Gene/Protein Disease Symptom Drug Enzyme Compound
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Adrenoleukodystrophy (ALD) is a progressive X-linked disorder that produces pathological changes, mainly in the adrenal cortex and the white matter of the central nervous system. The main biochemical abnormality is the accumulation of saturated unbranched fatty acids with a chain length of 24 or more, referred to as very-long-chain fatty acids (VLCFA). Affected children develop large zones of demyelination associated with perivascular lymphoctyic infiltrations resembling those seen in multiple sclerosis. Adults show a more chronic form of the disease, referred to as adrenomyeloneuropathy (AMN). AMN mainly involves the spinal cord ad peripheral nerves, although the cerebral hemispheres may also be affected. Approximately 15% of female carriers have nervous-system involvement that resembles AMN. It is well known that ALD may initially appear as a psychiatric disorder. In the present study, we have assessed the prevalence of cognitive impairment in a group of AMN patients and neurologically symptomatic ALD heterozygotes initially presenting primarily physical complaints. Sixty percent of these patients demonstrated significant neuropsychological impairment, most commonly a pattern of spared and impaired functions typical of a subcortical dementia. We suggest that this progressive cognitive impairment may underlie other behavioral deficits, affirming the significance of the psychological features of this genetically determined disorder.
Mol Chem Neuropathol 1990 Jun
PMID:Cognitive impairment in adult-onset adrenoleukodystrophy. 209 65

After administration (1 g/kg every other day for a total of five injections) of Triton WR-1339, the tonic, anterior (ALD) and phasic, posterior (PLD) latissimus dorsi muscles of the chicken underwent distinct pathological modifications. Some of the morphological alterations in the muscles paralleled those seen after administration of chloroquine, increased autophagic vacuole formation in the ALD muscle and swelling of the sarcoplasmic reticulum in the PLD muscle, but other changes were unique to Triton WR-1339. These included loss of myofilaments and whole myofibrils, indentation of the sarcolemma as well as increased numbers of ribosomes in the ALD muscle and swelling of the T-tubular system in the PLD muscle. These results are compared with other lysosome mediated pathologies, as well as with other myopathies.
Virchows Arch B Cell Pathol Incl Mol Pathol 1981
PMID:Skeletal muscle myopathy caused by triton WR-1339. 611 38

Fiber splitting was studied in the tonic, anterior (ALD) and phasic, posterior (PLD) latissimus dorsi muscles using three experimental models, denervation, chloroquine administration and Triton WR-1339 administration. Fiber splitting was observed in the PLD in all three models, but in the ALD only after chloroquine administration. A basement membrane was always present in the split fibers, and acid phosphatase was localized between the split fibers in the PLD. However, no evidence of lysosomal involvement in the fiber splitting process was observed.
Virchows Arch B Cell Pathol Incl Mol Pathol 1982
PMID:Fiber splitting in tonic and phasic skeletal muscles following denervation, chloroquine and triton WR-1339 treatments. 612 77

Isozymes of myosin have been localized with respect to individual fibers in differentiating skeletal muscles of the rat and chicken using immunocytochemistry. The myosin light chain pattern has been analyzed in the same muscles by two-dimensional PAGE. In the muscles of both species, the response to antibodies against fast and slow adult myosin is consistent with the speed of contraction of the muscle. During early development, when speed of contraction is slow in future fast and slow muscles, all the fibers react strongly with anti-slow as well as with anti-fast myosin. As adult contractile properties are acquired, the fibers react with antibodies specific for either fast or slow myosin, but few fibers react with both antibodies. The myosin light chain pattern slow shows a change with development: the initial light chains (LC) are principally of the fast type, LC1(f), and LC2(f), independent of whether the embryonic muscle is destined to become a fast or a slow muscle in the adult. The LC3(f), light chain does not appear in significant amounts until after birth, in agreement with earlier reports. The predominance of fast light chains during early stages of development is especially evident in the rat soleus and chicken ALD, both slow muscles, in which LC1(f), is gradually replaced by the slow light chain, LC1(s), as development proceeds. Other features of the light chain pattern include an "embryonic" light chain in fetal and neonatal muscles of the rat, as originally demonstrated by R.G. Whalen, G.S. Butler- Browne, and F. Gros. (1978. J. Mol. Biol. 126:415-431.); and the presence of approximately 10 percent slow light chains in embryonic pectoralis, a fast white muscle in the adult chicken. The response of differentiating muscle fibers to anti-slow myosin antibody cannot, however, be ascribed solely to the presence of slow light chains, since antibody specific for the slow heavy chain continues to react with all the fibers. We conclude that during early development, the myosin consists of a population of molecules in which the heavy chain can be associated with a fast, slow, or embryonic light chain. Biochemical analysis has shown that this embryonic heavy chain (or chains) is distinct from adult fast or slow myosin (R.G. Whalen, K. Schwartz, P. Bouveret, S.M. Sell, and F. Gros. 1979. Proc. Natl. Acad. Sci. U.S.A. 76:5197-5201. J.I. Rushbrook, and A. Stracher. 1979. Proc Natl. Acad. Sci. U.S.A. 76:4331-4334. P.A. Benfield, S. Lowey, and D.D. LeBlanc. 1981. Biophys. J. 33(2, Pt. 2):243a[Abstr.]). Embryonic myosin, therefore, constitutes a unique class of molecules, whose synthesis ceases before the muscle differentiates into an adult pattern of fiber types.
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PMID:Distribution and properties of myosin isozymes in developing avian and mammalian skeletal muscle fibers. 617 31

A candidate gene for X-linked adrenoleukodystrophy (ALD) has been identified via positional cloning strategies. We now report messenger RNA expression in fibroblasts from 6 unrelated ALD patients. Four patients lacked the normal 4.2 kb transcript, three of them having deletions of the ALD gene. A fifth patient with a deletion of 1.6 kb had a smaller 4.0 kb transcript. The last patient had a normal sized transcript and a missense mutation at base 1258 leading to Glu-291-Lys substitution in a region of the candidate gene protein which is conserved in the 70 kD peroxisomal membrane protein. These results provide further evidence that this candidate gene is indeed the ALD gene.
Hum Mol Genet 1993 Nov
PMID:Abnormal messenger RNA expression and a missense mutation in patients with X-linked adrenoleukodystrophy. 790 10

Adrenoleukodystrophy is a severe genetic demyelinating disease associated with an impairment of beta-oxidation of very long chain fatty acids (VLCFA) in peroxisomes. Earlier studies had suggested that a deficiency in VLCFA CoA synthetase was the primary defect. A candidate adrenoleukodystrophy gene has recently been cloned and was found unexpectedly to encode a putative ATP-binding cassette transporter. We have raised monoclonal antibodies against this protein, that detect a 75kDa band. This protein was absent in several patients with adrenoleukodystrophy. Immunofluorescence and immunoelectron microscopy showed that the adrenoleukodystrophy protein (ALDP) is associated with the peroxisomal membrane. Distinct immunofluorescence patterns were observed in cell lines from patients with Zellweger syndrome (a peroxisomal biogenesis disorder) belonging to different complementation groups.
Hum Mol Genet 1994 Feb
PMID:The gene responsible for adrenoleukodystrophy encodes a peroxisomal membrane protein. 800 93

The intracellular movement of cholesterol is an important regulated step in the process of steroidogenesis. However, the molecular mechanisms by which cholesterol is translocated to key organelles, including the mitochondria, remains poorly understood. Lipid transfer proteins may have an important function in this process. One candidate lipid transfer protein is sterol carrier protein 2 (SCP2). This 13.2 kDa protein enhances the movement of cholesterol between vesicles and isolated mitochondria. It also stimulates mitochondrial pregnenolone synthesis. When introduced into intact cells, anti-SCP2 antibodies reduce steroid secretion. Moreover, expression of SCP2 in COS cells engineered to produce progestins increases steroid formation. SCP2 is abundant in steroidogenic glands and the pattern of SCP2 gene expression is consistent with a role for the protein in hormone synthesis: SCP2 transcripts are more prominent in the most steroidogenic compartments of the ovary and tropic hormones that stimulate steroidogenesis increase SCP2 gene expression. Other evidence that suggests that SCP2 plays important roles in cellular function includes a remarkable conservation of primary structure across species. The mechanisms by which SCP2 promotes intracellular sterol movement have not been elucidated. The protein appears to bind sterols and is synthesized with a 20 amino acid N-terminal "pro-" sequence that may serve to target SCP2 to mitochondria. In addition, the C-terminus of SCP2 contains a peroxisome-targeting sequence. SCP2 is derived from a large gene that encodes transcripts that are translated into larger proteins of 30 and 58 kDa. The 58 kDa protein, which has some structural homologies with thiolases, seems to be specifically targeted to peroxisomes whereas SCP2 has a broader subcellular distribution. The significance of the peroxisome association of SCP2 and steroidogenesis has not been disclosed. However, diseases of peroxisome function, including adrenoleukodystrophy and Zellweger syndrome, have notable deficits in steroid and bile acid metabolism, thus linking peroxisomes and steroidogenesis. SCP2 is deficient in fibroblasts of patients with these diseases.
J Steroid Biochem Mol Biol 1993 Dec
PMID:Sterol carrier protein 2: a role in steroid hormone synthesis? 827 32

In a clinical trial for the management of adrenoleukodystrophy, we analyzed the effect of erucic acid (a component of Lorenzo's oil) on platelet number, fatty acid composition, and function. Analysis of variance was performed to compare platelet counts before starting treatment with Lorenzo's oil and at 6 and 12 months. We measured platelet fatty acid composition in subjects and control patients and correlated these values with their platelet counts using discriminant analysis. After 6 months, the mean platelet count decreased from 247,000/mm3 to 169,000/mm3 (+/- 1 standard deviation 58,000,n =39), P < 0.0001 compared to 18 subjects on a control diet having a mean baseline platelet count of 259,000/mm3 (+/- 1 standard deviation 67,000, n = 19) and at 6 months 267,000/mm3 (+/- 1 standard deviation 71,000). We found at P < 0.05 that the platelet counts showed a strong inverse relationship with erucic acid levels and other omega 9 fatty acids that form from the administration of the erucic acid component of Lorenzo's oil. Morphologic and platelet sizing measurements suggest that the physical properties of platelets may also be affected by erucic acid. Our studies show that the ingestion of erucic acid affects platelet biology. This indicates that platelet counts and properties are influenced by monounsaturated fatty acids, in addition to the well-known effects of polyunsaturated fatty acids. In areas of the world where erucic acid is widely ingested, the biology of platelets in these populations may be affected.
Biochem Mol Med 1996 Apr
PMID:Effect of erucic acid on platelets in patients with adrenoleukodystrophy. 873 90

A 9.7 kb segment encompassing exons 7-10 of the adrenoleukodystrophy (ALD) locus of the X chromosome has duplicated to specific locations near the pericentromeric regions of human chromosomes 2p11,10p11, 16p11 and 22q11. Comparative sequence analysis reveals 92-96% nucleotide identity, indicating that the autosomal ALD paralogs arose relatively recently during the course of higher primate evolution (5-10 million years ago). Analysis of sequences flanking the duplication region identifies the presence of an unusual GCTTTTTGC repeat which may be a sequence-specific integration site for the process of pericentromeric-directed transposition. The breakpoint sequence and phylogenetic analysis predict a two-step transposition model, in which a duplication from Xq28 to pericentromeric 2p11 occurred once, followed by a rapid distribution of a larger duplicon cassette among the pericentromeric regions. In addition to facilitating more effective mutation detection among ALD patients, these findings provide further insight into the molecular basis underlying a pericentromeric-directed mechanism for non-homologous interchromosomal exchange.
Hum Mol Genet 1997 Jul
PMID:Interchromosomal duplications of the adrenoleukodystrophy locus: a phenomenon of pericentromeric plasticity. 921 66

The peroxisomal disorders represent a group of inherited metabolic disorders that derive from defects of peroxisomal biogenesis and/or from dysfunction of single or multiple peroxisomal enzymes. We described earlier an 8 1/2 year-old with a history of progressive developmental delay, micronodular cirrhosis, and elevated very long chain fatty acids in plasma and skin fibroblasts. These findings were felt to be compatible with both neonatal adrenoleukodystrophy (nALD) and Zellweger syndrome (ZS). This patient is now 21 years old and his clinical course, inconsistent with either nALD or ZS, led us to examine his peroxisomal status in light of a possible new peroxisomal disease. The normal levels of bile acid precursors found in this patient suggest that peroxisomal beta-oxidation is functional. The activities of dihydroxyacetone phosphate acyltransferase and oxidation of lignoceric acid and phytanic acid were 14, 17, and 15% of the control, respectively. This partial activity for oxidation and the normal levels of bile acid precursors suggests that this patient has peroxisomes containing beta-oxidation enzymes. Western blot analysis of subcellular organelles showed that beta-oxidation enzyme proteins are present at normal levels in catalase-negative peroxisomes of density equivalent to normal peroxisomes. The presence of acyl-CoA oxidase and 3-ketoacyl-CoA thiolase in catalase-negative peroxisomes suggests that both peroxisomal targeting signal-1 (PTS-1), and peroxisomal targeting signal-2 (PTS-2)-mediated protein transport processes into peroxisomes are normal in this patient. These findings of catalase-negative peroxisomes of normal density and normal PTS-1 and PTS-2 import machinery with partial peroxisomal functions clearly demonstrate that this patient differs from those with known disorders of peroxisomal biogenesis.
Biochem Mol Med 1997 Aug
PMID:Biochemical features of a patient with Zellweger-like syndrome with normal PTS-1 and PTS-2 peroxisomal protein import systems: a new peroxisomal disease. 925 85


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