Lysosomal and Other Storage Diseases



Lysosomal and Other Storage Diseases





Storage material (complex lipid, saccharide, or protein) accumulates in lysosomes due to genetically determined deficiency of a catabolic enzyme.

Inheritance recessive, usually autosomal, occasionally X-linked.

Only specific treatment: enzyme replacement therapy for MPS 1, Gaucher, Fabry disease.

See Tables 84.1, 84.2, 84.3 and 84.4. Below are notes about selected conditions.








Table 84.1 Selected Lipidoses




























































































































Disorder Defective enzyme Clinical features Diagnosis
GM2 gangliosidoses Hexosaminidase Infantile- to adult-onset phenotypes from infantile encephalopathy with macular cherry-red spots to adult-onset spinal muscular atrophy Hexosaminidase A, B levels in blood, leukocytes.
GM1 gangliosidoses β-galactosidase    
Infantile form   Infantile encephalopathy, organomegaly, skeletal involvement, cherry-red spot (50%), corneal haze (occasionally) Oligosaccharide pattern in urine; enzyme activity (leukocytes, fibroblasts)
Late infantile form   Onset age 1–3 yr: dementia, seizures, ataxia, dysarthria, spastic quadriplegia. No organomegaly. Same
Fabry disease α-galactosidase X-linked. Purple skin lesions, painful hands and feet, renal disease, leg edema, stroke. ERT effective in reducing symptoms; some still need renal transplant. Enzyme activity (plasma, leukocytes); mutation analysis
Gaucher disease β-glucosidase   “Gaucher cells” in bone marrow; enzyme activity (leukocyte, fibroblasts); mutation analysis
Infantile neuronopathic   Onset age 3 mo: dementia, organomegaly, poor suck and swallowing, opisthotonos, spasticity, seizures; usually fatal before age 2 years.  
Juvenile neuronopathic   Variable onset of mental defect, splenomegaly, incoordination, seizures, tics  
Adult nonneuronopathic   Splenomegaly (sometimes in infancy) and bony involvement; Ashkenazi Jewish predilection; no neurologic disease. ERT effective.  
Adult neuronopathic   Splenomegaly, bony involvement, seizures, dementia.  
Niemann-Pick disease     Path: foam (“mulberry”) cells in bone marrow
Infantile neuronopathic, type A Sphingomyelinase Infantile encephalopathy, organomegaly, cherry-red spot (30%), lung infiltrates, especially Ashkenazi Jewish Enzyme activity (fibroblasts, leukocytes)
Juvenile nonneuronopathic, type B Sphingomyelinase Hepatosplenomegaly Same as type A
Juvenile neuronopathic, type C Cholesterol esterification induction Onset at any age: ataxia, dystonia, dementia; seizures in 50% hepatosplenomegaly variable. Vertical supranuclear gaze palsy characteristic. Impaired cholesterol esterification in fibroblasts.
Farber disease Acid-ceramidase Early infantile painful swollen joints, subcutaneous nodules, organomegaly, enlarged heart, dysphagia, vomiting, normal or impaired mentation Enzyme activity (fibroblasts, leukocytes)
Wolman disease Acid lipase Early infantile organomegaly, vomiting, diarrhea, jaundice, variable CNS involvement Calcified adrenals; foam cells in bone marrow; enzyme studies (leukocytes)
Refsum disease Phytanic acid α-hydroxylase Night blindness, retinitis pigmentosa, ataxia, demyelinating neuropathy, ichthyosis Serum phytanic acid
Cerebrotendinous xanthomatosis Mitochondrial enzyme 27-sterol hydroxylase (CYP 27) Static encephalopathy in first decade; adolescent or adult-onset cataracts, tendon xanthomas, ataxia, spasticity Mutations in sterol 27-hydroxylase gene
Neuronal ceroid lipofuscinoses CLN1, CLN2, CLN3, CLN4, CLN5 gene products   Electron microscopic examination of tissue; (skin, nerve, muscle, or rectal biopsy)
Infantile (Haltia-Santavuori) Palmitoyl-protein thioesterase enzyme (CLN1 gene) Infantile onset: progressive visual loss, retinal degeneration, myoclonic jerks, microcephaly. Abnormal electroretinogram  
Late infantile (Jansky-Bielschowsky) Tripeptidyl peptidase 1 (CLN2 gene) Onset at age 1–4 yr: seizures, ataxia, dementia, then visual deterioration, retinal degeneration. Abnormal electroretinogram  
Juvenile form (Spielmeyer-Sjögren) CLN3 gene product Onset age 5–10 yrs: progressive visual loss, pigmentary retinal degeneration, then seizures, dementia. Abnormal electroretinogram  
Adult (Kufs)   Adult onset: dementia, ataxia, seizures, myoclonus  
ERT, Enzyme replacement therapy.








Table 84.2 Leukodystrophies



























































Clinical disorder Defective enzyme Clinical features Diagnosis
Krabbe leukodystrophy      
Infantile form Galactocerebrosidase Onset age 3–6 mo: irritability, spasticity, seizures, fevers; developmental slowing then regression; eventual blindness due to optic atrophy, decerebrate posturing, absent tendon reflexes, vegetative state; usually fatal within 2 years Infantile form: increased CSF protein. All types: slow nerve conduction, enzyme studies (serum, leukocytes, fibroblasts)
Juvenile form Galactocerebrosidase Juvenile onset: dementia, optic atrophy, pyramidal tract signs  
Adult form Galactocerebrosidase Adult onset: slowly progressive dementia, optic atrophy, pyramidal signs  
Metachromatic leukodystrophy      
Late-infantile form Sulfatase A Onset age 1–2 yr: walking difficulty with weakness, ataxia, or spasticity; dementia, optic atrophy, loss of tendon reflexes; eventual quadriplegia, vegetative state All types: increased CSF protein (except in adult-onset), increased excretion of urine sulfatides, slow nerve conduction; enzyme studies (leukocytes, fibroblasts). Sural nerve biopsy: metachromatic lipids; characteristic “tuffstone” bodies on electron microscopy
Juvenile form Sulfatase A Onset age 3–10 yr: dememtia, gait difficulty, neuopathy, high CSF protein; slower  
Adult form Sulfatase A Adult-onset dementia, ataxia, pyramidal signs  
Without sulfatase A deficiency Sulfatase A activator Same as late infanitile or juvenile form  
Multiple sulfatase deficiency (mucosulfatidosis) Many sulfatases Features of both MLD and mucopolysaccharidosis.
Onset at age 1–2 yr: developmental delay then regression, seizures, mildly coarse facial features, ichthysis, organomegaly, skeletal changes		 Similar to MLD; in addition: increased urine GAG; deficiencies of multiple sulfatases in cultured fibroblasts
GAG, glycosaminoglycans.

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Jul 27, 2016 | Posted by in NEUROLOGY | Comments Off on Lysosomal and Other Storage Diseases

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