caused by homozygosity or compound heterozygosity for mutations of the facilitated glucose transporter 2 gene (GLUT2). Glycogen accumulates in renal tubular cells and they fail to reabsorb multiple filtered solutes because of impairment in GLUT2-mediated efflux of glucose. We describe a 10-year-old male child with GLUT2 deficiency who produced massive amounts of 3-deoxyfructose (3-DF) in the kidneys. Since 3-DF is a detoxification product of a potent glycating agent, 3-deoxyglucosone, a precursor of advanced glycation end-products, this suggests a massive accumulation of glucose within tubular cells probably as a consequence of GLUT2 deficiency. The level of 3-DF in the urine of this atypical patient, who also manifested renal glomerular hyperfiltration, microalbuminuria, and glomerular mesangial expansion, was higher than in any patient examined with diabetes mellitus. Elevated levels of glucose and/or its metabolites in renal tubular cells may be necessary but not sufficient for the development of both the renal tubulopathy and diabetic-like glomerular disease in GLUT2 deficiency.
Adult↗
The rate of de novo galactose synthesis in patients with galactose-1-phosphate uridyltransferase deficiency.
Using both a continuous infusion of isotopically labeled [1-13C]galactose with a steady-state analysis and a single injection kinetic approach, we have calculated the apparent galactose appearance rate (GAR) in patients with galactose-1-phosphate uridyltransferase deficiency and control subjects. With the steady-state protocol, the GAR in 18 patients less than 18 years of age was 1.34+/-0.53 mg/kg/h (mean+/-SD) and was significantly greater than the mean of 0.56+/-0.01 mg/kg/h (p=0.004) in five patients above 18 years of age. Patients who were given a priming dose of [1-13C]galactose had a reduced GAR compared to those without a priming dose, 0.73+/-0.05 (n=9) vs 1.46+/-0.62 (n=14)mg/kg/h (p=0.005). The GAR in controls was lower than in patients ranging from 0.58 to 0.68 mg/kg/h in children and 0.07-0.09 mg/kg/h in adults. In the single bolus studies the plasma [13C]galactose enrichment decreased in a biexponential pattern suggesting at least a two-compartment system. The calculated GAR in three adult patients was similar to that found in them by the continuous infusion technique. The GAR in patients suggests the source of galactose for the continued elevation of galactose metabolites as well as the basis for the long-term complications in galactosemia despite restricted dietary galactose intake.
Adolescent↗
Phosphoinositide deficiency due to inositol depletion is not a mechanism of lithium action in brain.
The "inositol depletion hypothesis" has been widely held to be the explanation for both the effect of lithium on brain function, apropos of its use in mood disorders, and on the impairment of development and induction of embryonic malformations in diverse organisms. The essence of the hypothesis is that a deficiency in cellular myo-inositol (Ins), secondary to lithium inhibition of inositol monophosphatase and/or multiple inositol polyphosphate phosphatase activities with trapping of Ins as inositol phosphates, leads to a depression of phosphatidylinositol (PtdIns) and a secondary impairment in inositide signaling. However, the ability of relatively low micromolar levels of Ins to reduce mammalian PtdIns synthetase activity in vivo has never been adequately tested. We have generated a lethal murine brain Ins deficiency model and measured PtdIns content using a novel MALDI-TOF MS method. Our results show that in the most severe Ins deficiency ever recorded in a mammal, the brain PtdIns levels do not decrease. We conclude that PtdIns deficiency due to "inositol depletion" is not a mechanism of lithium action in brain, and that Ins plays another unidentified role in the mammalian brain.
Animals↗
Extended [13C]galactose oxidation studies in patients with galactosemia.
Since patients with galactose-1-phosphate uridyltransferase (GALT) deficiency have considerable endogenous galactose formation and only limited urinary excretion of galactose metabolites, there must be mechanisms for disposal of the sugar. Otherwise, a steady-state could not be maintained and there would be continuous body accumulation of galactose and alternate pathway products. Previous studies quantitating the amount of galactose handled by oxidation to CO2 focused on short collection periods of expired air after administering isotopically labeled galactose mainly designed for discerning differences in the capacity to oxidize the sugar in relation to genotype. Assuming that there may be more extensive oxidation than that observed in short-term studies in order to dispose the daily galactose burden, we have examined the amount of [1-13C]galactose oxidized to 13CO2 over a 24-h period after either a single bolus or continuous IV administration by 11 patients with classic galactosemia including patients homozygous for the Q188R gene mutation. As much as 58% of the administered galactose was oxidized to 13CO2 in 24 h. The pathways involved remain to be determined but a significant amount may be metabolized by non-GALT pathways since a patient homozygous for gene deletion had an oxidative capability. We conclude that classic patients have the ability to slowly oxidize galactose to CO2 in 24 h in amounts comparable to that which a normal handles in approximately one-fifth the time. This capacity enables the galactosemic to maintain a balance of galactose disposal with the galactose burden imposed by endogenous formation and dietary intake.
Adolescent↗
MR diffusion imaging and MR spectroscopy of maple syrup urine disease during acute metabolic decompensation.
Maple syrup urine disease (MSUD) is an inborn error of amino acid metabolism, which affects the brain tissue resulting in impairment or death if untreated. Imaging studies have shown reversible brain edema during acute metabolic decompensation. The purpose of this paper is to describe the diffusion-weighted imaging (DWI) and spectroscopy findings during metabolic decompensation and to assess the value of these findings in the prediction of patient outcome. Six patients with the diagnosis of MSUD underwent conventional MR imaging with DWI during acute presentation with metabolic decompensation. Spectroscopy with long TE was performed in four of the six patients. Follow-up examinations were performed after clinical and metabolic recovery. DWI demonstrated marked restriction of proton diffusion compatible with cytotoxic or intramyelinic sheath edema in the brainstem, basal ganglia, thalami, cerebellar and periventricular white matter and the cerebral cortex. This was accompanied by the presence of an abnormal branched-chain amino acids (BCAA) and branched-chain alpha-keto acids (BCKA) peak at 0.9 ppm as well as elevated lactate on proton spectroscopy in all four patients. The changes in all six patients were reversed with treatment without evidence of volume loss or persistent tissue damage. The presence of cytotoxic or intramyelinic edema as evidenced by restricted water diffusion on DWI, with the presence of lactate on spectroscopy, could imply imminent cell death. However, in the context of metabolic decompensation in MSUD, it appears that changes in cell osmolarity and metabolism can reverse completely after metabolic correction.
3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
Loss of murine Na+/myo-inositol cotransporter leads to brain myo-inositol depletion and central apnea.
myo-Inositol (Ins) and its polyphosphoinositide derivatives that are important in membrane signaling have long been held to play a special role in brain metabolism. As polyphosphoinositides turn over rapidly and are exceptionally abundant in nervous tissue, high Ins levels in the range of 2-15 mm that have been observed in brain may be necessary to maintain the rates of phosphoinositide synthesis in diverse membrane locations within neurons. Cellular concentration gradients of this magnitude indicate a dependence on active Ins transport, especially at the time of growth and differentiation. The Na(+)/myo-inositol cotransporter (SMIT1 or SLC5A3) gene is highly expressed prenatally in the central nervous system and placenta. To gain more insight into brain Ins metabolism, while ascertaining the importance of SMIT1 as a transporter, we generated mice with a homozygous targeted deletion of this gene. Newborn SMIT1(-/-) animals have no evidence of SMIT1 mRNA, a 92% reduction in the level of brain Ins, an 84% reduction in whole body Ins, and expire shortly after birth due to hypoventilation. Gross pathologic and light microscopic examinations of each organ, as well as the placenta, of embryonic day 18.5 fetuses at near term gestation were normal. Based on [(3)H]acetate incorporation into phospholipids of lung tissue explants, immunostaining of lung tissue for surfactant protein A, B, and C, and electron microscopic examination of alveolar cells, there was no evidence of abnormal pulmonary surfactant production by type 2 pneumocytes in lung. Although no histologic lesions were detected in the nervous system, electrophysiological studies of the brainstem pre-Bötzinger respiratory control center demonstrated an abnormal rhythm discharge with periods of central apnea. The cause of death can be explained by the regulatory defect in brainstem control of ventilation. This model demonstrates the critical importance of SMIT1 in the developing nervous system. The high affinity SMIT1 transporter is responsible for the Ins concentration gradient in the murine fetal-placental unit.
Alleles↗
Newborn screening by tandem mass spectrometry for medium-chain Acyl-CoA dehydrogenase deficiency: a cost-effectiveness analysis.
OBJECTIVE: To determine whether newborn screening by tandem mass spectrometry (MS/MS) for medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is cost-effective versus not screening and to define the contributions of disease, test, and population parameters on the decision. METHODS: A decision-analytic Markov model was designed to perform cost-effectiveness and cost-utility analyses measuring the discounted, incremental cost per life-year saved and per quality-adjusted life-year saved of newborn screening for MCADD compared with not screening. A hypothetical cohort of neonates made transitions among a set of health states that reflected clinical status, morbidity, and cost. Outcomes were estimated for time horizons of 20 and 70 years. Probabilities and costs were derived from a retrospective chart review of a 32-patient cohort treated over the past 30 years at the Children's Hospital of Philadelphia, clinical experience with MCADD patient management, patient-family interviews, cost surveys, state sources, and published studies. In addition to older patients who came to medical attention by symptomatic presentation, our patient group included 6 individuals whose MCADD had been diagnosed by supplemental newborn screening. Estimates of the expected net changes in costs and life expectancy for MCADD screening were used to compute the incremental cost-effectiveness ratios. Sensitivity analyses were performed on key input variables, and 95% confidence intervals (CIs) were computed through second-order Monte Carlo simulations. RESULTS: In our base-case analysis over the first 20 years of life, the cost of newborn screening for MCADD was approximately 11,000 dollars(2001 US dollars; 95% CI: <0-33,800 dollars) per life-year saved, or 5600 dollars (95% CI: <0-17,100 dollars) per quality-adjusted life-year saved compared with not screening. Over a 70-year horizon, the respective ratios were approximately 300 dollars (95% CI: <0-13,000 dollars) and 100 dollars (95% CI: <0-6900 dollars). The results were robust when tested over plausible ranges for diagnostic test sensitivity and specificity, MCADD prevalence, asymptomatic rate, and screening cost. CONCLUSIONS: Simulation modeling indicates that newborn screening for MCADD reduces morbidity and mortality at an incremental cost below the range for accepted health care interventions. At the 70-year horizon, the model predicts that almost all of the additional costs of screening would be offset by avoided sequelae.
Acyl-CoA Dehydrogenase↗
In vivo pyruvate detected by MR spectroscopy in neonatal pyruvate dehydrogenase deficiency.
We present a unique finding of an elevated level of pyruvate at 2.37 ppm revealed by in vivo MR spectroscopy of a female neonate. Low fibroblast pyruvate dehydrogenase (PDH) complex activity subsequently confirmed a diagnosis of PDH deficiency. Abnormalities of brain development consistent with PDH deficiency were also evident on fetal and postnatal MR images. To our knowledge, this is the first report of pyruvate being shown in vivo in a child and the first report of MR spectroscopy aiding in the diagnosis of inborn error in pyruvate metabolism before confirmation by conventional enzymatic testing. This finding has potential implications for earlier diagnosis in patients with defects in mitochondrial metabolism.
Abnormalities, Multiple↗
Biliary atresia associated with a fatty acid oxidation defect.
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3-Hydroxyacyl CoA Dehydrogenases↗
The mutation spectrum of the facilitative glucose transporter gene SLC2A2 (GLUT2) in patients with Fanconi-Bickel syndrome.
We report a total of 23 novel mutations of the SLC2A2 ( GLUT2) gene in 49 patients with a clinical diagnosis of Fanconi-Bickel syndrome (FBS). Molecular genetic analysis has now been performed in more than 50% of the 109 FBS cases from 88 families that we have been able to locate world-wide since the original report in 1949. In these 49 patients, 33 different SLC2A2 mutations (9 missense, 7 nonsense, 10 frameshift, 7 splice-site) have been detected. Thus, our results confirm that mutations of SLC2A2 are the basic defect in patients with FBS. Mutations of SLC2A2 were detected in historical FBS patients in whom some of the characteristic clinical features (hepatorenal glycogen accumulation, glucose and galactose intolerance, fasting hypoglycemia, a characteristic tubular nephropathy) and the effect of therapy were described for the first time. Mutations were also found in patients with atypical clinical signs such as intestinal malabsorption, failure to thrive, the absence of hepatomegaly, or renal hyperfiltration. No single prevalent SLC2A2 mutation was responsible for a significant number of cases. In a high percentage (74%) of FBS patients, the mutation is homozygous, so we conclude that the prevalence of SLC2A2 mutations is relatively low in most populations. No mutational hot spots within SLC2A2 or even within homologous sequences among the genes for facilitative glucose transporters were detected.
Alternative Splicing↗