The clinical spectrum and developmental features of mucolipidosis type IV, a recessive lysosomal ... more The clinical spectrum and developmental features of mucolipidosis type IV, a recessive lysosomal storage disorder, are presented. The evaluation was based on information from the clinical charts and information obtained from the families of 20 patients between the ages of 2 to 17 years. The clinical manifestations of the disease, profound psychomotor retardation and visual impairment, appear during the first year of life. Definitive diagnosis is made by electron microscopy which reveals storage organelles typical of the mucolipidoses. This study details, for the first time, the heterogeneity of the ophthalmologic features, specifically as pertains to the age of onset, degree and clinical course of the corneal opacities, and the retinal involvement. Although the top developmental level was found to be 12 to 15 months in language and motor function, the course of the disease is protracted for some children, who show only a slight improvement, and others, little if any deterioration de...
To the Editor.— We read with interest the presentation by Amir et al1 concerning the clinical spe... more To the Editor.— We read with interest the presentation by Amir et al1 concerning the clinical spectrum and natural history of mucolipidosis type IV. Based on their experience with 20 patients, they try to provide guidelines for the clinical diagnosis of this lysosomal storage disease. It appears that severe visual impairment (due mainly to corneal opacities, myopia, and retinal degeneration) and psychomotor retardation are the cardinal features of this entity. However, corneal clouding and mild motor delay in their early stages may frequently be missed by even experienced pediatricians and we recently examined a 15-month-old boy who was referred to us for evaluation of a possible congenital myopathy.
Autosomal recessive congenital ichthyosis (ARCI) is a rare and heterogeneous skin cornification d... more Autosomal recessive congenital ichthyosis (ARCI) is a rare and heterogeneous skin cornification disorder presenting with generalized scaling and varying degrees of erythema. Clinical manifestations range from lamellar ichthyosis (LI), congenital ichthyosiform erythroderma (CIE) through the most severe form of ARCI, Harlequin ichthyosis (HI). We used homozygosity mapping, whole‐exome and direct sequencing to delineate the relative distribution of pathogenic variants as well as identify genotype‐phenotype correlations in a cohort of 62 Middle Eastern families with ARCI of various ethnic backgrounds. Pathogenic variants were identified in most ARCI‐associated genes including TGM1 (21%), CYP4F22 (18%), ALOX12B (14%), ABCA12 (10%), ALOXE3 (6%), NIPAL4 (5%), PNPLA1 (3%), LIPN (2%) and SDR9C7 (2%). In 19% of cases, no mutation was identified. Our cohort revealed a higher prevalence of CYP4F22 and ABCA12 pathogenic variants and a lower prevalence of TGM1 and NIPAL4 variants, as compared to data obtained in other regions of the world. Most variants (89%) in ALOX12B were associated with CIE and were the most common cause of ARCI among patients of Muslim origin (26%). Palmoplantar keratoderma associated with fissures was exclusively a result of pathogenic variants in TGM1. To our knowledge, this is the largest cohort study of ARCI in the Middle‐Eastern population reported to date. Our data demonstrate the importance of population‐tailored mutation screening strategies and shed light upon specific genotype‐phenotype correlations.
Mucolipidosis IV, a recently recognized metabolic storage disease, is characterized clinically by... more Mucolipidosis IV, a recently recognized metabolic storage disease, is characterized clinically by corneal opacity in infancy, full facial features, and psychomotor retardation. Electron microscopy of cells from a 2-year-old affected girl revealed multiple cytoplasmic storage bodies. Cultured amniotic fluid cells, in two subsequent pregnancies, demonstrated similar abnormal storage bodies. Electron microscopic examination of various uncultured tissues from one abortus demonstrated abnormal inclusions in the cells of the brain, cornea, con]unctiva, and other epithelial tissues, thus confirming the prenatal diagnosis. This suggests that mucolipidosis IV is an autosomal recessive trait and demonstrates the efficacy of electron microscopy in the prenatal diagnosis of metabolic storage diseases whose biochemical defect is yet unknown.
Abstract Fibroblasts from patients with the Hunter syndrome are deficient in a specific protein, ... more Abstract Fibroblasts from patients with the Hunter syndrome are deficient in a specific protein, designated "Hunter corrective factor," which is required for the degradation of sulfated mucopolysaccharide. This factor has now been purified 120-fold from normal human urine by (NH4)2SO4 fractionation, gel chromatography on Sephadex G-200, passage through anti-albumin Sepharose to remove albumin, a major contaminant, and finally, preparative polyacrylamide gel electrophoresis. The last procedure separates two "isofactors," which are probably charge isomers; both differ in charge from the Hunter factor derived from fibroblast secretions. The molecular weight of urinary Hunter factor is estimated at 65,000 by polyacrylamide gel electrophoresis and 114,000 by gel filtration. The most highly purified preparation of urinary Hunter factor shows a single protein component in polyacrylamide gel electrophoresis at pH 8, but can be resolved into several bands by isoelectric focusing in polyacrylamide gel. It is free of the common lysosomal glycosidases and sulfatases, as well as of factors effective in other mucopolysaccharidoses (Hurler, Scheie, Sanfilippo A and B, and Maroteaux-Lamy). The Hunter corrective factor accelerates the degradation, by Hunter fibroblasts, of dermatan sulfate labeled in the sulfate or galactosamine moieties, as well as of exogenously added proteodermatan [35S]sulfate. The effect of the factor persists in the recipient cells with a half-life of 2 days.
The cellular localization of glycoprotein and ganglioside sialidases in normal and I-cell-disease... more The cellular localization of glycoprotein and ganglioside sialidases in normal and I-cell-disease cultured fibroblasts has been investigated. Cellular organelles have been separated on a colloidal silica gradient. The subcellular distribution of these enzymes indicated that the glycoprotein sialidase is mainly a lysosomal hydrolase, whereas the ganglioside sialidase is primarily located in the plasma membranes. The latter isoenzymes is tightly bound to these membranes and thus could not be extracted by homogenization in the presence of Triton X-100. The interpretation of this finding and its relation to the pathochemistry of sialidase-deficient disorders is discussed.
The mucopolysaccharidoses are progressive disorders involving multiple organ systems and the excr... more The mucopolysaccharidoses are progressive disorders involving multiple organ systems and the excretion and storage of excess mucopolysaccharides (McKusick and Neufeld, 1982). The mode of inheritance is autosomal recessive for all except one, Hunter syndrome, where sex-linked inheritance is the rule. The abnormal storage is caused by the impairment of mucopolysaccharide catabolism, and specific hydrolase deficiencies account for the widely varying severity and phenotypes observed with these disorders. Fifteen types and subtypes of mucopolysaccharidoses have been characterized (Table I) (McKusick and Neufeld, 1982).
Metachromatic leukodystrophy is a lysosomal storage disorder caused by the deficiency of arylsulf... more Metachromatic leukodystrophy is a lysosomal storage disorder caused by the deficiency of arylsulfatase A. The disease occurs panethnically, with an estimated frequency of 1/40,000. Metachromatic leukodystrophy was found to be more frequent among Arabs living in two restricted areas in Israel. Ten families with affected children have been found, three in the Jerusalem region and seven in a small area in lower Galilee. Whereas all patients from the Jerusalem region are homozygous for a frequent mutant arylsulfatase A allele, five different mutations were found in the families from lower Galilee. In patients of Muslim Arab origin, we have found a G86-->D, a S96-->L, and a Q190-->H substitution. Two different defective arylsulfatase A alleles, characterized by a T274-->M and a R370-->W substitution, respectively, have been found among the Christian Arab patients. All mutations were introduced into the wild-type arylsulfatase A cDNA. No enzyme activity could be expressed f...
The clinical spectrum and developmental features of mucolipidosis type IV, a recessive lysosomal ... more The clinical spectrum and developmental features of mucolipidosis type IV, a recessive lysosomal storage disorder, are presented. The evaluation was based on information from the clinical charts and information obtained from the families of 20 patients between the ages of 2 to 17 years. The clinical manifestations of the disease, profound psychomotor retardation and visual impairment, appear during the first year of life. Definitive diagnosis is made by electron microscopy which reveals storage organelles typical of the mucolipidoses. This study details, for the first time, the heterogeneity of the ophthalmologic features, specifically as pertains to the age of onset, degree and clinical course of the corneal opacities, and the retinal involvement. Although the top developmental level was found to be 12 to 15 months in language and motor function, the course of the disease is protracted for some children, who show only a slight improvement, and others, little if any deterioration de...
To the Editor.— We read with interest the presentation by Amir et al1 concerning the clinical spe... more To the Editor.— We read with interest the presentation by Amir et al1 concerning the clinical spectrum and natural history of mucolipidosis type IV. Based on their experience with 20 patients, they try to provide guidelines for the clinical diagnosis of this lysosomal storage disease. It appears that severe visual impairment (due mainly to corneal opacities, myopia, and retinal degeneration) and psychomotor retardation are the cardinal features of this entity. However, corneal clouding and mild motor delay in their early stages may frequently be missed by even experienced pediatricians and we recently examined a 15-month-old boy who was referred to us for evaluation of a possible congenital myopathy.
Autosomal recessive congenital ichthyosis (ARCI) is a rare and heterogeneous skin cornification d... more Autosomal recessive congenital ichthyosis (ARCI) is a rare and heterogeneous skin cornification disorder presenting with generalized scaling and varying degrees of erythema. Clinical manifestations range from lamellar ichthyosis (LI), congenital ichthyosiform erythroderma (CIE) through the most severe form of ARCI, Harlequin ichthyosis (HI). We used homozygosity mapping, whole‐exome and direct sequencing to delineate the relative distribution of pathogenic variants as well as identify genotype‐phenotype correlations in a cohort of 62 Middle Eastern families with ARCI of various ethnic backgrounds. Pathogenic variants were identified in most ARCI‐associated genes including TGM1 (21%), CYP4F22 (18%), ALOX12B (14%), ABCA12 (10%), ALOXE3 (6%), NIPAL4 (5%), PNPLA1 (3%), LIPN (2%) and SDR9C7 (2%). In 19% of cases, no mutation was identified. Our cohort revealed a higher prevalence of CYP4F22 and ABCA12 pathogenic variants and a lower prevalence of TGM1 and NIPAL4 variants, as compared to data obtained in other regions of the world. Most variants (89%) in ALOX12B were associated with CIE and were the most common cause of ARCI among patients of Muslim origin (26%). Palmoplantar keratoderma associated with fissures was exclusively a result of pathogenic variants in TGM1. To our knowledge, this is the largest cohort study of ARCI in the Middle‐Eastern population reported to date. Our data demonstrate the importance of population‐tailored mutation screening strategies and shed light upon specific genotype‐phenotype correlations.
Mucolipidosis IV, a recently recognized metabolic storage disease, is characterized clinically by... more Mucolipidosis IV, a recently recognized metabolic storage disease, is characterized clinically by corneal opacity in infancy, full facial features, and psychomotor retardation. Electron microscopy of cells from a 2-year-old affected girl revealed multiple cytoplasmic storage bodies. Cultured amniotic fluid cells, in two subsequent pregnancies, demonstrated similar abnormal storage bodies. Electron microscopic examination of various uncultured tissues from one abortus demonstrated abnormal inclusions in the cells of the brain, cornea, con]unctiva, and other epithelial tissues, thus confirming the prenatal diagnosis. This suggests that mucolipidosis IV is an autosomal recessive trait and demonstrates the efficacy of electron microscopy in the prenatal diagnosis of metabolic storage diseases whose biochemical defect is yet unknown.
Abstract Fibroblasts from patients with the Hunter syndrome are deficient in a specific protein, ... more Abstract Fibroblasts from patients with the Hunter syndrome are deficient in a specific protein, designated "Hunter corrective factor," which is required for the degradation of sulfated mucopolysaccharide. This factor has now been purified 120-fold from normal human urine by (NH4)2SO4 fractionation, gel chromatography on Sephadex G-200, passage through anti-albumin Sepharose to remove albumin, a major contaminant, and finally, preparative polyacrylamide gel electrophoresis. The last procedure separates two "isofactors," which are probably charge isomers; both differ in charge from the Hunter factor derived from fibroblast secretions. The molecular weight of urinary Hunter factor is estimated at 65,000 by polyacrylamide gel electrophoresis and 114,000 by gel filtration. The most highly purified preparation of urinary Hunter factor shows a single protein component in polyacrylamide gel electrophoresis at pH 8, but can be resolved into several bands by isoelectric focusing in polyacrylamide gel. It is free of the common lysosomal glycosidases and sulfatases, as well as of factors effective in other mucopolysaccharidoses (Hurler, Scheie, Sanfilippo A and B, and Maroteaux-Lamy). The Hunter corrective factor accelerates the degradation, by Hunter fibroblasts, of dermatan sulfate labeled in the sulfate or galactosamine moieties, as well as of exogenously added proteodermatan [35S]sulfate. The effect of the factor persists in the recipient cells with a half-life of 2 days.
The cellular localization of glycoprotein and ganglioside sialidases in normal and I-cell-disease... more The cellular localization of glycoprotein and ganglioside sialidases in normal and I-cell-disease cultured fibroblasts has been investigated. Cellular organelles have been separated on a colloidal silica gradient. The subcellular distribution of these enzymes indicated that the glycoprotein sialidase is mainly a lysosomal hydrolase, whereas the ganglioside sialidase is primarily located in the plasma membranes. The latter isoenzymes is tightly bound to these membranes and thus could not be extracted by homogenization in the presence of Triton X-100. The interpretation of this finding and its relation to the pathochemistry of sialidase-deficient disorders is discussed.
The mucopolysaccharidoses are progressive disorders involving multiple organ systems and the excr... more The mucopolysaccharidoses are progressive disorders involving multiple organ systems and the excretion and storage of excess mucopolysaccharides (McKusick and Neufeld, 1982). The mode of inheritance is autosomal recessive for all except one, Hunter syndrome, where sex-linked inheritance is the rule. The abnormal storage is caused by the impairment of mucopolysaccharide catabolism, and specific hydrolase deficiencies account for the widely varying severity and phenotypes observed with these disorders. Fifteen types and subtypes of mucopolysaccharidoses have been characterized (Table I) (McKusick and Neufeld, 1982).
Metachromatic leukodystrophy is a lysosomal storage disorder caused by the deficiency of arylsulf... more Metachromatic leukodystrophy is a lysosomal storage disorder caused by the deficiency of arylsulfatase A. The disease occurs panethnically, with an estimated frequency of 1/40,000. Metachromatic leukodystrophy was found to be more frequent among Arabs living in two restricted areas in Israel. Ten families with affected children have been found, three in the Jerusalem region and seven in a small area in lower Galilee. Whereas all patients from the Jerusalem region are homozygous for a frequent mutant arylsulfatase A allele, five different mutations were found in the families from lower Galilee. In patients of Muslim Arab origin, we have found a G86-->D, a S96-->L, and a Q190-->H substitution. Two different defective arylsulfatase A alleles, characterized by a T274-->M and a R370-->W substitution, respectively, have been found among the Christian Arab patients. All mutations were introduced into the wild-type arylsulfatase A cDNA. No enzyme activity could be expressed f...
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