·综述 ·
L ysosoma l storage d isorders
Yong QU△
(Department of Genetic Testing, Kaiser Permanente, Southern California, 4580 Electronics Place, Los Angeles, CA 90039,
USA)
SUMM ARY Lysosomal storage disorders (LSD s) are genetic defects caused by lysosomal hydrolase deficiencies. These
deficiencies lead to substrate accumulation affecting cells, tissues and organs. Detecting abnormal compound excretion and
deficient enzymes assist diagnosis of these disorders for treatment and p revention. This m ini review summarizes clinical
p resentations and diagnostic workup of LSD s and updates the new development in the area.
KEY WO RD S Lysosomal storage diseases; Mucopolysaccharidoses; O ligosaccharidoses; Mucolip idoses; Sphingolip ido2
ses
Lysosomes are single membrane2bound organelles containing
many hydrolytic enzymes involved in the degradation of a variety
of biologicalmacromolecules. If one ormore enzyme is deficient,
the accumulation of these molecules is inevitable. Lysosomal
storage disorders (LSD s) rep resent a group of over 45 distinct
genetic diseases and are characterized by intracellular accumula2
tion of these compounds. U sually, babies with LSD s are born
normal. W hen the harmful molecules build up to a certain
threshold, patients start to show symp tom s, such as coarsening of
the facial features, organomegaly, dysostosismultip lex and losing
developmental m ilestones. Then, the patients will deteriorate
with retarded growth and development. Unrelenting p rogression
p roceeds, sometimes, slowly, but steadily.
LSD s can be divided into several categories according to the
compounds stored in the body, such as, mucopolysaccharidoses
(MPS) , oligosaccharidoses (OS) , mucolip idoses (ML ) , and
sphingolip idoses. This m ini review will use one or two examp les
in each of these categories to illustrate clinical symp tom s, en2
zymes deficient in disorders and diagnostic p rocedures. O ther ly2
sosomal disorders, such as Pompe disease, lip id storage diseases
and lysosomal transport defects will not be discussed here.
1 M ucopolysacchar idoses(M PS)
MPS are p rototypes of LSD s due to storage of glycosam ino2
glycans ( GAG). GAG molecules are long, unbranched polysac2
charide chains, made up of repeating disaccharide units rich in
sulfate group s. They are found in connective tissue, cartilage
and the nervous system. There are six major types of MPS[ 1, 2 ].
A ll are inherited in an autosomal recessive pattern excep t type
Ⅱ, Hunter disease, which is X2linked.
Patients with MPS usually show symp tom s beyond six
months of age. There is a broad spectrum of clinical p resenta2
tion, usually with coarse facial features, corneal clouding, dys2
ostosis multip lex, short stature, kyphosis, stiff joints, hepato2
sp lenomegaly, cardiac comp lications, and mental retardation.
These patients excrete large amounts of abnormal mucopolysac2
charides: dermatan, heparan and keratan sulfates, which can be
detected using thin2layer chromatography ( TLC) and /or electro2
phoresis. D iagnostic work2up usually starts with a urine screen2
ing assay followed by enzyme confirmation test using p lasma,
leukocytes or fibroblasts. DNA mutation analysis can be done on
the diagnosed patients to p rovide a reliable way for p renatal diag2
nosis in future p regnancies and fam ily carrier studies as needed.
MPS type Ⅰ, Hurler disease ( including Scheie and Hurl2
er/Scheie) , is caused by deficiency ofα2iduronidase. MPS Ⅱ,
Hunter disease, is the result of iduronate sulfatase deficiency.
Patients with Hurler or Hunter diseases excrete dermatan and
heparan sulfates that can be detected by an MPS urine screening
test. Sanfilippo patients (MPS Ⅲ) may have one of the four en2
zyme deficiencies: heparan N 2sulfatase, α2N 2acetylglucosam ini2
dase, acetyl2CoA: α2glucosam inide2N2acetyl transferase, and N2
acetyl2α2D2glucosam inide262sulfatase. Insufficient activity from
these enzymes can lead to Sanfilippo type A, B, C, and D, re2
spectively. These patients excrete heparan sulfate in abnormally
large amounts. Patients with MPS Ⅳ, Morquio syndrome, lack
one of the enzymes, galactose262sulfatase (Morquio A) orβ2gal2
actosidase (Morquio B). They only excrete keratan sulfate as the
abnormal compound. Maroteaux2Lamy disease, type Ⅵ, is
caused by deficient arylsulfatase B activity and can be screened
by finding dermatan sulfate excretion. Sly disease, type Ⅶ,
shows variable patterns of mucopolysaccharide excretion on a
TLC p late. Plasmaβ2glucuronidase is a reliable test to identify
Sly patients.
Case 1: An eighteen2month2old boy was seen due to severe
infection. On the MR I, cerebral atrophy was observed. On the
physical exam, the patient had coarse facial features, lip s thick2
ened with a large tongue and hirsute. A urine screening test for
LSD s revealed highly increased excretions of dermatan and hepa2
ran sulfates. Lysosomal enzyme tests on the leukocytes showed
almost undetectable iduronate sulfatase activity. The patient was
diagnosed with Hunter disease.
Case 2: A four2year2old boy was seen in a metabolic clinic
for a mental retardation work2up. The patient developed normally
at first. By age one, he had frequent infections with slower de2
velopment. A t age two, the boy started hyperactivity with aggres2
sive behavior. On the physical exam ination, he had coarse hair,
m ild hepatosp lenomegaly with delayed speech development, p ro2
gressive dementia with cortical atrophy visible on CT scanning.
U rine screening tests showed a heavy band of heparan sulfate.
Enzyme studies in fibroblasts confirmed that he had Sanfilippo
type A with heparan N2sulfatase deficiency.
2 O ligosacchar idoses ( O S) and m ucolip idoses(ML )
OS and ML may also be called glycop roteinoses. Enzymes
removing oligosaccharides from glycop rotein are deficient in OS
so that glycop rotein cannot be comp letely degraded. In ML, N2
acetylglucosam ine212phosphotransferase is reduced or absent,
causing multip le enzyme accumulation in extracellular space with
a reduction inside the lysosomes.
Glycop roteinoses, in general, clinically resemble the muco2
polysaccharidoses, with coarse facial features, skeletal deform i2
ties, p rogressive neurological degeneration and mental impair2
ment, seizures, visceral involvement; some may have angiokera2
toma, cherry2red retinal spots, and hearing loss. However, MPS
tests are often negative for these patients. Thin2layer chromato2
graphy can detect abnormal urinary excretion of oligosaccharides
and free sialic acid. The definitive diagnosis should be confirmed
by enzyme study in p lasma, leukocytes or fibroblasts.
OS include the following disorders (with deficient enzyme in
parenthesis) :α2mannosidosis (α2mannosidase ) ,β2mannosido
△Corresponding author’s e2mail, yongqu4580@ yahoo. com
·001·
北 京 大 学 学 报 ( 医 学 版 )
JOURNAL OF PEKING UN IVERSITY(HEALTH SC IENCES) Vol. 38 No. 1 Feb. 2006
sis (β2mannosidase) , α2fucosidosis (α2fucosidase) , sialidosis
(α2neuram inidase, also called ML Ⅰ) , galactosialidosis (p ro2
tective p rotein ) , aspartylglucosam inuria ( aspartylglucosam ini2
dase) , and Schindler disease (α2N2acetylgalactosam inidase).
A ll are inherited in an autosomal recessive pattern.
Traditionally, the term mucolip idosis type Ⅰ is also used
for sialidosis. ML Ⅱ ( also called I2cell disease) and ML Ⅲ
( also called p seudo2Hurler polydystrophy) are associated with
the deficiency of the same enzyme, N2acetylglucosam ine212phos2
photransferase, which is involved in post2translational modifica2
tion of lysosomal enzymes. W ithout this modification, the phos2
phomannosyl recognition marker will be absent. Therefore, mul2
tip le lysosomal enzymes will not be targeted into lysosomes for
p roper function. A s a result, there will be reduced activities of
multip le enzymes inside cells. These enzymes will accumulate in
the extracellular space resulting in highly elevated p lasma en2
zyme levels. ML Ⅱ is more severe with early onset. ML Ⅲ is
m ilder with later onset, p robably due to retained residue enzyme
activities.
Case: An 112month2old girl, born with swollen gum, was e2
valuated for very advanced dysostosis multip lex. By 11 months,
she had slightly coarse facial features with p sychomotor retarda2
tion and m ild hepatosp lenomegaly. A lysosomal urine screening
test showed two abnormal bands on oligosaccharide TLC p late
with highly elevated p lasma β2glucuronidase activity. Further
confirmative tests revealed highly elevated p lasma activity and re2
duced leukocyte activity of multip le lysosomal enzymes, reaching
a diagnosis ofML Ⅱ.
3 Sph ingolip idoses
Sphingolip ids are comp lex membrane lip idswhich are deriv2
atives of ceram ide ( composed of a C218 am ino alcohol sphingo2
sine and a long2chain fatty acid ) with various polar head
group s[ 3 ]. They can be classified into three main categories: cer2
ebrosides (with single sugar) , sphingomyelins (with phosphoryl2
choline or phosphorylethanolam ine) and gangliosides (with sev2
eral sugar units containing sialic acid residues). Sphingolip ido2
ses are disorders in the catabolism of sphingolip ids due to defi2
ciencies of lysosomal hydrolases breaking down these comp lex
membrane lip ids.
Sphingolip ids are found mainly in the brain and other nerve
tissues. Therefore, sphingolip idoses usually p resent with p rimary
disturbances in the nervous system, such as p rogressive p sycho2
motor retardation, seizures, spasticity, irritability, some with
leukodystrophy, cherry2red macula spots, angiokeratoma, hepa2
tosp lenomegaly, and foam cells in the bone marrow. Most diag2
noses are based on clinical manifestation and enzyme studies.
Some of these disorders may be detected by oligosaccharide anal2
ysis using TLC technique. Patients with these disorders usually
have negative MPS test results.
Sphingolip idoses include the following disorders (with defi2
cient enzyme in parenthesis) : N iemann2Pick disease A and B
( sphingomyelinase ) , Gaucher disease ( glucocerebrosidase ) ,
Fabry disease ( ceram ide trihexosidase) , Farber disease ( ceram2
idase) , GM1 gangliosidosis (β2galactosidase) , GM2 gangliosido2
sis (β2hexosam inidase A and B) , metachromatic leukodystrophy
( arylsulfatase A) and Krabbe disease (β2galactocerebrosidase).
A ll are autosomal recessive disorders excep t Fabry disease,
which is X2linked.
Case: A 162month2old boy was seen in a genetic clinic for
losing m ilestones. The patient was able to babble at 6 months of
age, sit up at 10 months, and reach and grasp objects at 12
months. By 14 months, the boy could no longer sit2up; at 15
months, no more roll over. He could not hold an object by 16
months of age. On the physical exam, there were no dysmorphic
features, no organomegaly, and no cherry2red spots. The urine
oligosaccharide analysis revealed four abnormal bands. Lysosom2
al enzyme studies p roved that the patient hadβ2galactosidase de2
ficiency and both parents are obligate carriers with 50% of the
enzyme activity. GM1 gangliosidosis was the diagnosis.
4 New developm en t
Traditionally, the treatment of LSD s focuses on managing
the symp tom s of the diseases, such as painkilling drugs, cardiac
intervention, and kidney dialysis if needed. For the past decade,
two new developments in LSD s have emerged and lead to imp res2
sive p rogress. One is treatment; and the other, newborn screen2
ing [ 4 ] .
Before 1991, bone marrow and organ transp lantations were
attemp ted in treating LSD s. The results varied due to donor vari2
ations and the high mortality risk of the p rocedure. If the engraft2
ment was successful, leukocyte enzyme activity normalized, and
organomegaly decreased, but skeletal abnormalities and brain
function remained largely unchanged. Some patients continued to
deteriorate[ 5 ]. In 1991, enzyme rep lacement therapy was used
for the first time to treat one specific disease, such as alglucerase
for Gaucher disease type Ⅰ, which is particularly common a2
mong A shkenazi Jews. After enzyme rep lacement therapy, many
Gaucher patients have experienced decreasing organ size (within
6 months) , dim inishing bone pains with imp roved growth and
development. Due to remarkable success of this treatment, to2
day, some patients with Fabry and Hurler (MPS Ⅰ) diseases
are also undergoing enzyme rep lacement therapy[ 6 ]. The results
are very p rom ising.
The availability of new treatments stimulates interest in new2
born screening for lysosomal storage disorders, since many chil2
dren with LSD s could benefit from early diagnosis and interven2
tion. Now, two techniques are available for newborn screening of
some LSD s[ 7, 8 ]. In a recent paper, W ang et al[ 9 ] described the
method of measuring at least six lysosomal enzyme activities on a
single p latform, suitable for newborn screening. The fast p ro2
gress in the research for diagnosing and treating LSD s is bringing
hope to patients with these disorders and their fam ilies.
References
[ 1 ] Neufeld EF, Muenzer J. The mucopolysaccharidoses[M ] / /Scriver
CR, Beaudet AL, Valle D, SlyW S. The metabolic and molecular
bases of inherited disease, 8 th ed. New York:McGraw2H ill, 2001:
3421 - 34521
[ 2 ] Nyhan WL, Ozand PT. A tlas of metabolic diseases [ M ]. New
York: Chapman & HallMedical, 1998: 440 - 486.
[ 3 ] Barth PG. Sphingolip ids[M ] / / Fernandes J, Saudubray JM, Van
den Berghe G. Inborn metabolic diseases: diagnosis and treatment,
2nd ed. Berlin: Sp ringer2Verlag, 1995: 375 - 382.
[ 4 ] M illington DS. Newborn screening for lysosomal storage disorders
[ J ]. Clin Chem, 2005, 51: 808 - 809.
[ 5 ] KrivitW , Shap iro EG. Bone marrow transp lantation for storage dis2
eases [ M ] / /Desnick RJ. Treatment of genetic diseases. New
York: Churchill L ivingstone, 1991: 203 - 222.
[ 6 ] Desnick RJ. Enzyme rep lacement and enhancement therap ies for ly2
sosomal diseases[ J ]. J InheritMetab D is, 2004, 27: 385 - 410.
[ 7 ] Chamoles NA, B lanco M, Gaggioli D. D iagnosis of a2L2iduronidase
deficiency in dried bloodspots on filter paper: the possibility of
newborn diagnosis[ J ]. Clin Chem, 2001, 47: 780 - 781.
[ 8 ] Gerber SA, Scott CR, Turecek F, et al. D irect p rofiling of multi2
p le enzyme activities in human cell lysates by affinity chromatogra2
phy/ electrosp ray ionization mass spectrometry: app lication to clini2
cal enzymology[ J ]. Anal Chem, 2001, 73: 1651 - 1657.
[ 9 ] W ang D, Eadala B, Sadilek M, et al. Tandem mass spectrometric
analysis of dried blood spots for screening of mucopolysaccharidosis
I in newborns[ J ]. Clin Chem, 2005, 51: 898 - 900.
(Received 2005210212)
( Edited by ZHAO Bo)
·101·Yong QU 溶酶体贮积病
溶酶体贮积病
Yong QU
(Department of Genetic Testing, Kaiser Permanente, Southern California, 4580 Electronics Place, Los Angeles, CA 90039, USA)
[关键词 ] 溶酶体贮积病 ;粘多糖累积病 ;寡糖贮积病 ; 粘脂质累积病 ;鞘脂类代谢障碍
[中图分类号 ] R589 [文献标识码 ] A [文章编号 ] 16712167X (2006) 0120100203
《北京大学学报 (医学版 ) 》第八届编辑委员会第一次会议纪要
《北京大学学报 (医学版 ) 》(以下简称《学报 》)第八届编辑委员会第一次全体会议于 2005年 12月 22日在北京大学医学
部图书馆 408会议室召开。《学报 》第八届编辑委员会主编、全国人大常委会副委员长、北京大学医学部主任韩启德院士 ,《学
报 》常务副主编、北京大学常务副校长、医学部常务副主任柯杨教授出席了本次会议。会议由《学报 》副主编、北京大学医学部
副主任方伟岗教授主持。《学报 》编委、各二级单位科研部门代表及《学报 》编辑部全体成员出席了会议。
柯杨教授首先对学报近几年的工作给予了充分的肯定。她指出 :《学报 》始终坚持“学术至上 ,质量第一 ”的原则 ,是国内
同类高等学校医学学报中的品牌 ,具有北医特色。《学报 》的成就与两个因素密切相关 :一个是编辑部全体工作人员的团结协
作 ,另一个是各届编委、学术骨干的无私支持。
《学报 》副主编、编辑部主任周传敬编审代表《学报 》第七届编辑委员会汇报工作。5年来共召开编委定稿会 37次 ;出版
学报正刊 30期 ,增刊 2期 ,共 32期 ,包括《九十年校庆专刊 》、《SARS防治研究专刊 》和其他重点号 18期。《学报 》2001年 12
月入选新闻出版总署“中国期刊方阵 ”“双百期刊 ”层面 , 2003年被美国医学文献分析和联机检索系统 (MEDL INE)及其《医学
索引 》( IM )收录 , 2004年和 2005年连续入选“第三届中国百种杰出学术期刊 ”和“第四届中国百种杰出学术期刊 ”名单 ,入选
2004年中国科技期刊 CSCD (中国科学引文数据库 ,中国科学院文献情报中心 )影响因子 300名排行表 , 2004年入选《中文核
心期刊要目总览 (第 4版 ) 》综合性医药卫生类核心期刊 ,并荣获教育部优秀科技期刊一等奖。根据《中国科技期刊引证报告
(中国科学技术信息研究所 ) 》公布的数据 ,《学报 》影响因子由 2001年 0. 295升至 2004年 0. 634,总被引频次由 2001年 463
次 (他引率 0. 93)升至 2004年 739次 (他引率 0. 97)。
与会编委就《学报 》是否办成 Open Access (OA )期刊 ,是否改成英文版 ,以及《学报 》的功能定位等问题展开了热烈的讨
论。
1.关于《学报 》是否办成 Open Access(OA)期刊的问题 :方伟岗教授指出 , OA是一种很好的形式 ,发展前景很好。马大龙
教授谈到 ,办 OA期刊有很大的意义 ,很多科研文章的背后有大量的数据支持 ,由于不存在版面的限制 ,可以将这些信息放到
网络上 ,供读者参考、分析。但 OA同样存在一些问题 ,例如因审稿程序不严谨而可能降低数据的可信度 ;国内外各个杂志的
格式不统一 ,给交叉检索造成一定的困难。贾弘禔教授说 ,随着网络的发展 ,期刊的出版也会有大的变革 , 目前的纸质出版物
很可能有一部分会被淘汰 ,因此一定要搞电子版刊物 ,要扩大影响。韩济生院士、林志彬教授、黎晓新教授等也都认为 ,《学
报 》在网上开放是必要的。
2. 关于《学报 》是否改成英文版 :编委们认为 ,改英文版问题应该慎重 ,以免影响国内读者阅读和引用 ,目前可以根据情况
登一部分英文稿。林志彬教授、丁洁教授等提出 ,《学报 》论文的英文摘要应该更详细些 ,提供主要数据。
3.关于《学报 》的功能定位问题 :韩启德院士谈到 ,大学办学报的模式是
经济的产物。《学报 》作为北京大学医学部自
己的刊物 ,应成为学术园地 ,可以以新闻的形式公布医学部的科研成果 ,研讨大家所关心的学术问题 ,而不仅仅是发表学术论
文。办刊思路上如果能突破 ,会将刊物办得非常活泼 ,读者不只看到学术文章 ,还可以看到国外其他相应工作的有关情况 ,以
及其他丰富的学术信息。柯杨教授谈到 ,学报的定位问题一直存在困惑。目前《学报 》在国内刊物中是质量较好的 ,但是否要
前瞻性地看一下 ,考虑 5年以后会是什么样。《学报 》可以增加一些趣味性的、评论性的内容 ,可以发表研究人员撰写的科研综
述 ,这是教科书里没有的内容 ,既能供读者参考借鉴 ,又可以减少其他相关研究人员的工作量 ,使大家都受益。《学报 》如此改
革 ,可能需要相应萎缩一部分内容 ,而同时又拓展另一部分内容。韩济生院士、王夔院士、唐朝枢教授、贾弘禔教授、林三仁教
授、陈贵安教授、姚晨教授和李凯教授分别就《学报 》办刊模式、栏目设置问题、国际合作问题、统计学审稿中的问题等发了言。
韩启德主编对会议进行了总结。他说 ,今后《学报 》的定位仍然是学术刊物 ,围绕着学术进行 ,但是不要在乎被 SC I收录、
影响因子、国内排名等 ,不要在乎《学报 》是否走向国际 ,要把《学报 》办成全面反映北医学术面貌、提供丰富学术信息的北医全
体师生的园地 ,以学报为名的一份学术杂志。可以借鉴 N ature, Science的形式。《学报 》的栏目可以逐步改成 :述评、评论性文
章 (一些新的思路、尖锐的观点 )、科研新闻、综述 (反映某个有重大进展的领域 )、科研论文 (有大篇幅的 ,也有短的 )、学科交
叉 (包括临床与基础的交叉 )、学者访谈、新书介绍等等。在栏目设置上 ,可以成熟一个发展一个 ,不必一步到位。网络版的问
题要作为专题来研究 ,网络版的内容可以更灵活一些。
·201·
北 京 大 学 学 报 ( 医 学 版 )
JOURNAL OF PEKING UN IVERSITY(HEALTH SC IENCES) Vol. 38 No. 1 Feb. 2006