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PubMed1978

[Pathophysiology of sulfatide metabolism in metachromatic leukodystrophy].

Metachromatic leucodystrophies (MLD) comprise a small group of heredodegenerative disorders of the nervous system. Deficiency of sulfatide-sulfatase or arylsulfatase A is the common defect in all forms of MLD leading to lysosomal sulfatide storage in the nervous tissue and in the kidney. On the basis of animal experiments, experiments with cultured fibroblasts of the patients as well as ultrastructural studies in a case of prenatal MLD, the following pathomechanism is proposed: 1. Lysosomal degradation of a large portion newly synthetised sulfatide normally regulating the net synthesis and incorporation of sulfatide into myelin, causes early accumulation of sulfatide in lysosomes of myelinating cells and in neurons in the genetic deficiency of arylsulfatase A. 2. Early accumulation of sulfatide does not lead to disturbance in myelination. Demyelination occurs possibly by storage of a cytotoxic compound, psychosin sulfate, also a substrate for the missing enzyme. Prevention of MLD is possible by prenatal diagnosis of arylsulfatase A deficiency in cultured amniotic cells. Enzyme substitution of the missing arylsulfatase A is possible by exogenous uptake of the enzyme in cultured fibroblasts. Thereby the defect of sulfatide degradation can be corrected. Although principles of enzyme substitution have been demonstrated, the problems of treating patients with MLD with arylsulfatase A infusions have yet to be overcome.

Animals↗

PubMed1975

Prenatal metachromatic leukodystrophy.

In a family with a metachromatic leukodystrophy patient, two further pregnancies at risk were monitored by amnion cell culture. In one case, a normal baby was predicted and born. In the other case, a prenatal deficiency of arylsulfatase A was found. The diagnosis of metachromatic leukodystrophy was confirmed biochemically in various organs of the fetus by the deficiency of arylsulfatase A. The residual enzyme activity was shown to have an abnormal pH optimum and an increased heat stability. Ultrastructural studies revealed lipid storage in the myelinating nervous system and in the liver. For the interpretation of morphological results, it was indispensable to analyze an age-matched control fetus.

Arylsulfatases↗

PubMed1977

Enzymic detection of metachromatic leukodystrophy patients and heterozygotes.

Two unrelated families with metachromatic leukodystrophy have been examined for the leukocyte enzyme arylsufatase A. The enzyme activities clearly reflect an autosomal recessive mode of inherence. All four parents showed heterozygote enzyme levels 40-60 percent of the control range while the two affected children had less than 20 percent normal activity. The two sibs of one affected child were shown to be heterozygote carriers. A simple screening method for sulfatase activity in tears has been developed which distinguished between metachromatic leukodystrophy patients and a control population which included other neurological disorders. Enzyme screening on tears may also be used to detect other lysosomal storage diseases including Tay-Sachs and Fabry disease.

Adult↗

PubMed1976

Arylsulfatases A and B in metachromatic leukodystrophy and Maroteaux-Lamy syndrome: studies with 4-methylumelliferyl sulfate.

Metachromatic leukodystrophy and Maroteaux-Lamy syndrome can be diagnosed by assay of leukocyte or fibroblast arylsulfatase A and B activity with the fluorogenic substrate 4-methylumbelliferyl sulfate. The arylsulfatases are extracted into a 27000 x g supernatant by sonication in 0.9% sodium chloride and then separated with CM-32 on columns or in test tubes. In 0.05 M sodium acetate pH 6.0, arylsulfatase A is not absorbed while arylsulfatase B is retained by the resin. The arylsulfatase B is then eluted from the resin with 0.3 M sodium chloride. The arylsulfatase A activity obtained from normal leukocytes and fibroblasts is linear for the initial 10 minutes of the reaction, is stimulated 3-fold by 6 mM lead acetate and inhibited 80% by 0.24 mM silver nitrate. After separation with CM-32, the arylsulfatase B activity is stimulated 3-fold by Triton X-100 (0.1%). Arylsulfatase A but not arylsulfatase B is destroyed by heat (60 degrees). Both leukocyte and fibroblast arylsulfatase A activity was reduced to 11% of control values in metachromatic leukodystrophy. Essentially no arylsulfatase B activity was detected in cells from patients with Maroteaux-Lamy syndrome. Metachromatic leukodystrophy heterozygotes but not Maroteaux-Lamy syndrome heterozygotes can also be distinguished by this method. A heat inactivation technique utilizing the differential thermal stabilities of the two enzymes for diagnosis of patients with Marotezux-Lamy syndrome is also described. The advantages of these 4-methylumbelliferyl sulfate assay procedures over the p-nitrocatechol sulfate method of assay are greater sensitivity, selectivity for the desired enzyme and potential for use in large scale testing.

Arylsulfatases↗

PubMed1976

Clinical and ultrastructural ocular histopathologic studies of adult-onset metachromatic leukodystrophy.

A twin brother and sister with adult-onset metachromatic leukodystrophy developed progressive central acuity loss and optic disk pallor. Both had normal electroretinograms and fluorescein angiography. Postmortem examination of the sister's eyes by histochemistry and electron microscopy revealed ganglion cell loss and optic atrophy. Cerebroside sulfate had accumulated in optic nerve glial cells. Optic atrophy was more advanced than in previously reported cases of infantile-onset metachromatic leukodystrophy. The pathologic process seemed to be retrograde optic nerve degeneration due to abnormal myelin metabolism.

Adult↗

PubMed1978

The ultrastructure of the retina in adult metachromatic leukodystrophy.

A 46-year-old woman afflicted with biochemically proven metachromatic leukodystrophy had only mild optic atrophy shortly before her death. Repeated earlier ophthalmoscopic examinations had not revealed any retinal abnormalities. Light microscopy of the retina showed strong acid phosphatase activity in both enlarged ganglionic cells and pigment epithelial cells. Demyelination of both optic nerves was not noted. Ultrastructurally, membranous lysosomal residual bodies were confined to ganglionic cells. We found lipofuscin material in pigment epithelial cells, but also within metachromatic leukodystrophy-specific residual bodies of ganglionic cells. The presence of lipofuscin represents the "wear-and-tear" phenomenon, possibly enhanced by the metachromatic leukodystrophy.

Acid Phosphatase↗

PubMed1978

Low arylsulphatase A activity in a family without metachromatic leukodystrophy.

A low arylsulphatase A activity was noted in the leukocytes and cultured skin fibroblasts of a child without any other symptoms of metachromatic leukodystrophy. Although the mother had a level of arylsulphatase commensurate with heterozygosity for the classical metachromatic leukodystrophy gene, the father had a variant gene giving an unusually low in vitro level of this enzyme. In combination (the proband), these two genes gave rise to a very low in vitro activity without any apparent disease. In screening for metachromatic leukodystrophy, a low arylsulphatase A level is not necessarily indicative of this disease, if a clinically normal parent shows an unusually low level of this enzyme.

Arylsulfatases↗

PubMed1979

Arylsulphatase A and B in juvenile metachromatic leukodystrophy.

A series of five living patients with juvenile metachromatic leukodystrophy (MLD), ten first-degree relatives, and a number of controls were subjected to biochemical investigations including quantitative determination of arylsulphatase A (ASA) and B (ASB) activities in peripheral leukocytes and polyacrylamide disc gel elctrophoresis of arylsulphatases. Five relatives were family members of four previously deceased patients with juvenile MLD. The mean ASA activity of the patients was 1.3 nmol of p-nitrocatechol sulphate hydrolysed in 30 min per mg protein. It was 84 nmol in the relatives, 129 nmol in other neurological patients and 136 nmol in normal controls. The corresponding ASB activity was 38 nmol in the patients, 49 nmol in the relatives, and 99 nmol in normal controls. An extremely low ASB activity, 3.4 nmol, was found in one relative. No ASA band could be visualised in the enzyme electrophoretic patterns of the patients' leukocytes but the bands representing ASB appeared normal. Seven relatives showed ASA bands weaker than normal, and the relative with low ASB activity exhibited very weak ASB band. The low ASB activity in the patients and heterozygotes may be a characteristic feature of the slowly progressive juvenile type MLD diagnosed in the present series.

Adult↗

PubMed1978

Clinical course of adult metachromatic leukodystrophy presenting as schizophrenia. A report of two living cases in siblings.

Adult metachromatic leukodystrophy is a demyelinating disease due to an inherited lack of arylsulfatase A activity. The purpose of this paper is to present the characteristics of this disorder as they occurred chronologically in two siblings, prior to and subsequent to the appearance of gross neurological deficits. A deficit in spatial relationships, as contrasted with verbal abilities, was observed initially in both cases at age 13. Initial psychiatric symptoms were noted at age 16 and 18, with both patients being diagnosed subsequently as schizophrenic. Gross neurological deficits were observed 2 and 13 years, respectively, after the appearance of psychiatric symptoms. A deficit in spatial relationships may be a very sensitive early indicator of adult metachromatic leukodystrophy.

Adolescent↗

PubMed1978

Proximal renal tubular acidosis in metachromatic leukodystrophy.

A 2-year-old girl affected with the late infantile form of metachromatic leukodystrophy had a persistent and moderate metabolic acidosis. Renal functional studies demonstrated the presence of decreased tubular reabsorption of sodium, bicarbonate and some amino acids. Other tubular functions, including distal urinary acidification and concentrating mechanism were normal. Glomerular filtration rate was moderately decreased. Metachromatic inclusions were demonstrated along the nephron by histochemistry and electron microscopy. Tubular dysfunction in metachromatic leukodystrophy could have been overlooked until now given the severity of the neurological picture.

Acidosis, Renal Tubular↗

PubMed1978

Adult metachromatic leukodystrophy. Arylsulphatase-A values in four generations of one family and some reflections about the genetics.

The authors describe an investigation of Adult Metachromatic Leukodystrophy in a Dutch family, of which two persons were affected. The studies of leukocyte arylsulphatase-A activity were made in 47 members of 4 generations of the same family. The propositus, a 30-year old man, showed a conspicious organic brain syndrome, that progressed in two years to a complete dementia. His leukocyte, liver and kidney arylsulphatase-A activities (ASA) were very low; leukocyte-ASA activity increased after aceto-salicylate. His brother had died at 34 years, after a progressive debelitating neuropsychiatric illness of eight years; postmortem metachromatic leukodystrophy was diagnosed. In all living family members, urine and leukocyte arylsulphatase-A activities were determined. The findings are discussed in relation to the genetics and pathogenesis of this adult form of metachromatic leukodystrophy. Allelic heterozygoty is proposed as inheritance model in this family. Suggestions for further research are made.

Adult↗

PubMed1978

Computed tomography in late-infantile metachromatic leukodystrophy.

Computed tomography of 2 patients with late-infantile metachromatic leukodystrophy (MLD) demonstrated generalized white matter lucency and moderate ventricular enlargement. CAT scan findings in other white matter diseases likely to be confused clinically with MLD are sufficiently dissimilar to allow differentiation.

Brain↗

PubMed1979

Juvenile-onset metachromatic leukodystrophy: biochemical and electrophysiologic studies.

A 15-year-old girl with juvenile-onset metachromatic leukodystrophy (MLD) had markedly decreased leukocyte arylsulfatase A activity and low levels of leukocyte beta galactosidase and serum acid phosphatase. There was marked slowing of nerve condition velocity, and metachromasia was seen in biopsied sural nerve. Leukocyte arylsulfatase A activity was decreased in all members of the girl's family, and sural nerve action potentials were abnormal in two asymptomatic siblings. Electrophysiologic studies combined with biochemical studies may aid in the identification of presymptomatic metachromatic leukodystrophy homozygotes or asymptomatic heterozygotes.

Adolescent↗

PubMed1979

Ocular findings in metachromatic leukodystrophy. An electron microscopic and enzyme study in different clinical and genetic variants.

Histopathological studies of the eyes from three patients affected with the infantile form of metachromatic leukodystrophy (MLD) showed the storage of metachromatic complex lipids in the retinal ganglion cells, in the optic nerve and the ciliary nerves, as well as the storage of a mucopolysaccharide-like material in the nonpigmented epithelium of the ciliary body. The lesions were limited to the optic, ciliary, and sensory nerves in a fourth patient with the juvenile form of the disorder. These morphological aspects, which are probably related to differences in sulfatase A activities, may explain the variability of the ocular manifestations in metachromatic leukodystrophy. Seven children affected with infantile MLD or with mucosulfatidosis were examined by conjunctival biopsy. Typical lesions of the sensory nerves were obvious and allowed the diagnosis of the disease. However, it seemed impossible to separate the different forms by histopathological studies only. The tear enzymes were assayed in most of the cases and demonstrated a profound deficiency of arylsulfatase A, or of arylsulfatase A and B, in the classical MLD and in mucosulfatidosis, respectively.

Cerebroside-Sulfatase↗

PubMed1976