The pericentric inversion of chromosome 16 [inv(16)(p13q22)] is a characteristic karyotypic abnormality associated with acute myeloid leukemia, most commonly of the M4Eo subtype. The 16p and 16q breakpoints were pinpointed by yeast artificial chromosome and cosmid cloning, and the two genes involved in this inversion were identified. On 16q the inversion occurred near the end of the coding region for CBF beta, also known as PEBP2 beta, a subunit of a heterodimeric transcription factor regulating genes expressed in T cells; on 16p a smooth muscle myosin heavy chain (SMMHC) gene (MYH11) was interrupted. In six of six inv(16) patient samples tested, an in-frame fusion messenger RNA was demonstrated that connected the first 165 amino acids of CBF beta with the tail region of SMMHC. The repeated coiled coil of SMMHC may result in dimerization of the CBF beta fusion protein, which in turn would lead to alterations in transcriptional regulation and contribute to leukemic transformation.

In recent years, acyl dihydroxyacetone phosphate [acyl-DHAPt) has been shown to be a precursor of glycerolipids and glycerol-ether lipids.'.' Acyl-DHAP was discovered as a rapidly labeled lipid that was formed in crude mitochondrial fraction from 3'Pi or y-32P[ATP].3 This rapid labeling was due to the enzymatic dephosphorylation and rephosphorylation of endogenous acyl-DHAP present in the crude mitochondrial fraction (equation 1): Acyl-DHAP 2-/-Acyl-DHA (1) ADP ATP Acyl-DHAP was later shown to be biosynthesized by a direct acylation of DHAP with acyl-CoA. catalyzed by DHAP acyltransferase (EC 2.3.1.42) (equation 2):4

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A point mutation in the gene for human serum cholinesterase was identified that changes Asp-70 to Gly in the atypical form of serum cholinesterase. The mutation in nucleotide 209, which changes codon 70 from GAT to GGT, was found by sequencing a genomic clone and sequencing selected regions of DNA amplified by the polymerase chain reaction. The entire coding sequences for usual and atypical cholinesterases were compared, and no other consistent base differences were found. A polymorphic site near the C terminus of the coded region was detected, but neither allele at this locus segregated consistently with the atypical trait. The nucleotide-209 mutation was detected in all five atypical cholinesterase families examined. There was complete concordance between this mutation and serum cholinesterase phenotypes for all 14 heterozygous and 6 homozygous atypical subjects tested. The mutation causes the loss of a Sau3A1 restriction site; the resulting DNA fragment length polymorphism was verified by electrophoresis of 32P-labeled DNA restriction fragments from usual and atypical subjects. Dot-blot hybridization analysis with a 19-mer allele-specific probe to the DNA amplified by the polymerase chain reaction distinguished between the usual and atypical genotypes. We conclude that the Asp-70 -* Gly muta-

Eight new cases of autopsy-confirmed or suspected neonatal adrenoleukodystrophy (NALD) are presented together with new biochemical data on very-long-chain fatty acids (VLCFA) and plasmalogens and a review of all previously published cases. The clinical, biochemical, and histopathologic abnormalities characteristic of this newly recognized form of adrenoleukodystrophy are analyzed in detail and compared to the principal characteristics of the similar disorder, the cerebrohepatorenal syndrome of Zellweger (ZS). Using strict pathologic criteria for the diagnosis of NALD, we find that, despite many clinical resemblances, NALD and the ZS are distinguishable on the basis of histology and peroxisomal biochemistry. Patients with NALD demonstrate adrenal atrophy, systemic infiltration by abnormal lipid-laden macrophages, and elevations of saturated VLCFA. In contrast, patients with ZS have chondrodysplasia, glomerulocystic disease of the kidney, central nervous system dysmyelination, and elevations of unsaturated as well as saturated VLCFA, but they lack adrenal atrophy. We conclude that NALD and the ZS probably represent at least two different genetic defects.

The Zellweger cerebro-hepato-renal syndrome is a genetic disease characterized by the absence of peroxisomes and deficiency of glycerol-ether lipids in several tissues. We measured the activity of dihydroxyacetone phosphate (DHAP) acyltransferase, a peroxisomal enzyme with a major role in ether lipid synthesis, in fibroblasts and leukocytes from patients with Zellweger syndrome. Control skin and amniotic-fluid fibroblasts had normal activity of DHAP acyltransferase (0.28 to 0.3 nmol per minute per milligram of protein), whereas fibroblasts from three patients with Zellweger syndrome had deficient activity (0.013 +/- 0.006 nmol per minute per milligram of protein). The activity of the enzyme in leukocytes and levels of plasmalogens (the major class of cellular glycerol-ether lipids) in erythrocytes were also deficient in a patient, but normal levels of leukocyte enzyme and erythrocyte plasmalogens were found in her parents. Other enzymes of the acyl DHAP pathway exhibited alterations in fibroblasts from patients with Zellweger syndrome, and the activity of the glycerophosphate acyltransferase was also reduced. These results support prior studies emphasizing the role of peroxisomes and the acyl DHAP pathway in cellular ether lipid synthesis, establish Zellweger syndrome cells as valuable for elucidating peroxisomal functions, and provide prenatal and postnatal diagnostic assays as well as potential therapeutic strategies for Zellweger syndrome.

Chronic feeding of 1-O-octadecyl-sn-glycerol (batyl alcohol) to patients suffering from congenital deficiency in tissue ether glycerolipids showed an increase in the plasmalogens content of their erythrocytes. However, nothing is known about the ether lipid content of other tissues in these patients. Feeding 1-O-heptadecyl-sn-glycerol to young rats showed that this uncommon ether lipid was incorporated to a high extent into the plasmalogens of all tissues except brain. Comparative studies with other precursors, such as 3-O-heptadecyl-sn-glycerol, heptadecanol and heptadecanoic acid, indicated a stereospecific incorporation of the dietary 1-O-alkyl-sn-glycerols into tissue plasmalogens without cleavage of the ether bond. Dietary ether lipids were also shown to be transferred from mothers to suckling rats, but not from pregnant rats to fetuses. The implication of these results to possible dietary ether lipid therapy for patients suffering from peroxisomal disorders is discussed.

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