NEUROLOGICAL REVIEW SECTION EDITOR: DAVID E. PLEASURE, MD Insights Into the Diagnosis and Treatment of Lysosomal Storage Diseases David A. Wenger, PhD; Stephanie Coppola, BS; Shu-Ling Liu, MD ysosomal storage diseases (LSDs) are a group of genetic disorders that result from de- fective lysosomal metabolism or export of naturally occurring compounds. Signs and symptoms are variable both within and between disorders depending on the location and extent of storage. Many patients develop neurologic symptoms that become obvi- Lous from the newborn period to adulthood. Diagnosis of suspected patients can usually be made by measuring the activity of an enzyme or concentration of a metabolite in easily obtained tissue samples. Based on the considerable diagnostic experience of our laboratory, we aid the physician in selecting the appropriate tests to perform. Hematopoietic stem cell transplantation and enzyme replacement therapy are already available or in clinical trials for a number of LSDs. Early diagnosis is critical, especially since those patients who are treated before significant symptoms arise have the best chance for a positive outcome. Arch Neurol. 2003;60:322-328 The LSDs are a group of genetic disorders the nervous system. While the genes re- that result from the accumulation of stor- sponsible for almost all of the defined LSDs age products due to a defect in a hydro- have been cloned, this information may not lytic enzyme, activator protein, transport be useful for diagnosing a patient initially protein, or enzyme required for the cor- presenting to the practicing physician. Mea- rect processing of other lysosomal pro- surement of a panel of lysosomal enzymes teins. About 40 different genes have been and/or identification of storage products is identified as sites for mutations resulting in a more definitive method for diagnosing new an LSD. A large number of mutations have patients.2 As effective treatment for some of been delineated for most disorders, and this these disorders becomes more of a reality, contributes to the wide clinical spectra ob- it is critical that patients be diagnosed as served in patients with a deficiency of a nec- early as possible. There are even initiatives essary protein. As a group, LSDs occur in to institute newborn screening for LSDs to approximately 1 in 5000 to 8000 births in identify presymptomatic individuals who the United States, Europe, and Australia.1 may be candidates for early therapeutic in- Therefore, about 500 to 800 people are born tervention. However, this may result in ad- each year with an LSD in the United States. ditional problems because predicting the While some of these disorders result in clinical course in untreated patients is not purely nonneurologic manifestations (eg, reliable, especially in the later-onset forms Gaucher disease type 1), many others are of most LSDs. characterized by a wide range of neuro- Since 1973, our laboratory has diag- logic symptoms, with or without somatic nosed an LSD in more than 2600 pa- features, presenting from birth to adult- tients. In this review, we outline some clini- hood. Owing to the complexity of the stor- cal features that should signal a request for age products and differences in their tissue testing, with a focus on those diseases re- distribution and rates of accumulation, the quiring special diagnostic attention, dis- disease can cause pathologic changes in mul- cuss the difficulties in making a progno- tiple organ systems or can be confined to sis in newly diagnosed patients, and present the possibilities for therapy in cur- From the Department of Neurology, Jefferson Medical College, Philadelphia, Pa. rent use or under development. This re- (REPRINTED) ARCH NEUROL / VOL 60, MAR 2003 WWW.ARCHNEUROL.COM 322 ©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 Presenting Features in Lysosomal Storage Diseases With Prominent Neurologic Findings Samples Presenting Signs Acceptable Treatment Disease Defective Protein and Symptoms for Diagnosis* Options† GM1 gangliosidosis‡ Acid ␤-galactosidase IO: hypotonia, DD, coarse facial features, HM, CRS (±) L, P, F SC,§ HSCT LO: DD, ataxia, dysarthria, PR, dystonia GM2 gangliosidosis, Hexosaminidase A IO: hypotonia, hyperacusis, DD, CRS L, P, F SC, HSCT B variant, Tay-Sachs LO: ataxia, dystonia, psychoses, PR disease‡ GM2 gangliosidosis, HexosaminidaseA&B Similar to Tay-Sachs disease L, P, F SC O variant, Sandhoff disease‡ GM2 gangliosidosis, GM2 activator protein Similar to Tay-Sachs disease F, CSF SC AB variant‡ Fabry disease‡ ␣-Galactosidase Acroparesthesia, pain crises, corneal opacities, fatigue, L, F SC, ERT, HSCT angiokeratomas Gaucher disease, types Glucocerebrosidase HSM, DD, strabismus, Sz, myoclonus, horizontal L, F SC, ERT, HSCT 2 and 3‡ supranuclear gaze palsy Niemann-Pick type A‡ Sphingomyelinase HSM, hypotonia, DD, CRS (±) L, F SC Niemann-Pick type C1‡ NPC1 Neonatal onset: jaundice, HSM, hypotonia F SC, HSCT LO: emotional lability, ataxia, dystonia, HSM (±), VSO Niemann-Pick type C2‡ NPC2 Similar to Niemann-Pick type C1 F SC Metachromatic Arylsulfatase A Late IO: weakness, hypotonia, DD, genu recurvatum L, F, U SC, HSCT leukodystrophy‡ JO: weakness, PR, ataxia, behavior changes AO: pyramidal or cerebellar signs, behavior changes, psychoses, dementia Krabbe disease‡ Galactocerebrosidase IO: spasticity, irritability, hypotonia, fisting, DD L, F SC, HSCT LO: spastic paraparesis, weakness, burning paresthesia, ataxia, weakness, vision loss ␣-Mannosidosis‡ ␣-Mannosidase DD, hearing loss, mildly coarse facial features (large jaw), L, F SC, HSCT mild DM ␤-Mannosidosis‡ ␤-Mannosidase DD, MR, hearing loss, mild facial coarsening, angiokeratomas L, F SC Sialidosis, Sialidase IO: NIFH, DD, coarse facial features, DM, HSM, PR, L, F SC Mucolipidosis I‡ renal disease LO: myoclonus, CRS, ataxia, visual defects Sialic acid storage Transport protein IO: severe DD, fair hair and skin, HSM, coarse facial features L, F SC disease, Salla LO: hypotonia, MR, ataxia, DD, speech delay, coarse facial disease‡ features Galactosialidosis‡ Protective protein, Neonatal onset: NIFH, HSM, severe DD L, F SC cathepsin A IO and late IO: coarse facial features, HSM, kidney and heart defects, DD, DM, MR LO: coarse facial features, DM, corneal clouding, MR, ataxia, Sz, CRS(±) Fucosidosis‡ ␣-L-fucosidase Spasticity, DD, coarse facial features, DM, MR, L, F SC, HSCT angiokeratomas MPS I (Hurler and ␣-L-iduronidase Coarse facial features, DD, DM, MR, hearing loss, corneal L, F SC, HSCT, ERT Hurler-Scheie)‡ clouding, hernias MPS II (Hunter) Iduronate-2-sulfatase DD, DM, hearing loss, coarse facial features, joint stiffness F, P SC, HSCT, ERT MPS III A (Sanfilippo) Glucosamine-N-sulfatase Aggressive behavior, DD, mildly coarse facial features, F SC, HSCT hirsute, coarse hair, mild DM MPS III B‡ ␣-N-Ac-glucosaminidase Similar to MPS III A P, F SC MPS III C AcCoA: Similar to MPS III A F SC ␣-glucosaminide-N- acetyltransferase MPS III D N-acetylglucosamine-6- Similar to MPS III A F SC sulfatase MPS VII‡ ␤-Glucuronidase NIFH, DM, DD, coarse facial features, HSM, MR L, F SC, HSCT, ERT (continued) view will mainly concentrate on disorders diagnosed in signs and symptoms of those LSDs with neurologic in- our laboratory. volvement. Lysosomal storage diseases should be con- sidered among the disorders to be ruled out in any in- CLINICAL FEATURES dividual experiencing developmental delay, loss of learned THAT COULD SUGGEST AN LSD skills, ataxia, seizures, weakness, and dementia. This is especially true if the individual is regressing after a pe- The diagnosis of an LSD initially requires a physician to riod of relatively normal development and the disorder consider whether the patient’s clinical features suggest seems progressive. While many features are not specific this possibility. The Table presents some of the initial and could result from genetic or environmental factors, (REPRINTED) ARCH NEUROL / VOL 60, MAR 2003 WWW.ARCHNEUROL.COM 323 ©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 Presenting Features in Lysosomal Storage Diseases With Prominent Neurologic Findings (cont) Samples Presenting Signs Acceptable Treatment Disease Defective Protein and Symptoms For Diagnosis* Options† Mucolipidosis II‡ UDP-N-Ac-glucosaminyl Coarse facial features, DD, weakness, DM, gingival P, F SC, HSCT phosphotransferase hyperplasia, macroglossia Mucolipidosis IV Mucolipin 1 DD, corneal opacities, retinal degeneration, strabismus F SC Multiple sulfatase Sulfatase modifier protein DD, ichthyosis, coarse facial features, deafness, mild DM, PR L, F SC deficiency‡ Neuronal Ceroid Palmitoyl-protein Vision loss, motor dysfunction, hypotonia, DD, MR L, F SC, HSCT Lipofuscinosis 1 thioesterase 1 Neuronal Ceroid Tripeptidyl peptidase 1 Sz, motor dysfunction, DD, MR, ataxia, dementia L, F SC Lipofuscinosis 2 Saposin defect, MLD Saposin B Similar to JO MLD F, U SC type‡ Saposin defect, Saposin C Similar to Gaucher disease, type 3 F SC Gaucher type‡ Saposin defect, Prosaposin HSM, DD, motor abnormalities, exaggerated FSC generalized type‡ Moro reflex, MR Aspartylglucosaminuria Aspartylglucosaminidase Delayed speech, motor clumsiness, mildly coarse facial L, F, U SC features, behavioral problems Farber disease‡ Acid ceramidase Painful and swollen joints, nodules, DD, hoarse cry, hypotonia L, F SC, HSCT Wolman disease‡ Acid lipase HSM, vomiting, diarrhea, anemia, PR L, F SC, HSCT Schindler disease ␣-N-acetylgalactosaminidase