AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Classification of Lysosomal Storage Diseases
• Glycogen Storage Disease Type II
• Mucopolysaccharidoses
• I-Cell Disease and Pseudo-Hurler Polydystrophy
• Schindler Disease
• Alpha-mannosidosis and Beta-mannosidosis
• Wolman Disease, Cholesteryl Ester Storage Disease, and Niemann-Pick Disease
• Acknowledgments
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Classification of Lysosomal Storage Diseases
• Glycogen Storage Disease Type II
• Mucopolysaccharidoses
• I-Cell Disease and Pseudo-Hurler Polydystrophy
• Schindler Disease
• Alpha-mannosidosis and Beta-mannosidosis
• Wolman Disease, Cholesteryl Ester Storage Disease, and Niemann-Pick Disease
• Acknowledgments
• References

Definitions

Lysosomes are subcellular organelles responsible for the physiologic turnover of cell constituents containing catabolic enzymes requiring a low optimum pH to function.

Lysosomal storage diseases describe a heritable group of heterogeneous human disorders characterized by the accumulation of undigested macromolecules intralysosomally, resulting in an increase in the size and number of these organelles and ultimately in cellular dysfunction and clinical abnormalities.

Lysosomal storage diseases are generally classified by the accumulated substrate and they include sphingolipidoses, glycoproteinoses, mucolipidoses, mucopolysaccharidoses (MPSs), and others.

The concept of lysosomal storage disease has been expanded to include deficiencies in lysosomal enzymes, deficiencies in the noncatalytic lysosomal proteins, and more general abnormalities in lysosomal function occurring in the lysosome.

New developments in 2005 and 2006

Therapy is increasingly promising, albeit expensive. Enzyme replacement therapy appears extraordinarily effective for patients with Gaucher disease types I and III, Fabry disease, and Hurler-Scheie syndrome. In persons with Gaucher disease, a chemokine, CCL18, has been identified as a biomarker for clinical development that reflects disease severity and treatment responsiveness (Cox, 2005).

Manifestations

Although these abnormalities result in substrate accumulation, the underlying mechanisms relating to the pathologic effects are not entirely clear. However, the distribution of the accumulating material does determine which organs are affected. In particular, neurons that are incapable of cell division are commonly impaired because of the accumulation of undegraded material and lack of cell turnover. Cells of the mononuclear phagocyte system are especially rich in lysosomes and so are frequently affected by lysosomal storage diseases.

Lysosomal storage diseases may result in a severe neurodegenerative phenotype. Milder or later onset phenotypes have been identified and are related to residual enzyme activity. Such subtypes and variants show that even at low enzyme activity levels (as low as 1-5% of normal), a severe neurologic course can be modified into a milder, often nonneurologic, phenotype.

Pathophysiology

Recent advances in molecular genetics have shifted the focus both in gene products and genes themselves. The defective genes in most of these genetic diseases have been isolated and characterized and the specific mutations identified. At the gene level, genetic heterogeneity is complex despite similar phenotypes, biochemistry, and enzyme defects.

In 2003, Peters noted that hematopoietic cell transplantation (HCT) has been used as effective therapy for selected inherited metabolic diseases (IMDs), including Hurler (MPS IH) and Maroteaux-Lamy (MPS VI) syndromes, childhood-onset cerebral X-linked adrenoleukodystrophy (X-ALD), globoid-cell leukodystrophy, metachromatic leukodystrophy, alpha-mannosidosis, osteopetrosis, and others. It is a promising treatment for a variety of lysosomal storage diseases, which otherwise can be fatal.

Testing

In general, according to Parkinson-Lawrence et al in 2006, immune assays provide a direct practical application for the early detection, diagnosis, and prognosis of those with lysosomal storage disorder. Multiplexing of these assays may provide a platform to allow newborn screening for multiple lysosomal storage disorders.

CLASSIFICATION OF LYSOSOMAL STORAGE DISEASES

Section 3 of 11  

• Authors and Editors
• Introduction
• Classification of Lysosomal Storage Diseases
• Glycogen Storage Disease Type II
• Mucopolysaccharidoses
• I-Cell Disease and Pseudo-Hurler Polydystrophy
• Schindler Disease
• Alpha-mannosidosis and Beta-mannosidosis
• Wolman Disease, Cholesteryl Ester Storage Disease, and Niemann-Pick Disease
• Acknowledgments
• References

More than 40 lysosomal storage diseases are described.

• Glycogen storage disease type II (alpha-glucosidase)
• Mucopolysaccharidoses
• • MPS type IH, Hurler syndrome (alpha-L-iduronidase)
  • MPS type I H/S, Hurler-Scheie syndrome
  • MPS type I S, Scheie syndrome
  • MPS type II A, Hunter syndrome, severe (iduronate sulfatase)
  • MPS type II B, Hunter syndrome, mild (iduronate sulfatase)
  • MPS type III A-D, Sanfilippo syndrome (heparan N-sulfatase)
  • MPS type IV A, Morquio syndrome, classic (galactose 6-sulfatase)
  • MPS type VI, Maroteaux-Lamy syndrome (arylsulfatase B)
  • MPS type VII, Sly syndrome (beta-glucuronidase)
• Mucolipidosis II (I-cell disease) and mucolipidosis III (phosphotransferase)
• Schindler disease/Kanzaki disease (alpha-N-acetylgalactosaminidase)
• • In a 1995 report, Kanzaki noted that Schindler disease and Kanzaki disease are caused by a deficient lysosomal enzyme, alpha-N-acetylgalactosaminidase (EC 3.2.1.49).
  • Two German children were first described in 1987, and two Dutch children were recently described in 1993. These children were similar clinically, and their conditions were characterized by marked neuroaxonal dystrophy of an infantile onset. In these children, type 1 was named Schindler disease.
  • An adult patient with profuse angiokeratoma corporis diffusum but minimum involvement in the nervous system was reported in 1987 from Japan. This disease (type 2) was named Kanzaki disease (OMIM 104170).
• Glycoprotein degradation
• Alpha-mannosidosis and beta-mannosidosis
• Fucosidosis
• • Fucosidosis is a rare autosomal recessive lysosomal storage disease.
  • Its main clinical findings are progressive neuromotor deterioration, seizures, coarse facial features, dysostosis multiplex, angiokeratoma corporis diffusum, visceromegaly, recurrent respiratory infections, and growth retardation.
  • Fucosidosis type I rapidly evolves toward a progressive neurologic deterioration and death.
• Sialidosis
• • In 2003, Rodriguez Criado noted that sialidosis (OMIM 256550) is an autosomal recessive disorder resulting from mutations in the NEU gene, located in 6p21.3.
  • This condition leads to deficiency of alpha-N-acetyl neuraminidase (sialidase) activity, causing an accumulation of its substrates, oligosaccharides, in the lysosomes of various organs and tissues and an increased presence in urine and other organic fluids.
  • Sialidosis is associated with progressively impaired vision, macular cherry-red spots, and myoclonus (sialidosis type I) or with skeletal dysplasia, Hurlerlike phenotype, dysostosis multiplex, mental retardation, and hepatosplenomegaly (sialidosis type II) (Lukong, 2001).
• Aspartylglucosaminuria (AGU)
• • A deficiency of functional aspartylglucosaminidase (AGA) causes AGU, which is a lysosomal storage disease. In 1999, Aronson noted that AGU (OMIM 208400) is an autosomal recessive lysosomal storage disease caused by defective degradation of aspartate (Asn)-linked glycoproteins.
  • AGU mutations occur in the gene (AGA) for glycosylasparaginase, the enzyme necessary for hydrolysis of the protein oligosaccharide linkage in Asn-linked glycoprotein substrates undergoing metabolic turnover.
  • Loss of glycosylasparaginase activity leads to accumulation of the linkage unit Asn-GlcNAc in tissue lysosomes. Storage of this fragment affects the pathophysiology of neuronal cells most severely.
  • Patients notably experience decreased cognitive abilities, skeletal abnormalities, and facial grotesqueness.
  • The progress of the disease is slower than in many other lysosomal storage diseases. Patients appear healthy during infancy and generally live from 25-45 years.
• Carbohydrate-deficient glycoprotein syndrome
• • Patients with carbohydrate-deficient glycoprotein syndrome can present with dysmorphic features, hypotonia, ataxia, a convergent squint, nystagmus, myopia, progressive retinal degeneration, developmental delay, pericardial effusion, esotropia, retinitis pigmentosa, and strabismus.
  • Carbohydrate-deficient glycoprotein syndrome can be confirmed by serum levels of carbohydrate-deficient transferrin.
  • MRI can show atrophy of the cerebellum and brain stem and hypointensity in the pallidum on diffusion-weighted images, suggesting deposits of metal substances.
  • In the cerebellum, proton magnetic resonance spectroscopy can show decreased concentrations of N-acetylaspartate and a complex of glutamine and glutamate (Glx), while the concentration of myo-inositol is increased, indicating neuronal impairment and gliosis.
  • In the parietal lobe, concentration of Glx can be increased, possibly reflecting dysfunction caused by liver injury.
• Wolman and cholesterol ester storage disease (acid lipase)
• Farber disease, disseminated lipogranulomatosis (ceramidase)
• • Farber disease is a rare lysosomal storage disease characterized by the accumulation of ceramide in tissues because of acid ceramidase deficiency. The detection of low levels of acid ceramidase is diagnostic of the condition.
  • Histopathology shows foam cells and granulomatous infiltration. Ultramicroscopically, curvilinear tubular bodies are present as comma-shaped tubular structures consisting of two single membranes separated by a clear space in dermal fibroblasts.
  • Banana bodies, variably membrane-bound structures that have a spindle and usually a curved shape, are found predominantly in Schwann cells of peripheral nerves.
  • Radiography can show diffuse osteopenia, underdevelopment of the terminal phalanges, and reduced long bone diameters.
  • Farber disease starts to manifest in patients aged 4 months as a hoarse cry or swollen tender joints followed by subcutaneous nodules, flesh-colored papules, and periarticular tumors or nodules.
  • Reports exist of coarse facial features and xanthoma, such as papules on the face and hands.
  • This disease is fatal in the first years of life.
• Niemann-Pick disease
• • Niemann-Pick disease type A (sphingomyelinase)
  • Niemann-Pick disease type B (sphingomyelinase)
  • Niemann-Pick disease C1 (NPC1)
  • Niemann-Pick disease C2
  • Niemann-Pick disease is not the same entity as Pick disease. Pick disease is a progressive illness that affects brain function, eventually causing loss of verbal skills and problem-solving abilities. Pick disease accounts for 5% of all dementias. Its basis is usually a genetic defect. Pick disease has subtypes, including classic Pick disease, also referred to as Constantinidis type A Pick disease. Classic Pick disease has Pick bodies. This is contrasted with other Pick disease subtypes, including Constantinidis type B (corticobasal degeneration) and type C (dementia lacking distinctive histology). Pick disease can clinically resemble Alzheimer disease. Both Pick disease and Alzheimer disease are not commonly confused with Niemann-Pick disease.
• Gaucher disease types I, II, and III (beta-glucosidase)
• • Gaucher disease, a common lysosomal storage disease, is associated with mutations at the acid beta-glucosidase (GCase) locus.
  • Great phenotypic variety exists in the nonneuronopathic form (type I), ranging from clinically asymptomatic to massive hepatomegaly, hypersplenism, growth retardation in children, and extensive involvement of bone and lungs.
  • Acute (type II) or subacute (type III) forms with neurologic manifestations exist.
  • Enzyme replacement therapy has become available and has resulted in a reduction in liver and spleen volume and consequently improved anemia and thrombocytopenia in most patients. OGT-918 (N-butyldeoxynojirimycin) is showing promise in patients with Gaucher disease.
• Krabbe disease, infantile globoid-cell leukodystrophy (galactosylceramidase)
• • Krabbe disease manifests in infants with central nervous system manifestations of spasticity, irritability, motor regression, and seizures associated with a positive family history.
  • A form of late-onset Krabbe disease can manifest with asymmetrical peripheral neuropathy associated with pyramidal signs and with electrophysiologic examination showing slowing of nerve conduction velocities.
• Fabry disease (alpha-galactosidase A)
• • In 2003, Mohrenschlager performed an extensive survey of this condition. Fabry disease is also referred to as angiokeratoma corporis diffusum universale because it manifests with generalized angiokeratomas.
  • This disease is uncommon and inherited as an X chromosome–linked lysosomal storage disease.
  • The deficient enzyme, alpha-galactosidase A (alpha-gal A), causes the accumulation of neutral glycosphingolipids within vascular endothelial lysosomes.
  • Fabry disease can involve the skin, kidneys, heart, and brain.
  • The disease manifests primarily in affected hemizygous men and, to some extent, heterozygous women (carriers).
  • Clinical manifestations include angiokeratomas, irregularities in sweating, edema, scant body hair, painful sensations, and manifestations of cardiovascular, gastrointestinal, renal, ophthalmologic, phlebologic, and respiratory involvement.
  • A deficiency of alpha-gal A in serum, leukocytes, tears, tissue specimens, or cultured skin fibroblasts can define the diagnosis in men.
• Multiple sulfatase deficiency (sulfatases)
• • Multiple sulfatase deficiency is caused by mutations in the gene encoding the human C (alpha)-formylglycine–generating enzyme.
  • Multiple sulfatase deficiency is an inborn error of metabolism that combines the clinical features of late infantile metachromatic leukodystrophy and MPS.
  • Multiple sulfatase deficiency (OMIM 272200) is an autosomal recessive leukodystrophy associated with the deficiency of 7 sulfatases.
  • Clinical manifestations include ichthyosis, broad thumbs and index fingers, progression of the neurologic symptoms, and hepatosplenomegaly.
• GM1 gangliosidosis and Morquio B disease (beta-galactosidase)
• • In 2000, Gosele noted that the Morquio syndrome is a rare autosomal recessive MPS.
  • Morquio syndrome is characterized by a reduced activity of N-acetylgalactosamine-6-sulfate-sulfatase (type A), or beta-galactosidase (type B). This deficiency leads to a lysosomal storage disease with accumulation of keratan sulfate and chondroitin-6-sulfate in connective tissue, bones, and teeth.
  • Pathology of the skeletal system, aortic valvular disease, and dental abnormalities occur.
  • In the eyes, diffuse corneal opacification and alterations of the trabecular meshwork occur, occasionally leading to glaucoma.
• Galactosialidosis (protective protein)
• • Galactosialidosis is an autosomal recessive lysosomal storage disease caused by a combined deficiency of lysosomal beta-galactosidase and neuraminidase as a result of a primary defect in the protective protein/cathepsin A (PPCA).
  • This disease can manifest with gargoylism, macular cherry-red spots, angiokeratoma, vertebral deformities, epilepsy, action myoclonus, and ataxia. Its onset is variable.
• GM2 gangliosidosis, Tay-Sachs and Sandhoff diseases (hexosaminidase)
• • Tay-Sachs disease (TSD), Sandhoff disease (SD), and variants are caused by deficient activity of the lysosomal enzymes hexosaminidase A (HA) and total hexosaminidase (TH), ie, hexosaminidase A plus B, respectively.
  • These diseases manifest with early and fatal neurologic disease.
• Cystinosis (cysteine transporter)
• • In 2003, Kalatzis reviewed cystinosis. Cystinosis is a lysosomal transport disorder characterized by an intralysosomal accumulation of cystine, the disulfide of the amino acid cysteine. It is the most common inherited cause of the renal Fanconi syndrome.
  • Various clinical forms exist, infantile, juvenile, and ocular, based on age of onset and severity of symptoms.
  • The causative gene is CTNS. CTNS encodes cystinosin, a novel 7 transmembrane domain (TM) protein.
  • Cystinosin is a lysosomal membrane protein that requires 2 lysosomal targeting signals: a classic GYDQL motif in its C-terminal tail and a novel conformational motif, the core of which is YFPQA, situated in the fifth inter-TM loop. Cystinosin is the lysosomal cystine transporter, and its activity is H⁺ driven.
• Sialic acid storage disease (sialic acid transporter)
• • In 2003, Kleta reviewed this disease.
  • Sialic acid storage disease results in developmental delays and growth retardation. It is part of the group of allelic lysosomal sialic acid storage disorders, Salla disease, and infantile free sialic acid storage disease (ISSD).
  • Because of defective free sialic acid transport out of lysosomes, these diseases are derived from mutations in the SLC17A5 gene coding for the protein sialin.
• Pyknodysostosis (cathepsin K)
• • Pyknodysostosis is a rare sclerosing bone disorder that has an autosomal trait.
  • It is characterized by short stature, brachycephaly, short and stubby fingers, open cranial sutures and fontanelle, and diffuse osteosclerosis, where multiple fractures of long bones and osteomyelitis of the jaw are frequent complications.
• Metachromatic leukodystrophy (galactose-3-sulfatase)
• • Metachromatic leukodystrophy is characterized by dysmyelination caused by a deficiency of arylsulfatase A.
  • Metachromatic leukodystrophy is both a dysmyelinating and a demyelinating disease.
  • The main clinical forms are infantile or juvenile, but some forms appear at adulthood.
• Galactosialidosis (neuraminidase, beta-galactosidase, protective protein)
• Neuronal ceroid lipofuscinosis, infantile (palmityl protein thioesterase)
• • Neuronal ceroid lipofuscinosis is also known as Batten-Bielschowsky disease.
  • This condition is a group of neurodegenerative disorders associated with various progressive symptoms including seizures, dementia, visual loss, and cerebral atrophy.
• Neuronal ceroid lipofuscinosis, late infantile (carboxypeptidase)
• Cobalamin deficiency type F (cobalamin transporter)

A common finding in MPS is pathologic states of the eye, which can include corneal opacification, retinopathy, optic nerve swelling and atrophy, ocular hypertension, and glaucoma (Ashworth, 2006).

GLYCOGEN STORAGE DISEASE TYPE II

Section 4 of 11  

• Authors and Editors
• Introduction
• Classification of Lysosomal Storage Diseases
• Glycogen Storage Disease Type II
• Mucopolysaccharidoses
• I-Cell Disease and Pseudo-Hurler Polydystrophy
• Schindler Disease
• Alpha-mannosidosis and Beta-mannosidosis
• Wolman Disease, Cholesteryl Ester Storage Disease, and Niemann-Pick Disease
• Acknowledgments
• References

Glycogen storage disease type II, or acid alpha-glucosidase (acid maltase) deficiency, is an inherited disorder of glycogen metabolism resulting from defective activity of the lysosomal enzyme alpha-glucosidase in tissues of affected individuals. In turn, this defect results in intralysosomal accumulation of glycogen of normal structure in numerous tissues.

Clinical presentations

Two major presentations are (1) infantile acid maltase disease, or Pompe disease, and (2) slowly progressive acid maltase disease.

Infantile acid maltase disease, or Pompe disease, is rapidly progressive and usually has an onset in the first 6 months of life. This manifestation is also characterized by macroglossia; progressive cardiomegaly; and rapidly progressive motor weakness with hypotonia, as indicated by feeding and respiratory difficulties. Death prior to age 2 years may be due to cardiorespiratory failure.

Slowly progressive acid maltase disease is characterized by an onset of symptoms in childhood or adult life. Affected individuals may have progressive proximal weakness with manifestations limited to the skeletal muscles. Respiratory dysfunction with early ventilatory insufficiency may be out of proportion to the degree of limb weakness.

Genetic features

The mode of inheritance is autosomal recessive, and the gene encoding for acid alpha-glucosidase has been localized to chromosome arm 17q23.

The disorder is genetically heterogeneous with missense, nonsense, and frameshift mutation, as well as splice-site and partial deletions.

Phenotypic expression is variable, and the severity is probably correlated with residual acid alpha-glucosidase activity.

Laboratory and imaging findings

Laboratory tests may show increased serum creatine kinase (CK) levels.

Electromyographic (EMG) studies may show myopathic features associated with fibrillation potentials, positive waves, bizarre high-frequency discharge, and myotonic discharges. In adult patients, EMG abnormalities are more evident in the paraspinal muscles than elsewhere.

Electrocardiographic findings of short P-R interval, giant QRS complexes, and left ventricular or biventricular hypertrophy

In infantile forms, massive cardiomegaly is shown on chest radiography.

Results of pulmonary function tests show markedly decreased vital capacity, maximal breathing capacity, maximal expiratory, and inspiratory static pressure, as well as early diaphragmatic fatigue.

Diagnosis and differential diagnosis

The clinical diagnosis of glycogen storage disease type II is confirmed by absent or reduced activity in the slowly progressive form of acid glucosidase in muscle biopsy samples and cultured fibroblasts. Prenatal diagnosis is made by measuring alpha-glucosidase activity in cultures of amniotic cells and samples of chorionic villus.

The differential diagnosis includes Duchenne muscular dystrophy, dystrophy of the limb girdle dystrophy, and polymyositis

Management

Conventional treatment for cardiorespiratory problems is indicated.

Definitive therapy is not currently available.

Enzyme therapy, gene replacement, or both are theoretically feasible, and research in these treatments is in progress. Recombinant human enzyme alpha-glucosidase (rhGAA) has recently been designated an orphan drug by the FDA. It has shown improved infant survival without requiring invasive ventilatory support compared with historical controls without treatment.

Epidemiology

In 2005, Marsden et al compiled a report of physician narratives from an epidemiologic study regarding infantile-onset Pompe disease. In this report, the most common presenting symptom was hypotonia (75%), and muscle weakness was a presenting symptom in 59% of patients. Additionally, the sign most commonly noted during the physical examination was hypotonia (82%); respiratory distress, cardiomegaly, weakness, and cardiac failure were frequently reported but percentages were not specified. Progression of the disease was accompanied by increased respiratory distress (72%), hypotonia (66%), and cardiac failure (58%). The most frequent supportive treatments were cardiac medications (52%) and oxygen supplementation (35%).

MUCOPOLYSACCHARIDOSES

Section 5 of 11  

• Authors and Editors
• Introduction
• Classification of Lysosomal Storage Diseases
• Glycogen Storage Disease Type II
• Mucopolysaccharidoses
• I-Cell Disease and Pseudo-Hurler Polydystrophy
• Schindler Disease
• Alpha-mannosidosis and Beta-mannosidosis
• Wolman Disease, Cholesteryl Ester Storage Disease, and Niemann-Pick Disease
• Acknowledgments
• References

Mucopolysaccharides

Mucopolysaccharides are sulfated polymers composed of a central protein moiety attached to repeating disaccharide branches normally degraded into inorganic sulfated monosaccharides in lysosomes.

Dermatan sulfate consists of alternating units of L-iduronic acid and N-acetylgalactosamine, usually found in the matrix of many different connective tissues.

Heparan sulfate is formed by the joining of a uronic acid (D-glucuronic acid or L-iduronic acid) alternating with N-acetylglucosamine and is associated with the cell plasma membrane of almost all cells.

Keratan sulfate is made of D-galactose residues alternating with N-acetylglucosamine and is found largely in cartilage, nucleus pulposus, and cornea.

Chondroitin sulfate is composed of D-glucuronic acid and N-acetylgalactosamine and is largely found in cartilage and cornea.

Mucopolysaccharidoses

MPSs result from abnormal degradation of glycosaminoglycans such as dermatan sulfate, keratan sulfate, heparan sulfate, and chondroitin sulfate resulting in organ accumulation and eventual dysfunction. Glycosaminoglycans or mucopolysaccharides are normally a component of the cornea, cartilage, bone, connective tissue, and the reticuloendothelial system and are therefore target organs for excessive storage. The catabolic enzymes involved in the breakdown of glycosaminoglycans or mucopolysaccharides are deficient. Ten known enzyme deficiencies give rise to 6 distinct MPSs.

The stepwise degradation of the glycosaminoglycans requires 4 glycosidases, 5 sulfatases, and 1 nonhydrolytic transferase. The MPSs share similar clinical features of a chronic and progressive course, multisystem involvement, organomegaly, dysostosis multiplex, and abnormal facies. Mode of transmission is autosomal recessive except for MPS II, which is X-linked. A variety of mutations are described, and correlation of genotype with disease severity is beginning to emerge from mutation analysis.

In general, MPS are progressive disorders, characterized by involvement of multiple organs, including brain, liver, spleen, heart and blood vessels and many are associated with coarse facial features, clouding of the cornea and mental retardation. Diagnosis can often be made by examination of urine, which reveals increased concentration of glycosaminoglycan fragments.

Clinical presentations

MPS type I includes Hurler, Hurler-Scheie, and Scheie syndromes. Alpha-L-iduronidase, which cleaves terminal L-iduronic acid residues from both dermatan and heparan sulfate, is deficient.

• MPS type I H (Hurler syndrome)
• • Excretion of dermatan sulfate and heparan sulfate in the urine is increased in a ratio of 2 to 1.
  • A chromosomal abnormality occurs in chromosome arm 4p16.3.
  • This is a progressive disorder with multiple organ and tissue involvement leading to death by age 10 years.
  • Affected newborns appear healthy.
  • At age 6-24 months, hepatosplenomegaly, skeletal deformities, coarse facial features, enlarged tongue, prominent forehead, and joint stiffness develop.
  • Patients may be large in infancy, but a deceleration of growth occurs at age 6-18 months.
  • Developmental delay is present by age 12-24 months, with a maximum functional age obtainable at 2-4 years, followed by progressive deterioration.
  • Patients develop only limited language skills because of the developmental delay, chronic hearing loss, and enlarged tongue.
  • Most children with Hurler syndrome have recurring upper respiratory tract and ear infections, noisy breathing, and persistent copious nasal discharge.
  • Ophthalmologic manifestations include corneal clouding and glaucoma. Blindness may develop.
  • Neurologic manifestations include communicating hydrocephalus with increased intracranial pressure due to decreased resorption of cerebrospinal fluid (CSF).
  • Life expectancy is markedly reduced with average age of death at 5 years and nearly all succumb by 10 years.
• MPS type I H/S
• • This form is intermediate between the Hurler syndrome and Scheie syndrome.
  • It is characterized by progressive somatic involvement, with little or no intellectual deterioration.
  • Corneal clouding, joint stiffness, deafness, valvular heart disease (occurring in the early to middle teenaged years), and micrognathism occur.
  • Neurologic manifestations include pachymeningitis cervicalis, compression of the cervical cord due to mucopolysaccharide accumulation in the dura, but communicating hydrocephalus appears to be uncommon in patients with normal intelligence.
  • Onset of symptoms is observed at age 3-8 years, and survival to adulthood is common.
  • Cardiac involvement and upper airway obstruction lead to mortality.
• MPS type I S
• • Biochemical findings are identical to type I Hurler syndrome, but the clinical features are less severe because of different mutations within the same gene coding for alpha-L-iduronidase on chromosome 4.
  • Mildly coarsened facies occurs.
  • Joints are stiffened, and the skeletal abnormalities are most pronounced in the hands, with claw hand deformity. Patients can have a stiff painful foot, pes cavus, and genu valgum.
  • Patients achieve normal stature and have normal intelligence.
  • Neurologic manifestations include pachymeningitis cervicalis and deafness. Entrapment neuropathy such as carpal tunnel syndrome is common.
  • Ocular findings include glaucoma, corneal clouding, and retinal degeneration.
  • Respiratory symptoms of obstructive airway disease cause sleep apnea.
  • Cardiac symptoms of aortic valvular disease with stenosis and regurgitation occur due to buildup of mucopolysaccharides on valves and chordae tendinea.
  • Life expectancy is longer than in Hurler syndrome and is dependent on degree of cardiac involvement.
  • Onset of symptoms is usually after 5 years, with the diagnosis commonly made in patients aged 10-20 years.
• MPS type II (Hunter syndrome)
• • Iduronate-2 sulfatase (known as the Hunter corrective factor), which specifically removes the sulfate group from the 2 position of L-iduronic acid in dermatan sulfate and in heparan sulfate, is deficient.
  • Transmission is X-linked recessive, with the abnormality mapped to Xq27/28.
  • The distinctive feature of MPS II is the occurrence of a pebbly ivory-colored skin lesion over the back, upper arms, and lateral aspects of the thigh, but its presence or absence does not correlate with the severity of the disease.
  • The phenotype is variable, ranging from a severe form similar to Hurler syndrome to a mild form analogous to MPS I S.
  • In the severe form, the somatic features include coarse facial features, short stature, skeletal deformities, and joint stiffness.
  • The onset of the disease usually occurs in patients aged 2-4 years, with progressive neurologic involvement and somatic involvement.
  • Eye findings include severe retinal degeneration, but the cornea remains clear with 1 recorded exception.
  • The neurologic symptoms include hearing impairment and compression neuropathy.
  • Neurologic involvement may include mental retardation and moderate-to-severe communicating hydrocephalus with increased intracranial pressure after age 7-10 years. Extensive neurologic involvement similar to late stages of Sanfilippo syndrome precedes death, which usually occurs at age 10-15 years.
  • • Cardiac manifestations include severe diffuse coronary artery disease.
    • Skeletal abnormalities are described as dysostosis multiplex with a large skull with thickened calvaria, premature closure of the lambdoidal and sagittal sutures, shallow orbits, enlarged J-shaped sella, abnormal spacing of teeth with dentigerous cysts, and anterior hypoplasia of lumbar vertebra with kyphosis.
    • The diaphyses of the long bones are enlarged with irregular appearances of the metaphyses. Epiphyseal centers are not well developed.
    • The pelvis is usually poorly formed with small femoral heads and coxa valga. The clavicles are short, thickened, and irregular.
    • The ribs have been described as oar-shaped, narrowed at their vertebral ends and flat and broad at their sternal ends.
    • Phalanges are shortened and trapezoidal in shape with widening of the diaphysis.
  • In the mild form, intelligence is preserved and patients survive into late adulthood but with obvious somatic involvement.
  • The somatic features may be similar to those of Hunter syndrome but with greatly reduced rate of progression.
  • The eye findings include corneal opacities detected only by slit-lamp examination, retinal dysfunction, and chronic papilledema.
  • Patients may survive into the fifth or sixth decades of life, with the longest known survival to age 87 years.
  • Mortality results from cardiorespiratory dysfunction (ie, obstructive airway disease, cardiac failure due to valvular dysfunction, myocardial thickening, pulmonary hypertension, coronary artery narrowing, myocardial disease).
• MPS type III (Sanfilippo syndrome)
• • This is a biochemically diverse but clinically similar group of 4 types (A, B, C, and D).
  • Deficiencies in heparan N-sulfatase (type A), alpha N-acetylglucosaminidase (type B), acetyl CoA:alpha-glucosaminide acetyltransferase (type C), and N-acetylglucosamine 6-sulfatase (type D) can occur. All 4 enzymes are required for the degradation of heparan sulfate. All 4 forms have autosomal recessive inheritance.
  • • Alpha-N-acetylglucosaminidase is required for removal of the N-acetylglucosamine residues that exist in heparan sulfate or are generated during lysosomal degradation of this polymer by the action of acetyl CoA transferase.
    • Heparan N-sulfatase (deficiency occurs in MPS III A) is specific for sulfate groups linked to the amino group of glucosamine.
    • The enzyme deficient in the very rare MPS III D is localized to chromosome arm 12q14 by in situ hybridization.
    • MPS III C is not characterized by a deficient hydrolase, but rather, a deficient catalyst for the acetylation of the glucosamine amino groups that have become exposed by the action of heparan-N-sulfatase.
  • The distinguishing feature is severe central nervous system degeneration but only mild somatic disease.
  • The onset of clinical features usually occurs at age 2-6 years in a previously normal child.
  • Presenting features can include hyperactivity with aggressive behavior, delayed development, coarse hair, hirsutism, sleep disorders, and mild hepatosplenomegaly.
  • Incidence of false-negative results is usually high in the urinary screening test for MPS.
  • Gastrointestinal symptoms include recurrent and severe diarrhea.
  • Neurologic manifestations include delayed speech development, severe hearing loss, and seizures. Deterioration is severe by age 6-10 years and is accompanied by severe rapid deterioration in social and adaptive skills. Progressive dementia occurs, with cortical atrophy visible on CT scanning. Sleep disturbances and insomnia are common.
  • Severe behavioral problems occur, with poor attention span, uncontrollable hyperactivity, temper tantrums, destructive behavior, and physical aggression.
  • Although any of the 4 types may be difficult to distinguish clinically, type A is the most severe, with earlier onset, more rapid progression of symptoms, and shorter survival. Type B may be heterogeneous, with severe and mild forms reported even within the same family. Type C appears to be intermediate between type A and milder type B forms. Type D appears heterogeneous also.
• MPS type IV (Morquio syndrome)
• • MPS IV results from defective degradation of keratan sulfate.
  • Two enzyme deficiencies are recognized: N-acetylgalactosamine-6-sulfatase (also known as galactose-6-sulfatase) in type IV A, and beta-galactosidase in type IV B.
  • MPS IV A is localized to chromosome arm 16q24.
  • The somatic manifestations include short trunk dwarfism and a skeletal dysplasia (spondyloepiphyseal) distinct from that of the other MPSs, with joint laxity, genu valgus, kyphosis, growth retardation with short trunk and neck, and a waddling gait and a tendency to fall.
  • Typical skeletal anomalies include dwarfism with short trunk, platyspondyly, odontoid hypoplasia, kyphosis, hyperlordosis, scoliosis, ovoid deformities of the vertebrae, genu valgum, ulnar deviation of the wrist, valgus deformity of the elbow, inclination of the distal ends of the radius and ulna toward each other, deformities of the metacarpals and short phalanges and epiphyses, deformities of the tubular bones, widened metaphyses, and osteoporosis. Joints tend to be hypermobile secondary to ligamentous laxity, but decreased joint mobility can occur in the large joints, especially hips, knees, and elbows.
  • Odontoid hypoplasia occurs with instability resulting in atlantoaxial subluxation as well as cervical myelopathy; this is also reported in MPS I and VII.
  • Extraskeletal manifestation may include mild corneal clouding, hepatomegaly, cardiac valvular lesion, and small teeth with abnormally thin enamel and frequent caries formation. Unusual facial features (eg, coarsening of facies, prognathism, broad mouth) are commonly found.
  • Cardiac signs of aortic regurgitation or congenital heart defects may be present.
  • Birth is normal, with onset of symptoms at age 1-3.5 years, although the diagnosis is usually established in patients aged 3-15 years.
• MPS type VI (Maroteaux-Lamy syndrome)
• • A deficiency in arylsulfatase B (ie, N-acetylgalactosamine 4-sulfatase) occurs. It hydrolyses the sulfate group in the 4 position of N-acetylgalactosamine residues of dermatan sulfate.
  • The chromosome abnormality is localized to 5q13-q14.
  • The phenotype similar to Hurler syndrome involves preservation of intelligence and excretion of predominantly dermatan sulfate in urine. Corneal clouding and hepatosplenomegaly also occur.
  • The gene abnormality is located in chromosome arm 5q13.3.
  • Severe skeletal anomalies occur, with limitation of joint movement and stunted linear growth in early childhood.
  • Cardiac involvement is related to aortic and mitral valvular dysfunction from thickened calcified stenotic valves.
  • Neurologic complications include hydrocephalus secondary to pachymeningitis, nerve entrapment syndrome, and myelopathy from dural thickening or vertebral body abnormalities or both.
  • Death typically occurs from heart failure.
• MPS type VII (Sly syndrome)
• • MPS VII is caused by a deficiency in beta-glucuronidase, which removes the glucuronic acid residues present in dermatan sulfate, heparan sulfate, and chondroitin sulfates.
  • The abnormality is localized to chromosome arm 7q21.1-q22.
  • Excessive urinary excretion of dermatan and heparan sulfate occurs.
  • An abnormal gene location on chromosome arm 7q21.1-q22 produces a milder form of later onset.
  • Features include dysmorphic facies, protruding sternum, hepatosplenomegaly, umbilical hernia, thoracolumbar gibbus, marked vertebral deformities, find corneal opacities, moderate mental deficiency, and radiologic changes of moderately severe dysostosis multiplex.
  • The distinguishing features are excess glycosaminoglycan excretion and granulocytes showing striking coarse metachromatic granules.

Diagnosis

Glycosaminoglycan fragments are generated by alternative pathways and are excreted in the urine.

Simple enzyme assays are available for the diagnosis of MPS from fibroblast, leukocyte, or serum samples.

Because heterozygous individuals are identified on the basis of enzyme activity, the diagnosis can be difficult. However, it is becoming more definitive as specific mutations are identified. Prenatal diagnosis is made by means of amniocentesis or chorionic villus biopsy.

Management

Supportive management, with particular attention to respiratory and cardiovascular complications, hearing loss, and hydrocephalus, can greatly improve the quality of life of patients and caregivers.

Exogenous enzyme replacement therapy has been considered, and results for treatment of MPS type I with recombinant human alpha-L-iduronidase (Aldurazyme) have improved some clinical manifestations of the disorder. On April 30, 2003, the US Food and Drug Administration approved for patients with MPS type I H and type I H/S.

Gene therapy has shown promising results on animal models, but no human studies have been performed, to the authors' knowledge.

Modest success has been reported with bone marrow therapy in altering the course of some MPSs, and various clinical trials are underway to define the factors that affect outcome, such as the type of MPS disorder, the age at time of transplantation, and donor status. Bone marrow therapy has been most successful in treating MPS I and some mild cases of MPS II and MPS VI. In MPS I, treatment is most effective when initiated before age 2 years and before the onset of significant mental retardation.

When successful, bone marrow therapy reduces hepatosplenomegaly, increases joint mobility, decreases airway obstruction, and improves cardiac function; it also stabilizes mental status. However, bone marrow therapy does not correct skeletal disorders or return lost retinal function.

Other therapies, including the transplantation of umbilical cord blood, are under consideration.

Angiokeratoma corporis diffusum without recognizable enzyme deficiencies is not an MPS and appears to be a distinct clinical entity with a benign course (Kelly, 2006).

I-CELL DISEASE AND PSEUDO-HURLER POLYDYSTROPHY

Section 6 of 11  

• Authors and Editors
• Introduction
• Classification of Lysosomal Storage Diseases
• Glycogen Storage Disease Type II
• Mucopolysaccharidoses
• I-Cell Disease and Pseudo-Hurler Polydystrophy
• Schindler Disease
• Alpha-mannosidosis and Beta-mannosidosis
• Wolman Disease, Cholesteryl Ester Storage Disease, and Niemann-Pick Disease
• Acknowledgments
• References

Both I-cell disease (mucolipidosis II) and the pseudo-Hurler polydystrophy (mucolipidosis III) result from abnormalities in lysosomal enzyme transport in which the newly synthesized lysosomal enzymes are secreted into the extracellular medium instead of being targeted correctly to lysosomes.

The defective enzyme is UDP-N-acetylglucosamine lysosomal enzyme N-acetylglucosamine 1-phosphotransferase. This enzyme that catalyzes the first step in the synthesis of the mannose 6-phosphate recognition marker, which mediates lysosomal enzymes to reach their target lysosome after being processed in the Golgi complex. Its mode of transmission is autosomal recessive. The clinical and radiographic features of this condition are similar to those of Hurler syndrome but with the absence of excess mucopolysacchariduria.

Clinical presentation

Mucolipidosis type II

Mucolipidosis type II, or I-cell disease, is characterized by severe psychomotor retardation with an early onset of signs and symptoms. It has a rapidly progressive course of failure to thrive and developmental delay leading to death by age 5-8 years, usually from cardiorespiratory complications.

Birth weight and length are below the reference range. General somatic findings are similar to those of the Hurler phenotype, with coarse facial features, craniofacial abnormalities, restricted joint movement despite generalized hypotonia, gingival hyperplasia (unique clinical feature), high forehead, puffy eyelids, prominent epicanthal fold, flat nasal bride, anteverted nostrils, and macroglossia.

Skeletal abnormalities include kyphoscoliosis, anterior beaking and wedging of the vertebral bodies, a lumbar gibbus deformity, widening of the ribs, proximal pointing of the metacarpals, congenital hip dislocation, fractures, bilateral talipes equinovarus, and claw hand deformity.

Gastrointestinal findings include hepatomegaly with umbilical and inguinal hernia. Splenomegaly is minimal.

Respiratory infections and otitis media are frequent.

Ophthalmologic findings include corneal opacities on slit-lamp examination noted as diffuse stromal granularities.

Cardiomegaly and cardiac murmurs from valvular insufficiency are common.

Mental retardation may be severe and slowly progressive; however, the motor development is more severely affected than mental development.

Mucolipidosis type III (pseudo-Hurler polydystrophy)

Mucolipidosis type III is characterized by a milder disorder with later onset of clinical signs and symptoms (age, 2-4 y). The phenotype is similar to that of Hurler syndrome without mucopolysacchariduria.

Skeletal findings include claw-hand deformities, scoliosis, and progressive destruction of the hip joint resulting in a waddling gait and short stature. The skeletal dysplasia affects the hand, hips, elbows, and shoulders.

Radiographic findings of dysostosis multiplex are moderately severe, and characteristic findings include low iliac wing with hypoplastic bodies, flattening and irregularity of the proximal femoral epiphyses with valgus deformity of the femoral necks, underdevelopment of the posterior parts of the vertebral bodies of the dorsal spine, and hypoplasia of the anterior third of the vertebral bodies in the lumbar spine, which are more severely affected in males than in females.

Ophthalmologic findings include corneal clouding, mild retinopathy, and hyperopic astigmatism.

Cardiac valvular involvement such as aortic insufficiency occurs by the end of the first decade of life, but symptomatic insufficiency is rare.

Puberty is normal.

Nearly 50% of reported patients have some learning disability or mental retardation.

Life expectancy is not certain, but patients survive to the fourth or fifth decade of life.

Pathologic features

A characteristic feature of mucolipidosis type II is the presence of numerous membrane-bound vacuoles containing electron-lucent or fibrillogranular material in the cytoplasm of mesenchymal cells, especially fibroblasts, called inclusion bodies.

The skeletal system is severely affected.

Lamellar bodies are found in the spinal ganglia neurons and the anterior horn cells in the nervous system, with only minimal alterations observed in Schwann cells around unmyelinated axons.

Diagnosis

Homozygous individuals

Lysosomal enzyme activities in serum or in cultured fibroblasts can be measured to identify homozygous individuals. A 10- to 20-fold increase in serum beta-hexosaminidase, iduronate sulfatase, and arylsulfatase A is diagnostic. If cultured fibroblasts are used, the characteristic pattern of lysosomal enzyme deficiencies may be used, as can the ratio of extracellular to intracellular enzyme activities.

The assay of phosphotransferase activity in the WBCs or in cultured fibroblasts can be measured directly in prenatal diagnosis. Reports have shown the possibility of performing phosphotransferase assays on chorionic villi at 9 weeks' gestation.

The diagnosis can be made from amniocentesis, using the elevated lysosomal enzyme activity of amniotic fluid and the decreased activity of lysosomal enzymes in cultured amniotic cells as criteria for diagnosis. This is reliable but can only be used in the late second trimester.

Heterozygous individuals

The 2 criteria used to identify the heterozygous individuals at risk for the carrier state are the levels of phosphotransferase in fibroblasts and WBCs and the levels of serum beta-hexosaminidase.

Treatment

No specific or definitive treatment exists. Symptomatic treatment with antibiotics is indicated for frequent respiratory infections.

Physical therapy may slow the progression of joint immobility in patients with mucolipidosis III.

Reports mention some favorable response to bone marrow transplantation in mucolipidosis III.

SCHINDLER DISEASE

Section 7 of 11  

• Authors and Editors
• Introduction
• Classification of Lysosomal Storage Diseases
• Glycogen Storage Disease Type II
• Mucopolysaccharidoses
• I-Cell Disease and Pseudo-Hurler Polydystrophy
• Schindler Disease
• Alpha-mannosidosis and Beta-mannosidosis
• Wolman Disease, Cholesteryl Ester Storage Disease, and Niemann-Pick Disease
• Acknowledgments
• References

Schindler disease results from the deficient activity of the enzyme alpha-N-acetylgalactosaminidase (alpha-galactosidase B), with the accumulation of sialylated-asialo-glycopeptide and oligosaccharide with alpha-N-acetylgalactosamilnyl residues. Two major types exist: type I and type II.

Clinical presentations

Type I, or infantile-onset neuroaxonal dystrophy, results in normal development is normal at 9-15 months. The neurodegenerative course is rapid, with severe psychomotor retardation. Cortical blindness occurs, and myoclonic seizures are noted by age 3-4 years. Spasticity and decorticate posturing also occur. The onset is signaled by sudden falling episodes and startle reactions. No visceral signs of storage disease are present. Facies are normal, no organomegaly is present, and no skeletal or dermatologic abnormalities occur.

Type II results in mild intellectual impairment with angiokeratoma corporis diffusum. Somatic findings include slightly coarse facies with an enlarged nasal tip, a depressed nasal bridge, and thick lips. No organomegaly or skeletal deformity is noted.

Dermatologic findings in type II include dry skin that is densely peppered with tiny, deep red-to-purple maculopapules ranging in diameter from <1 mm to 3 mm distributed over the entire body from the face and fingers to the axillae, breasts, lower abdomen, groin, buttocks, and upper thighs. Similar telangiectasias are noted on the lips and on the oral and pharyngeal mucosa. Ophthalmologic findings include dilated blood vessels on the conjunctiva and the fundi.

Laboratory findings

In type I, normal findings are noted on CBC count and CSF and blood chemistry tests. Skeletal radiographic studies show diffuse severe osteopenia, and brain CT scans and MRIs show generalized atrophy of the brainstem, cerebellum, and cortex

In type II, findings on routine laboratory studies are normal. EMG or nerve conduction velocity studies may reveal some decreased amplitude in the sensory fibers suggestive of a peripheral neuroaxonal degeneration.

Pathology

The characteristic feature is that of abundant spheroids in terminal and preterminal axons.

Type I has no histologic evidence of lysosomal pathology, whereas type II has cytoplasmic vacuoles with amorphous or filamentous material in granulocytes, monocytes, and lymphocytes, especially observed on electromicroscopy of endothelial cells of blood and lymphatic vessels, sweat glands, and axons.

Diagnosis

The diagnosis is established by abnormal urinary oligosaccharide and glycopeptide profiles and by the determination of the alpha-N-acetylgalactosaminidase activity in various sources.

The prenatal diagnosis is made by demonstrating the enzyme defect in chorionic villi or cultured amniocytes.

Genetics

This is an autosomal recessive disorder. The gene has been localized to chromosomal region 22q13.1-13.2.

Treatment

No specific treatment exists for type I or type II disease. Supportive management is indicated.

ALPHA-MANNOSIDOSIS AND BETA-MANNOSIDOSIS

Section 8 of 11  

• Authors and Editors
• Introduction
• Classification of Lysosomal Storage Diseases
• Glycogen Storage Disease Type II
• Mucopolysaccharidoses
• I-Cell Disease and Pseudo-Hurler Polydystrophy
• Schindler Disease
• Alpha-mannosidosis and Beta-mannosidosis
• Wolman Disease, Cholesteryl Ester Storage Disease, and Niemann-Pick Disease
• Acknowledgments
• References

Lysosomal alpha-mannosidase is a major exoglycosidase in the glycoprotein degradation pathway. A deficiency of this enzyme causes the lysosomal storage disease alpha-mannosidosis. Lysosomal alpha-D-mannosidase is involved in the catabolism of N-linked glycoproteins through the sequential degradation of high-mannose, hybrid, and complex oligosaccharides.

Beta-mannosidosis is an autosomal recessive lysosomal storage disease resulting from a deficiency of the lysosomal enzyme beta-mannosidase. The clinical manifestations of this disease in reported human cases are heterogeneous, ranging from relatively mild to moderately severe.

The enzyme cleaves the beta-mannoside linkage of the disaccharide Man-beta 1,4-GlcNAc. Genetic deficiency of this enzyme activity results in pathologic manifestation of the lysosomal storage disease beta-mannosidosis (OMIM 248510), which is characterized by accumulation and excretion of undegraded storage products containing beta-1,4 linkages.

Clinical presentation

In 2001, Sun noted that alpha-mannosidosis can be divided into the infantile phenotype (or type I) and the juvenile-adult phenotype (or type II) according to its clinical manifestations. Virtually all patients have psychomotor retardation, facial coarsening, and some degrees of dysostosis multiplex.

Frequent clinical findings include recurrent bacterial infections, deafness, hepatomegaly, and lenticular or corneal opacities. The more severe infantile phenotype includes rapid mental deterioration, obvious hepatosplenomegaly, more severe dysostosis multiplex, and often death before age 12 years.

More-normal early development, followed by gradual appearance of mental retardation characterizes the milder juvenile-adult phenotype. Hearing loss is particularly prominent in patients with type II.

In 1998, Alkhayat reviewed the manifestations of beta-mannosidosis. He noted that beta-mannosidosis manifests with varying degrees of neurologic findings that encompass degrees of mental retardation (except for 2 cases), hearing loss and speech impairment, hypotonia, epilepsy, and peripheral neuropathy. No evidence exists for severe dysmyelination, as observed in caprine and bovine beta-mannosidosis. Angiokeratoma corporis diffusum can also occur.

Other clinical symptoms of beta-mannosidosis include angiokeratomata, susceptibility to upper and lower respiratory tract infections, facial dysmorphism, and skeletal abnormalities.

An African 14-year-old boy has been described with deficient beta-mannosidase activity, bilateral thenar and hypothenar amyotrophy, electrophysiologically demonstrable demyelinating peripheral neuropathy, and cytoplasmic vacuolation of skin fibroblasts and lymphoid cells.

Dermal fibroblasts, bone marrow, and endothelial cells from these patients show cytoplasmic vacuolation. Affected individuals have a profound reduction in beta-mannosidase activity in plasma, fibroblasts, and leukocytes.

Diagnosis

Peripheral blood smears can reveal lymphocytes with vacuoles and neutrophils with some granules resembling Reilly bodies observed in MPS. Patients with alpha-mannosidosis have an immunodeficiency at both the humoral and cellular level.

MRI findings in patients with mannosidosis include diploic space widening with underdevelopment of the sinuses, prominent periventricular Virchow-Robin spaces and perioptic CSF spaces, a tight foramen magnum sometimes associated with a cervical syrinx, and markedly widened perioptic CSF spaces with papilledema. Deforming arthropathy may occur as part of the spectrum of skeletal abnormalities observed in mannosidosis.

Treatment

Successful bone marrow transplantation in a child with a severe form of alpha-mannosidosis type I with complete resolution of the recurrent sinopulmonary disease and organomegaly, improvement in the bony disease, and stabilization of neurocognitive function has been reported.

WOLMAN DISEASE, CHOLESTERYL ESTER STORAGE DISEASE, AND NIEMANN-PICK DISEASE

Section 9 of 11  

• Authors and Editors
• Introduction
• Classification of Lysosomal Storage Diseases
• Glycogen Storage Disease Type II
• Mucopolysaccharidoses
• I-Cell Disease and Pseudo-Hurler Polydystrophy
• Schindler Disease
• Alpha-mannosidosis and Beta-mannosidosis
• Wolman Disease, Cholesteryl Ester Storage Disease, and Niemann-Pick Disease
• Acknowledgments
• References

Wolman disease and cholesteryl ester storage disease

Lysosomal acid lipase is the essential enzyme for hydrolysis of triglycerides and cholesteryl esters in lysosomes. Its deficiency produces 2 human phenotypes: Wolman disease and cholesteryl ester storage disease.

The more severe course of Wolman disease is caused by genetic defects of lysosomal acid lipase that leave no residual enzyme activity. Wolman disease is also called primary familial xanthomatosis with involvement and calcification of the adrenal glands.

Wolman disease has accumulation of both triglycerides and cholesteryl esters, while cholesteryl ester storage disease has mainly elevated cholesteryl esters. Lysosomal acid lipase genotypes determine the level of residual enzymatic activity, resulting in the severity of the phenotype.

Wolman disease is fatal in infancy, and cholesteryl ester storage disease is a milder form and usually manifests in adulthood.

Wolman disease results from an inherited deficiency of lysosomal acid lipase (EC 3.1.1.13). This enzyme is essential for the hydrolysis of cholesteryl esters and triacylglycerols derived from endocytosed lipoproteins. Because of a complete absence of lysosomal acid lipase activity, patients with Wolman disease accumulate progressive amounts of Wolman disease and triacylglycerols in affected tissues.

Clinical presentation

Wolman disease is characterized by severe diarrhea and malnutrition leading to death during infancy. Fever, abdominal distension, vomiting, and jaundice can also occur. Hepatosplenomegaly is present. It is inherited in an autosomal recessive manner. All patients with Wolman disease have adrenal-gland calcification.

Diagnosis

Abdominal CT findings, elevated blood acid phosphatase levels, and histologic findings and intestinal biopsy can be used to establish a diagnosis of Wolman syndrome. CT scanning shows an enlarged liver with decreased density and heavily calcified adrenal glands.

Ultrasonography reveals an enlarged liver with normal echogenicity, adrenal calcification, and thickening of bowel loops.

Treatment

In mouse gene therapy, in the form of gene transfer via intravenously administered adenovirus, has been used to correct deficiency states, such as Wolman disease and cholesteryl ester storage disease.

In 2000, Krivit reported a case of Wolman disease cured with a bone marrow transplant.

Niemann-Pick disease

Niemann-Pick disease is a rare inherited autosomal recessive lipid-storage disease. The pathognomonic intracellular accumulation of sphingomyelin results in the production and accumulation of foam cells.

Niemann-Pick disease types A and B are caused by deficiency of the acid sphingomyelinase activity. Type A Niemann-Pick disease is a severe neurodegenerative disorder of infancy that leads to death by age 3 years, whereas type B disease has a later age at onset, little or no neurologic involvement, and survival of most patients into adulthood. Patients with both types have hepatosplenomegaly.

Adult patients under neuroleptic treatment met all phenotypic and biochemical criteria for Niemann-Pick disease type B. These patients had chronic psychiatric disorders and low blood levels of high-density lipoprotein (HDL) cholesterol.

The Niemann-Pick C protein (NPC1) is required for cholesterol transport from late endosomes and lysosomes to other cellular membranes. Mutations in NPC1 cause lysosomal lipid storage and progressive neurologic degeneration.

Prenatal diagnosis of Niemann-Pick disease types A and B is routinely accomplished by sphingomyelinase assay. For Niemann-Pick disease type C, demonstration of abnormal intracellular cholesterol trafficking is a complex procedure, and mutational analysis (ie, NPC1 or NPC2/HE1 gene) can be feasible.

ACKNOWLEDGMENTS

Section 10 of 11  

• Authors and Editors
• Introduction
• Classification of Lysosomal Storage Diseases
• Glycogen Storage Disease Type II
• Mucopolysaccharidoses
• I-Cell Disease and Pseudo-Hurler Polydystrophy
• Schindler Disease
• Alpha-mannosidosis and Beta-mannosidosis
• Wolman Disease, Cholesteryl Ester Storage Disease, and Niemann-Pick Disease
• Acknowledgments
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, Pieter R Kark, MD, to the development and writing of this article.

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Classification of Lysosomal Storage Diseases
• Glycogen Storage Disease Type II
• Mucopolysaccharidoses
• I-Cell Disease and Pseudo-Hurler Polydystrophy
• Schindler Disease
• Alpha-mannosidosis and Beta-mannosidosis
• Wolman Disease, Cholesteryl Ester Storage Disease, and Niemann-Pick Disease
• Acknowledgments
• References

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Article Last Updated: Nov 2, 2006