Mitochondrial carnitine-acylcarnitine translocase deficiency presenting as sudden neonatal death.

A breast-fed female infant died suddenly in the neonatal period at 31 hours of age with profound macrovesicular fatty infiltration of liver, kidney, and muscle on postmortem examination, suggestive of a defect in fatty acid beta-oxidation. Fatty acid and palmitoyl-carnitine oxidation studies and direct enzyme study of cultured skin fibroblasts suggested a deficiency in the oxidation of long-chain fatty acids distal to carnitine palmitoyl-transferase I and before long-chain acyl-coenzyme A dehydrogenases. Deficient activity of carnitine-acylcarnitine translocase was demonstrated with intermediate levels of activity in the infant's parents, consistent with autosomal recessive inheritance. Fatty acid oxidation studies showed deficient oxidation of fatty acids at all chain lengths from C10:0 to C24:0, with partially reduced oxidation of C26:0 fatty acid, indicating the occurrence of a single mitochondrial carnitine-acylcarnitine translocase and demonstrating the requirement in vivo for L-carnitine for mitochondrial transport of all medium- and long-chain fatty acyl moieties. The disorder may have been precipitated in this breast-fed infant by poor initial feeding, fasting stress, and the long-chain triglycerides of human milk. The severity of the disorder prompted prenatal diagnosis, and affected siblings were excluded in two subsequent pregnancies by fatty acid oxidation in cultured chorionic villus cells and amniocytes.

Relation between delayed impairment of cerebral energy metabolism and infarction following transient focal hypoxia-ischaemia in the developing brain.

Phosphorus magnetic resonance spectroscopy (31P MRS) was used to determine whether focal cerebral injury caused by unilateral carotid artery occlusion and graded hypoxia in developing rats led to a delayed impairment of cerebral energy metabolism and whether the impairment was related to the magnitude of cerebral infarction. Forty-two 14-day-old Wistar rats were subjected to right carotid artery ligation, followed by 8% oxygen for 90 min. Using a 7T MRS system. 31P brain spectra were collected during the period from before until 48 h after hypoxia-ischaemia. Twenty-eight control animals were studied similarly. In controls, the ratio of the concentration of phosphocreatine ([PCr]) to inorganic orthophosphate ([Pi]) was 1.75 (SD 0.34) and nucleotide triphosphate (NTP) to total exchangeable phosphate pool (EPP) was 0.20 (SD 0.04): both remained constant. In animals subjected to hypoxia-ischaemia, [PCr] to [Pi] and [NTP] to [EPP] were lower in the 0- to 3-h period immediately following the insult: 0.87 (0.48) and 0.13 (0.04), respectively. Values then returned to baseline level, but subsequently declined again: [PCr] to [Pi] at -0.02 h-1 (P < 0.0001). [PCr] to [Pi] attained a minimum of 1.00 (0.33) and [NTP] to [EPP] a minimum of 0.14 (0.05) at 30-40 h. Both ratios returned towards baseline between 40 and 48 h. The late declines in high-energy phosphates were not associated with a fall in pHi. There was a significant relation between the extent of the delayed impairment of energy metabolism and the magnitude of the cerebral infarction (P < 0.001). Transient focal hypoxia-ischaemia in the 14-day-old rat thus leads to a biphasic disruption of cerebral energy metabolism, with a period of recovery after the insult being followed by a secondary impairment some hours later.

Correlation between umbilical arterial flow and placental morphology.

Umbilical artery blood velocity waveforms were compared with the morphological aspects of the vascular bed of 30 placentas using quantitative methods. An abnormal pulsatility index was found to be highly correlated with a lower number of arteries in the tertiary stem villi as well as a lower placental weight and birth weight. The reduction in the number of arteries seems to be due to an early developmental arrest of placental angiogenesis and is partly compensated for by increased formation of capillaries in the terminal villi, since the number of capillaries is independent of the number of arteries.

Prenatal findings in generalized amyoplasia.

Amyoplasia is a rare, sporadic condition characterized by different degrees of maldevelopment of the skeletal muscles, which are replaced by fibrous and fatty tissue. In this report, we present a case of generalized amyoplasia presenting at 19 weeks' gestation. The most striking finding was the absence of fetal movements, resulting in severe multiple congenital contractures, hydrops, and polyhydramnios. At autopsy, histological examination of the skeletal muscle showed small groups of poorly developed fibres within areas of fat. This report suggests that generalized amyoplasia could be a common cause of severe forms of multiple congenital contractures, but is probably underdiagnosed at post-mortem because of inadequate examination of muscles. Definitive diagnosis is important in determining the risks of recurrence in these cases.

Classification of perinatal deaths.

PIP: Accurate classification of perinatal deaths is instrumental in efforts to improve the perinatal mortality rate (PNMR). Accurate records should be maintained on birth weight, gestational age, a simple classification of cause of death (possibly the "Wigglesworth" or the author's system), a classification system correlated with birth weight/gestation of dead and live births, and, where possible, detailed coding such as the International Classification of Diseases (ICD) or the Systematized Nomenclature of Medicine (SNOMED). The fetal loss rate in Great Britain is reported as a minimum of 0.1% per week for pregnancies from 22 weeks until term. Obstetric or neonatal management can affect the level of mortality. Terminations due to malformations performed before the 24th week are found to account for a 50% decline in the PNMR. PNMR is affected also by birth weight and the occurrence of multiple births. Neonatal care that prolongs the survival of sick or malformed neonates may decrease PNMR or increase infant death rates. Analysis of trends in PNMR must consider demographic changes such as an increase in preterm multiple births due to fertility treatment. Perinatal deaths may be classified by cause with a variety of systems. The ICD system is a single axis classification which uses three digit codes for primary causes and a fourth and fifth digit for detailed subcategories, which can be accessed in a alphabetically-organized index. SNOMED provides six different fields of information, including topography, morphology, aetiology, function, disease, and procedure. Five subordinate fields are identified and linked to topographic body sites. Choice of classification systems is considered to be based on availability of information and the needs for subsequent analysis. Two other systems of classification are available in the UK. The Aberdeen system is based on maternal factors, but the disadvantage is the high number of unexplained deaths. The Hey et al. system codes by fetal and neonatal factors and does not require modern investigative techniques, but the detail is highly variables from case-to-case and hospital-to-hospital. The author's system is based on routine autopsies of external conditions. Four groupings are identified, including macerated normally-formed stillborn infants, congenital anomalies (stillbirth or neonatal death), conditions associated with prematurity, and fresh stillbirths presumed asphyxiated. A fifth category groups infants dying of specific conditions such as toxoplasmosis.^ieng

Unusual association of cerebral and renal abnormalities.

A 37-week male infant is reported with microbrachycephaly, micrognathia, a cleft palate, a small tongue and a patent ductus arteriosus. Postmortem examination revealed micropolygyria, absence of the olfactory bulbs and tracts, absence of the corpus callosum, marked hydrocephalus and abnormal midbrain structures and basal ganglia. The cerebellum was very small with an absent vermis. There was widespread impacted PAS-positive secretion distending the distal tubules within the cortex of the kidney, with scattered microcyst formation and occasional partly sclerosed glomeruli.

Two techniques for electron opaque staining of elastic fibres using tannic acid in fresh and formalin fixed tissue.

Two electron microscopic staining techniques, one using tannic acid-glutaraldehyde as a fixative, and the other using tannic acid-uranyl acetate solution as a stain on ultra-thin sections of glutaraldehyde fixed material, were directly compared for elastic fibre staining on several human and animal tissues. Various concentrations of tannic acid were compared using both techniques. The two techniques were also compared on formalin fixed tissues. The use of tannic acid-uranyl acetate solution as a stain on processed tissue is by far the more consistent technique and achieves equally good results on glutaraldehyde or formalin fixed tissue. It is suggested that the use of the term tannic acid technique/method should be reserved for this particular method to achieve a meaningful interpretation of results in scientific papers.

Transthoracic herniation of the fetal lung: bagpipe lung.

We describe a case of subtotal herniation of a lung through an intercostal space into an extrathoracic (axillary) position that occurred in a 16-week-old fetus. There was no malformation of the thoracic wall other than the hiatus at the site of herniation. The left and the right lungs were of similar size and weights and the lung/body weight ratio was normal. Histology revealed no difference between the normal and the abnormally positioned lung. We were unable to find a report of a similar case of the condition, which has implications for concepts of lung development.

Epithelial cell morphology and airspace size in hypoplastic human fetal lungs associated with oligohydramnios.

The relative frequency of different types of respiratory epithelial cells in normal fetal lungs (control, CON) and hypoplastic lungs associated with oligohydramnios (OH) was determined at the electron microscopic level and airspace size was measured. At 24+ weeks CON lungs had 82.4 +/- 1.2% undifferentiated cells, 15.9 +/- 1.2% type II cells, and 1.7 +/- 0.4% type I cells (n = 3), whereas OH lungs had 94.6 +/- 2.1% undifferentiated cells, 5.4 +/- 2.1% type II cells, and no type I cells (n = 3). At 36+ weeks CON lungs had 7.8 +/- 3.4% undifferentiated cells, 46.1 +/- 3.1% type II cells, and 46.1 +/- 1.4% type I cells (n = 3), whereas OH lungs had 37.7 +/- 1.2% undifferentiated cells, 42.5 +/- 1.7% type II cells, and 19.8 +/- 0.8% type I cells (n = 3). Differences between CON and OH lungs in the proportions of undifferentiated and type I cells at 36+ weeks were highly significant (p less than .001), whereas type II cell proportions did not differ significantly in either age group. The proportion of lung occupied by airspaces increased from 38.3% at 24+ weeks to 68.7% at 36+ weeks in CON lungs but only from 26.7% to 35.7% in OH lungs. The differences between the groups were significant at both 24+ weeks (p less than .01) and 36+ weeks (p less than .001). Mean airspace size in CON lungs varied from 2.8 x 10(-6) mm2 at 24+ weeks to 4.4 x 10(-6) mm2 at 36+ weeks and in OH lungs from 1.7 x 10(-6) mm2 at 24+ weeks to 2.7 x 10(-6) mm2 at 36+ weeks. These results give quantitative expression to the severity of impaired morphologic maturation in OH lungs.

Lethal arthrogryposis multiplex congenita: a pathological study of 21 cases.

Twenty-one cases of arthrogryposis multiplex congenita, which had resulted in death soon after birth or had been aborted following prenatal diagnosis, were studied. Histochemical and histological study of muscle indicated that 11 cases were of myogenic origin, including congenital muscular dystrophy in 10 cases from six families and nemaline rod myopathy in one. Neurogenic causation was established in five cases, including three with intra-uterine anoxic-ischaemic damage and two siblings with a severe form of cerebro-ocular-facio-skeletal syndrome. Causation remained uncertain in five. Unusual features included atrophy or amyoplasia of the diaphragm associated with lung hypoplasia in 10 cases and evidence of birth trauma in seven cases. One pair of siblings had subcutaneous tissue of doughy consistency and another pair had bladder hypertrophy. Familial recurrence was seen most often in cases with evidence of myogenic origin. We consider that neuropathology and muscle histochemistry are essential aids in determining the risks of recurrence in this group of lethal conditions which defy analysis by syndrome recognition techniques.

Biochemical and morphometric analyses in hypoplastic lungs.

We report the results of biochemical and morphometric studies on lungs of infants with bilateral lung hypoplasia either with or without oligohydramnios (OH or NOH) in comparison with findings in normally grown lungs. The OH and NOH lungs were equally hypoplastic in terms of DNA content but OH lungs had a significantly lower disaturated phosphatidylcholine (DSPC) concentration than NOH or normal lungs, apart from a subgroup with gastrointestinal or airway obstruction. Hydroxyproline concentration in OH lungs was higher than that in NOH or normal lungs. Desmosine concentrations did not differ significantly between groups despite the obvious lack of elastin in the septal crests of the OH group on histology. Morphometry revealed low lung volume, low radial alveolar counts, low alveolar numbers, and low alveolar surface area in both OH and NOH groups. Alveoli and alveolar ducts constituted a higher proportion of lung volume in NOH than in OH lungs. The similarity of most morphometric indices in the two groups implies that maturation does not depend on quantitative elaboration of airways and alveoli. The finding of impaired epithelial maturation despite the high hydroxyproline concentration in the OH lungs suggests an abnormality in epithelial-mesenchymal interaction that is not present in the equally small lungs of the NOH group.

Failure of elastin development in hypoplastic lungs associated with oligohydramnios: an electronmicroscopic study.

Pulmonary hypoplasia associated with oligohydramnios results in delayed maturation of fetal lung as assessed at light microscope level. Using an elastin-specific electron-microscopic staining technique, we report absent elastic tissue development in the septal crests of these lungs even at term.

Short stature/short limb skeletal dysplasia with severe combined immunodeficiency and bowing of the femora: report of two patients and review.

We report two patients with severe combined immunodeficiency and short stature/short limb skeletal dysplasia. Case 1 presented at birth with rhizomelic shortening of the extremities and bowing of the femora. She developed clinical signs of severe combined immunodeficiency at 13 months and died at 21 months. Case 2 had severe prenatal shortening and bowing of the extremities and a small, malformed chest. Symptoms of severe combined immunodeficiency and severe failure to thrive developed soon after birth and she died at 5 months. The diagnosis of severe combined immunodeficiency in our patients was based on their clinical course and necropsy findings, supported in case 1 by the results of immune function tests. The results of investigation of immune function (immunoglobulins, lymphocyte subpopulations, lymphocyte function) are very variable in this syndrome as in other variants of severe combined immunodeficiency. Bone histopathology in both patients showed grossly irregular costochondral junctions, but normal transition of proliferating to hypertrophic chondrocytes. These cases belong to early lethal type 1 short limb skeletal dysplasia with severe combined immunodeficiency. Review of previously published cases with severe combined immunodeficiency and well documented skeletal findings show eight patients with prenatal onset of bowing and shortening of the extremities and metaphyseal abnormalities. These include two sib pairs concordant for the skeletal changes. In these cases, adenosine deaminase levels were not reported. An additional four published cases with associated adenosine deaminase deficiency had only mild metaphyseal abnormalities, but subsequently showed no linear growth.(ABSTRACT TRUNCATED AT 250 WORDS)

Type IV collagen in developing human lung: a comparison between normal and hypoplastic fetal lungs.

Human lung tissue obtained from 24 aborted fetuses of varying gestational ages (beyond 24 weeks) was examined for immunolocalisation of type IV collagen, using monoclonal antibody. Twelve cases of lung hypoplasia associated with oligohydramnios were compared with 12 normally developed lungs over the same gestational age range acting as control. Type IV collagen was located in alveolar septa and subepithelial basement membranes in all the lungs examined but showed less prominently in hypoplastic lungs than in control lungs of a similar gestational age. The findings suggest a potential role of type IV collagen in maturation of the developing human lung.

Low amniotic pressure in oligohydramnios--is this the cause of pulmonary hypoplasia?

The mechanism by which oligohydramnios produces lung hypoplasia is not understood. The current theory that extrinsic compression of the fetal thorax causes hypoplasia, either by inhibiting breathing movements or by squeezing out lung liquid, is not supported by observational or experimental data, or by our finding of decreased amniotic pressure around the fetus in oligohydramnios. We hypothesize that lung hypoplasia results from excess loss of lung liquid because of a reduction in amniotic pressure, and hence an increase in the alveolar-amniotic pressure gradient. The magnitude of this increased pressure gradient is calculated to exceed the small standing tracheal pressure; thus low amniotic pressure overcomes the normal laryngeal retentive mechanisms and allows a larger quantity of lung liquid to escape. In the prevention of pulmonary hypoplasia, a role is suggested for the instillation of artificial amniotic fluid to restore normal amniotic pressure.