Lysosomal Storage Disease

Updated: Feb 24, 2023
  • Author: Stephen L Nelson, Jr, MD, PhD, FAACPDM, FAAN, FAAP, FANA; Chief Editor: George I Jallo, MD  more...
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Lysosomes are subcellular organelles responsible for the physiologic turnover of cell constituents. They contain catabolic enzymes, which require a low pH environment in order to function optimally.

Lysosomal storage diseases describe a heterogeneous group of dozens of rare inherited disorders characterized by the accumulation of undigested or partially digested macromolecules, which ultimately results in cellular dysfunction and clinical abnormalities. Organomegaly, connective-tissue and ocular pathology, and central nervous system dysfunction may result. Classically, lysosomal storage diseases encompassed only enzyme deficiencies of the lysosomal hydrolases. More recently, the concept of lysosomal storage disease has been expanded to include deficiencies or defects in proteins necessary for the normal post-translational modification of lysosomal enzymes (which themselves are often glycoproteins), activator proteins, or proteins important for proper intracellular trafficking between the lysosome and other intracellular compartments.

More than 50 lysosomal storage diseases have been described, some of which are discussed in this article. Age of onset and clinical manifestations may vary widely among patients with a given lysosomal storage disease, and significant phenotypic heterogeneity between family members carrying identical mutations has been reported. Lysosomal storage diseases are generally classified by the accumulated substrate and include the sphingolipidoses, oligosaccharidoses, mucolipidoses, mucopolysaccharidoses (MPSs), lipoprotein storage disorders, lysosomal transport defects, neuronal ceroid lipofuscinoses and others.

New developments

Therapy is increasingly promising, albeit expensive. Enzyme replacement therapy (ERT) appears safe and effective for peripheral manifestations in patients with Gaucher disease types I and III, Fabry disease, mucopolysaccharidosis I (Hurler, Hurler-Scheie, and Scheie syndromes), mucopolysaccharidosis II (Hunter syndrome), mucopolysaccharidosis VI (Maroteaux-Lamy syndrome), Pompe disease, and recently Batten disease (neuronal ceroid lipofuscinoses, CLN2). Efforts are underway to develop enzyme replacement options for several other disorders. Thus far, ERT has been largely unsuccessful in improving central nervous system manifestations of the lysosomal storage diseases, putatively due to difficulty in penetrating the blood-brain barrier. This has led to active clinical trials evaluating the safety and efficacy of intrathecal enzyme delivery in several lysosomal storage diseases (see

Accumulated data indicate that hematopoietic stem cell transplantation may be effective under optimal conditions in preventing the progression of central nervous system symptoms in neuronopathic forms of lysosomal storage diseases (such as Krabbe disease), including some of the mucopolysaccharidoses, oligosaccharidoses, sphingolipidoses, and lipidoses as well as peroxisome disorders such as X-linked adrenoleukodystrophy. Although longitudinal natural history data are limited, published guidelines are available to assist with decisions related to the pursuit of transplantation and whether to use bone marrow or umbilical cord blood–derived cells. In general, transplantation yields the best results when performed early in the course of the disease (ie, in an asymptomatic affected sibling of a child with a lysosomal storage disorder), in centers with experience in performing transplantations to treat inherited metabolic disorders, and in patients healthy enough to tolerate the conditioning and transplantation regimen.

Some evidence indicates that at least in certain disorders, combination ERT and hematopoietic stem cell transplantation together might be superior to hematopoietic stem cell transplantation alone in patients who are appropriate candidates.

The availability of both ERT and hematopoietic stem cell transplantation has prompted ongoing consideration of newborn screening efforts to diagnose lysosomal storage diseases. Although screening for these disorders has not been widely implemented, the potential to treat these disorders is likely to drive further efforts at development.

Gene therapy is experimental but in the future may help correct both somatic and neurologic abnormalities in a lysosomal storage disorder. [1, 2]

New developments and tests for disease can be followed by reviewing the Lysosomal Storage Disease Network, Online Mendelian Inheritance in Man, [3] and GeneTests [4] websites.


Although single gene defects typically result in substrate accumulation, the precise underlying pathophysiologic mechanisms that lead to clinical symptoms are not entirely clear. The distribution of accumulating material correlates with which organs are affected. Cells of the mononuclear phagocyte system are especially rich in lysosomes and thus are frequently affected by lysosomal storage diseases.

Neurons and glia are commonly affected, likely because of the relative paucity of cell turnover in the central nervous system, yet non-neuronopathic forms of lysosomal storage disease exist. Lysosomal storage diseases may result in a severe neurodegenerative phenotype. Milder (typically later-onset or adult-onset) phenotypes have been identified and are generally related to the degree of residual enzyme activity.


Although in general the accumulation of undegraded substrate is thought to relate to the cellular dysfunction and death that accompanies lysosomal storage diseases, the precise mechanisms underlying this degeneration are incompletely defined. The pattern of neuronal degeneration in subtypes of lysosomal storage diseases may be surprisingly cell-type specific. In some cases, substrate accumulation is also associated with sequestration of important component molecules, leading to a relative deficiency state. [5]

The lysosome serves as a central component of the endosomal-lysosomal system. This system is crucial for the maintenance of normal cellular metabolism, working in conjunction with the chaperone-mediated autophagy and ubiquitin-proteasomal systems. Abnormal function of this system may lead to ectopic dendritic sprouting (a feature relatively unique to lysosomal storage diseases) and impaired recycling of glutamatergic AMPA receptors. Neuroaxonal spheroid formation is a feature of the ganglioside storage diseases, Niemann-Pick types A and C, and a-mannosidosis, implicating a shared pathology that leads to the production of these compact accumulations of mitochondria and tubulovesicular bodies.


The constellation of dysmorphic features (coarse facies, macroglossia), bony abnormalities (dysostosis multiplex), cardiac involvement (arrhythmia or cardiomegaly), hepatosplenomegaly, ophthalmologic signs (corneal clouding or macular cherry-red spot), and neurological features may lead to clinical suspicion of a lysosomal storage disease. Symptoms are typically gradually progressive rather than episodic, as occurs with other neurometabolic disorders. Neurological symptoms can include developmental delay, hypotonia, epilepsy (complex partial or myoclonic), peripheral neuropathy, intellectual disability, ataxia, and/or spasticity.

Screening can be performed via skeletal radiography to look for evidence of dysostosis multiplex (seen in many of the lysosomal storage diseases), abdominal ultrasonography to identify hepatosplenomegaly, and echocardiography to evaluate for cardiac involvement. Hearing screening results may be abnormal in some cases. Ophthalmologic consultation may be helpful in identifying corneal clouding or cherry-red spot. A peripheral blood smear may reveal white blood cell vacuoles (granular, fingerprint lipid whorls, zebra bodies, or autophagic vacuoles) that may provide important diagnostic clues. Urine can be screened for elevated excretion of oligosaccharides (oligosaccharidoses) and glycosaminoglycans (mucopolysaccharidoses). Blood chitotriosidase (an enzymatic marker of macrophage activation) may be elevated.

Definitive testing is most efficiently performed by enzymatic activity measurement in a reference laboratory, typically in peripheral white blood cells (although skin fibroblasts may also be used or even necessary in some cases). For some disorders, enzyme activity can be measured in dried filter paper blood spots, and, occasionally, enzyme activity measurement in other tissues such as muscle can have utility. Urine enzyme activity measurements are seldom helpful, although urine substrate excretion can provide useful information (see screening above). In some cases, confirmatory DNA mutation analysis may be indicated.

Additionally, the availability of next generation sequencing (NGS) has made early identification of most of these disorders relatively simple and fast. Many of the genes are on panels available from various companies, and results can be obtained within several weeks. For those patients with normal panel, whole exome sequencing offers broader coverage and may increase the yield of detecting abnormalities.


Classification of Lysosomal Storage Diseases

More than 50 lysosomal storage diseases have been described. They are classified below, and a few are described in detail in the subsequent sections.

Glycogen storage disease type II

This glycogenosis is caused by deficiency of acid maltase, a lysosomal enzyme. (See Glycogen Storage Disease Type II for detailed information. Also see the Medscape Reference article Genetics of Glycogen-Storage Disease Type II (Pompe Disease).) Two types are as follows:

  • Infantile-onset Pompe disease

  • Late-onset Pompe disease


Many mucopolysaccharidoses can be detected via urine glycosaminoglycan assay. Also see the Medscape Reference articles Mucopolysaccharidosis and Mucopolysaccharidoses Types I-VII. Note the following types:

  • MPS type IH, Hurler syndrome (alpha-L-iduronidase deficiency)

  • MPS type I H/S, Hurler-Scheie syndrome

  • MPS type IS, Scheie syndrome

  • MPS type II A, Hunter syndrome, severe (iduronate sulfatase deficiency)

  • MPS type II B, Hunter syndrome, mild (iduronate sulfatase deficiency)

  • MPS type III A-D, Sanfilippo syndrome (heparan N -sulfatase deficiency)

  • MPS type IV A, Morquio syndrome, classic (galactose 6-sulfatase deficiency)

  • MPS type VI, Maroteaux-Lamy syndrome (arylsulfatase B deficiency)

  • MPS type VII, Sly syndrome (beta-glucuronidase deficiency)

See the following Medscape Reference articles for more information:


The mucolipidoses consist of the following:

  • Mucolipidosis I: This term that has been used to describe sialidosis. (Also see the Medscape Reference article Sialidosis (Mucolipidosis I).)

  • Mucolipidosis II (I-cell disease) (See I-Cell Disease and Pseudo-Hurler Polydystrophy for detailed information. Also see the Medscape Reference article I-Cell Disease (Mucolipidosis Type II).)

  • Mucolipidosis III (phosphotransferase deficiency) (See I-Cell Disease and Pseudo-Hurler Polydystrophy for detailed information.)

  • Mucolipidosis IV (mucolipidin 1 deficiency): Clinical features include psychomotor retardation, corneal clouding, and retinopathy. Screening may be accomplished by screening serum gastrin levels, which are typically significantly elevated.


Many oligosaccharidoses can be detected by screening urine for oligosaccharide accumulation.

  • Schindler disease/Kanzaki disease (alpha-N -acetylgalactosaminidase deficiency) (See Schindler Disease for detailed information.)

  • Alpha-mannosidosis and beta-mannosidosis (See Alpha-Mannosidosis and Beta-Mannosidosis for detailed information.)

  • Alpha-fucosidosis: Clinical features include progressive neuromotor deterioration, seizures (including myoclonic seizures), coarse facial features, dysostosis multiplex, angiokeratoma corporis diffusum, hepatosplenomegaly, and growth retardation.

  • Sialidosis (mucolipidosis I; alpha-N -acetyl neuraminidase [sialidase] deficiency) (Also see the Medscape Reference article Sialidosis (Mucolipidosis I).)

  • Aspartylglucosaminuria (aspartylglucosaminase deficiency): The progress of this disease is slower than many other lysosomal storage diseases. Patients appear healthy during infancy and generally live 25-45 years. Clinical features include intellectual disability, neurobehavioral symptoms, milder skeletal abnormalities, hepatosplenomegaly, and facial coarsening.


The lipidoses include the following:

  • Niemann-Pick disease types C and D (Also see the Medscape Reference article Genetics of Niemann-Pick Disease.) [6]

  • Neuronal ceroid lipofuscinoses

  • Wolman disease (acid lipase deficiency, mild form cholesterol ester storage disease) (See Wolman Disease and Cholesteryl Ester Storage Disease for detailed information.) [7, 8]


The sphingolipidoses are as follows:

  • Niemann-Pick disease type A (sphingomyelinase deficiency) and Niemann-Pick disease type B (sphingomyelinase deficiency) (Also see the Medscape Reference article Genetics of Niemann-Pick Disease.)

  • Gaucher disease types I, II, and III (beta-glucosidase deficiency) (Also see the Medscape Reference article Gaucher Disease.)

  • Krabbe disease, infantile globoid-cell leukodystrophy (galactosylceramidase deficiency) (Also see the Medscape Reference article Krabbe Disease.)

  • Fabry disease (alpha-galactosidase A) (Also see the Medscape Reference article Fabry Disease.)

  • GM1 gangliosidosis and Morquio B disease (beta-galactosidase deficiency) (Also see the Medscape Reference article GM1 Gangliosidosis.)

  • GM2 gangliosidoses: These include Tay-Sachs disease (hexosaminidase A deficiency) and Sandhoff disease (hexosaminidase A and B deficiency) (Also see the Medscape Reference article GM2 Gangliosidoses.)

  • Metachromatic leukodystrophy (arylsulfatase A deficiency) (Also see the Medscape Reference article Metachromatic Leukodystrophy.)

  • Farber disease, disseminated lipogranulomatosis (ceramidase deficiency): Farber disease starts to manifest in infancy as a hoarse cry or swollen tender joints followed by the development of subcutaneous nodules, flesh-colored papules, and periarticular tumors or nodules. Clinical features include coarsening facial features, osteopenia, and neurodegeneration. Histopathology shows foam cells and granulomatous infiltration. Ultramicroscopically, curvilinear tubular bodies are present as comma-shaped tubular structures consisting of 2 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.

  • Multiple sulfatase deficiency (sulfatase-modifying factor-1 mutation): Mutation in SUMF1 leads to deficiency of 7 sulfatases. The resulting disorder combines features of metachromatic leukodystrophy and mucopolysaccharidosis. Clinical features include proptosis, ichthyosis, broad thumbs and index fingers, progressive leukoencephalopathy, and hepatosplenomegaly.

  • Galactosialidosis (cathepsin A deficiency): Mutation in CTSA leads to a combined deficiency of lysosomal beta-galactosidase and neuraminidase as a result of a primary defect in the protective protein/cathepsin A (PPCA). Clinical features include coarse facial features, macular cherry-red spots, angiokeratomas, dysostosis multiplex, epilepsy, myoclonus, and ataxia.

Lysosomal transport diseases

The lysosomal transport diseases are as follows:

  • Cystinosis (cystine transporter deficiency): Clinical features include nephropathy (most common inherited cause of renal Fanconi syndrome), short stature, myopathy, corneal crystals, and possibly neurodegeneration in adulthood. Screening can be performed via cystine level assay in leukocytes. It can be treated with cysteamine. (Also see the Medscape Reference article Cystinosis.)

  • Sialic acid storage disease (Salla disease; sialic acid transporter deficiency): Clinical features include hypotonia, spasticity, ataxia, intellectual disability, growth retardation, and epilepsy. It is more common in the Finnish population owing to a founder effect. It may be detected by assay of free sialic acid levels in urine.


Glycogen Storage Disease Type II

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. [9]

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 arm 17q23.

The disorder is genetically heterogeneous with missense, nonsense, and frameshift mutations, 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 capacity, 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.


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 US Food and Drug Administration (FDA). It has shown improved infant survival without requiring invasive ventilatory support compared with historical controls without treatment.


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%). [10]


I-Cell Disease and Pseudo-Hurler Polydystrophy


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 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

The clinical presentation for the various types is below.

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.


Diagnostic considerations are discussed below.

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 white blood cells and the levels of serum beta-hexosaminidase.


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

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, manifests at 9-15 months; until then, neurologic development is normal. 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 less than 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 cerebrospinal fluid (CSF) examination, 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.


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.


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.


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


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


Alpha-Mannosidosis and Beta-Mannosidosis

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 and Wolfe 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. [11] 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 et al reviewed the manifestations of beta-mannosidosis. They 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. [12] 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.

A 14-year-old African 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.


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


The first enzyme replacement therapy for alpha-mannosidosis, velmanase alfa (Lamzede), was approved in February 2023. Alpha-mannosidase catalyzes the degradation of accumulated mannose-containing oligosaccharides. Deficiency of alpha-mannosidase causes an intralysosomal accumulation of mannose-rich oligosaccharides in various tissues. Velmanase alfa provides an exogenous source of alpha-mannosidase; it eventually internalizes via binding to the mannose-6-phosphate receptor on the T-cell surface and is transported into lysosomes, where it is thought to exert enzyme activity. 

Approval for this rare disease included a study of 25 patients who were randomized to weekly velmanase alfa treatment or placebo for 52 weeks. Serum oligosaccharide declined by 77.6% at 52 weeks in patients treated with velmanase alfa compared with 24.1% in the placebo group. Similar improvement was observed in placebo patients after switching to active treatment. [13]   

Another study among patients participating in the clinical development (n = 33; 14 adults, 19 pediatrics) showed serum oligosaccharide levels were significantly reduced at 12 months (-72.7%, p < 0.001). Physical improvement as measured by the 3-minute stair climb test was also improved at 12 months (+9.3%; p = 0.013), which remained statistically significant at last observation (+13.8%; p = 0004), with a more pronounced improvement detected in the pediatric group. [14]  

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. [15]


Wolman Disease and Cholesteryl Ester Storage Disease

Lysosomal acid lipase (LAL) is the enzyme necessary for the hydrolysis of triglycerides and cholesteryl esters from endocytosed lipoproteins in lysosomes. Its deficiency produces 2 human phenotypes: Wolman disease and cholesteryl ester storage disease (CESD).

The more severe phenotype, Wolman disease (familial xanthomatosis with calcification of the adrenal glands), features accumulation of both triglycerides and cholesteryl esters, while the milder phenotype, cholesteryl ester storage disease, leads mainly to cholesteryl ester storage. The lysosomal acid lipase genotype determines the level of residual enzymatic activity and correlates with the severity of the phenotype.

Wolman disease is typically fatal in infancy, while the CESD form is a milder, heterogeneous form that often manifests in late childhood or adulthood.

Clinical presentation

Both forms of the disease are inherited in an autosomal recessive manner. The Wolman disease phenotype is characterized by severe diarrhea and malnutrition in infancy. Nearly all patients with Wolman disease have adrenal-gland calcification. Patients with both forms of LAL deficiency may present with fever, abdominal distension, and vomiting. Hepatosplenomegaly is a frequent feature, accompanied by elevated transaminase levels. Fatty infiltration, followed by progression to hepatic fibrosis and cirrhosis, may lead to misdiagnosis as nonalcoholic steatohepatitis (NASH) and related conditions. Hyperlipidemia and early-onset atherosclerosis may be prominent.


Characteristic abdominal CT findings (enlarged liver with decreased density and calcified adrenal glands), elevated blood acid phosphatase levels, and histologic findings on liver tissue of microvesicular steatosis suggest a diagnosis of Wolman syndrome.

Ultrasonography typically reveals an enlarged liver with normal echogenicity, adrenal calcification, and thickening of bowel loops. Hypercholesterolemia, bone marrow foam cells, and vacuolated blood lymphocytes may also be observed.

Diagnostic confirmation of Wolman disease/CESD is via measurement of lysosomal acid lipase activity in peripheral blood mononuclear cells or cultured fibroblasts and/or via direct DNA mutation analysis of the LAL gene.


Manifestations of Wolman disease have been successfully treated in a few cases with bone marrow transplantation, although long-term outcomes are unknown and treatment-associated morbidity and mortality are significant.

The FDA approved sebelipase alfa (Kanuma) in December 2015 for enzyme replacement in patients with lysosomal acid lipase deficiency (LAL-D).  Sebelipase alfa is a recombinant form of human LAL. Approval was based on data from the ARISE clinical trials and a supporting open-label extension study comprising infant, pediatric, and adult patients with LAL-D. Results showed significant benefit in terms of survival (67%, or 6 out of 9) in patients with the infant form of LAL-D beyond 12 months, compared with 0 out of 21 patients in an untreated historical cohort. In pediatric and adult patients with LAL-D (ages included 4 to 58 years), enzyme replacement treatment resulted in larger reductions from baseline in ALT values and liver fat content, as measured by MRI, compared with placebo. Reduced ALT values were generally seen within 2 weeks. Treated patients also had significant improvements in lipid parameters, including LDL-C, HDL-C, non-HDL-C, and triglycerides, compared to placebo. Continued improvements in ALT, LDL-C, and HDL-C were seen in patients treated with sebelipase alfa for up to 36 weeks. [16, 17]


Batten Disease

Batten disease, or neuronal ceroid lipofuscinosis, refers to a group of disorders iinherited in autosomal recessive fashion that are associated with missing lyosomal enzymes that result in lipofuscin buld-up within neurons and resultant progressive neurological impairments, including seizures, developmental regresssion, vision impairment, motor dysfunction, and eventually death. There are a variety of types due to different missing enzymes that present at various ages.

Clinical presentation

CLN2, the only treatable form, most commonly presents with seizures and/or ataxia in the late-infantile period (around 2–4 years old), often in combination with language delay initially followed by global regression and including motor and visual deterioration followed by an early death. This should always be in the differential diagnosis for any child in this age group with new onset seizures, especially in the setting of developmental delay or regression. 


When clinical signs suggest an NCL, TPP1 enzyme activity to test for CLN2, along with palmitoyl-protein thioesterase enzyme activity assay to rule out CLN1 disease, should be done early. Given the heterogeneity of presentations, however, NGS with panels can be much more cost-effective and timely, since the various NCL subtypes can overlap in age and clinical presentation. 


No specific treatment can reverse the symptoms of Batten disease. In 2017, however, the FDA approved an enzyme replacement therapy called cerliponase alfa (Brineura) for CLN2 that has been shown to slow or halt the progression of symptoms. [18, 19]