Virginia D. Black

BIOCHEMICAL AND MORPHOLOGICAL PEROXISOMAL DEFECTS IN ZELLWEGER SYNDROME

The report of absent peroxisomes and distorted mitochondria in liver and kidney of Zellweger syndrome suggested that the manifestations may be secondary to disturbed function of these organelles. The associated question of persistence of peroxisomal enzyme activity in the absence of peroxisomes was equally provocative.Liver and intestinal biopsies from a patient with Zellweger syndrome were assayed for 3 peroxisomal enzymes. Catalase was present in both tissues in normal concentrations but was not sedimentable at 10,000 rpm for 30 min. Cyanide-insensitive β -oxidation of palmitoyl-CoA and dihydroxyacetone phosphate acyltransferase were not detectable in liver. Absence of the former could explain the reported accumulations of very long-chain fatty acids. The acyltransferase is essential in the synthesis of plasmalogens which are widely distributed in membranes but whose functions are poorly understood.Peroxisomes could not be found in liver or intestine by EM. Mitochondria were normal. Rare, very small bodies were noted in intestine some of which were DAB-positive (catalase-containing).These findings provide the first unequivocal evidence of a deficiency in peroxisomal enzymes in human disease. Zellweger syndrome may result from an interruption in peroxisomal formation.

1363 OUTCOME OF INBORN VS. TRANSPORTED HIGH-RISK INFANTS

The outcome of 694 births of infants weighing <1500 grams from two sources was compared. 301 births occurred in 5 metro area hospitals (MH) with Level I nursery facilities; the high-risk infants were transported to Level III nurseries. 393 infants were born in University Hospital (UH) where Level III intrapartum and neonatal care are available. Fetal deaths were twice as frequent in the MH population as in the UH group, 25 vs. 12.5% (p <.01). Neonatal deaths were slightly increased in the MH, 37 vs. 30% but not to a significant degree. Infant deaths occurred in 3 and 4% respectively in MH and UH. Outcome at approximately 12-24 months was the same in both groups. Because 61% of the UH population in this weight group comes from in utero transport patients from the region, this population was reviewed. Fetal deaths occurred in 9.5% of total maternal transport births. Neonatal deaths were similarly reduced (27%) and outcome slightly improved 33%. When the in utero transport patients from the MH were credited back to these hospitals the fetal death rate was 22% compared to the UH rate of 17% (p=NS). Maternal transport patients constitute a population which differs from that of the MH and UH. Data on maternal complications, neonatal morbidity, birth weight, gestational age, socioeconomic status, type of transport and long-term outcome in relation to these factors is in preparation.

DEFINING POLYCYTHEMIA: A REAPPRAISAL

The first cases of neonatal polycythemia were described over 25 years ago. To date, controversy still exists as to what critical level of hematocrit (hct) should be utilized to define this syndrome. The most common definition has been a venous hct of 65% or greater. Values as low as 60% or as high as 70% have also been suggested. In addition, the relationship between polycythemia and hyperviscosity is poorly described. We re-evaluated the definition of polycythemia based on neonatal symptoms and long-term outcome at 1-2 yrs of age and evaluated the relationship between hct and viscosity. The subjects were infants referred for further screening because of high hcts. Viscosity measurements were made using the methods and standards of Gross et al. (1973). Viscosity and venous hct were coded for 225 infants. Follow-up was available on 158 (70%). Among infants studied, elevated viscosity measurements were not limited to those with venous hct of 65% or greater. Eleven percent of infants had an abnormal viscosity, although hct was less than 65%. The enrollment mechanism did not permit identification of the lowest hct at which abnormal viscosity could be found. Infants whose venous hcts were between 65 and 69% were as likely to have neonatal symptoms as infants with hcts between 60 and 64%. Infants with markedly abnormal hcts (>69%) had similar neonatal courses. Infants with symptoms in more than one organ system varied from 26-30% of each group. Similarly, outcome measurements were not different among the three groups. No evidence of long-term sequelae was found in 44-65% of the children. In conclusion, determinations of a critical level of hct does not fully account for the effects of neonatal hyperviscosity. It is also likely that additional factors influence peripheral blood flow and must be considered when attempting to predict which infants with elevated hcts will have neonatal symptoms or long-term sequelae.

Neonatal Polycythemia and Hyperviscosity Syndrome

In fant henatocr i t var ies w i t h both gestat ional age and postnatal age. It has been assuned that the r i s e i n hematccrit vh ich occurs frcm f i r s t t o t h i r d tr imester i s an adaptation t o increase oxygen needs and the r e l a t i v e in t rauter ine hypoxia. Three decades ago nwborns w i t h markedly elevated hematocrits and se r i ous cardiorespiratory d is t ress were described. Often the symptomatic in fant was the rec ip ient o f a twin-to-twin transfusion. These ear ly case reports are the f i r s t docunented cases o f what I s now described as neonatal polycythemia. I n 1966, Baun (1) i den t i f i ed an elevated v iscos i ty I n blood frcm in fants who were polycythemic. This elevat ion i n v iscos i ty was believed t o decrease peripheral blood flow and hence might explain the pathology asxxriated w l t h nematal polycythemla. A new condition, neonatal hyperviscosity, was described. It i s c m but inaccurate t o equate neonatal polycythemla and neonatal hyperviscoslty. The de f l n i t l ons o f each are speclfi c and, although overlapping, do not exact ly define the sane population. Neonatal polycythemla i s most c m l y described as a venous hematocrit of 65%. Levels as lw as 60% o r as high as 70% have a lso been suggested. Variat ions i n sample s i t e o r postnatal age ccnpomd the d i f f i c u l t y i n def in ing neonatal polycythemla. Linderkzrw ( 3 ) and Gat t i (2) have d e r s t r a t e d the v a r i a b i l i t y between cap i l l a r y and venous henatocr i t values. Shohat (4) was able t o d a m s t r a t e dynmic changes i n both venous henatocr i t and v iscos i ty m e a s u r m t s . By two hours o f age there I s a l i nea r cor re la t ion between cord blood hematocrlt and venous hematocrlt. Thus, cord blood hematocrit may be a re l i ab le technique for i n i t i a l screening. However, t h i s technique may miss lnfants who becum? polycythemic as a resu l t o f acute placental transfusion. Neonatal hyperviscosity re fers t o a character is t ic of b l d vhich increases w i t h henatocrit. Several other factors a lso contribute t o the v iscos i ty of whole blood. Pmng these are large p lasm proteins and s t i f f ness o f the red blood c e l l mmbrane. Newborn p l a m has a lower v iscos i ty ccmpared t o adult p l asm since the concentration of plasma proteins i s lower i n the newborn. Standards f o r v iscos i ty measurements are avai lable frcm several authors. H Y p e r v i ~ o ~ l t y has been defined as a value more than two standard deviations f r a mean cord v iscos i ty . Whole blood v lscos i ty i s dependent on the shear ra te studied. Viscosity measurements are therefore glven over several shear rates. Use of the v iscos i ty standards avai lable suggest t ha t 2-62 o f newborn lnfants have hyperviscosity. While hematocrit and v l x o s l t y are closely correlated the cont r ibu t ion of other factors t o v iscos i ty mke it irrposslble t o equate the two conditions. At the higher hem t o c r i t leve ls a l l polycythemic ln fants are hyperviscous. S m infants without polycythemla have abnormal whole blood v iscos i ty . S m polycythemic lnfants are hyperviscous. I n the r m i n d e r of t h i s r e v i w the c l i n i c a l signs and outcane associated w i t h the two ccndit ions w i l l be descussed. Infants w l t h polycythemia and hyperviscosity often present w i t h cardiorespiratory signs which mimic cyanotic consenltal heart disease. Tachypnea, tachycardia, cyanosis, and awea have a l l been described as we1 l as p u l m a r y hypertension. Central nervous system signs are c m including the non spec i f i c f ind ings of i r r i t a b i l i t y , rapid s ta te changes, vasarator i ns tab i l i t y , lethargy, poor tone, and poor feeding. Early repor ts o f polycythemic infants frequently reported seizures. Prospect ive screening o f in fants has i den t i f i ed fw w i th neonatal seizures. Obvious cent ra l nervous system hemorrhage i s a lso mc m . More recent ly there has becane Increasing evidence that polycythemia/hyperviscosity i s a frequent cause o f necrot lz ing enterm01 i t i s (NEC) when It appears i n the t e n infant. Polycythemlc infants mdergolng p a r t i a l p l a s m exchange w l t h f resh frozen plasma seem pa r t i cu la r l y vulnerable t o developing a spect r u n o f gast ro in tes t ina l in jur ies . Pnemtos l s I n tes t i na l i s has a lso been seen I n many of these in fants w l t h a range o f gastroi n tes t i na l signs. Renal fal lure, thrcmbaytopenia, and v a r l w s other henatologic f indings have a lso been reported. Hypoglycemia i s c m l y assoc ia ted w i t h polycythemia and may be o f greater magnitude than appreciated since the determination o f plasma glucose overest i mates whole blood glucose. Peripheral blood f low may be severely ccmprcmised and has inproved f o l l w i n g plarnaphoresis. Outcam fol lowing neonatal polycythemla/hyperviscosity i s la rge ly dependent upon the method used t o ident i fy the subjects. Seriously canprcmlsed in fants as o r i g i n a l l y described are not the ru le . Most infants have svmptms tha t are less obvious. The most symptomtic infants I n ear ly studies had developnental delays and neurologic handicaps. Prospective screening ident l f les a group o f in fants f o r rvkm the outcane remains controversial . Several authors have f a i l e d t o shcw s lgn l f i can t impairment a t 1-6 years. Our studies suggest t ha t there are c l ea r di f ferences between polycythemlc ln fants and a canparison group a t two years o f age. Pa r t i a l p l asm exchange appears t o Inprove sensory o u t c m . A l l studies o f prospectively ident i f ied polycythenic in fants suggest t ha t mental developrent i s not s i gn i f i can t l y affected.

835 RELATIONSHIP BETWEEN DEXTROSTIX, PLASMA AND WHOLE BLOOD GLUCOSE IN THE RANGE 0 - 100 MG|[sol]|DL

Two laboratory measurements frequently made in the newborn period are Dextrostix (Ames) and hematocrit; yet the relationship between Dextrostix, plasma glucose and whole blood glucose values has not been described. Umbilical vein and peripheral vein blood samples were studied for whole blood, plasma and red cell glucose (YSI Model 23A) and were compared to values obtained using the Dextrostix read by eye. Dextrostix predicted whole blood glucose (R = .83, slope of regression = 1.1, not significantly different from 1.0). Plasma glucose was underestimated by the Dextrostix (R = .64, slope = .70 in the range measured in vivo (30-100 mg.dl−1). Measurements in vitro were carried out using umbilical vein blood during incubation with and without added glucose to determine the relationship between plasma and whole blood glucose at the lower glucose levels. No statistically significant difference was observed between plasma and whole blood glucose at these low levels. Dextrostix reflected both of these levels. No clinically significant error would have been made using the Dextrostix.In vivo, red cell glucose fell more quickly than plasma glucose at values greater than 100. Below that level, plasma and red cell glucose fell at similar rates. However, preliminary data from infants with polycythemia/hyperviscosity reveal red cell glucose values lower than would be predicted by the plasma glucose value alone.