Clinical Aspects of Neuronal Forms of Lysosomal Storage Disorders. Part 2
Clinical aspects of neuronal forms of lysosomal storage disorders. Part 2.
L. B. Jardim • M.M. Villanueva • C.F.M. Souza • C.B.O. Netto
L. B. Jardim ()
Department of Internal Medicine, Universidade Federal do Rio Grande do Sul; Medical Genetics Service, Hospital de Clinicas de Porto Alegre,
Rua Ramiro Barcelos 2350
90035-903, Porto Alegre, Brazil,
e-mail:
M.M. Villanueva • C.F.M. Souza • C.B.O. Netto
Medical Genetics Service, Hospital de Clinicas de Porto Alegre, Brazil.
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Abstract
The purpose of this review is to describe state of the art related to the neurological phenotypes of lysosomal storage diseases. Primary neuronal involvement isfocused and not neurological complications secondary to a disrupted adjacent tissue. This distinction is probably very relevant, in the light of new potential therapies. Clinical presentation and follow-up, genetic and epidemiological data, and pathology were focused. Although prospective studies on the natural history have been hampered by the rarity and short survival of these patients, several longitudinal observations on the neurological manifestations were already published, and received particular attention. Levels of evidence were also included and some have been shown that at least some brain injuries related to lysosomal disease will be prone to therapy. While this goal is not achieved, better clinical studies are necessary in the majority of these disorders. Repeated measurements of disease progression, using responsive scoring systems, in larger samples of cases are needed in order to better clarify natural history of these disorders.
• Take-home message:State of the arton neurological impairment of lysosomal diseases has been reviewed, focusing on the clinical evidences on natural history, genetic determinants and modulating factors.
• Running head: Neuronal findings in LSD
• References to electronic databases
Acetyl-CoA-glucosaminide-N-acetyltransferase deficiency E.C 2.3.1.78
Acid ceramidase deficiency EC 3.5.1.23
Acid sphingomyelinase deficiency EC 3.1.4.12
-fucosidase deficiency EC 3.2.1.51
α-L-iduduronidase deficiency E.C 3.2.1.76
α-mannosidase deficiency EC 3.2.1.24
α-mannosidosis OMIM #248500
α-N-acetylgalactosaminidase deficency EC 3.2.1.49
α-N-acetylglucosaminidase deficiency E.C 3.2.1.50
α -N-acetyl-neuroaminidase EC 3.2.1.18
Arylsulfatase A deficiency EC 3.1.6.8
Aspartylglucosaminuria OMIM +208400
ß-galactosidase and neuraminidase deficiency EC 3.4.16.5
ß-galactosidase deficiency E.C. 3.2.1.23
ß-glucuronidase deficiency E.C 3.2.1.31
ß-mannosidase deficiency EC 3.2.1.25
ß-mannosidosis OMIM #248510
Cathepsin D deficiency EC 3.4.23.5
Ceroid-lipofuscinosis neuronal, 4A, adult form, OMIN %204300
Ceroid-lipofuscinosis neuronal, 4B, adult form, OMIM %162350
Ceroid-lipofuscinosis neuronal, CLN10, congenital form OMIN #610127
Ceroid-lipofuscinosis neuronal, CLN1, infantile form, OMIM #256730
Ceroid-lipofuscinosis neuronal, CLN3, juvenile form, OMIM #204200
Ceroid-lipofuscinosis neuronal, CLN2, late-infantile OMIM #204500
Ceroid-lipofuscinosis neuronal, 8, Northern epilepsy variant OMIM #610003).
Farber disease OMIM +228000
Fucosidosis OMIM #230000
Galactocerebrosidase deficiency E.C 3.2.1.46
Galactosialidosis OMIM +256540
Gaucher disease type I OMIN #230800
Gaucher disease type II OMIN #230900
Gaucher disease type III OMIN #231000
Gaucher disease type III C OMIN #231005.
Gaucher disease perinatal lethal OMIN #608013
Glucocerebrosidase E.C. 3.2.1.45.
GM2 activator protein deficiency: OMIM #272750.
GM1 gangliosidosis infantile form OMIM #230500
GM1 gangliosidosis late-infantile form OMIN #230600
GM1 gangliosidosis adult form OMIN #230650.
Heparin-N-sulfatase deficiency E.C 3.10.1.1
Hexosaminidase A deficiency EC 3.2.1.52.
Iduronate-2-sulfatase deficiency E.C 3.1.6.13
Krabbe disease KD OMIM# 245200
Metachromatic leukodystrophy OMIM# 230500
MPS I,Hurler syndrome OMIM #607014.
MPS I, Hurler Scheie syndromeOMIN #607015,
MPS I, Scheie syndrome OMIN #607016
MPS II, Hunter syndrome OMIM +309900
MPS III A, Sanfilippo A syndrome MIM #252900
MPS III B, Sanfilippo B syndrome OMIM #252920
MPS III C, Sanfilippo C syndrome OMIN #252930
MPS III D, Sanfilippo D syndrome OMIN #252940
MPS VII, Sly syndrome OMIM #253220
Mucolipidin gene OMIN *605248
Multiple sulfatase deficiency OMIM #272200
N-acetylglucosamine-1-phosphotransferase alpha/beta-subunits deficiency E.C 2.7.8.15.
N-acetylglucosamine-1-phosphotransferase gamma subunit deficiency E.C 2.7.8.17
N-acetylglucosamine-6-sulfatase deficiency E.C 3.1.6.14
N-aspartyl-beta-glucosaminidase EC 3.5.1.26
Niemann-Pick disease type A OMIN #257200.
Niemann-Pick disease type B OMIN #607616
Niemann-Pick disease type C1 MIM #257220
Niemann-Pick disease type C2 MIN #607625
NPC1 gene *607623
NPC2 gene *601015
Palmitoyl-protein thioesterase-1 deficiency E.C 3.1.2.22
Protein activator saposin B deficiency OMIM# 249900
Sandhoff disease OMIM #268800
Schindler disease OMIM #609241
Sialidosis type I OMIM #256550
Sulfatase-modifying factor-1 gene OMIN ٭607939
Tay-Sachs disease: OMIM #272800.
Tripeptidyl peptidase 1 deficiency1 E.C 3.4.14.9
• Abbreviations
AC acid ceramidase
AGU aspartylglucosaminuria
ANCL neuronal ceroid-lipofuscinosis, form adult, Kuf's disease
ARSA arylsulfatase A
ASM acid sphingomyelinase
BAER brain auditory evoked response
BMT bone marrow transplantation
CLP curvilinear profile
CNS central nervous system
CSF cerebrospinal fluid
CT computed tomography
EEG electroencephalogram
EIKD early infantile Krabbe disease
EM electronic microscopy
EMG electromyogram
ERG electroretinogram
ERT enzyme replacement therapy
FGE formylglycine-generating enzyme
FUCA1 -fucosidase
GAGs glycosaminoglycans
GALC galactocerebrosidase
GD Gaucher disease
GLD Globoid cells leukodystrophy
GNPTAB alpha/beta-subunits of the N-acetylglucosamine -1-phosphotransferase
GNPTG gamma subunit of N-acetylglucosamine-1-phosphotransferase
GROD granular osmiophilic deposits (GROD)
GUS beta-glucuronidase
HDL-C high-density lipoprotein cholesterol
Hex A hexosaminidase A
HLA-DR major histocompatibility complex, class I
1H-MRSI proton magnetic resonance spectroscopic imaging
HSEM horizontal saccadic eye movement
INCL infantile neuronal ceroid-lipofuscinosis, Santavuori-Haltia
IQ intelligence quotient
JNCL juvenile neuronal ceroid-lipofuscinosis, Batten disease, Spielmeyer-Vog
KD Krabbe disease
LINCL late-infantile neuronal ceroid-lipofuscinosis, Jansky-Bielschowsky
LMN lower motor neuron
LOKD late-onset Krabbe disease
LOTS late-onset Tay-Sachs
LSD lysosomal storage disorders
MAN2B1 mannosidase, alpha
MANBA mannosidase, beta A
ML mucolipidosis
MLD metachromatic leukodystrophy
MPS mucopolysaccharidoses
MPS IH Hurler syndrome
MPS IH/S Hurler-Scheie syndrome
MPS IS Scheie syndrome
MPS II Hunter syndrome
MPS III Sanfilippo syndrome
MRI magnetic resonance imaging
MSD multiple sulfatase deficiency
NAGA α-N-acetylgalactosaminidase
NCL neuronal ceroid lipofuscinosis
NCV nerve conduction velocity
NE neuronal ceroid-lipofuscinosis, Northern epilepsy variant
NEU1 alpha-N-acetyl neuroaminidase
NGD neuronopathic Gaucher disease
NPA Niemann Pick disease type A
NPB Niemann Pick disease type B
NPC Niemann Pick disease type C
OMA oculomotor apraxia
PAS periodic acid-schiff stain
PNS peripheral nervous system
PPCA protective protein/cathepsin A
PPGB beta-galactosidase and neuraminidase
PPT1 palmitoyl-protein thioesterase-1
SAP saposins
SIF saccade initiation failure
SUMF1 sulfatase-modifying factor-1 gene
TSD Tay-Sachs disease
TNF tumoral necrosis factor
TPP1 tripeptidyl peptidase 1
TUNEL TdT-mediated dUTP-biotin nick end-labelling
VSEM vertical saccadic eye movement
VSPG supranuclear vertical gaze palsy
VEP visual evoked potentials BAER
WM white matter
“Third page”
• Details of the contributions of individual authors,
L.B.Jardim: conception and planning of the manuscript; writing of the first draft of the majority of sphingolipidoses, and of neuronal ceroid lipofuscinosis; review and critique of the final version. L.B. Jardim is the guarantor for the article, accepts full responsibility for
the work and/or the conduct of the study, had access to the data, and controlled the
decision to publish.
M.M. Villanueva: writing of the first draft of Gaucher and Niemann-Pick diseases sections; review of the final version.
C.F.M.Souza: writing of the first draft of
C.B.O.Netto: writing the first draft of mucopolysaccharidoses; English review.
All authors confirm that they have no competing interests for declaration.
Since this is a review, ethics approval was not required.
Introduction
The lysosomal storage disorders (LSDs) are a family of human genetic diseases caused by the defective activity of lysosomal enzymes and other related proteins: any defect that prevents the catabolism of molecules in the lysosome, or the egress of molecules from the lysosome, induces the storage of undegraded molecules in these subcellular organelles.
The overall frequency of LSD is estimated to be approximately 1 in 8000 live births. Some of these disorders show founder effects in geographically isolated or demographic transition populations, due to genetic drift. A high incidence of some LSD in a population can be either due to a genetic proximity between their marriages, or to some selective advantage for the carrier state in the particular settings (Jeyakumar et al 2005).
Many of these disorders are characterized by severe neurological impairment, which is almost always untreatable. Progressive neuronal dysfunction and death occur in these conditions. Contrarily to the former points of view relating signs and symptoms to the mechanical disruption of the cell, secondary to storing of undegradable materials, for most of the neuronal LSD the pathogenesis also involves neuronal dysfunction, sometimes independent from the storage burden (Wraith 2002; Jeyakumar et al 2005).
Neurological involvement can also be secondary to substract accumulation in adjacent tissue, however. This distinction seems to be very pertinent, in the light of new potential therapies. A better understanding about the cascade of events resulting in neuronal involvement will certainly help the development of new therapeutic approaches, and it is possible that clinical information gattered up to now, can help us in achieving this target. Neurological problems which are secondary complications of storage materials, such as spinal cord compressions in MPS I, IV or VI, or cerebrovascular accidents in Fabry disease, are beyond the scope of the present review. Several recent publications gave accounts on these fields, and appeared elsewhere (Kachur et al 2000; Moore et al 2007; Khanna et al, 2007; Al Sawaf et al 2008; Vougioukas et al 2001; Montaño et a, 2007).Supportive treatment should not be overlooked: it should be pursued, since it certainly increases quality of life in these disorders.
This review presents the state of art on the neurological phenotypes of the primary neuronal forms of LSD in two parts. Part 1, printed part, includes summaries of the neurological phenotypes as well as genetic characteristics and levels of evidence, as well as some insights gleaned from various clinical observations. Part 2 (electronic) presents a detailed review of the clinical characteristics of each neuronal LSD.
The present review focuses on clinical aspects of the neurological LSD – clinical presentation, genetic and epidemiological data, and pathology, when known. Established genotype-phenotype correlations in LSD with neuronal involvement were briefly mentioned in Table 2, including those mutations that prevent against neuronal manifestations.
Due to rarity and to the short survival of the majority of the neuronal LSD, prospective studies are very scarce and the knowledge about the natural history or progression rate was inferred from anecdotal reports. Longitudinal observations on the neurological manifestations received particular attention, when available. When natural history studies were lacking, clinical course observations on neurological endpoints after an intervention were also mentioned. The pathogenetic cascades and a review on management will be described with detail elsewhere (Scarpa et al and Schiffman et al, in the present JIMD issue).
- Sphingolipidosis
Sphingolipids are a class of lipids derived from the aliphatic amino alcohol sphingosine. The three main types of sphingolipids are, from the simplest to the most complex ones: ceramide, sphingomyelin, and the glycosphingolipids ( including cerebrosides and gangliosides). Defects in the degradation of these macromolecules produce the LSD collectively called sphingolipidosis (SL).
Sphingolipids are often found in neural tissue. Sulfatide and galactocerebroside are very important constituents of myelin, being synthetized by olygodendrocytes and Schwann cells. Several others are synthetized by neurons, and play an important role in both signal transmission and cell recognition. For instance, ceramide modulates either neurite formation and neuronal apoptosis (Buccoliero et al, 2002). , and gangliosides act as modulators of dendritogenesis (Walkley et al 1999). Since these lipids are synthetized in neural tissue, the storage produced by a SL most frequently affects the central and peripheral neurvous systems (CNS and PNS).
Eight SL are neuronopathic: GM2 and GM1 gangliosidoses, Gaucher disease types 2 and 3, Niemann-Pick types A and B, Niemann-Pick type C, Metachromatic leucodistrophy, Krabbe disease (or globoid cell leukodystrophy), and Farber disease.
1. 1 GM2 Gangliosidosis
GM2 gangliosidosis (GM2) are LSD due to the storage of GM2 ganglioside in the lysosomes. Deficient activity of the hexosaminidase A (Hex A)can be secondary to mutations in alpha subunit or in beta subunit of the enzyme. Mutations in the alpha subunit result in GM2 gangliosidosis called Tay-Sachs disease (TSD), or Variant B. Mutations of the beta-subunit cause Sandhoff disease, or Variant 0. Incomplete degradation of GM2 can also be secondary to a deficiency of the GM2 activator protein, related to the AB variant of GM2 gangliosidosis (Gravel et al 2001; Sandhoff et al 2001).
GM2 is a component of the cell plasma membrane which modulates cell signal transduction events, like synaptic activities and, in neuronal ontogenesis, neurite sprouting. Storage of GM2 ganglioside seemed to be the main cause of neuronal dysfunction, by inducing aberrant dendrite sprouting and synaptic activities during neuronogenesis (Sandhoff et al 1971; Gravel et al 2001; Sandhoff et al 2001).
Variant B, or Tay Sachs disease
This condition is mostly seen in Ashkenazi Jewish communities, where the carrier rate for TSD is about one in 30 and the former incidence of disease was about one in 3600 live births. As the result of extensive genetic carrier screening programs in this population, the incidence has been reduced by greater than 90% (Kaback 2000). In the general population, the incidence is of 1 in 222 000 live births (Meikle et al 1999)
There are three general subgroups of Variant B, according to ages at onset: (a) the classical infantile form, (b) juvenile, and (c) late onset forms (called chronic or adult forms). Sibs with classical form always present a very similar picture. In contrast, intrafamilial heterogeneity was repeatedly reported among late onset forms, suggesting that factors other than the specific mutation are modulating the clinical presentation (Neudorfer et al 2005; Maegawa et al 2006).
Children with the classical form start with an exaggerated, non-adaptable startle response to stimuli in the first months of life. Soon thereafter, loss of milestones and a pendular nistagmus appear. By the eighth month, there is marked axial hypotonia with limb spasticity and blindness. Eletroretinogram and papillary responses to light are normal. Cherry red spots can be seen in the macula, consisting of a large whitish circular zone, corresponding to ganglion cells storage and degeneration (Figure E-1). Since the fovea is devoid of most inner retinal layers, including ganglion cells, it is spared and appears in the center of the white zone. The size of the cranium increases continuously after birth, due to a true megalencephaly. At the end stages of the disease, ventricles can enlarge in an ex vacuum manner and seizures are present in the second year. End stage is reached with a vegetative state with decerebration and cachexia (Sandhoff et al 2001; Lyon et al 2006). This severe, classical form of Tay Sachs disease can be seen as a stereotype for other early infantile sphingolipidoses, pointing to possible common pathogenetic pathways (Figure 1 and Table 3).
MRI and CSF are unremarkable. There is no evidence of visceral, skeletal, and peripheral nerve involvement. Nerve conduction velocities remain normal, suggesting that ganglioside storage does not affect peripheral myelin. Autopsy findings included enlarged and heavy brain, swollen neurons throughout the CNS, meganeurites, loss of neurons, and GM2 storage (Sandhoff et al 2001; Lyon et al 2006).
In the late onset forms (subacute, juvenile, chronic and adult; LOTS) of variant B, balance problems and difficulty climbing stairs were the most frequent presenting complaints (Neudorfer et al 2005). LOTS can take one or more of the following forms: a lower motor neuron disease, a cerebellar ataxia, a psychiatric syndrome, dementia, a pyramidal and or extrapyramidal syndrome (dystonia), and polyneuropathy (Frey et al 2005; Lyon et al 2006; Shapiro et al 2008). Language and visuospatial skills can be normal for several years, whereas memory and executive functioning were already impaired. This asymmetry raised the hypothesis of a subjacent cerebellar dysfunction (Zaroff et al 2004). Unlike the infantile form, there is no cherry red spot in LOTS. Peculiar abnormalities of saccades, with hypometria, transient decelerations, and premature termination of saccades were seen in patients with varied disease durations, suggesting the involvement of pontine nucleus raphe interpositus or dorsal vermis (Rucker et al 2004) (Table 3). Loss of vision occurs much later than in the acute infantile form of the disease, due to optic atrophy and/or retinitis pigmentosa. A vegetative state with decerebrate rigidity develops by the end stages of disease. In some cases, the disease pursues a particularly aggressive course, culminating in death in two to four years.
Mild cortical and cerebellar atrophies can be seen by neuroimaging, whereas EMG can reveal lower motor neuron (LMN) involvement (Neudorfer et al 2005; Frey et al 2005). As in the classical Tay Sachs disease, neurophysiological studies of peripheral nerves were always normal.
The rate of progression is not well known. Maegawa et al (2006) presented some estimates, based on a cohort of 21 patients with juvenile GM2. Those authors reported, for instance, a survival estimate of 14.5 years after disease onset (95% confidence interval: 11.7–17.3).
Autopsy findingsusually show abundant lipid accumulation in CNS neurons and neuronal losses related to the phenotypic manifestations during life. Histochemistry demonstrated diffuse neuronal GM2 storage in the brainstem, in Purkinje andgranular cells of the cerebellum, and/or in anterior horns of the spinal cord, in good correlation with clinical observations (Rapin et al 1976; Benninger et al 1993; Kornfeld2008).
Variant Zero, or Sandhoff disease
The variant 0 of GM2 gangliosidosis is quite rare, with a carrier frequency of 1/600 in general populations (Cantor and Kaback 1985). Founder effects were found in the Christian Maronite community of Cyprus (Drousiotou et al 2000), and in a Creole population of Argentina (Dodelson de Kremer et al 1985).
As in Tay Sachs disease, Sandhoff disease can be subdivided in early-onset and juvenile or late onset forms. Ages at onset, disease duration, neurological and ophthalmological pictures are quite similar to those found in Tay Sachs disease, meaning that the GM2 ganglioside is the main storage material in variant 0. Distinction can be done, sometimes, because some Sandhoff disease patients present with enlarged liver and spleen (Figure 1), skeletal changes similar to GM1 gangliosidosis (Figure E-2), foam cells in bone marrow, and the presence of some oligosaccharides in urine (Sandhoff et al 2001; Lyon et al 2006)).
Due to its rarity, virtually nothing is known about the natural history or intrafamilial variability of Sandhoff disease.
In anatomo-pathology studies, lesions are similar to those found in Tay Sachs disease, except that neuronal inclusions are more polymorphic (Lyon et al 2006).