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ABSTRACT: Inborn metabolic errors causing lysosomal storage, such as β-galactosidase deficiency (GM1 gangliosidosis [GM1]), have well-recognized effects on cellular function and morphology. In some classically “neuronal” storage diseases, including GM1, neuroradiologic observations of infants have suggested a delay in myelination on the basis of persistently “immature” signal intensities monitored over time. We sought to evaluate in a semiquantitative fashion the pattern and degree of myelination in two infantile GM1 patients, one boy and one girl, autopsied at 15 months of age. We assigned myelination degrees for defined sites on an ordinal scale of 0 to 4, and compared them to published population-based values for autopsied infants. In both patients, earlier-myelinating structures were comparable in development to that expected for postconceptional age, whereas later-myelinating structures were delayed. These data correlate well with the neuroradiologic diagnosis of myelination delay in these infants and suggest that the metabolic defect has a primary influence on myelin development, in addition to effects related to neuronal storage. Furthermore, our analysis by light and electron microscopy and lectin histochemistry of both CNS and systemic tissues, several of which had not been described, add to the understanding of the stored material in different cell types.

Summary: Autopsy samples were obtained from a 12.5-year-old girl who died with a neurologic disorder consisting of myoclonus, myoclonic epilepsy, spasticity, strabismus, and mild mental retardation but no hepatosplenomegaly. Studies in leukocytes, cultured skin fibroblasts, brain, liver, and spleen of this patient revealed glucosylceramide ß-glucosidase (EC 3.2.1.45, glucocerebrosidase) activity about 10% of controls, and well in the range found in samples from Gaucher disease patients. Extraction of the lipids from liver and spleen with chloroform-methanol (2:1) did not show accumulation of glucosylceramide or other lipid. Examination of the lipids in brain by high performance liquid chomatography revealed the presence of glucosylceramide, which is not found in brain samples from controls. Pathologic examination of the liver and spleen revealed no evidence of Gaucher disease. The brain showed many degenerative lesions and loss of neurons. There was no complementation of glucocerebrosidase activity when the cells from this patient were hybridized with cells from patients with Type 1 or Type 2 Gaucher disease. The reason for the lack of glucosylceramide storage in the liver and spleen has not been determined.

Autopsy samples were obtained from a 12.5-year-old girl who died with a neurologic disorder consisting of myoclonus, myoclonic epilepsy, spasticity, strabismus, and mild mental retardation but no hepatosplenomegaly. Studies in leukocytes, cultured skin fibroblasts, brain, liver, and spleen of this patient revealed glucosylceramide β-glucosidase (EC 3.2.1.45, glucocerebrosidase) activity about 10 of controls, and well in the range found in samples from Gaucher disease patients. Extraction of the lipids from liver and spleen with chloroform-methanol (2:1) did not show accumulation of glucosylceramide or other lipid. Examination of the lipids in brain by high performance liquid chomatography revealed the presence of glucosylceramide, which is not found in brain samples from controls. Pathologic examination of the liver and spleen revealed no evidence of Gaucher disease. The brain showed many degenerative lesions and loss of neurons. There was no complementation of glucocerebrosidase activity when the cells from this patient were hybridized with cells from patients with Type 1 or Type 2 Gaucher disease. The reason for the lack of glucosylceramide storage in the liver and spleen has not been determined.

Perbenzoylated gluco- and galactocerebrosides were separated and quantitated with a modification of existing HPLC methodology. A linear gradient of 0.9–18.4% dioxane in hexane was used to separate the derivatives on a pellicular silica column heated to 65°C. The elevated temperature was the major modification that permitted the separation. This system was compared to a previously reported silica column/isopropanol in hexane system.

Three unrelated North American cases with slowly progressive forms of GM1gangliosidosis were found to have two unique point mutations and a 9 bp insertion in the coding region of the gene encoding β-galactosidase. Case 1 was noted to have a 9 bp insertion {CAGAATTTT} on one allele between nucleotides 730 and 731 with no other mutations identified in the other allele. In case 2, two point mutations were found: a unique G→A transition at nucleotide 602 causing an Arg→His substitution in codon 201 (mutation R201H); and a previously identified G→T transition at nucleotide 1527 causing a Trp→Cys substitution in codon 509 (mutation W509C), which has been noted in adult and chronic forms of GM1gangliosidosis. Case 3 had a unique point mutation (A→G transition at nucleotide 797) resulting in a Asn→Ser amino acid substitution in codon 266 (mutation N266S), with no other mutations found in the same or the other allele. Single-strand conformation polymorphism performed on over 100 controls did not demonstrate the presence of the point mutations R201H or N266S. Also, the mutant proteins coded by the two point mutations did not show enzymatic activity in the Cos-1 cell expression system confirming that these mutations are associated with low enzyme activity. ( J Child Neurol1997;12:242—247).

In this report, we have summarized our 9-year experience of over 100 proven cases of lysosomal storage disease using electron microscopic evaluation of skin biopsies as a screening tool. The skin biopsy was very specific in establishing the diagnosis in only two disorders, namely neuronal ceroid lipofuscinosis and mucolipidosis IV. Although the biopsy was not diagnostic in other categories of storage diseases, it proved to be highly sensitive and provided valuable clues to direct further investigations on the basis of morphologic appearance of stored material and the cell type affected. Only in two cases of biochemically proven lysosomal storage disease was the morphologic diagnosis unable to be confirmed. We have compared the cost of screening for storage disorders using skin biopsy with the cost of performing multiple lysosomal enzyme assays. Our findings indicate that the skin biopsy, although more expensive than a single enzyme assay, provides an efficient, rapid, cost-effective tool to screen for more than 35 lysosomal storage disorders. (J Child Neurol1996;11:301-308).

Moyamoya disease is an idiopathic disorder characterized by progressive occlusion of the internal carotid and anterior and middle cerebral arteries, with formation of an extensive abnormal collateral circulation at the base of the brain. Many neurosurgical procedures have been designed to bypass these occluded vessels. The results of one of these procedures, modified encephaloduroarteriosynangiosis was reviewed in five children followed for 3½ to 19½ years. Modified encephaloduroarteriosynangiosis performed unilaterally in one and bilaterally in four of the children, appeared to halt neurologic deterioration, despite angiographic progression, in four of the five children. (J Child Neurol1991;6:24-31).

Six children who sustained head trauma of varying degrees experienced self-limited cortical blindness—complete bilateral visual loss associated with normal pupillary responses to light. In five cases associated with relatively minor head trauma, full visual function returned within 24 hours. In the other case, associated with parietal and occipital contusions, the period of complete blindness was prolonged, lasting 1 week, followed by a striking recovery over an additional week. A bilateral inferior altitudinal visual field deficit has persisted over 6 years, with emergence of a complicated migraine syndrome. Sequential computed tomographic (CT) scans over a 4-year period demonstrate bioccipital and right parietal injury, correlating clinical and anatomic findings. This case is the first description of prolonged transient post-traumatic cortical blindness in a child with CT correlation. It underscores the clinical, radiographic, and pathophysiologic differences between syndromes of brief and prolonged transient post-traumatic cortical blindness in childhood. (J Child Neurol1986;1:206-210).

Two full-term unrelated infants developed herpetic lesions at the site of scalp fetal monitor electrodes several days after uncomplicated labor and vaginal delivery. The mothers had been asymptomatic during pregnancy. In addition to the scalp vesicles, one infant had unilateral herpetic conjunctivitis; the other infant had vesicles on the face without ocular involvement. Both babies had cerebro-spinal fluid (CSF) pleocytosis and elevated protein. Herpes virus was cultured from the vesicles and CSF. Computed tomography showed low density areas in the frontotemporal regions. On follow-up, seizures persisted and neurologic development was impaired. These patients illustrate the potential risk of infection when internal fetal monitoring is used in low risk pregnancies.

Central nervous system–directed antisense therapy ameliorates symptoms in a severe neuromuscular disorder in mice.