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 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- ousL from the newborn period to adulthood. Diagnosis of suspected patients can usually be made by measuring the activity of an 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 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 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 , 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 teins. About 40 different genes have been and/or identification of storage products is identified as sites for 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 , Jefferson Medical College, Philadelphia, Pa. rent use or under development. This re-

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Samples Presenting Signs Acceptable Treatment Disease Defective Protein and Symptoms for Diagnosis* Options† GM1 ‡ Acid ␤-galactosidase IO: , DD, coarse facial features, HM, CRS (±) L, P, F SC,§ HSCT LO: DD, , dysarthria, PR, dystonia GM2 gangliosidosis, 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, ‡ GM2 gangliosidosis, GM2 activator protein Similar to Tay-Sachs disease F, CSF SC AB variant‡ ‡ ␣-Galactosidase Acroparesthesia, pain crises, corneal opacities, fatigue, L, F SC, ERT, HSCT Gaucher disease, types HSM, DD, strabismus, Sz, , 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 Late IO: weakness, hypotonia, DD, genu recurvatum L, F, U SC, HSCT ‡ JO: weakness, PR, ataxia, behavior changes AO: pyramidal or cerebellar signs, behavior changes, psychoses, ‡ Galactocerebrosidase IO: spasticity, irritability, hypotonia, fisting, DD L, F SC, HSCT LO: spastic paraparesis, weakness, burning paresthesia, ataxia, weakness, vision loss ␣-‡ ␣- 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 , Sialidase IO: NIFH, DD, coarse facial features, DM, HSM, PR, L, F SC 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 ‡ Protective protein, Neonatal onset: NIFH, HSM, severe DD L, F SC 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(±) ‡ ␣-L- Spasticity, DD, coarse facial features, DM, MR, L, F SC, HSCT angiokeratomas MPS I (Hurler and ␣-L- 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, 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, , 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,

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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 hyperplasia, 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, HSM, DD, motor abnormalities, exaggerated FSC generalized type‡ Moro reflex, MR Delayed speech, motor clumsiness, mildly coarse facial L, F, U SC features, behavioral problems ‡ Acid Painful and swollen , nodules, DD, hoarse cry, hypotonia L, F SC, HSCT Wolman disease‡ Acid lipase HSM, , , anemia, PR L, F SC, HSCT ␣-N-acetylgalactosaminidase DD, blindness, Sz, spasticity, PR L, P, F SC Pompe disease ␣-Glucosidase Hypotonia, DD, cardiac enlargement F SC, ERT

Abbreviations: AO, adult onset; CSF, cerebrospinal fluid; CRS, cherry-red spots; DD, developmental delay; DM, dysostosis multiplex; ERT, enzyme replacement therapy; F, ; HSCT, hematopoietic stem cell transplantation; HM, ; HSM, ; IO, infantile onset; JO, juvenile onset; LO, late onset; L, leukocytes; MLD, metachromatic leukodystrophy; MPS, ; MR, mental retardation; NIFH, nonimmune fetal hydrops; P, plasma; PR, psychomotor regression; Sz, seizures; SC, supportive care; U, urine; VSO, vertical supranuclear ophthalmoplegia. *These are the samples that have been used to diagnose a given disorder by measurement of a biochemical parameter. Molecular studies can be performed on any DNA-containing sample. †HSCT is not available for all patients with a given diagnosis, and ERT may be in use or only at the stage of preclinical trials. The use of these treatmentsinafew patients does not necessarily indicate a successful outcome. ‡Diseases diagnosed in our laboratory. §SC indicates any procedure performed to alleviate pain, discomfort, and seizures and may include splenectomy and kidney transplantation when indicated.

diagnostic testing should be performed. A systematic study result in significant differences in the ability to handle of disease possibilities, including mitochondrial, peroxi- the potential substrates. somal, and lysosomal, should be considered. The samples Mutations in 3 separate genes can result in patients required for the study of each group of disorders may be who are clinically similar to each other and store GM2 different, and a given diagnostic laboratory usually does . GM2 gangliosidosis should be considered in not perform tests for all disorders. For those LSDs diag- any infant who is losing interest in his or her surround- nosed in our laboratory, whole heparinized blood sent ings and has spasticity, hyperacusis, and macular cherry- at room temperature permits the isolation of leukocytes red spots. Defining the genetic type is critical for accu- and plasma to use for screening. Using our considerable rate genetic counseling of family members and subsequent diagnostic experience, test selection is based on a pa- prenatal testing. The finding of low hexosaminidase A tient’s clinical history, other test results, and sugges- activity due to mutations in the ␣-chain in leukocytes tions from the physician. and/or plasma confirms the diagnosis of Tay-Sachs dis- Purely neurologic symptoms in the absence of ad- ease. While the number of cases of Tay-Sachs disease ditional findings, such as coarse facial features, bone ab- among the Ashkenazi Jewish community has dropped dra- normalities, and hepatosplenomegaly, signal the need for matically since the institution of the carrier testing pro- testing for GM1 and GM2 gangliosidoses, metachro- gram in the early 1970s, the number of non-Jewish cases matic leukodystrophy (MLD), and Krabbe disease. The has not declined. Patients with the so-called B1 variant onset of GM1 gangliosidosis (low acid ␤-galactosidase of Tay-Sachs disease have normal hexosaminidase A ac- in both leukocytes and plasma) can occur at any age from tivity when measured using the heat denaturation method. birth to adulthood. Patients with the infantile form have However, the use of the sulfated derivative of the syn- initial symptoms related to the storage of GM1 ganglio- thetic substrate for screening will diagnose all patients side in the brain, keratan sulfate in connective tissue, and who have a defect in the ␣-chain of hexosaminidase A. and oligosaccharides in the . Other pa- The finding of low hexosaminidase A and B activity in- tients with low ␤-galactosidase activity can have purely dicates a diagnosis of Sandhoff disease. In addition to the neurologic signs, including dysarthria, and only mild bone many mutations identified in the ␣- and ␤-chains of hex- and somatic problems, or they may have only severe bone osaminidase A and B, there are infants with similar clini- involvement (mucopolysaccharidosis [MPS] IVB, Morquio cal features who have defects in the GM2 activator pro- B). Different mutations in the ␤-galactosidase can tein that is required for the of GM2 ganglioside

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 by hexosaminidase A. These rare patients have normal these patients do not have carrier levels of any sulfa- hexosaminidase A and B activity measured with all syn- tases. It should also be noted that there are some pa- thetic substrates, but they can be identified by the accu- tients who have normal ASA activity but have defects in mulation of GM2 ganglioside in cerebrospinal fluid.3 Ad- a activator protein known as saposin B. The ditional studies could identify the (s) in the GM2 few individuals who have been identified clinically re- activator protein gene. While most patients with defects semble those with juvenile MLD. Such patients excrete in the lysosomal metabolism of GM2 ganglioside have excess in urine, and molecular analysis of the infantile forms, adolescents and adults with cerebellar saposin gene can usually identify a mutation(s) in the sa- ataxia, symptoms resembling amyotrophic lateral scle- posin B region. rosis, and psychiatric problems should have their hex- Another relatively common disorder with signifi- osaminidase levels measured. cant diagnostic problems is Niemann-Pick type C (NPC). Metachromatic leukodystrophy is one of the LSDs This is because the neurologic features are variable, it can- causing the most problems with regard to accurate pa- not be ruled out by relatively simple tests performed in tient identification. Arylsulfatase A (ASA) activity is mea- leukocytes or plasma, and “variants” have biochemical sured in individuals of any age with evidence of weak- findings that are difficult to interpret. Testing for NPC ness, mental regression, psychiatric problems, or white is often requested by neurologists who have exhausted matter changes on magnetic resonance imaging. Low ASA other options by more straightforward testing. Patients activity could indicate a diagnosis of MLD. However, ow- range in age from neonates with nonimmune fetal hy- ing to the high frequency of the so-called pseudodefi- drops to adults with evidence of dystonia and vertical su- ciency (Pd) allele, this diagnosis must be confirmed by pranuclear ophthalmoplegia.6 Many patients with the additional studies. The major cause of pseudodefi- “classic” form have a history of jaundice at birth, but this ciency is a mutation in the polyadenylation signal that can be resolved with phototherapy. They can appear nor- results in only about 10% of the normal amount of ASA mal until the middle of the first or second decade, when messenger RNA.4 About 1 in 7 individuals in the gen- they develop inappropriate behavior and drop in school eral population are heterozygous for this polymor- performance. Some, but not all, have significant hepa- phism. Therefore, about 1 in 200 individuals, whether tosplenomegaly. Diagnosis requires cultured skin fibro- completely normal or with neurologic problems, is ho- blasts for special studies to detect excess free choles- mozygous for this mutation and has low (5%-15% of nor- terol using filipin staining and, if positive, to measure mal) ASA activity. These low ASA values overlap those cholesterol esterification. Mutations in 2 different genes, found in patients confirmed to have MLD (MLD/MLD) NPC1 and NPC2, can cause NPC.7,8 DNA analysis is not and in carriers of MLD who have 1 MLD-causing muta- useful for screening patients, except in suspected cases tion and 1 Pd allele (MLD/Pd). Further complications arise in the Hispanic population of northern New Mexico and because MLD-causing mutations have been found on the southern Colorado, where one mutation in the NPC1 gene Pd allele.5 Since the Pd allele is so common, additional has been identified. mutations have occurred on the same copy of the ASA Patients with mild to severe neurologic symptoms gene. However, the accurate diagnosis of suspected pa- who also have evidence of short stature (dysostosis mul- tients is not difficult when proper samples are analyzed. tiplex), coarse facial features, hepatosplenomegaly, cor- First, ASA activity should be measured in leukocytes, and neal clouding, and other more subtle findings (eg, an- if low, DNA can be isolated from the remaining sample, giokeratomas) usually require a battery of testing to arrive and the presence of the Pd allele can be determined by at a definitive diagnosis. Symptoms may be present at birth polymerase chain reaction–based testing. If the Pd allele or become more obvious after a period of relatively nor- is not present and the clinical features suggest a leuko- mal development. While studies of oligosaccharides and dystrophy, the diagnosis of MLD is almost certain. If it glycosaminoglycans (mucopolysaccharides) in urine may is present, MLD must still be considered, and a first morn- be indicated, it is our opinion that this may only cause a ing voiding of urine should be analyzed for sulfatides. If delay in obtaining a diagnosis. Frequent false-negative excess sulfatides are being excreted, the diagnosis of MLD and false-positive results may influence the tests per- is confirmed. It is very important to obtain ASA values formed. In most cases, enzymatic or other (eg, sialic acid from the parents of all patients identified. About 1 in 14 content) tests are indicated anyway. About 10% of in- of the healthy parents has ASA activity near that of their fants born with nonimmune fetal hydrops have an LSD. affected child due to the frequency of the Pd allele. This These include MPS VII, mucolipidosis II, GM1 ganglio- is critical to know if the couple requests prenatal testing sidosis, sialidosis, galactosialidosis, Gaucher disease, Far- in subsequent pregnancies. The inheritance of the Pd al- ber disease, and NPC. While effective therapy is not cur- lele (without an additional mutation) from one parent rently available for these infants, genetic counseling and and an MLD-causing mutation from the other results in prenatal testing can be offered in subsequent pregnan- low ASA activity in any fetal sample (chorionic villi, cul- cies. However, for other disorders of oligosaccharide and tured trophoblasts, and amniotic fluid cells) received for GAG metabolism, early diagnosis could provide an op- testing. Having information regarding ASA values and the portunity for treatment, such as hematopoietic stem cell presence of the Pd allele in the parents results in accu- transplantation (HSCT) or enzyme replacement therapy rate pregnancy prediction. In addition, patients with mul- (ERT). tiple sulfatase deficiency have low activity for all sulfa- Most LSDs can be diagnosed by measuring the ac- tases, including ASA, and excrete sulfatides plus tivity of specific enzymes with commercially available syn- glycosaminoglycans in urine. However, the parents of thetic or radiolabeled natural substrates using a blood

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 sample.2 The finding of low activity for one enzyme and cially before neurologic symptoms are significant. This normal values for others usually results in a definitive requires educating physicians to recognize the early signs diagnosis. On the other hand, patients with mucolipi- of these disorders and possibly instituting screening meth- dosis II or III have greatly elevated enzyme values in ods that identify patients at or near birth before symp- plasma. The measurement of sialic acid content is use- toms are present. The screening methods proposed in- ful in screening for 4 genetic disorders. Using a leuko- clude measuring -associated membrane cyte sample, sialic acid content is measured in patients 1 and 2 and saposins in small plasma samples, using dried with nonimmune fetal hydrops, short stature, coarse fa- blood spots for enzyme analysis, and using tandem mass cial features, cherry-red spots, and/or myoclonic sei- spectrometry for measurement of analytes.10-13 Addi- zures. If the content of sialic acid is elevated, the test is tional testing would be required to make a definitive di- repeated without acid hydrolysis to determine if it is free agnosis. While such testing is theoretically possible, it or bound. High levels of bound sialic acid are found in does present some problems related to the need for ex- leukocytes and fibroblasts from patients with sialidosis pensive or life-threatening therapy in individuals iden- and galactosialidosis, and high levels of free sialic acid tified without a family history of a disorder. Of the 500 are found in leukocytes and fibroblasts from patients with to 800 individuals born each year in the United States sialic acid storage disease or and sialuria (not with the potential for developing an LSD, some will have an LSD). Additional studies may be necessary to con- very mild disease and may not require treatment, and oth- firm the diagnosis. Reliable prenatal testing is available ers will have disease so severe that treatment is not ben- for almost all LSDs using chorionic villi samples and cul- eficial. However, early diagnosis permits careful clinical tured amniotic fluid cells. evaluation of the individual so that treatment could be- gin as early as indicated to prevent serious complica- PROBLEMS IN ASCERTAINING A PROGNOSIS tions. IN A PATIENT WITH AN LSD POSSIBILITIES FOR TREATMENT OF LSDs Most infants who are diagnosed as having an LSD fol- low a rather predictable clinical course. The loss of any There have been recent improvements in the treatment gained skills and neurologic deterioration continue un- of patients with certain LSDs, even for those disorders til the death of the child, usually by . Predict- that can have significant neurologic involvement. The ing the clinical course in later-onset patients, especially Table presents the treatments that are in use, have been adolescents and adults, is nearly impossible. Accurately tried in a limited number of cases, or are under devel- predicting the clinical course has important implica- opment. One treatment that has shown promise in some tions not only in selecting candidates for therapy, but also patients is HSCT in presymptomatic or mildly affected in evaluating the effectiveness of the chosen mode of individuals. Many patients with Gaucher disease, MLD, therapy. There have been a number of methods pro- Krabbe disease, and MPS I have undergone transplanta- posed for determining the clinical course in newly diag- tion.14-16 Some of these patients were identified in utero nosed patients. While mutation analysis can be useful for or at birth because of family history, and others were predicting the possibility of neurologic involvement in mildly affected before receiving their transplant. Ini- some disorders, the large number of mutations identi- tially, most of the bone marrow donors for these pa- fied coupled with the fact that many patients are com- tients were HLA-identical siblings. However, it is ideal pound heterozygotes makes phenotype prediction diffi- to use noncarrier donors so that the highest level of ac- cult. For example, finding the N370S mutation in a newly tivity can be supplied by the donor cells. Recently, um- diagnosed patient with Gaucher disease indicates that bilical cord blood from unrelated donors has been used there will be no neurologic involvement. While know- in transplantation for patients with LSDs. It has been ing the genotype in a newly diagnosed patient may be shown in animal studies that donor blood macrophages useful for cataloging purposes and may aid in carrier test- eventually replace microglial cells in the brain of the re- ing in family members, it is no better than careful clini- cipient. In humans, this can take many months or even cal evaluation at predicting the clinical course. In our ex- years to accomplish. Therefore, HSCT may not be ben- perience, patients with late-onset forms of Krabbe disease eficial for those diseases that are progressing rapidly. With can show tremendous clinical variability, even between successful engraftment of donor HSC, enzyme levels in siblings who have the same genotype for the galactoce- leukocytes reach those of the donor, progression of the rebrosidase (GALC) gene.9 There is a strong suggestion disease slows, and eventually there can be an improve- that the onset of symptoms in these patients may occur ment in certain parameters, such as spinal fluid protein after a stressful insult, such as an infection or a blow to concentration, IQ, and magnetic resonance imaging. A the head. Also, there is little evidence that measuring re- number of patients with purely neurologic LSDs, such sidual enzymatic activity or combining this with studies as Tay-Sachs disease, have been given HSCT, but more of specific antigen levels in cultured cells aids in mak- time is needed to determine its effectiveness. While im- ing a prognosis. provement of somatic and hematologic features and sta- Recent reports provide evidence that ERT and HSCT bilization of some neurologic manifestations are usually can result in a significant improvement in the clinical noted after HSCT, skeletal abnormalities remain diffi- course if treatment is started when the individual is pre- cult to correct. symptomatic or only mildly affected. Therefore, there is Enzyme replacement therapy is now available or un- pressure to obtain a diagnosis as early as possible, espe- der investigation for a number of LSDs, including Gau-

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 cher disease, Fabry disease, NPB, MPS I, MPS II, MPS IVB, terial.24,25 In addition, numerous neural stem cell lines MPS VI, MPS VII, and Pompe disease.17-20 In most cases, have been isolated and characterized.26 When injected into recombinant human enzymes are produced in Chinese the developing brain, they have the potential to migrate hamster ovary cells, and following chemical modifica- and differentiate, providing a source of healthy replace- tion and purification, the enzymes are injected intrave- ment cells and enzymes that can be taken up by neigh- nously. The treatment of nonneuronopathic Gaucher dis- boring cells. However, before human trials are pro- ease by recombinant glucocerebrosidase activity is very posed, issues of safety and effectiveness must be addressed successful in reducing spleen size and correcting hema- by studies in larger animals for longer periods of time. tologic problems.17 The use of ERT to treat subacute neu- In conclusion, the diagnosis of most LSDs is rela- ronopathic Gaucher disease (type 3) has not been con- tively simple using easily obtained tissue samples, such as clusively demonstrated to prevent the onset and blood or cultured cells from a skin specimen. A progression of the neurologic symptoms. The rationale screen of indicated enzymes can result in a definitive di- for the use of ERT to treat the milder forms of MPS I and agnosis within a few days. Molecular analysis to identify II is to help the somatic manifestations in these patients the disease-causing mutations may or may not be subse- and to make their management easier for caregivers. Be- quently performed depending on the disorder. Carrier test- cause of the blood-brain barrier, there is little evidence ing for interested family members is usually available by that these enzymes reach the brain. One LSD that could enzymatic testing. One exception is Krabbe disease, where benefit greatly from ERT is Fabry disease. This X-linked normal polymorphisms in the GALC gene make a wide disease, caused by a deficiency of ␣-galactosidase activ- carrier and noncarrier range. Prenatal diagnosis using cho- ity, is characterized by burning paresthesias, kidney fail- rionic villus samples and cultured amniotic fluid cells is ure, strokes, and heart disease in both male hemizy- available for at-risk couples and for other family mem- gotes and female heterozygotes. Supplying the missing bers concerned about having an affected child. Treat- enzyme has been shown to greatly improve all aspects ment of presymptomatic individuals and those with mild of the disease.18,20 symptoms is limited to HSCT or ERT for some disorders. Substrate deprivation as an adjunctive treatment for The method of choice depends on the availability of a re- certain is receiving attention. Since combinant enzyme or a suitable HSCT donor and whether symptoms in the patients are thought to result from the there is a need to stop or reverse neurologic damage. With storage of undegraded substrate, a slower rate of accu- effective therapy becoming available for more disorders, mulation accomplished by decreasing the rate of synthe- it will be increasingly important to recognize the earliest sis of substrate might be effective. This is especially true presenting symptoms in patients and seek diagnostic help in patients with later-onset forms of some LDSs who we from a reliable laboratory. suspect have some residual enzymatic activity. If the rate of substrate synthesis was slowed until it was approxi- For further reference: mately equal to the rate of degradation, little additional Rosenberg RN, Prusiner SB, DiMauro S, Barchi RL, accumulation would occur. This theoretically could be eds. Molecular and Genetic Basis of Neurogical Disease. Bos- accomplished by compounds such as L-cycloserine, which ton, Mass: Butterworth-Heineman; 1997. inhibits a very early step in the synthesis of sphingolip- Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The ids, or N-butyldeoxygalactonojirimycin, which inhibits Metabolic and Molecular Bases of Inherited Disease. New the synthesis of derived from gluco- York, NY: McGraw-Hill Co; 2001. sylceramide.21,22 Mice with Sandhoff disease treated with To obtain information about sending samples, please N-butyldeoxynojirimycin had delayed onset of symp- visit our Web site at www.tju.edu/lysolab. toms and increased life span.23 It must be noted that sphin- golipids play very important functions in cellular me- Accepted for publication October 4, 2002. tabolism, including signal transduction, cell adhesiveness, Author contributions: Study concept and design (Dr and nerve impulse transmission, and modification of these Wenger and Ms Coppola); acquisition of data (Drs Wenger and other functions by these drugs in a developing child and Liu and Ms Coppola); analysis and interpretation of must be carefully tested in animal models before human data (Drs Wenger and Liu and Ms Coppola); drafting of trials are started. In addition, these drugs also have sig- the manuscript (Dr Wenger); critical revision of the manu- nificant side effects that may limit their use. The amount script for important intellectual content (Drs Wenger and of enzyme needed in ERT for Gaucher disease or Fabry Liu and Ms Coppola); obtained funding (Dr Wenger); ad- disease could possibly be lowered if an inhibitor of glu- ministrative, technical, and material support (Drs Wenger cosylceramide synthesis was also provided. and Liu and Ms Coppola); study supervision (Dr Wenger). While gene therapy and neural and embryonic stem This research was supported in part by grant DK38795 cell therapy to treat LSDs with neurologic involvement from the National Institutes of Health, Bethesda, Md. have been under investigation using the large number of We thank the many health care providers for sending available animal models, no protocols in humans are cur- samples for testing as well as clinical information on their rently in use. Much effort has been expended on the mouse patients. We are grateful to the technicians who have worked model of MPS VII. A large number of viral vectors con- in the Lysosomal Diseases Testing Laboratory since 1973. taining the human ␤-glucuronidase complementary DNA Corresponding author and reprints: David A. Wenger, have been developed, and when injected into the ven- PhD, Jefferson Medical College, Department of Neurology, tricles or the brain parenchyma of young mice, there is 1020 Locust St, Room 394, Philadelphia, PA 19107 evidence for and clearing of stored ma- (e-mail: [email protected]).

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 13. Clarke S. Tandem mass spectrometry: the tool of choice for diagnosing inborn REFERENCES errors of metabolism? Br J Biomed Sci. 2002;59:42-46. 14. Ringden O, Groth CG, Erikson A, Granqvist S, Mansson JE, Sparrelid E. Ten years’ 1. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage experience of bone marrow transplantation for Gaucher disease. Transplanta- disorders. JAMA. 1999;281:249-254. tion. 1995;59:864-870. 2. Wenger DA, Williams C. Screening for lysosomal disorders. In: Hommes FA, ed. 15. Vellodi A, Young EP, Cooper A, et al. Bone marrow transplantation for muco- Techniques in Diagnostic Human Biochemical Genetics: A Laboratory Manual. polysaccharidosis type I: experience in two British centres. Arch Dis Child. 1997; New York, NY: Wiley-Liss; 1991:587-617. 76:92-99. 3. Kotagal S, Wenger DA, Alcala H, Gomez C, Horenstein S. AB variant GM2 gan- 16. Krivit W, Aubourg P, Shapiro E, Peters C. Bone marrow transplantation for glo- gliosidosis: cerebrospinal fluid and neuropathological characteristics. Neurol- boid cell leukodystrophy, adrenoleukodystrophy, metachromatic leukodystro- ogy. 1986;36:438-440. phy, and Hurler syndrome. Curr Opin Hematol. 1999;6:377-382. 4. Gieselmann V, Polten A, Kreysing J, Von Figura K. Arylsulphatase A pseudode- 17. Grabowski GA, Leslie N, Wenstrup R. Enzyme therapy for Gaucher disease: the ficiency: loss of a polyadenylation signal and N-glycosylation site. Proc Natl Acad first 5 years. Blood Rev. 1998;12:115-133. Sci U S A. 1989;86:9436-9440. 18. Eng CM, Guffon N, Wilcox WR, et al. Safety and efficacy of recombinant human 5. Gieselmann V, Fluharty AL, Tonnesen T, Von Figura K. Mutations in the arylsul- ␣-galactosidase A replacement therapy in Fabry’s disease. N Engl J Med. 2001; fatase A pseudodeficiency allele causing metachromatic leukodystrophy. Am J 345:9-16. Hum Genet. 1991;49:407-413. 19. Kakkis ED, Muenzer J, Tiller GE, et al. Enzyme replacement therapy in muco- 6. Vanier MT, Wenger DA, Comly ME, Rousson R, Brady RO, Pentchev PG. Niemann- polysaccharidosis I. N Engl J Med. 2001;344:182-188. Pick group C: clinical variability and diagnosis based on defective cholesterol es- 20. Schiffmann R, Kopp JB, Austin HA III, et al. Enzyme replacement therapy in Fabry terification. Clin Genet. 1988;33:331-348. disease: a randomized controlled trial. JAMA. 2001;285:2743-2749. 7. Millat G, Marcais C, Tomasetto C, et al. Niemann-Pick C1 disease: correlations 21. Sundaram KS, Lev M. Inhibition of synthesis in the brains of mice between NPC1 mutations, levels of NPC1 protein and phenotypes emphasize the treated with L-cycloserine. J Res. 1985;26:473-477. functional significance of the putative sterol-sensing domain and of the cysteine- 22. Andersson U, Butters TD, Dwek RA, Platt FM. N-butyldeoxygalactonojirimycin: rich luminal loop. Am J Hum Genet. 2001;68:1373-1385. a more selective inhibitor of biosynthesis than 8. Millat G, Chikh K, Naureckiene S, et al. Niemann-Pick disease type C: spectrum N-butyldeoxynojirimycin, in vitro and in vivo. Biochem Pharmacol. 2000;59: of HE1 mutations and genotype/phenotype correlations in the NPC2 group. Am 821-829. J Hum Genet. 2001;69:1013-1021. 23. Jeyakumar M, Butters TD, Cortina-Borja M, et al. Delayed symptom onset 9. Wenger DA, Rafi MA, Luzi P, Datto J, Costantino-Ceccarini E. Krabbe disease: and increased life expectancy in Sandhoff disease mice treated with genetic aspects and progress toward therapy. Mol Genet Metab. 2000;70:1-9. N-butyldeoxynojirimycin. Proc Natl Acad SciUSA.1999;96:6388-6393. 10. Hua CT, Hopwood JJ, Carlsson SR, Harris RJ, Meikle PJ. Evaluation of the ly- 24. Ghodsi A, Stein C, Derksen T, Yang G, Anderson RD, Davidson BL. Extensive sosome-associated membrane protein LAMP-2 as a marker for lysosomal stor- ␤-glucuronidase activity in murine after adenovirus- age disorders. Clin Chem. 1998;44:2094-2102. mediated gene transfer to brain. Hum Gene Ther. 1998;9:2331-2340. 11. Chang MHY, Bindloss CA, Grabowski GA, et al. Saposins A, B, C, and D in plasma 25. Bosch A, Perret E, Desmaris N, Trono D, Heard JM. Reversal of pathology in the of patients with lysosomal storage disorders. Clin Chem. 2000;46:167-174. entire brain of mucopolysaccharidosis type VII mice after lentivirus-mediated gene 12. Chamoles NA, Blanco MB, Gaggioli D, Casentini C. Hurler-like phenotype: enzymatic transfer. Hum Gene Ther. 2000;11:1139-1150. diagnosis in dried blood spots on filter paper. Clin Chem. 2001;47:2098-2102. 26. Gage FH. Mammalian neural stem cells. Science. 2000;287:1433-1438.

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