Search PubMed⌕ Search

Biomedical subjects

H Pihko

Publications and source records attributed to H Pihko.

At least 37 records · Page 2Linked to original sources
PubMed1998

Pregnancy complications are frequent in long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency.

OBJECTIVE: Preeclampsia-related complications of pregnancy have been detected in carriers of long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency, a recently discovered disorder of mitochondrial fatty acid oxidation. Because no comprehensive study is available, we studied the frequency of pregnancy complications in mothers who had given birth to children with this disorder. STUDY DESIGN: Data of all pregnancies of 18 mothers to 28 diagnosed patients with long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency were reviewed retrospectively. From a total 79 pregnancies 16 early abortions were excluded; 63 pregnancies were included, and the fetus was affected in 29. RESULTS: One child born prematurely died neonatally but none of the mothers died. Preeclampsia, the syndrome of hemolysis, elevated liver enzymes, and low platelets, and acute fatty liver of pregnancy occurred in 31% and intrahepatic cholestasis in 10% of pregnancies with a long chain 3-hydroxyacyl-coenzyme A-deficient fetus but in none of the pregnancies with a healthy fetus. A total of 40% of affected neonates were born prematurely and 47% had growth restriction, whereas none of the healthy neonates were premature and growth restriction occurred in only 17% (p < 0.01). Prematurity and growth restriction could not be explained solely by the preeclampsia-related conditions. CONCLUSIONS: In pregnancies with a long-chain 3-hydroxyacyl-coenzyme A-deficient fetus the frequency of preeclampsia-related conditions is high. The results support the role of fatty acid accumulation in the pathogenesis of preeclampsia. Analysis for the prevalent mutation of this deficiency may be warranted in pregnancies with severe preeclampsia.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1998

Ophthalmologic findings in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency caused by the G1528C mutation: a new type of hereditary metabolic chorioretinopathy.

OBJECTIVE: The purpose of the study was to determine the nature and course of ophthalmic abnormalities in long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, a recently discovered disorder of mitochondrial fatty acid beta-oxidation. STUDY DESIGN: The study design was a cohort (case series). PARTICIPANTS: A retrospective review of the records of 15 children who had died during their first 2 years was performed. Also performed were a longitudinal reanalysis and cross-sectional clinical examination of four long-term survivors aged 5 to 31 years. MAIN OUTCOME MEASURES: Visual acuity, refraction, visual fields, ophthalmoscopy, fluorescein angiography, biometry, corneal topography, electroretinography (ERG), visual-evoked potentials (VEPs), color vision, and dark adaptation were measured. RESULTS: In seven children, ophthalmoscopic findings were within normal limits at 3 days to 13 months of age (median, 4.8 months). In 11 children, a granular retinal pigment epithelium (RPE), with or without pigment clumping in the macula, was seen at 4 months to 5 years of age (median, 9 months). Two long-term survivors, 16 and 31 years of age, eventually had circumscribed atrophy of the choroid, RPE, and retina, which coincided with a posterior staphyloma type 1. They had progressive axial myopia starting at 6 and 12 years of age and later paracentral scotomas leading to poor central vision. They suffered from early difficulty with mesopic vision, glare, and a severe generalized color vision deficiency that started as a tritanomaly. A third survivor was mildly myopic at 5 years of age. All four surviving patients had visually insignificant, flake-like supranuclear opacities in the lens. The ERG initially was normal but deteriorated during the first decade and later was unrecordable. The VEP responses remained fairly normal. Initially, angiography showed no blockade of the choroidal fluorescence because of the thin RPE. Filling of choroidal vessels was delayed, and the choriocapillaris and, later, larger choroidal vessels in the posterior pole became nonperfused. CONCLUSIONS: In LCHAD deficiency, the fundus is normal at birth (stage 1). Soon, however, pigment dispersion occurs in the RPE (stage 2), followed by circumscribed chorioretinal atrophy, occlusion of choroidal vessels, and deterioration of central vision, often with relative sparing of the peripheral fundus (stage 3). Finally, posterior staphylomas and central scotomas may develop (stage 4). Developmental cataract, progressive myopia, and deterioration of visual fields and color vision are new findings in LCHAD deficiency. The chorioretinopathy and abnormal ERG precede the development of myopia and posterior staphyloma, which, in turn, coincide with the loss of macular vision. The authors postulate that the RPE or choriocapillaris is primarily affected. Awareness of the characteristic ocular features is important because of an opportunity for dietary treatment, genetic counseling, and prenatal diagnosis.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1998

Neuroradiologic findings in children with mitochondrial disorders.

PURPOSE: We report the neuroradiologic findings in 25 children with various mitochondrial diseases. METHODS: Twenty-two children with a mitochondrial disorder had MR imaging of the brain and three children had CT studies. In all cases, the diagnosis was based on examination of muscle morphology, analysis of oxygen consumption and respiratory chain enzyme activity in isolated muscle mitochondria, and analysis of rearrangements of the mitochondrial DNA. RESULTS: Fifteen patients were found to have the classical syndromes of mitochondrial diseases. Four children had Kearns-Sayre syndrome, but only one had the typical neuroradiologic findings of basal ganglia and brain stem lesions, T2 hyperintensity of the cerebral white matter, and cerebellar atrophy; the others had nonspecific or normal findings. Eight patients had Leigh syndrome, and all showed changes in the putamina. Involvement of the caudate nuclei, globus pallidi, thalami, and brain stem was common, and diffuse supratentorial white matter T2 hyperintensity was seen in two of these patients. Three patients had mitochondrial encephalopathy with lactic acidosis and strokelike episodes (MELAS), with infarctlike lesions that did not correspond to the vascular territories. Ten children with complex I or IV deficiencies and abnormal muscle morphology had nonspecific imaging findings, such as atrophy and abnormal or delayed myelination. One patient with combined complex I and IV deficiency had extensive white matter changes. None of the patients with clinical encephalopathy had normal findings. CONCLUSION: MR imaging is helpful in the diagnosis of the classical mitochondrial diseases; however, nonspecific findings are common.

Adolescent↗
PubMed1998

Ophthalmic pathology in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency caused by the G1528C mutation.

PURPOSE: To define histopathologic features of a recently recognized chorioretinopathy associated with long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, a defect of mitochondrial fatty acid oxidation. METHODS: Both eyes were obtained at autopsy from a child who died of LCHAD deficiency, caused by the G1528C mutation, at the age of 14 months. Routine histopathology and light microscopic immunohistochemistry were performed, with a panel of 12 antibodies to epithelial, mesenchymal, neuronal, and inflammatory cells, using the avidin-biotinylated peroxidase complex method. RESULTS: The cells of the retinal pigment epithelium (RPE) were rarefied, flattened, and hypopigmented in the posterior pole. The RPE cells reacted normally with MAb Vim 34B to vimentin, and MAb CAM 5.2 and CY-90 for cytokeratin 8 and 18. Scattered among them were many pigment-laden macrophages, reactive with MAb PG-M1. A thin outer nuclear layer in the macular region suggested loss of photoreceptor cells. In routine stainings, patent choriocapillary vessels were sparse. However, a collapsed network of capillaries could be identified by MAb QBEND-10 to the CD34 epitope of vascular endothelial cells. In the peripheral fundus, the RPE and choriocapillaris were normal. CONCLUSIONS: The ophthalmopathologic findings corresponded to clinically defined stage 2 of the chorioretinopathy of LCHAD deficiency. Histopathologically, this chorioretinopathy can be classified as diffuse choroidal atrophy with loss of the choriocapillaris. The findings suggest a primary fault at the level of the RPE and choriocapillaris and a secondary macrophage response.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1997

Muscle-eye-brain disease: a neuropathological study.

A combination of congenital central nervous, ocular and muscular abnormalities is characteristic of muscle-eye-brain disease (MEB), of Fukuyama congenital muscular dystrophy (FCMD), and of Walker-Warburg syndrome (WWS). The nosological relationship of these inherited malformative disorders is still unestablished, although the genetic locus for FCMD has been excluded in MEB. We present the first postmortem neuropathological study of MEB based on 2 male patients. Apart from sharply limited occipital agyric areas, their brains showed coarse gyri with an abnormally nodular surface ("cobblestone cortex"). Both the cerebral and cerebellar cortices showed a total disorganization without horizontal lamination. The haphazardly oriented cortical neurons formed irregular clusters or islands, separated by gliovascular strands extending from the pia. The ocular abnormalities included a pronounced glial preretinal membrane. Although MEB shares the cobblestone cortex-type malformation with FCMD and WWS, the cerebral and ocular manifestations are less severe than in WWS. Furthermore, a consistently weak staining for laminin alpha2 chain (merosin) was found in muscle biopsy specimens from 4 MEB patients, while normal immunoreactivity was observed for the laminin beta2 chain, reported to be severely deficient in WWS. These findings support nosological independence of MEB.

Adult↗
PubMed1997

Growth impairment and growth hormone therapy in children treated for malignant brain tumours.

UNLABELLED: Eighty-two children with malignant brain tumours were treated according to the "8 in 1" chemotherapy protocol in Finland during 1986 to 1993. Thirty-seven with brain tumours not involving the hypothalamic-pituitary region are still alive and tumour-free. The growth and response to growth hormone (GH) therapy in these children was analysed. Children who received craniospinal irradiation had the most severe loss of height SDS, being -1.07 within 3 years of the diagnosis. Even children with no irradiation to the hypothalamic-pituitary axis had a mean change in height SDS of -0.5 after 3 years. Fifteen of 23 children who received craniospinal irradiation and two out of eight children who received cranial irradiation have received GH therapy. A catch-up growth response to the daily GH therapy with the mean dose of 0.7 IU/kg per week was complete in 3 years (+1.87 SDS), irrespective of craniospinal irradiation, in children who were treated at prepubertal age but was seen in none of the children who had reached pubertal age. CONCLUSION: Growth impairment and GH deficiency are common in children treated for malignant brain tumours. The response to GH therapy is good in prepubertal children in terms of increased growth velocity, although the final height is not yet known.

Adolescent↗
PubMed1997

Screening for connexin 32 mutations in Charcot-Marie-Tooth disease families with possible X-linked inheritance.

The X-linked dominant form of Charcot-Marie-Tooth disease (CMTX) is associated with mutations in a gene coding for the gap-junction protein connexin 32 (Cx32). We screened 32 CMT families with a pedigree pattern suggestive of X-linked inheritance for the presence of mutations in the coding region of Cx32 by direct sequencing. Five of the families had a CMT1 diagnosis, 24 had a CMT2 diagnosis and 3 patients had an unspecified CMT. Eight families with a Cx32 point mutation were detected. Five different mutations (four of them published previously) were found in six CMT2 families and one mutation was found in a sporadic CMT1 male patient. One of the mutations, Met194Val, is among the first described in the fourth transmembrane domain of Cx32. Two CMT2 families and the sporadic CMT1 patient had the same mutation, Arg22Gln. An additional, previously unpublished mutation, Arg75Trp, was found in a male patient with unspecified CMT, who subsequently was verified to have a variant Klinefelter syndrome with 48,XXYY karyotype. Our findings show the difficulty in distinguishing CMTX patients from CMT1 and CMT2 patients, and they emphasize the need for Cx32 mutation screening in families previously diagnosed with CMT2.

Charcot-Marie-Tooth Disease↗
PubMed1997

Hypoparathyroidism in a patient with long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency caused by the G1528C mutation.

Mitochondrial trifunctional protein (MTP), an enzyme complex participating in fatty acid beta-oxidation, is the potential site of two documented defects: long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) and MTP deficiencies. LCHAD deficiency usually manifests as hypoglycemia, with hepatopathy, hypotonia, cardiomyopathy, and retinopathy. Hypoparathyroidism has been detected in a patient with MTP deficiency. We now report on a patient with LCHAD deficiency and hypoparathyroidism, evidenced by hypocalcemia, hyperphosphatemia, and a low level of parathyroid hormone, in whom the parathyroid glands could not be located after death.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1997

Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency with the G1528C mutation: clinical presentation of thirteen patients.

Long-chain 3-hydroxyacyl-coenzyme A (CoA) dehydrogenase is one of three enzyme activities of the mitochondrial trifunctional protein. We report the clinical findings of 13 patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. At presentation the patients had had hypoglycemia, cardiomyopathy, muscle hypotonia, and hepatomegaly during the first 2 years of life. Seven patients had recurrent metabolic crises, and six patients had a steadily progressive course. Two patients had cholestatic liver disease, which is uncommon in beta-oxidation defects. One patient had peripheral neuropathy, and six patients had retinopathy with focal pigmentary aggregations or retinal hypopigmentation. All patients were homozygous for the common mutation G1528C. However, the enoyl-CoA hydratase and 3-ketoacyl-CoA thiolase activities of the mitochondrial trifunctional protein were variably decreased in skin fibroblasts. Dicarboxylic aciduria was detected in 9 of 10 patients, and most patients had lactic acidosis, increased serum creatine kinase activities, and low serum carnitine concentration. Neuroradiologically there was bilateral periventricular or focal cortical lesions in three patients, and brain atrophy in one. Only one patient, who has had dietary treatment for 9 years, is alive at the age of 14 years; all others died before they were 2 years of age. Recognition of the clinical features of long-chain 3-hydroxyacyl-CoA deficiency is important for the early institution of dietary management, which may alter the otherwise invariably poor prognosis.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1997

Improving outcome of malignant brain tumours in very young children: a population-based study in Finland during 1975-93.

Sixty-four children with malignant brain tumours diagnosed at less than 3 years of age were reported to the Finnish Cancer Registry from 1975 to 1993. The survival rate has improved significantly: the 5-year survival rate was 26% for all children, 13% for children diagnosed during 1975-85 (n = 30) and 40% for those diagnosed during 1986-93 (n = 34). Of the surviving children in 1986-93, 43% were categorized in Bloom's group I or II and could lead active lives without major disabilities. The remaining children had severe neurologic late complications, such as hemiplegia, intractable seizures, and mental retardation.

Age Factors↗
PubMed1996

Ototoxicity in children with malignant brain tumors treated with the "8 in 1" chemotherapy protocol.

BACKGROUND: Adjuvant chemotherapy has improved the outcome of childhood malignant brain tumors in large randomized trials. With increasing survival rates, treatment toxicity has become a matter of concern. Radiation therapy and cisplatinum are known to be ototoxic. METHODS: We evaluated the incidence and factors predisposing to ototoxicity in children treated with the "8 in 1" chemotherapy protocol in Finland during 1986--1993. Thirty-five of the 82 children survived for at least 1 year after diagnosis. Thirty of these children were old enough to have an audiogram. RESULTS: Seventeen of the 30 children had normal hearing, seven had hearing loss at high frequencies, and six (20%) had severe hearing loss in the speech range. The risk factors for severe hearing loss were young age, a high cumulative dose of cisplatinum, and deteriorating renal function. In the presence of these factors, the risk of severe hearing loss was over 50%. Hearing loss at high frequencies could occur after low cumulative doses of cisplatinum, but severe hearing loss correlated with high cumulative doses. CONCLUSIONS: Cisplatinum-induced hearing loss at high frequencies is common, but hearing loss in the speech range also occurs, particularly in children with predisposing factors, and may progress insidiously and rapidly. Therefore a hearing test before each "8 in 1" course is important.

Adolescent↗
PubMed1996

Quality of life in early adolescence: a sixteen-dimensional health-related measure (16D).

While data on the health-related quality of life (HRQOL) of adults are accumulating, very little is known about the HRQOL--and especially the perceived HRQOL--of children. In our study we introduced a 16-dimensional, generic self-assessment measure of HRQOL (16D) for early adolescents, and demonstrated its use with four populations of children aged 12-15: (1) 239 normal schoolchildren, (2) patients waiting for organ transplantation (n = 5), (3) patients with genetic skeletal dysplasias (n = 19), and (4) patients with epilepsy (n = 32). The HRQOL profiles of the patients differed significantly according to the diagnosis, giving support to its construct validity. The reliability of the measure was high: its repeatability coefficient was 91%. The quality of life ratings of the healthy boys and their parents differed on the dimensions of distress, vitality, speech, mental function, and discomfort and symptoms (p < 0.05). In addition, there were significant differences in the health-related valuations between the girls, boys and their parents. We conclude that the assessment of quality of life of adolescents should be based on data collected from the adolescents themselves. Further, the 16D is so far the only generic HRQOL measure designed specifically for this purpose. It is capable of differentiating the HRQOL of healthy adolescents as well as patients with various diagnoses. Our experience also indicates that it is easy to use, yet it seems comprehensive, reliable, and valid.

Adolescent↗
PubMed1996

Quality of life in pre-adolescence: a 17-dimensional health-related measure (17D).

Although interest in the health-related quality of life (HRQOL) of children has increased in the last years, validated methods for assessing the HRQOL- and especially the perceived HRQOL-of children have been missing. We introduced a 17-dimensional, illustrated, generic measure of perceived HRQOL (17D) for pre-adolescents, and demonstrated its application to three populations of children aged 8-11 years: (1) 244 normal schoolchildren; (2) 22 patients surviving organ transplantation and (3) 10 patients with genetic skeletal dysplasias. The HRQOL scores and profiles of the patients differed significantly according to the diagnosis, giving support to its construct validity. The reliability of the measure was high: its repeatability coefficient was 95%. As a structured interview of 20-30 minutes, the measurement burden is reasonable. We conclude that the assessment of quality of life of pre-adolescents can and should be based on data collected from the children themselves. Our initial experience indicates that 17D is comprehensive, reliable, and valid.

Bone Diseases, Developmental↗
PubMed1996

Severe hyperprostaglandin E syndrome with hyperthyroidism--studies of pathogenetic mechanisms.

Hyperprostaglandin E syndrome is a rare disease usually presenting with renal symptoms such as polyuria, polyhydramnios, hypercalciuria, hypokalaemia, and recurrent episodes of extreme fever, diarrhoea, and convulsions. We report a severe variant of this syndrome with obvious pain and prostaglandin E2 (PGE2)-stimulated hyperthyroidism, an association not previously described. Urinary excretion of PGE2 and its metabolite 7 alpha-hydroxy-5,11-diketotetranorprosta-1,16-dioic acid were markedly increased above normal levels (to 53.3 and 1895 ng/h per 1.73 m2, respectively). We studied oxidative capacity of peroxisomes and mitochondria, the sites where PGE2 oxidation takes place. A generalized mitochondrial disease could be ruled out and no deficiency was found in liver peroxisomal oxidases. The basic pathology of hyperprostaglandin E syndrome remains unsolved.

Cyclooxygenase Inhibitors↗
PubMed1996

Pathology of skeletal muscle and impaired respiratory chain function in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency with the G1528C mutation.

Lactic acidosis and mitochondrial abnormalities have been reported in long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency. We studied muscle morphology and the respiratory chain function in ten patients with LCHAD deficiency and the G1528C mutation. In eight cases the light microscopy of muscle specimens showed fatty infiltration and fibre degeneration. The degenerated fibres appeared as ragged red fibres in four cases. Electron microscopy revealed enlarged mitochondria often with swollen appearance in four out of seven patients. The number of mitochondria had also increased. Complex I associated enzyme activities in muscle mitochondria were decreased in five out of seven patients, and in three of them Complex II or II + III associated activities were also affected. We suggest that the reason for respiratory chain dysfunction and structural changes of mitochondria is the accumulation of toxic intermediates of fatty acid beta-oxidation in mitochondria. Because these changes may confound the differential diagnostics between LCHAD deficiency and respiratory chain defects, awareness of their frequency is important.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1996

Neuropsychologic late effects in children with malignant brain tumors treated with surgery, radiotherapy and "8 in 1" chemotherapy.

Sixty-eight children with malignant brain tumors were treated with the "8 in 1" chemotherapy protocol from 1986 to 1993 in Finland. The overall 5-year survival rate was 43%. Thirty-one children are still alive and tumor-free, and have been evaluated in the present study. Of these 31 children, 26% had hemi- or tetraplegia, 13% intractable seizures, and 30% attend special schools. The mean full scale (FS) IQ was 85 (range 45-138), 24% had an FSIQ value less than 70, and 36% more than 90. One-half of the survivors were placed in Bloom's group I or II, are able to lead an active life, and have only mild neurologic disabilities. In the other, neurologic late complications accumulated and these children were relegated to Bloom's group III or IV, with major disabilities such as hemiplegia, intractable epilepsy, or mental retardation. The most important prognostic factors were severe perioperative complications, young age at diagnosis, and cranial irradiation.

Adolescent↗
PubMed1996

Laminar cortical necrosis in MELAS syndrome: MR and neuropathological observations.

Laminar cortical necrosis has been described in many conditions of cellular energy depletion, such as hypoxia and hypoglycemia. In MELAS, a genetic defect in mitochondrial protein synthesis leads to impairment of oxidative phosphorylation, with subsequent insufficient energy production within the cell. Neurons are more vulnerable to energy depletion than glial cells and vascular elements, and among the layers of the cerebral cortex the lower laminae are more vulnerable than the superficial layers. We studied a child with severe MELAS syndrome two months before death with MR and compared the images to autopsy findings, including macroscopic specimens and light and electron microscopy. The MR images showed an excellent correlation with the neuropathological results and displayed the various degrees of damage to the brain tissue caused by deficient energy production. Acute laminar cortical necrosis was seen as swelling of the cortex with intracortical hyperintense bands in T2-weighted images. The subacute stage with focal cortical hemorrhage was displayed as hyperintensity of the gyral surface in T1-weighted and hypointensity in T2-weighted images, with T2-hyperintensity and swelling of the rest of the cortex and underlying white matter. Severe cortical atrophy represented the chronic stage.

Atrophy↗