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Lysosomal Storage Disorders

by Chin-To Fong, MD

Lysosomal enzymes break down macromolecules, either those from the cell itself (eg, when cellular structural components are being recycled) or those acquired outside the cell. Inherited defects or deficiencies of lysosomal enzymes (or other lysosomal components) can result in accumulation of undegraded metabolites. Because there are numerous specific deficiencies, storage diseases are usually grouped biochemically by the accumulated metabolite. Subgroups include

  • Mucopolysaccharidoses

  • Sphingolipidoses (lipidoses)

  • Mucolipidoses

The most important are the mucopolysaccharidoses and sphingolipidoses. Type 2 glycogenosis is a lysosomal storage disorder, but most glycogenoses are not. For a more complete listing of lysosomal storage disorders, see Table Lysosomal Storage Disorders.

Lysosomal Storage Disorders

Disease (OMIM Number)

Defective Proteins or Enzymes

Defective Genes (Chromosomal Location)

Comments

Mucopolysaccharidosis (MPS)

MPS I-H (Hurler’s syndrome; 607014)

MPS I-S (Scheie’s syndrome; 607016)

MPS I H/S (Hurler-Scheie syndrome; 607015)

α-l-Iduronidase

IDUA (4p16.3)*

Onset: In I-H, 1st yr

In I-S, > 5 yr

In I-H/S, 3–8 yr

Urine metabolites: Dermatan sulfate, heparin sulfate

Clinical features: Corneal clouding, stiff joints, contractures, dysostosis multiplex, coarse facies, coarse hair, macroglossia, organomegaly, intellectual disability with regression, valvular heart disease, hearing and vision impairment, inguinal and umbilical hernia, sleep apnea, hydrocephalus

Treatment: Supportive care, enzyme replacement, stem cell or bone marrow transplantation

MPS II (Hunter’s syndrome; 309900)

Iduronate sulfate sulfatase

IDS (Xq28)*

Onset: 2–4 yr

Urine metabolites: Dermatan sulfate, heparin sulfate

Clinical features: Similar to Hurler’s syndrome but milder and no corneal clouding

In mild form, normal intelligence

In severe form, progressive intellectual and physical disability, death before age 15

Treatment: Supportive care, stem cell or bone marrow transplantation

MPS III (Sanfilippo’s syndrome)

Onset: 2–6 yr

Urine metabolites: Heparin sulfate

Clinical features: Similar to Hurler’s syndrome but with severe intellectual disability and mild somatic manifestations

Treatment: Supportive care

Type III-A (252900)

Heparan-S-sulfate sulfamidase

SGSH (17q25.3)*

Type III-B (252920)

N -acetyl-D-glucosaminidase

NAGLU (17q21)*

Type III-C (252930)

Acetyl-CoA-glucosaminide N -acetyltransferase

(14)

Type III-D (252940)

N -acetyl-glucosaminine-6-sulfate sulfatase

GNS (12q14)*

MPS IV (Morquio’s syndrome

Onset: 1–4 yr

Urine metabolites: Keratin sulfate; in IV-B, also chondroitin 6-sulfate

Clinical features: Similar to Hurler’s syndrome but with severe bone changes including odontoid hypoplasia; possibly normal intelligence

Treatment: Supportive care

Type IV-A (253000)

Galactosamine-6-sulfate sulfatase

GALNS (16q24.3)*

Type IV-B (253010)

β-Galactosidase

GLB1 (3p21.33*—see also GM1 gangliosidosis, below)

MPS VI (Maroteaux-Lamy syndrome; 253200)

N -Acetyl galactosamine α-4-sulfate sulfatase (arylsulfatase B)

ARSB (5q11-q13)*

Onset: Variable but can be similar to Hurler’s syndrome

Urine metabolites: Dermatan sulfate

Clinical features: Similar to Hurler’s syndrome but normal intelligence

Treatment: Supportive care

MPS VII (Sly’s syndrome; 253220)

β-Glucuronidase

GUSB (7q21.11)*

Onset: 1–4 yr

Urine metabolites: Dermatan sulfate, heparin sulfate, chondroitin 4-, 6-sulfate

Clinical features: Similar to Hurler’s syndrome but greater variation in severity

Treatment: Supportive care, stem cell or bone marrow transplantation

MPS IX (hyaluronidase deficiency; 601492)

Hyaluronidase deficiency

HYAL1 (3p21.3-p21.2)*

Onset: 6 mo

Urine metabolites: None

Clinical features: Bilateral soft-tissue periarticular masses, dysmorphic features, short stature, normal intelligence

Treatment: Not established

Mucolipidosis (ML)

ML I

See Sialidosis type I (below)

ML II (I-cell disease; 252500)

N -Acetylglucosaminyl-1-phosphotransfeerase catalytic subunit

GNPTA (4q21-q23)

Onset: 1st yr

Urine metabolites: No mucopolysaccharides

Clinical features: Similar to Hurler’s syndrome but more severe; presence of phase-dense inclusion bodies in fibroblasts (I-cells)

Treatment: Supportive care

ML III (pseudo-Hurler’s polydystrophy)

N-acetylglucosaminyl-1-phosphotransfeerase

Onset: 2–4 yr

Urine metabolites: None

Clinical features: Similar to ML II but later onset and possible survival to adulthood

Treatment: Supportive care

Type III-A (252600)

Catalytic subunit

GNPTA (4q21-q23)*

Type III-C (252605)

Substrate-recognition subunit

GNPTAG (16p)*

ML IV

See Sialolipidosis (below)

Sphingolipidosis

GM1 gangliosidosis, generalized

Ganglioside β-galactosidase

GLB1 (3p21.33*; allelic to MPS IVB)

Type I (230500)

Type I onset: 0–6 mo

Urine metabolites: None

Clinical features: Coarse facies; clear cornea, cherry-red macular spot, gingival hyperplasia, organomegaly, dysostosis multiplex, hypertrichosis, angiokeratoma corporis diffusum, cerebral degeneration; death in infancy

Treatment: Supportive care

Type II (juvenile type; 230600)

Type II onset: 6–12 mo

Urine metabolites: None

Clinical features: Gait disturbance, spasticity, dystonia, loss of psychomotor milestones, mild visceromegaly and bone abnormality

Treatment: Supportive care

Type III (adult type; 230650)

Type III onset: 3–50 yr

Urine metabolites: None

Clinical features: Angiokeratoma corporis diffusum, spondyloepiphyseal dysplasia, dysarthria, cerebellar dysfunction; no macular red spots or visceromegaly

Treatment: Supportive care

GM2 gangliosidosis

Onset: In types I and II, 5–6 mo

In type III, 2–6 yr

Urine metabolites: None

Clinical features: Doll-like facies; cherry-red retina; early blindness; exaggerated startle reflex; initial hypotonia followed by hypertonia; psychomotor retardation followed by regression, seizures, and impaired sweating; death by age 5 yr

In type I, increased frequency in Ashkenazi Jews

Treatment: Supportive care

Type I (Tay-Sachs disease; 272800)

β-Hexosaminidase A

HEXA (15q23-q24)*

Type II (Sandhoff’s disease; 268800)

β-Hexosaminidase B

HEXB (5q13)*

Type III (juvenile type)

β-Hexosaminidase A

GM2 activator protein deficiency (Tay-Sachs disease AB variant, GM2A; 272750)

GM2 activator protein

GM2A (5q31.3-q33.1)*

Treatment: Supportive care, stem cell or bone marrow transplantation Same as that for GM2 types I and II

Niemann-Pick disease (see also Niemann-Pick disease types C and D, below)

Sphingomyelinase

SMPD1 (11p15.4-p15.1)*

Type A (257200)

Onset: < 6 mo

Clinical features: Growth delay, cherry-red retina, frequent respiratory infections, hepatosplenomegaly, vomiting, constipation, osteoporosis, lymphadenopathy, hypotonia followed by spasticity, sea-blue histiocytes on tissue biopsies, large vacuolated foam cells in bone marrow (NP cells), death by age 3 yr

Treatment: Supportive care, stem cell or bone marrow transplantation

Type B (607616)

Onset: Variable

Clinical features: Much milder symptoms, no neurologic involvement, survival to adulthood

Increased frequency in Ashkenazi Jews

Treatment: Supportive care, stem cell or bone marrow transplantation

Gaucher’s disease

Glucosylceramide β-glucosidase

GBA (1q21)*

Type I (adult or chronic form; 230800)

Onset: Childhood or adolescence

Urine metabolites: None

Clinical features: Hepatosplenomegaly, osteolytic lesions with bone pain, avascular necrosis of the femoral head, vertebral compression, thrombocytopenia, anemia

Increased frequency in Ashkenazi Jews

Treatment: Supportive care, splenectomy, enzyme replacement, bone marrow or stem cell transplantation

Type II (infantile form; 230900)

Onset: Infancy

Urine metabolites: None

Clinical features: Infantile hydrops, hepatosplenomegaly, dysphagia, bone lesions, hypertonicity, pseudobulbar palsy, laryngeal spasm, ichthyosis, developmental delay, hypersplenism, death by age 2 yr

Treatment: Supportive care

Type III (juvenile form, Norrbottnian type; 231000)

Onset: 4–8 yr

Urine metabolites: None

Clinical features: Similar to type II except milder, possible survival into adulthood

Treatment: Supportive care

Farber’s disease (lipogranulomatosis; 228000)

Ceramidase

ASAH (8p22-p21.3)*

Onset: First weeks of life

Urine metabolites: Ceramide

Clinical features: Lipogranulomatosis, periarticular subcutaneous nodules, irritability, hoarse cry, psychomotor and growth delay, respiratory insufficiency, histiocytosis in multiple tissues, nephropathy, hepatosplenomegaly, cherry-red macular spot

Milder variants sometimes divided into 7 subtypes according to severity

Treatment: Supportive care

Fabry’s disease (301500)

Trihexosylceramide α-galactosidase

GLA (Xq22)*

Onset: Childhood or adolescence

Urine metabolites: Globosylceramide

Clinical features: Painful crisis involving extremities and abdomen precipitated by stress, fatigue, or exercise; angiokeratoma; growth and pubertal delay; corneal dystrophy; renal failure; cardiomyopathy; MI and heart failure, hypertension; lymphedema; obstructive lung disease; strokes; seizures; death

Generally, only males affected but occasionally females

Treatment: Supportive care, enzyme replacement

Metachromatic leukodystrophy (250100)

  • Late infantile form

  • Juvenile form

  • Adult form

  • Pseudodeficiency form

Arylsulfatase A

ARSA (22q13.31)*

Onset: For late infantile form, 1–2 yr

For juvenile form, 4 yr to puberty

For adult form, any age after puberty

Urine metabolites: Sulfatides

Clinical features: Optic atrophy, gall bladder dysfunction, urinary incontinence, hypotonia, gait disturbance, hyporeflexia followed by hyperreflexia, bulbar palsies, ataxia, chorea, demyelination and developmental regression, increased CSF protein

In adult form, also schizophrenia-like symptoms pseudodeficiency characterized by mild decrease in enzyme activity without neurologic degeneration

Treatment: Supportive care, consideration of bone marrow or stem cell transplantation

Mucosulfatidosis (multiple sulfatase deficiency; 272200)

Sulfatase-modifying factor-1

SUMF1 (3p26)*

Onset: Infancy

Urine metabolites: Sulfatides, mucopolysaccharides

Clinical features: Similar to late infantile form of metachromatic leukodystrophy, plus ichthyosis and dysostosis multiplex

Treatment: Supportive care

Krabbe’s disease (245200)

  • Infantile form

  • Late infantile form

  • Juvenile form

  • Adult form

Galactosylceramide β-galactosidase

GALC (14q31)*

Onset: In infantile form, 3–6 mo

In late infantile and juvenile forms, 15 mo–17 yr

In adult form, variable

Urine metabolites: None

Clinical features: Growth delay, developmental delay followed by regression, deafness, blindness, vomiting, hyperirritability, hypersensitivity to stimuli, increased deep-tendon reflex, and spasticity; seizures; diffuse cerebral atrophy and demyelination; elevated CSF protein; peripheral neuropathy; episodic fever

In adult form, mentation generally preserved

Treatment: Supportive care, bone marrow or stem cell transplantation

Sphingolipid activator protein deficiencies

Onset: Infancy to early childhood

Urine metabolites: Sulfatides

Clinical features: In saposin B deficiency, features similar to those of metachromatic leukodystrophy

In saposin C deficiency, features similar to those of Gaucher’s disease type III

In prosaposin deficiency, features of saposin B and C deficiencies

Treatment: Supportive care; consideration of bone marrow or stem cell transplantation; for features of Gaucher’s disease, consideration of enzyme replacement

Prosaposin deficiency (176801)

Prosaposin

PSAP (10q22.1)*

Saposin B deficiency (sulfatide activator deficiency)

Saposin B

PSAP (10q22.1)*

Saposin C deficiency (Gaucher’s activator deficiency)

Saposin C

PSAP (10q22.1)*

Other lipidoses

Niemann-Pick disease (see also Niemann-Pick disease, types A and B, above)

Onset: Highly variable (early or late infancy, adolescence, adulthood)

Urine metabolites: None

Clinical features: Vertical gaze palsy, hepatosplenomegaly, neonatal jaundice, dysphagia, hypotonia followed by spasticity, seizures, cerebellar ataxia, dysarthria, psychomotor delay and degeneration, psychosis and behavioral problem, fetal ascites, foam cells and sea-blue histiocytes as in Niemann-Pick disease types A and B

Earlier onset associated with faster progression and shorter lifespan

Treatment: Supportive care

Type C1/Type D ((257220)

NPC1 protein

NPC1 (18q11-q12)*

Type C2 (607625)

Epididymal secretory protein 1 (HE1; NPC2 protein)

NPC2 (14q24.3)*

Lysosomal acid lipase deficiency (278000)

  • Wolman’s disease

  • Cholesteryl ester storage disease (CESD)

Lysosomal acid lipase

LIPA (10q24-q25)*

Onset: In Wolman’s disease, infancy

In CESD, variable

Urine metabolites: None

Clinical features: Growth failure; vomiting; diarrhea; steatorrhea; hepatosplenomegaly; hepatic fibrosis; pulmonary hypertension; adrenal calcification; xanthomatous changes in liver, adrenal glands, lymph nodes, bone marrow, small intestine, lungs, and thymus; hypercholesterolemia and normal to elevated plasma lipids; foam cells in marrow

In Wolman’s disease, death during infancy

In CESD, premature atherosclerosis

Treatment: For Wolman’s disease, no effective therapy

For CESD, statins plus a low-cholesterol diet helpful

Cerebrotendinous xanthomatosis (cholestanol lipidosis; 213700)

Sterol 27-hydroxylase

CYP27A (2q33-qter)*

Onset: Adolescence

Urine metabolites: Elevated 7-α-hydroxylated bile alcohol

Clinical features: Juvenile cataracts, tendon and skin xanthomas, xanthelasma, fractures, atherosclerosis, dementia, spinal cord paresis, cerebellar ataxia, developmental disability, pseudobulbar paralysis, leukodystrophy, peripheral neuropathy

Treatment: Chenodeoxycholic acid, statins

Neuronal ceroid lipofuscinosis

Onset: In infantile form, 6–12 mo

In late infantile form, 2–4 yr

In juvenile forms (including CLN9), 4–10 yr

In adult form, 20–39 yr

In variant infantile forms, 4–7 yr

In progressive epilepsy form, 5–10 yr

Urine metabolites: None

Clinical features: In infantile and late infantile forms, developmental delay, microcephaly, optic and cerebral atrophy, retinal degeneration, blindness, flexion contractures, hypotonia, ataxia, myoclonus, seizures, loss of speech, hyperexcitability, autofluorescence in neurons, granular osmiophilic deposits in cells, increased serum arachidonic acid, decreased linoleic acid

In juvenile and adult forms, features of above forms plus extrapyramidal signs, progressive loss of walking ability, school and behavioral difficulties

Treatment: Supportive care

Infantile form (CLN1, Santavuori-Haltia disease; 256730)

Palmitoyl-protein thioesterase-1

PPT1 (1p32)*

Late infantile form (CLN2, Jansky-Bielschowsky disease; 204500)

Lysosomal pepstatin-insensitive peptidase

CLN2 (11p15.5)*

Juvenile form (CLN3, Batten disease, Vogt-Spielmeyer disease; 204200)

Lysosomal transmembrane CLN3 protein

CLN3 (16p12.1)*

Adult form (CLN4, Kufs’ disease; 204300)

Palmitoyl-protein thioesterase-1

PPT1 (1p32)*

Variant late infantile form, Finnish type (CLN5; 256731)

Lysosomal transmembrane CLN5 protein

CLN5 (13q21-q32)*

Variant late infantile form (CLN6; 601780)

Transmembrane CLN6 protein

CLN6 (15q21-q23)*

Progressive epilepsy with intellectual disability (600143)

Transmembrane CLN8 protein

CLN8 (8pter-p22)*

CLN9 (609055)

Oligosaccharidosis and related disorders

Sialidosis (256550)

Neuraminidase 1 (sialidase)

NEU1 (6p21.3)*

Type I (cherry-red macular spot-myoclonus syndrome, mild form)

Onset: 8–25 yr

Urine metabolites: Increased sialyloligosaccharides

Clinical features: Cherry-red macular spot, insidious vision loss, cataracts, progressive myoclonus and ataxia, normal intelligence, increased deep tendon reflex

Treatment: Supportive care

Type II (congenital, infantile, juvenile, and childhood forms)

Onset: In congenital form, in utero

In infantile form, birth to 12 mo

In juvenile and childhood forms, 2–20 yr

Urine metabolites: Increased sialyloligosaccharides

Clinical features: All of features of type I plus coarse facies, hypotonia, hepatomegaly, ascites, inguinal hernia, growth delay, muscle wasting, laryngomalacia, dysostosis multiplex

Treatment: Supportive care

Galactosialidosis (Goldberg’s syndrome, combined neuraminidase and β-galactosidase deficiency; 256540)

  • Neonatal form

  • Late infantile form

  • Juvenile/adult form

Protective protein/cathepsin A (PPCA)

PPGB (20q13.1)*

Onset: In neonatal form, birth to 3 mo

In late infantile form, 1st mo

In juvenile/adult form, adolescence but with wide variability

Urine metabolites: Elevated sialyloligosaccharides but no free sialic acid

Clinical features: Coarse facies, corneal clouding, cherry-red macular spot, intellectual disability, seizures, dysostosis multiplex, hearing loss, hemangiomas, valvular heart disease

Treatment: Supportive care

Sialolipidosis (phospholipidosis; mucolipidosis IV, Berman disease; 252650)

MCOLN1 (19p13.3-p13.2)*

Onset: 1st yr

Urine metabolites: No mucopolysaccharides

Clinical features: Severe (Berman disease) and mild forms

Developmental delay, corneal opacities, visual deficiency, strabismus, hypotonia, increased deep tendon reflexes; no radiographic skeletal abnormality, macrocephaly, or organomegaly

Treatment: Supportive care

Mannosidosis

Onset: In type I, 3–12 mo

In type II, 1–4 yr

Urine metabolites: Mannose-rich oligosaccharides

Clinical features: Coarse facies, macrocephaly, macroglossia, cataracts, gingival hypertrophy, slight hepatosplenomegaly, dysostosis multiplex, hypotonia, hearing loss, bowed femur, pancytopenia, recurrent respiratory infections, immunodeficiency and autoimmunity, developmental disabilities

Treatment: Supportive care, consideration of bone marrow or stem cell transplantation

α-Mannosidosis (248500), type I (severe) or II (mild)

α-D-Mannosidase

MAN2B1 (19cen-q12)*

β-Mannosidosis (248510)

β-D-Mannosidase

MANBA (4q22-q25)*

Onset: 1–6 yr

Urine metabolites: Disaccharides, mannosyl-(1-4)- N -acetylglucosamine, heparin sulfate

Clinical features: Coarse facies, deafness, delayed speech, hyperactivity, genital angiokeratoma, tortuous conjunctival vessels

Treatment: Supportive care, consideration of bone marrow or stem cell transplantation

Fucosidosis (230000)

  • Type I (severe infantile form)

  • Type II (mild form)

α-L-Fucosidase

FUCA1 (1p34)*

Onset: In type I, 3–18 mo

In type II, 1–2 yr

Urine metabolites: Oligosaccharides

Clinical features: Short stature, growth delay, coarse facies, macroglossia, cardiomegaly, recurrent respiratory infections, dysostosis multiplex, hernias, hepatosplenomegaly, angiokeratoma, anhidrosis and elevated sweat chloride, developmental disability, hypotonia changing to hypertonia, cerebral atrophy, seizures, spastic quadriplegia, vacuolated lymphocytes

Most patients from Italy or southwestern US

Treatment: Supportive care, consideration of bone marrow or stem cell transplantation

Aspartylglucosaminuria (208400)

N -Aspartylglucosaminidase

AGA (4q32-q33)*

Onset: 2–6 yr

Urine metabolites: Aspartylglucosamine

Clinical features: Growth delay, microcephaly, cataracts, coarse facies, macroglossia, mitral insufficiency, hepatomegaly, diarrhea, hernias, recurrent respiratory infections, macro-orchidism, mild dysostosis multiplex, angiokeratoma corporis diffusum, acne, developmental disabilities, hypotonia, spasticity, cerebral atrophy, seizures, speech delay, hoarse voice

Increased frequency in Finnish populations

Treatment: Supportive care, consideration of bone marrow or stem cell transplantation

Winchester syndrome (277950)

Metalloproteinase-2

MMP2 (16q13)*

Onset: Early infancy

Urine metabolites: None

Clinical features: Short stature, coarse facies, corneal opacities, gingival hyperplasia, joint contractures, osteoporosis, kyphoscoliosis, vertebral compression, carpotarsal osteolysis, ankylosis of small joints of feet, diffuse thickened skin, hyperpigmentation, hypertrichosis

Treatment: Supportive care

Schindler’s disease

N -Acetyl-galactosaminidase

α-NAGA (22q13)*

Type I (infantile severe form; 609241)

Onset: 8–15 mo

Urine metabolites: Oligosaccharides and O-linked sialopeptides

Clinical features: Cortical blindness, optic atrophy, nystagmus, strabismus, osteopenia, joint contracture, muscular atrophy, developmental delay and regression, myoclonus, seizures, spasticity, hyperreflexia, decorticate posturing, neuraxonal dystrophy

Treatment: Supportive care

Type II (Kanzaki disease, adult-onset form; 609242)

Onset: Adulthood

Urine metabolites: Oligosaccharides and O-linked sialopeptides

Clinical features: Coarse facies, deafness, conjunctival and retinal vascular tortuosity, angiokeratoma corporis diffusum, telangiectasia, lymphedema, mild intellectual impairment, peripheral axonal neuropathy

Treatment: Supportive care

Type III (intermediate form; 609241)

Onset: Childhood

Urine metabolites: Oligosaccharides and O-linked sialopeptides

Clinical features: Intermediate between types I and II; variable and ranging from seizures and moderate psychomotor retardation to mild autistic features with speech and language delay

Treatment: Supportive care

Congenital disorders of N -glycosylation, type I (pre-Golgi glycosylation defects)

Onset: Mostly infancy or childhood

Clinical features (some or most of the following): Growth failure, prominent forehead with large ears, high-arched or cleft palate, strabismus, retinitis pigmentosa, pericardial effusion, cardiomyopathy, hepatomegaly, vomiting, diarrhea, liver fibrosis, primary ovarian failure, renal cysts, nephrosis, proximal tubulopathy, kyphosis, joint contractures, ectopic fat pads, orange-peel skin, muscle weakness, hypotonia, strokelike episodes, seizures, olivopontine hypoplasia, peripheral neuropathy, hypothyroidism, hyperinsulinism, factor XI deficiency, antithrombin III deficiency, thrombocytosis, decreased IgA and IgG, leukocyte adhesion defect (in type IIc), hypoalbuminemia, hypocholesterolemia, increased disialotransferrin and asialotransferrin bands when isoelectric focusing of serum transferrin is done

Treatment: Supportive care

CDG Ia (solely neurologic and neurologic-multivisceral forms; 212065)

Phosphomannomutase-2

PMM2 (16p13.3-p13.2)*

CDG Ib (602579)

Mannose (Man) phosphate (P) isomerase

MPI (15q22-qter)*

CDG Ic (603147)

Dolicho-P-Glc:Man9GlcNAc2-PP-dolichol glucosyltransferase

ALG6 (1p22.3)*

CDG Id (601110)

Dolicho-P-Man:Man5GlcNAc2-PP-dolichol mannosyltransferase

ALG3 (3q27)*

CDG Ie (608799)

Dolichol-P-mannose synthase

DPM1 (20q13.31)*

CDG If (609180)

Protein involved in mannose-P-dolichol utilization

MPUD1 (17p13.1-p12)*

CDG Ig (607143)

Dolichyl-P-mannose:Man-7-GlcNAc-2-PP-dolichyl-α-6-mannosyltransferase

ALG12 (22)*

CDG Ih (608104)

Dolichyl-P-glucose:Glc-1-Man-9-GlcNAc-2-PP-dolichyl-α-3-glucosyltransferase

ALG8 (11pter-p15.5)*

CDG Ii (607906)

α-1,3-Mannosyltransferase

ALG2 (9q22)*

CDG Ij (608093)

UDP-GlcNAc:dolichyl-P NAcGlc phosphotransferase

DPAGT1 (11q23.3)*

CDG Ik (608540)

β-1,4-Mannosyltransferase

ALG1 (16p13.3)*

CDG Il (608776)

α-1,2-Mannosyltransferase

ALG9 (11q23)*

Congenital disorders of N -glycosylation, type II (Golgi defects)

Same as for type I, except isoelectric focusing of serum transferrin shows increased monosialotransferrin, disialotransferrin, trisialotransferrin, and asialotransferrin bands

For type IIb, normal pattern

CDG IIa (212066)

Mannosyl-α-1,6-glycoprotein-β-1,2- N -acetylglucosminyltransferase

MGAT2 (14q21)*

CDG IIb (606056)

Glucosidase I

GCS1 (1p13-p12)*

CDG IIc (Rambam-Hasharon syndrome; 266265

GDP-fucose transporter-1

FUCT1 (11p11.2)*

CDG IId (607091)

β-1,4-Galactosyltransferase

B4GALT1 (9p13)*

CDG IIe (608779)

Oligomeric Golgi complex-7

COG7 (16p)*

Lysosomal transport defects

Sialuria

Infantile sialic acid storage disorder (269920)

Na phosphate cotransporter

SLC17A5 (6q14-q15)*

Onset: At birth

Urine metabolites: Increased free sialic acid

Clinical features: Growth failure, coarse facial features, dysostosis multiplex, nystagmus, ptosis, gingival hypertrophy, cardiomegaly, heart failure, hepatosplenomegaly, nephrosis, death at about age 1 yr

Treatment: Supportive care

Finnish type (Salla disease; 604369)

Na phosphate cotransporter

SLC17A5 (6q14-q15)*

Onset: 6–9 mo

Urine metabolites: Increased free sialic acid

Clinical features: Growth failure, developmental disability, ataxia, hypotonia, hypotonia, spasticity, dyspraxia, dysarthria, seizures, gait problems, athetosis; increased frequency in Finland

Treatment: Supportive care

French type (269921)

UDP-N-acetylglucosamine-2-epimerase/ N -acetylmannosamine kinase

GNE (9p12-p11)*

Onset: Infancy to early childhood

Urine metabolites: Increased free sialic acid

Clinical features: Coarse facies with normal growth, developmental delay, sleep apnea, hypoplastic nipples, hepatosplenomegaly, inguinal hernias, generalized hirsutism, seizures

Treatment: Supportive care

Neuronal ceroid lipofuscinosis (CLN3, CLN5, CLN6, CLN8)

See Other lipidoses, above

Cystinosis

Cystinosin (lysosomal cystine transporter)

CTNS (17p13)*

Infantile nephropathic form (219800)

Onset: 1st yr

Urine metabolites: Renal Fanconi syndrome

Clinical features: Growth failure, frontal bossing, photophobia, peripheral retinopathy with decreased acuity, corneal crystals and erosion, rickets, hepatosplenomegaly, pancreatic insufficiency, renal calculi, renal failure, renal Fanconi syndrome, decreased sweating, myopathy, dysphagia, cerebral atrophy, normal intelligence but neurologic deterioration in long-term survivors

Cystine accumulation throughout reticuloendothelial system, WBC, and cornea

Treatment: Replacement therapy for Fanconi syndrome, renal transplant for failure, cysteamine orally or as eyedrops, growth hormone

Late-onset juvenile form (219900)

Onset: 12–15 yr

Urine metabolites: Renal Fanconi syndrome

Clinical features: Similar to infantile form but milder

Treatment: Similar to that for infantile form

Adult non-nephropathic form (219750)

Onset: Early teens to adulthood

Urine metabolites: Renal Fanconi syndrome

Clinical features: Similar to infantile form but no renal disorders

Treatment: Cysteamine orally or as eyedrops, growth hormone

Other lysosomal disorders

Pycnodysostosis (265800)

Cathepsin K

CTSK (1q21)*

Onset: Early childhood

Urine metabolites: None

Clinical features: Short stature, frontal and occipital prominence, delayed closure of anterior fontanel, micrognathia, narrow palate, delayed eruption and persistence of deciduous teeth, hypodontia, aplasia or hypoplasia of clavicles, osteosclerosis, susceptibility to fracture, scoliosis, spondylolysis, brachydactyly, grooved nails

Treatment: Supportive care, growth hormone possibly helpful

Glutamyl ribose-5-phosphate storage disease (305920)

ADP-ribose protein hydrolase

Onset: 1st yr

Urine metabolites: Proteinuria

Clinical features: Coarse facies, hypotonia, muscle wasting and atrophy, loss of speech and vision, seizures, neurologic deterioration, optic atrophy, nephrosis, hypertension, renal failure, developmental disabilities

Treatment: Supportive care

Glycogen storage disease type 2 (Pompe’s disease)

See Table2sec19ch296

*Gene has been identified, and molecular basis has been elucidated.

OMIM = online mendelian inheritance in man (see database at http://www.ncbi.nlm.nih.gov/omim ).

Because reticuloendothelial cells (eg, in the spleen) are rich in lysosomes, reticuloendothelial tissues are involved in a number of lysosomal storage disorders, but generally, tissues richest in the substrate are most affected. Thus the brain, which is rich in gangliosides, is particularly affected by gangliosidoses, whereas mucopolysaccharidoses affect many tissues because mucopolysaccharides are present throughout the body.

Mucopolysaccharidoses (MPS)

MPS are inherited deficiencies of enzymes involved in glycosaminoglycan breakdown. Glycosaminoglycans (previously termed mucopolysaccharides) are polysaccharides abundant on cell surfaces and in extracellular matrix and structures. Enzyme deficiencies that prevent glycosaminoglycan breakdown cause accumulation of glycosaminoglycan fragments in lysosomes and cause extensive bone, soft tissue, and CNS changes. Inheritance is usually autosomal recessive (except for MPS type II).

Age at presentation, clinical manifestations, and severity vary by type. Common manifestations include coarse facial features, neurodevelopmental delays and regression, joint contractures, organomegaly, stiff hair, progressive respiratory insufficiency (caused by airway obstruction and sleep apnea), cardiac valvular disease, skeletal changes, and cervical vertebral subluxation.

Diagnosis is suggested by history, physical examination, bone abnormalities (eg, dysostosis multiplex) found during skeletal survey, and elevated total and fractionated urinary glycosaminoglycans. Diagnosis is confirmed by enzyme analysis of cultured fibroblasts (prenatal) or peripheral WBCs (postnatal). Additional testing is required to monitor organ-specific changes (eg, echocardiography for valvular disease, audiometry for hearing changes).

Treatment of MPS type I (Hurler’s disease) is enzyme replacement with α-l-iduronidase, which effectively halts progression and reverses all non-CNS complications of the disease. Hematopoietic stem cell (HSC) transplantation has also shown promise in early studies but is ineffective for CNS disease. The combination of enzyme replacement and HSC transplantation is under study.

Sphingolipidoses

Sphingolipids are normal lipid components of cell membranes; they accumulate in lysosomes and cause extensive neuronal, bone, and other changes when enzyme deficiencies prevent their breakdown. Although incidence is low, carrier rate of some forms is high. Gaucher’s disease is the most common sphingolipidosis. Others include Niemann-Pick, Tay-Sachs, Sandhoff’s, Fabry’s, Krabbe’s, and cholesteryl ester storage diseases and metachromatic leukodystrophy.

Gaucher’s Disease

Gaucher’s disease is a sphingolipidosis resulting from glucocerebrosidase deficiency, causing deposition of glucocerebroside and related compounds. Symptoms and signs vary by type but are most commonly hepatosplenomegaly or CNS changes. Diagnosis is by enzyme analysis of WBCs.

Glucocerebrosidase normally hydrolyzes glucocerebroside to glucose and ceramide. Genetic defects of the enzyme cause glucocerebroside accumulation in tissue macrophages through phagocytosis, forming Gaucher’s cells. Accumulation of Gaucher’s cells in the perivascular spaces in the brain causes gliosis in the neuronopathic forms. There are 3 types, which vary in epidemiology, enzyme activity, and manifestations.

Type I (nonneuronopathic) is most common (90% of all patients). Residual enzyme activity is highest. Ashkenazi Jews are at greatest risk; 1/12 is a carrier. Onset ranges from age 2 yr to late adulthood. Symptoms and signs include splenohepatomegaly, bone disease (eg, osteopenia, pain crises, osteolytic lesions with fractures), growth failure, delayed puberty, ecchymoses, and pingueculae. Epistaxis and ecchymoses resulting from thrombocytopenia are common. X-rays show flaring of the ends of the long bones (Erlenmeyer flask deformity) and cortical thinning.

Type II (acute neuronopathic) is rarest, and residual enzyme activity in this type is lowest. Onset occurs during infancy. Symptoms and signs are progressive neurologic deterioration (eg, rigidity, seizures) and death by age 2 yr.

Type III (subacute neuronopathic) falls between types I and II in incidence, enzyme activity, and clinical severity. Onset occurs at any time during childhood. Clinical manifestations vary by subtype and include progressive dementia and ataxia (IIIa), bone and visceral involvement (IIIb), and supranuclear palsies with corneal opacities (IIIc). Patients who survive to adolescence may live for many years.

Diagnosis

  • Enzyme analysis

Diagnosis is by enzyme analysis of WBCs. Carriers are detected, and types are distinguished by mutation analysis. Although biopsy is unnecessary, Gaucher’s cells—lipid-laden tissue macrophages in the liver, spleen, lymph nodes, or bone marrow that have a wrinkled tissue-paper appearance—are diagnostic.


Treatment

  • Types I and III: Enzyme replacement with placental or recombinant glucocerebrosidase

  • Sometimes miglustat, splenectomy, or stem cell transplantation

Enzyme replacement with placental or recombinant glucocerebrosidase is effective in types I and III; there is no treatment for type II. The enzyme is modified for efficient delivery to lysosomes. Patients receiving enzyme replacement require routine Hb and platelet monitoring, routine assessment of spleen and liver volume by CT or MRI, and routine assessment of bone disease by skeletal survey, dual-energy x-ray absorptiometry scanning, or MRI.

Miglustat (100 mg po tid), a glucosylceramide synthase inhibitor, reduces glucocerebroside concentration (the substrate for glucocerebrosidase) and is an alternative for patients unable to receive enzyme replacement.

Splenectomy may be helpful for patients with anemia, leukopenia, or thrombocytopenia or when spleen size causes discomfort. Patients with anemia may also need blood transfusions.

Bone marrow or stem cell transplantation provides a definitive cure but is considered a last resort because of substantial morbidity and mortality.


Niemann-Pick Disease

Niemann-Pick disease is a sphingolipidosis caused by deficient sphingomyelinase activity, resulting in accumulation of sphingomyelin (ceramide phosphorylcholine) in reticuloendothelial cells.

Niemann-Pick disease inheritance is autosomal recessive and appears most often in Ashkenazi Jews; 2 types, A and B, exist. Type C Niemann-Pick disease is an unrelated enzymatic defect involving abnormal cholesterol storage.

Type A patients have < 5% of normal sphingomyelinase activity. The disease is characterized by hepatosplenomegaly, failure to thrive, and rapidly progressive neurodegeneration. Death occurs by age 2 or 3 yr.

Type B patients have sphingomyelinase activity within 5 to 10% of normal. Type B is more variable clinically than type A. Hepatosplenomegaly and lymphadenopathy may occur. Pancytopenia is common. Most patients with type B have little or no neurologic involvement and survive into adulthood; they may be clinically indistinguishable from those with type I Gaucher’s disease. In severe cases of type B, progressive pulmonary infiltrates cause major complications.

Diagnosis

  • Prenatal screening

  • WBC sphingomyelinase assay

Both types are usually suspected by history and examination, most notably hepatosplenomegaly. Diagnosis can be confirmed by sphingomyelinase assay on WBCs and can be made prenatally by using amniocentesis or chorionic villus sampling.


Treatment

Bone marrow or stem cell transplantation is under investigation as a potential treatment option.


Tay-Sachs Disease and Sandhoff’s Disease

Tay-Sachs disease and Sandhoff’s disease are sphingolipidoses caused by hexosaminidase deficiency that causes severe neurologic symptoms and early death.

Gangliosides are complex sphingolipids present in the brain. There are 2 major forms, GM 1 and GM 2 , both of which may be involved in lysosomal storage disorders; there are 2 main types of GM 2 gangliosidosis, each of which can be caused by numerous different mutations.

Tay-Sachs disease

Deficiency of hexosaminidase A results in accumulation of GM 2 in the brain. Inheritance is autosomal recessive; the most common mutations are carried by 1/27 normal adults of Eastern European (Ashkenazi) Jewish origin, although other mutations cluster in some French-Canadian and Cajun populations.

Children with Tay-Sachs disease start missing developmental milestones after age 6 mo and develop progressive cognitive and motor deterioration resulting in seizures, intellectual disability, paralysis, and death by age 5 yr. A cherry-red macular spot is common.

Diagnosis is clinical and can be confirmed by enzyme assay.

In the absence of effective treatment, management is focused on screening adults of childbearing age in high-risk populations to identify carriers (by way of enzyme activity and mutation testing) combined with genetic counseling.


Sandhoff’s disease

There is a combined hexosaminidase A and B deficiency. Clinical manifestations include progressive cerebral degeneration beginning at 6 mo, accompanied by blindness, cherry-red macular spot, and hyperacusis. It is almost indistinguishable from Tay-Sachs disease in course, diagnosis, and management, except that there is visceral involvement (hepatomegaly and bone change) and no ethnic association.


Krabbe’s Disease

Krabbe’s disease is a sphingolipidosis that causes intellectual disability, paralysis, blindness, deafness, and pseudobulbar palsy, progressing to death.

Krabbe’s disease (galactosylceramide lipidosis, globoid cell leukodystrophy) is caused by an autosomal recessive galactocerebroside β-galactosidase deficiency.

It affects infants and is characterized by intellectual disability, paralysis, blindness, deafness, and pseudobulbar palsy, progressing to death.

Diagnosis is by detecting enzyme deficiency in WBCs or cultured skin fibroblasts.

Because bone marrow transplantation effectively delays onset of symptoms, prenatal testing or neonatal screening (routine in New York) is sometimes done.

Metachromatic Leukodystrophy

Metachromatic leukodystrophy is a sphingolipidosis caused by arylsulfatase A deficiency, which causes progressive paralysis and dementia resulting in death by age 10 yr.

In metachromatic leukodystrophy (sulfatide lipidosis), arylsulfatase A deficiency causes metachromatic lipids to accumulate in the white matter of the CNS, peripheral nerves, kidney, spleen, and other visceral organs; accumulation in the nervous system causes central and peripheral demyelination. Numerous mutations exist; patients vary in age at onset and speed of progression.

The infantile form is characterized by progressive paralysis and dementia usually beginning before age 4 yr and resulting in death about 5 yr after onset of symptoms. The juvenile form manifests between 4 yr and 16 yr of age with gait disturbance, intellectual impairment, and findings of peripheral neuropathy. Contrary to the infantile form, deep tendon reflexes are usually brisk. There is also a milder adult form.

Diagnosis is suggested clinically and by findings of decreased nerve conduction velocity; it is confirmed by detecting enzyme deficiency in WBCs or cultured skin fibroblasts.

There is no effective treatment.

Fabry’s Disease

Fabry’s disease is a sphingolipidosis caused by deficiency of α-galactosidase A, which causes angiokeratomas, acroparesthesias, corneal opacities, recurrent febrile episodes, and renal or heart failure.

Fabry’s disease (angiokeratoma corporis diffusum) is an X-linked deficiency of the lysosomal enzyme α-galactosidase A, which is needed for normal trihexosylceramide catabolism. Glycolipid (globotriaosylceramide) accumulates in many tissues (eg, vascular endothelium, lymph vessels, heart, kidney).

Diagnosis in males is clinical, based on appearance of typical skin lesions (angiokeratomas) over the lower trunk and by characteristic features of peripheral neuropathy (causing recurrent burning pain in the extremities), corneal opacities, and recurrent febrile episodes. Death results from renal failure or cardiac or cerebral complications of hypertension or other vascular disease. Heterozygous females are usually asymptomatic but may have an attenuated form of disease often characterized by corneal opacities.

Diagnosis is by assay of galactosidase activity—prenatally in amniocytes or chorionic villi and postnatally in serum or WBCs.

Treatment is enzyme replacement with recombinant α-galactosidase A (agalsidase beta) combined with supportive measures for fever and pain. Kidney transplantation is effective for treating renal failure.

Cholesteryl Ester Storage Disease and Wolman’s Disease

Cholesteryl ester storage disease and Wolman’s disease are sphingolipidoses caused by lysosomal acid lipase deficiency resulting in hyperlipidemia and hepatomegaly.

These diseases are rare, autosomal recessive disorders that result in accumulation of cholesteryl esters and triglycerides, mainly in lysosomes of histiocytes, resulting in foam cells in the liver, spleen, lymph nodes, and other tissues. Serum low-density lipoprotein (LDL) is usually elevated.

Wolman’s disease is the more severe form, manifesting in the first weeks of life with poor feeding, vomiting, and abdominal distention secondary to hepatosplenomegaly; infants usually die within 6 mo.

Cholesteryl ester storage disease is less severe and may not manifest until later in life, even adulthood, at which time hepatomegaly may be detected; premature atherosclerosis, often severe, may develop.

Diagnosis is based on clinical features and detection of acid lipase deficiency in liver biopsy specimens or cultured skin fibroblasts, lymphocytes, or other tissues. Prenatal diagnosis is based on the absence of acid lipase activity in cultured chorionic villi.

There is no proven treatment, but statins reduce plasma LDL levels, and cholestyramine combined with a low-cholesterol diet has reportedly alleviated other signs.

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