Genotypic and phenotypic spectrum of cytosolic phosphoenolpyruvate carboxykinase deficiency.

OBJECTIVES: Pathogenic biallelic variants in PCK1 coding for the cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) cause PEPCK-C deficiency, a rare disorder of gluconeogenesis presenting with hypoglycemia, lactic acidosis, and hepatopathy. To date, there has been no systematic analysis of its phenotypic, biochemical, and genetic spectrum. METHODS: All currently published individuals and a novel patient with genetically confirmed PEPCK-C deficiency were included. Clinical, biochemical, and genetic findings were analyzed. Protein and in-silico prediction score modeling was applied to analyze potential variant effects. RESULTS: Thirty-two individuals from 25 families were found, including one previously unreported patient. The typical biochemical pattern was hypoglycemia triggered by catabolic situations, elevated urinary concentrations of tricarboxylic acid cycle metabolites, mildly elevated alanine and aspartate aminotransferase and elevated lactate concentrations in serum. Plasma glutamine concentrations were elevated in some patients and may be a suitable marker for newborn screening. With adequate treatment, biochemical abnormalities usually normalized following a hypoglycemic episode. Symptom onset usually occurred in infancy with a broad range from neonatal age to adulthood. Regardless of the genotype, different phenotypes with a broad clinical spectrum were found. To date, eight genotypes with nine different PCK1 variants were identified, of which alleles with the recurrent variant c.925G > A; p.(Gly309Arg) are predominant and appear to be endemic in the Finnish population. Protein modeling suggests altered manganese- and substrate-binding as superordinate pathomechanisms. CONCLUSIONS: Environmental factors appear to be the main determinant for the phenotype in patients with biallelic variants in PCK1. Based on the biochemical pattern, PEPCK-C deficiency is a recognizable cause of childhood hypoglycemia. It is a treatable disease and early diagnosis is important to prevent metabolic derailment and morbidity. Newborn screening can identify at least a sub-cohort of affected individuals through elevated glutamine concentrations in dry blood.

Ethanol-induced apoptotic neurodegeneration and fetal alcohol syndrome.

The deleterious effects of ethanol on the developing human brain are poorly understood. Here it is reported that ethanol, acting by a dual mechanism [blockade of N-methyl-D-aspartate (NMDA) glutamate receptors and excessive activation of GABA(A) receptors], triggers widespread apoptotic neurodegeneration in the developing rat forebrain. Vulnerability coincides with the period of synaptogenesis, which in humans extends from the sixth month of gestation to several years after birth. During this period, transient ethanol exposure can delete millions of neurons from the developing brain. This can explain the reduced brain mass and neurobehavioral disturbances associated with human fetal alcohol syndrome.

Aromatic L-amino acid decarboxylase deficiency: clinical features, drug therapy and follow-up.

BACKGROUND: Aromatic L-amino acid decarboxylase (AADC) deficiency is a disorder of biogenic amine metabolism resulting in generalized combined deficiency of serotonin, dopamine and catecholamines. Main clinical features are developmental delay, muscular hypotonia, dystonia, oculogyric crises and additional extraneurological symptoms. Response to therapy has been variable and unsatisfactory; the overall prognosis is guarded. METHODS: To gain more insight into this rare disorder we collected clinical and laboratory data of nine German patients. All patients were clinically examined by one investigator, and their responses to different drug regimes were evaluated by the patients' charts. RESULTS: Symptoms were obvious from early infancy. Later, main neurological features were truncal muscular hypotonia, hypokinesia, oculogyric crises and rigor. Three patients had single seizures. All patients presented distinct extraneurological symptoms, such as hypersalivation, hyperhidrosis, nasal congestion, sleep disturbances and hypoglycaemia. In CSF all patients revealed the pattern typical of AADC with decreased concentrations of homovanillic and 5-hydroxyindoleacetic acid and elevated concentration of 3-ortho-methyldopa. Diagnosis was confirmed by measurement of AADC activity in plasma in all patients. Drug regimes consisted of vitamin B6, dopamine agonists, MAO inhibitors and anticholinergics in different combinations. No patient achieved a complete recovery from neurological symptoms, but partial improvement of mobility and mood could be achieved in some. CONCLUSION: AADC deficiency is a severe neurometabolic disorder, characterized by muscular hypotonia, dystonia, oculogyric crises and additional extraneurological symptoms. Medical treatment is challenging, but a systematic trial of the different drugs is worthwhile.

Coenzyme Q(10) is decreased in fibroblasts of patients with methylmalonic aciduria but not in mevalonic aciduria.

The content of coenzyme Q(10) (CoQ(10)) was examined in skin fibroblasts of 10 patients with mevalonic aciduria (MVA) and of 22 patients with methylmalonic aciduria (MMA). Patients with these inborn errors of metabolism are thought to be at risk for CoQ(10) depletion either by direct inhibition of the proximal pathway of CoQ(10) synthesis (MVA) or indirectly by inhibition of mitochondrial energy metabolism (MMA). We demonstrated that CoQ(10) concentrations were not significantly different from controls in MVA patients, suggesting that there may be upregulatory effects. On the other hand the CoQ(10) content in fibroblasts of patients with MMA was significantly reduced.

Prediction of outcome in isolated methylmalonic acidurias: combined use of clinical and biochemical parameters.

Objectives Isolated methylmalonic acidurias (MMAurias) are caused by deficiency of methylmalonyl-CoA mutase or by defects in the synthesis of its cofactor 5'-deoxyadenosylcobalamin. The aim of this study was to evaluate which parameters best predicted the long-term outcome. Methods Standardized questionnaires were sent to 20 European metabolic centres asking for age at diagnosis, birth decade, diagnostic work-up, cobalamin responsiveness, enzymatic subgroup (mut(0), mut(-), cblA, cblB) and different aspects of long-term outcome. Results 273 patients were included. Neonatal onset of the disease was associated with increased mortality rate, high frequency of developmental delay, and severe handicap. Cobalamin non-responsive patients with neonatal onset born in the 1970s and 1980s had a particularly poor outcome. A more favourable outcome was found in patients with late onset of symptoms, especially when cobalamin responsive or classified as mut(-). Prevention of neonatal crises in pre-symptomatically diagnosed newborns was identified as a protective factor concerning handicap. Chronic renal failure manifested earlier in mut(0) patients than in other enzymatic subgroups. Conclusion Outcome in MMAurias is best predicted by the enzymatic subgroup, cobalamin responsiveness, age at onset and birth decade. The prognosis is still unfavourable in patients with neonatal metabolic crises and non-responsiveness to cobalamin, in particular mut(0) patients.

Looking beyond the basal ganglia: the spectrum of MRI changes in methylmalonic acidaemia.

We report imaging abnormalities from 5 brain MR examinations in 4 children with methylmalonic acidaemia between the ages of 20 days and 31 months. In addition to bilateral basal ganglia lesions (pallidum) observed in 3 of 4 children, we found signs of delayed brain maturation (myelination delay, immature gyral pattern, incomplete opercularization) in all children and signs of a white matter disorder in the 3 older children. Unexpectedly, brainstem and cerebellar changes were present in all children. Reviewing the brain imaging changes reported for methylmalonic acidaemia, we discuss the findings and patterns observed in our patients. We postulate that delayed myelination and signs of a white matter disorder as well as brainstem and cerebellar involvement are common findings and may be due to a chronic neurotoxic effect on the developing and ageing brain.

Neurodegeneration and chronic renal failure in methylmalonic aciduria--a pathophysiological approach.

In the last decades the survival of patients with methylmalonic aciduria has been improved. However, the overall outcome of affected patients remains disappointing. The disease course is often complicated by acute life-threatening metabolic crises, which can result in multiple organ failure or even death, resembling primary defects of mitochondrial energy metabolism. Biochemical abnormalities during metabolic derangement, such as metabolic acidosis, ketonaemia/ketonuria, lactic acidosis, hypoglycaemia and hyperammonaemia, suggest mitochondrial dysfunction. In addition, long-term complications such as chronic renal failure and neurological disease are frequently found. Neuropathophysiological studies have focused on various effects caused by accumulation of putatively toxic organic acids, the so-called 'toxic metabolite' hypothesis. In previous studies, methylmalonate (MMA) has been considered as the major neurotoxin in methylmalonic aciduria, whereas more recent studies have highlighted a synergistic inhibition of mitochondrial energy metabolism (pyruvate dehydrogenase complex, tricarboxylic acid cycle, respiratory chain, mitochondrial salvage pathway of deoxyribonucleoside triphosphate (dNTP)) induced by propionyl-CoA, 2-methylcitrate and MMA as the key pathomechanism of inherited disorders of propionate metabolism. Intracerebral accumulation of toxic metabolites ('trapping' hypothesis') is considered a biochemical risk factor for neurodegeneration. Secondary effects of mitochondrial dysfunction, such as oxidative stress and impaired mtDNA homeostasis, contribute to pathogenesis of these disorders. The underlying pathomechanisms of chronic renal insufficiency in methylmalonic acidurias are not yet understood. We hypothesize that renal and cerebral pathomechanisms share some similarities, such as an involvement of dicarboxylic acid transport. This review aims to give a comprehensive overview on recent pathomechanistic concepts for methylmalonic acidurias.

Diagnostic work-up and management of patients with isolated methylmalonic acidurias in European metabolic centres.

The long-term outcome of patients with methylmalonic aciduria (MMA) is still uncertain due to a high frequency of complications such as chronic renal failure and metabolic stroke. The understanding of this disease is hampered by a huge variation in the management of these patients. The major aim of this study was to evaluate the current practice in different European metabolic centres. A standardized questionnaire was sent to 20 metabolic centres asking for standard procedures for confirmation of diagnosis, testing cobalamin responsiveness, dietary treatment, pharmacotherapy, and biochemical and clinical monitoring. Sixteen of 20 metabolic centres (80%) returned questionnaires on 183 patients: 89 of the patients were classified as mut(0), 36 as mut(-), 13 as cblA, 7 as cblB, and 38 as cblA/B. (1) Confirmation of diagnosis: All centres investigate enzyme activity by propionate fixation in fibroblasts; six centres also perform mutation analysis. (2) Cobalamin response: Ten centres follow standardized protocols showing large variations. A reliable exclusion of nonspecific effects has not yet been achieved by these protocols. (3) Long-term treatment: In cobalamin-responsive patients, most centres use hydroxocobalamin (1-14 mg/week i.m. or 5-20 mg/week orally), while two centres use cyanocobalamin. All cobalamin-nonresponsive patients and most cobalamin-responsive patients are supplemented with L: -carnitine (50-100 mg/kg per day). Fourteen centres use intestinal decontamination by antibiotic therapy. Most centres follow D-A-CH (n = 6) or Dewey (n = 4) recommendations for protein requirements. Fourteen centres regularly use precursor-free amino acid supplements. Standardized monitoring protocols are available in seven centres, again showing high variability.

Age-related decreases in the thyrotropin (TSH) responsiveness to thyrotropin-releasing-hormone (TRH) stimulation and to the inhibitory effect of triiodothyronine (T3); in vitro study on superfused rat pituitaries.

The effect of age on the thyrotropic function was investigated in vitro by superfusing pituitary fragments obtained from 2-3-month- and 24-month-old male Wistar rats with medium 199 (GIBCO) and by measuring basal TSH secretion and TSH response to a 6-min pulse of TRH (10 nM): a/ in the absence and b/ in the presence of T3 (100 nM). TSH was measured by RIA in 3-min fractions with rat TSH materials from the NIADDK. The TRH-induced TSH release elicited by pituitary fragments from the old rats was decreased in comparison to that found in young animals. Addition of T3 to the superfusion medium did not alter basal TSH release but significantly decreased the TSH secretory response to TRH in the young rats. This response was not modified in the old animals. Our results suggest that aging induces not only a TSH hyporesponsiveness to TRH stimulation but also a decrease of this responsiveness to the inhibitory effect of T3 which could be related to a decreased TSH synthesis and to an age-related impairment of T3 action on the thyrotrophs.

Serum thyroglobulin in hospitalized chronic geriatric patients: its relationship to age, non-thyroidal illness, goitre and thyroid dysfunction in a follow-up study.

The objectives were to determine whether the serum thyroglobulin (TG) level is influenced by age or by non-thyroidal illness (NTI) of the aged, to investigate the constancy of the TG level after 1- and 2-month intervals and to investigate if the TG level could help to differentiate whether a subnormal thyrotrophin (TSH) level in a geriatric patient is caused by autonomous thyroid function, by age or by NTI. Two-hundred and twenty-six non-selected, chronic hospitalized patients over 60 years old and 82 healthy adults (20-40 years) participated in the study, and TSH, thyroxine, free thyroxine, triiodothyronine and TG were estimated. In 122 euthyroid geriatric patients with normal TSH the mean TG was normal (12.18 micrograms/l), but elevated (> 45 micrograms/l) TG values occurred more often than in healthy control persons (15/122 vs 3/82; chi 2(1) = 4.54, p = 0.03). The severity of the clinical state of the euthyroid patients had no influence on the TG values. If TG was measured after 1 and/or 2 months, in only 3/123 non-selected geriatric patients was there a fluctuation between the normal and abnormal range (versus fluctuation of the corresponding TSH values in 19/123 cases; chi 2(1) = 12.78, p = 0.0012). In 28 patients with subnormal TSH, a normal TG value had a predictive value of 0.6 to exclude autonomous thyroid function. Age and NTI of the geriatric patients have no significant influence on their mean TG level but high TG levels occur more often, even in euthyroid patients. The predictive value of TG is not sufficiently high to allow a clear differentiation of whether a subnormal TSH is caused by autonomous thyroid function or by the age process or by NTI. Nevertheless, the advantage of TG estimation to be more constant than TSH could be of benefit in screening studies.

Thyroid autoantibodies in hospitalized chronic geriatric patients: prevalence, effects of age, nonthyroidal clinical state, and thyroid function.

OBJECTIVE: To investigate the effect of age, clinical condition, and thyroid function on the prevalence of thyroid autoantibody positivity in hospitalized chronic geriatric patients. DESIGN: A screening study of hospitalized chronic geriatric patients. PARTICIPANTS: 249 non-selected, hospitalized, chronic geriatric patients more than 60 years of age and 81 20 to 40-year-old healthy persons. MEASUREMENTS: Thyrotropin (TSH); thyroxine (T4) and free thyroxine (FT4); and triiodothyronine (T3), thyroglobulin (Tg), antibodies against thyroid peroxidase (AbTPO) and antibodies against thyroglobulin (AbTg) estimation in a screening study. RESULTS: AbTPO positivity (AbTPO+) was found more often than AbTg positivity (AbTg+) (15.3% vs 9.2%, P = .04), one being positive (Ab+) in 19.3%. The occurrence was higher in females than males (Ab+:27.1% vs 7.1%, P < .001; AbTPO+:21.9% vs 5.1%, P < .001; AbTg+:13.2% vs 3.1%, P = .0052). Among the Ab+ patients, AbTPO was more often positive than AbTg (40/48 vs 21/48, P < .001). The sensitivity, specificity, and positive predictive value of Ab positivity to detect a thyroid disorder were 0.35, 0.85 and 0.38, respectively. Within the population of euthyroid geriatric patients, the occurrence of AbTg+ (chi 2(2) = 8.65, P = .013) and Ab+ (chi 2(2) = 8.02, P = .018) correlated positively with the age of the patients, and there was also a female predominance (AbTPO+ 18% vs 3.7% in the males; AbTg+ 13% vs 2.4%; Ab+ 25.8% vs 6.1%). When compared with 20 to 40-year-old subjects, only the euthyroid > or = 80-year-old patients showed a significantly higher occurrence of Ab+ (26.2% vs 9.9% chi 2(1) = 5.64, P = .017). In the euthyroid > or = 80-year-old females, AbTPO+ was 25%, AbTg:22.2%, and Ab+: 36.1%!. The nonthyroidal clinical state of the euthyroid patients did not correlate with the antibody prevalence. CONCLUSIONS: In hospitalized chronic geriatric patients, AbTg and especially AbTPO positivity is frequent, even in euthyroid patients without goiter. This aspecific Ab positivity in the euthyroid state correlates to the age, but not to the severity of the nonthyroidal clinical condition of the patients and explains why the Ab positivity is not predictive enough for thyroid dysfunction in this subpopulation. Thus, in hospitalized chronic geriatric patients the AbTg and AbTPO titers should be examined only in cases where thyroid screening (TSH) reveals abnormal results.

Follow up of thyroid hormone parameters in chronically ill geriatric patients: screening for thyroid disorders at hospital admission justified.

UNLABELLED: The objective of this study was to investigate if screening of chronically ill geriatric patients for thyroid dysfunction is justified just upon hospital admission. TSH was measured in 124 patients at hospital admission and 11-86 (Median 37) days afterwards. FT4 was measured in cases with subnormal, suppressed or elevated TSH (43 cases). Out of 81 patients with normal (0.5-3.6 mU/l) TSH, the control value was subnormal (0.1-<0.5 mU/l) in 6 and elevated (>3.6 mU/l) in one case, but in none of the patients became suppressed (<0.1 mU/l). In 13/30 patients with subnormal TSH the control value was normal but in none of the patients suppressed or elevated. On the contrary, all cases with suppressed (N=9) or elevated (N=4) TSH remained in the same ranges at follow up. Low (<13 pmol/l, N=3) or elevated (>27 pmol/l, N=5) initial FT4 levels did not change in the follow up as well. Out of 35 patients with normal FT4, one became low and another elevated. Improvement or worsening of the clinical state in the follow up did not correlate to changes of TSH. The prevalence of unsuspected thyroid dysfunctions were 11.3% (hyperthyroidism clinical: 4, subclinical: 5, hypothyroidism clinical: 3, subclinical: 2 cases). All cases except one with subclinical hypothyroidism were detected by the initial screening. Only one patient with clinical hyperthyroidism was initial misinterpreted as having subclinical disease. CONCLUSIONS: In chronically ill geriatric patients investigated at hospital admission, a measurable TSH practically excludes hyperthyroidism in the follow up. Suppressed TSH levels remain suppressed but subnormal levels should be controlled because their normalization frequently occur in the follow up. Screening upon hospital admission is sensitive enough to detect cases of thyroid dysfunction and justified by their high prevalence.

[Prognosis and life expectancy in patients with hyperthyroidism]. / Prognose und Lebenserwartung bei Hyperthyreosen.

The term "hyperthyroidism" comprises several different diseases of which two have to be distinguished particularly: 1. hyperthyroidism with Graves' disease: the immunopathogenesis of Graves' disease allows a symptomatic therapy only; therefore its prognosis is not as good as for the 2. autonomous hyperthyroidism ("toxic goiter"), which can be cured definitely by operation or radioiodine therapy. Both diseases may aggravate under iatrogenic iodine exposure (iodine-containing drugs or X-ray contrast media) to a thyroid storm; this most severe kind of hyperthyroidism still leads to death in almost 40% of the patients.

[Results of fractionated radioiodine therapy in 696 patients with hyperthyroidism and 690 patients with non-toxic goiter]. / Ergebnisse der fraktionierten Radiojodtherapie bei 696 Hyperthyreosen und 690 blanden Strumen.

During the course of twenty years 696 patients with hyperthyroidism and 690 cases of non-toxic goitre were treated with 131I in fractionated activities and controlled on an average 4,4 (1-18) years later. Treatment strategy included three special features: a. the first and any further activity amounted to not more than 1.85 MBq per g estimated thyroid weight; b. each therapeutic activity was accompanied by oral prednisone or prednisolone for 2-6 weeks; and c. after completion of radiotherapy each patient was put on thyroid medication which was not interrupted for purposes of control. Therefore, the rate of post-irradiation hypothyroidism could not be determined. All patients were found to be permanently euthyroid and none of the former hyperthyroid patients had relapsed. 84% of the hyperthyroid goitres and 78% of the non-toxic goitres had disappeared completely, 14% and 21%, respectively, were markedly reduced. Complete disappearance of the goitre was achieved with the first 131I activity in 35% of the patients with hyperthyroidism and in 48% of the non-toxic goitres, whereas 34% of the first and 35% of the second group required a second activity; the rest received three or more activities. The mean total activities of 131I necessary for complete reduction of the goitres depended on their size and amounted to 292, 507 and 1136 MBq, respectively, in euthyroid goitres with sizes, I, II and III. The corresponding figures in hyperthyroid goitres were 403, 577 and 1129 MBq, respectively. 314 patients had endocrine ophthalmopathy which was cured in 54% and significantly improved in 37%.

[Subtotal thyroidectomy as a superior therapeutic principle in the treatment of endocrine ophthalmopathy: a comparison with retrobulbar irradiation and thyrostatic therapy alone]. / Subtotale Thyreoidektomie als überlegenes Therapieprinzip bei der Behandlung der endokrinen Ophthalmopathie: Ein Vergleich mit Retrobulbärbestrahlung bzw. alleiniger thyreostatischer Therapie.

In order to investigate the influence of near total thyroidectomy on the course of endocrine ophthalmopathy (E.O.) in patients with Graves' disease, 29 patients with goitre and E.O. were classified before and after (up to 18 months) operation by use of a special ophthalmopathy index. 14 patients without goitre served as controls; they get only antithyroid drug treatment (ADT) (E.O. I and II, n = 7) or additional retoorbital irradiation (E.O. III and IV, n = 7, linear accelerator, 20 Gray). 20 out of 29 operated patients showed an improvement in the E.O., 4 a deterioration, 5 were unchanged. 3 out of 7 not operated patients with mild E.O. showed an amelioration during ADT, 4 no change. Additional radiotherapy in 7 patients with severe E.O. caused an improvement in the clinical condition of 3 patients, 3 patients deteriorated and 1 patient showed no change. It is concluded that adequate near total thyroidectomy has a positive effect on the clinical course of E.O. in patients with Graves' disease and E.O.

Moderate weight reduction in an outpatient obesity intervention program significantly reduces insulin resistance and risk factors for cardiovascular disease in severely obese adolescents.

Background. Metabolic risk factors like insulin resistance and dyslipidemia are frequently observed in severly obese children. We investigated the hypothesis that moderate weight reduction by a low-threshold intervention is already able to reduce insulin resistance and cardiovascular risk factors in severely obese children. Methods. A group of 58 severely obese children and adolescents between 8 and 17 years participating in a six-month-long outpatient program was studied before and after treatment. The program included behavioral treatment, dietary education and specific physical training. Metabolic parameters were measured in the fasting state, insulin resistance was evaluated in an oral glucose tolerance test. Results. Mean standard deviation score of the body mass index (SDS-BMI) in the study group dropped significantly from +2.5 ± 0.5 to 2.3 ± 0.6 (P < 0.0001) after participation in the program. A significant decrease was observed in HOMA (6.3 ± 4.2 versus 4.9 ± 2.4, P < 0.03, and in peak insulin levels (232.7 ± 132.4 versus 179.2 ± 73.3 µU/mL, P < 0.006). Significant reductions were also observed in mean levels of hemoglobin A(1c), total cholesterol and LDL cholesterol. Conclusions. These data demonstrate that already moderate weight reduction is able to decrease insulin resistance and dyslipidemia in severely obese children and adolescents.