Peroxisomal diseases.
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Congenital Abnormalities↗
Biomedical subjects
H W Moser
Publications and source records attributed to H W Moser.
Color vision defects in adrenomyeloneuropathy.
The relationship between abnormal color vision and adrenomyeloneuropathy (AMN) was investigated in 27 AMN patients and 31 age-matched controls by using the Farnsworth-Munsell 100 Hue test. Twelve (44%) of 27 patients showed test scores significantly above normal. The axes of bipolarity determined by the testing differed widely between the patients with abnormal scores, compatible with the notion that different alterations in visual pigment genes occur in different AMN kindreds. These observations confirm our earlier impression that the frequency of abnormal color vision is increased in these kindreds, and it supports our contentions that (1) AMN (and its companion, adrenoleukodystrophy) are very closely linked to the visual pigment loci at Xq28 and (2) this proximity might provide the opportunity to observe contiguous gene defects.
Adrenal Gland Diseases↗
Childhood adrenoleukodystrophy. Failure of intensive immunosuppression to arrest neurologic progression.
Cyclophosphamide in a dosage of 350 to 700 mg/m2/d was administered for five to 11 days to four patients with childhood adrenoleukodystrophy (ALD) and to one patient with the adult cerebral form of the disease. The rate of neurologic progression in the four patients with childhood ALD did not differ from that of 167 untreated patients with childhood ALD surveyed previously.
Adrenoleukodystrophy↗
Prenatal diagnosis of rhizomelic chondrodysplasia punctata.
Plasmalogen biosynthesis and phytanic acid oxidation activity were measured in cultured chorionic villus samples or amniocytes from four pregnancies at risk for the rhizomelic form of chondrodysplasia punctata (RCDP). Normal results were obtained in three of the samples and post-natal examination or fetal ultrasound studies confirmed that the fetuses were unaffected. Chorionic villus culture in one case demonstrated defective plasmalogen biosynthesis and lack of phytanic acid oxidation. Pregnancy was interrupted at 10 weeks. Immunoblot studies of post-mortem fetal tissues showed that peroxisomal 3-oxoacyl-coenzyme A thiolase was present in the unprocessed form, a finding we had previously demonstrated in RCDP. These results establish that RCDP can be identified prenatally.
Amniocentesis↗
Peroxisomal integral membrane proteins in livers of patients with Zellweger syndrome, infantile Refsum's disease and X-linked adrenoleukodystrophy.
Livers from seven patients with peroxisome disorders, three with Zellweger syndrome, one with infantile Refsum's syndrome and three with X-linked adrenoleukodystrophy, were analysed by immunoblotting. The bifunctional protein catalysing two peroxisomal beta-oxidation reactions was deficient in all Zellweger livers and in the infantile Refsum's liver, consistent with the absence of morphologically recognizable peroxisomes. Three peroxisomal integral membrane proteins (IMPs) (69, 53 and 22 kDa) were present in normal amounts in all the Zellweger and adrenoleukodystrophy samples and they sedimented in a membrane fraction. These membrane proteins were also present in the infantile Refsum's liver. We suggest, on the basis of these results, that aberrant peroxisomal membranes may be present in Zellweger syndrome and that the defect is in the transport of matrix proteins into the organelle.
Adrenoleukodystrophy↗
Galactosylceramide-beta-galactosidase deficiency in association with cherry red spot.
A 13-month-old white girl was the product of a normal pregnancy and delivered by caesarean section for breech presentation. Regression of motor milestones started by 11 months, when delayed language development was also noted. She was normocephalic without major dysmorphic features or organomegaly. Fundus examination disclosed a subtle cherry red spot bilaterally. No startle response was elicited. By 17 months she was extremely irritable and unable to tolerate liquids; there was symmetrical spasticity and florid cherry red spots. She died at 18 months of age. A systematic search for conditions associated with a cherry red spot was unrevealing. The absence of galactosylceramide galactosidase activity was unexpected and was confirmed on three occasions in two laboratories. Lactosylceramide I content, an enzyme thought to be identical to galactosylceramide-beta-galactosidase, was significantly decreased. The presence of a cherry red spot in Krabbe's disease, indicative of neuronal storage, has not been previously recognized. The existence of this variant has implications for genetic and biochemical studies.
Brain↗
Auditory brainstem response and audiologic findings in adrenoleukodystrophy: its variant and carrier.
Auditory brain stem response, auditory sensitivity, speech discrimination function, acoustic reflex threshold, and reflex decay were studied in seven children with adrenoleukodystrophy (ALD), nine adults with adrenomyeloneuropathy (AMN), one child with neonatal ALD, and two carriers of ALD. Significant auditory dysfunctions were found in only two patients; a retrocochlear type auditory disorder in one child with ALD, and a profound deafness in a child with neonatal ALD. None of the patients showed significant abnormality in acoustic reflex threshold and reflex decay except for one patient with ALD who showed a slightly elevated reflex threshold. All but two ALD patients showed significantly prolonged wave latencies and interwave intervals. The latency values revealed the highest incidence of abnormality in the I to III interval; this was followed by the III to V interval, then by wave I. Significantly, one child with asymptomatic ALD and both heterozygous female relatives showed abnormal ABRs, demonstrating the high sensitivity of ABR in detection of the existence of pathophysiological condition in subclinical or presymptomatic ALD.
Adolescent↗
Research on Rett syndrome: strategy and preliminary results.
The research strategy presented here involves four assumptions: (1) Rett syndrome exists; (2) a single cause will eventually be found to account for the majority of cases presently assigned to this disease category; (3) it is genetically determined; and (4) it represents a neurodegenerative disorder that can be defined by quantitative studies of nervous system structure and function. The strategy proposed here involves the comprehensive study of 100 patients with the classic Rett syndrome phenotype. Studies include the (1) search for a diagnostic marker; (2) high-resolution cytogenetic banding techniques, (3) quantitative morphologic studies of postmortem brain tissue as well as neurochemical analyses including autoradiographic techniques, radioimmunoassays, and in situ hybridization; and (4) positron emission tomography studies of cerebral glucose metabolism and neurotransmitters.
Adolescent↗
The peroxisome: nervous system role of a previously underrated organelle. The 1987 Robert Wartenberg lecture.
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Abnormalities, Multiple↗
Frequent alterations of visual pigment genes in adrenoleukodystrophy.
Both adrenoleukodystrophy (ALD) and red/green color blindness have been mapped to the distal long arm of the human X chromosome (Xq28). Color-vision defects are frequently associated with ALD, and study of the red and green visual pigment genes in eight ALD kindreds has shown frequent structural changes including deletions and possible intragenic recombinations. Such changes may reflect chromosomal events underlying both ALD and the associated visual defects and should help define both the structural gene responsible for ALD and physical genetic relationships in the Xq28 region.
Adrenoleukodystrophy↗
Adrenoleukodystrophy carrier state presenting as a chronic nonprogressive spinal cord disorder.
Females who are heterozygous for adrenoleukodystrophy (ALD) can be identified biochemically. Since most carriers for this disease are asymptomatic, their diagnosis usually occurs only after neurologically abnormal male relatives have been investigated. We describe a woman with a chronic nonprogressive spinal cord syndrome secondary to the ALD heterozygote state. The neurologic condition in this patient suggests that the diagnosis of ALD should be considered in women with evidence of white matter disease.
Adrenoleukodystrophy↗
Phenotype heterogeneity among hemizygotes in a family biochemically screened for adrenoleukodystrophy.
We report on two clinically, neurologically normal relatives of a boy affected by adrenoleukodystrophy (ALD); they were found repeatedly to have the biochemical defect of an ALD hemizygote. The assay consisted in the determination of very-long-chain fatty acids in lyophilized and reconstituted plasma. While no evidence of neurologic disease (leukodystrophy or myeloneuropathy) was present in these hemizygotes, adrenocortical insufficiency provoking compensatory high ACTH release was found in both. These findings should be taken into consideration when counseling families in which cases with clinically expressed ALD are represented in several generations.
Adrenoleukodystrophy↗
Farber disease: pathologic diagnosis in sibs with phenotypic variability.
We describe new pathologic findings in two sibs with Farber lipogranulomatosis. The first child, a 3-month-old boy, presented with only hepatosplenomegaly and had a fulminant clinical course suggestive of malignant histiocytosis. The second child, a 5 1/2-month-old girl, had the typical clinical presentation of Farber disease, with hoarseness and painful swollen joints. At autopsy, storage material was demonstrated in the second child at laryngeal and periarticular subcutaneous sites. Visceral involvement was prominent in both sibs, although not typical of the disease, and included a newly described nephropathy with elevated urine ceramide levels. Liver and spleen contained massive histiocytic infiltrates in association with elevated ceramide levels. Lymph nodes also contained histiocytic infiltrates but without the sinusoidal involvement typical of proliferative histiocytic disorders. These two cases demonstrate new pathologic anomalies in Farber disease, indicating that biochemical analyses of biopsy specimens may be necessary to establish the diagnosis of Farber disease when atypical clinical and morphologic anomalies are present.
Amidohydrolases↗
A new dietary therapy for adrenoleukodystrophy: biochemical and preliminary clinical results in 36 patients.
A new dietary regimen has been administered for periods ranging from 60 days to 1 1/2 years in 34 patients with various forms of X-linked adrenoleukodystrophy (ALD), as well as in 1 patient with neonatal ALD and 1 patient with infantile Refsum's disease. The diet combines the administration of a glyceryl trioleate oil (GTO) with the dietary restriction of very-long-chain fatty acids (VLFA), particularly hexacosanoic acid (C26:0). Reductions in the levels of plasma C26:0 and other VLFA were achieved in 25 of the 36 patients. Fifteen of these 25 patients were treated for more than 100 days. The mean reduction of the plasma C26:0 level was 53% (range, 22 to 73%) in these 15 patients. While the focus of the study was on biochemical variables, comparison of pre- and post-diet studies of peripheral nerve function showed improvement in 1 patient with adrenomyeloneuropathy (AMN) and 1 heterozygote. In contrast, 2 patients with ALD onset in childhood developed new neurological deficits while on therapy. We conclude that it is possible to lower plasma VLFA levels in ALD patients. A clinical trial is indicated to test whether this approach can alter the neurological progression in patients with AMN or in symptomatic heterozygotes, and to determine whether it can prevent the onset of neurological disability in asymptomatic persons who have the biochemical defect of ALD.
Adrenoleukodystrophy↗
Linkage of adrenoleukodystrophy to a polymorphic DNA probe.
Linkage studies between X-linked adrenoleukodystrophy and a cloned deoxyribonucleic acid fragment (St14), which detects polymorphisms in the distal end of the long arm of the X chromosome (Xq27-28), have shown no recombination in six families. The lod score for these data (and another kindred reported earlier is 13.766 at recombination fraction (theta) = 0.0. These data permit assignment of adrenoleukodystrophy carrier status in family members at risk, supplementing the chemical measurement of very-long-chain fatty acids.
Adrenoleukodystrophy↗
Neuronal lipidosis and neuroaxonal dystrophy in cerebro-hepato-renal (Zellweger) syndrome.
Neuropathological examination of three males with cerebro-hepato-renal (Zellweger) syndrome (CHRS) revealed selective neuronal lipidosis and neuroaxonal dystrophy of the dorsal nucleus of Clarke and lateral cuneate nucleus. This lipidotic alteration was visualized as perikaryal or axonal enlargements with cytoplasmic striations. With the light microscope, the striated material was birefringent and resistant to traditional lipid stains; ultrastructurally, it was composed of lipid clefts, lamellae and lamellar-lipid profiles; biochemically, the affected region contained large amounts of cholesterol esterified to very long-chain fatty acids, both saturated and monounsaturated. This metabolic lesion, though localized to specific sensory neurons, suggests that a more generalized defect in neuronal fatty acid metabolism may be operative in CHRS.
Adrenoleukodystrophy↗
A sibship with a mild variant of Zellweger syndrome.
A mild variant of Zellweger (cerebro-hepato-renal) syndrome was diagnosed in male and female siblings aged 7 and 2 years. They had mild facial dysmorphia, moderate psychomotor retardation, tapetoretinal degeneration, sensorineural deafness and hepatomegaly. Ultrastructural examination of a liver biopsy in the younger patient revealed the absence of recognizable peroxisomes. In both patients plasma levels of pipecolic acid, phytanic acid, trihydroxycoprostanoic acid and dihydroxycoprostanoic acid were elevated. The very long chain fatty acid C26:0 and the C26:0/C22:0 fatty acid ratio were elevated in plasma, but less than in classical Zellweger syndrome. In cultured fibroblasts, deficient acyl-CoA:dihydroxyacetone phosphate acyltransferase and increased concentrations of C26:0 as well as C26:1 very long chain fatty acids were found within the ranges previously established for patients with classical Zellweger syndrome. Particle-bound catalase was absent in fibroblasts. Despite the relatively mild clinical expression the biochemical abnormalities found in these patients are the result of a general peroxisomal dysfunction similar to the changes in classical Zellweger syndrome.
Acyltransferases↗
Cherry red spot in association with galactosylceramide-beta-galactosidase deficiency.
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Cells, Cultured↗