Multifocal White Matter Lesions Associated with the
D313Y Mutation of the a-Galactosidase A Gene
Malte Lenders1., Thomas Duning2., Michael Schelleckes1, Boris Schmitz1,3, Sonja Stander4, Arndt Rolfs5,
Stefan-Martin Brand3, Eva Brand1*
1Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology, University Hospital Muenster, Muenster, Germany, 2Department of Neurology,
University Hospital Muenster, Muenster, Germany, 3Institute for Sports Medicine, Molecular Genetics and Cardiovascular Disease, University Hospital Muenster, Muenster,
Germany, 4Department of Dermatology, University Hospital Muenster, Muenster, Germany, 5Albrecht-Kossel-Institute for Neuroregeneration, University of Rostock,
White matter lesions (WML) are clinically relevant since they are associated with strokes, cognitive decline, depression, or
epilepsy, but the underlying etiology in young adults without classical risk factors still remains elusive. Our aim was to
elucidate the possible clinical diagnosis and mechanisms leading to WML in patients carrying the D313Y mutation in the a-
galactosidase A (GLA) gene, a mutation that was formerly described as nonpathogenic. Pathogenic GLA mutations cause
Fabry disease, a vascular endothelial glycosphingolipid storage disease typically presenting with a symptom complex of
renal, cardiac, and cerebrovascular manifestations. We performed in-depths clinical, biochemical and genetic examinations
as well as advanced magnetic resonance imaging analyses in a pedigree with the genetically determined GLA mutation
D313Y. We detected exclusive neurologic manifestations of the central nervous system of the ‘‘pseudo’’-deficient D313Y
mutation leading to manifest WML in 7 affected adult family members. Furthermore, two family members that do not carry
the mutation showed no WML. The D313Y mutation resulted in a normal GLA enzyme activity in leukocytes and severely
decreased activities in plasma. In conclusion, our results provide evidence that GLA D313Y is potentially involved in neural
damage with significant WML, demonstrating the necessity of evaluating patients carrying D313Y more thoroughly. D313Y
might broaden the spectrum of hereditary small artery diseases of the brain, which preferably occur in young adults without
classical risk factors. In view of the existing causal therapy regime, D313Y should be more specifically taken into account in
Citation: Lenders M, Duning T, Schelleckes M, Schmitz B, Stander S, et al. (2013) Multifocal White Matter Lesions Associated with the D313Y Mutation of the a-
Galactosidase A Gene. PLoS ONE 8(2): e55565. doi:10.1371/journal.pone.0055565
Editor: Raphael Schiffmann, Baylor Research Institute, United States of America
Received November 6, 2012; Accepted December 27, 2012; Published February 5, 2013
Copyright: ? 2013 Lenders et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This manuscript was supported by Genzyme GmbH, Germany. The manuscript print cost was supported by Genzyme Corporation, Germany. The
funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: AR, EB and TD have received speaker fees and research support from both Shire HGT and Genzyme Corporation. This also does not alter
the authors’ adherence to all the PLOS ONE policies on sharing data and materials.
* E-mail: Eva.Brand@ukmuenster.de
. These authors contributed equally to this work.
White matter lesions (WML) are clinically relevant since they
are associated with a variety of neurological disorders, e. g. strokes,
cognitive decline, depression, or epilepsy . WML are frequently
documented in brain MRI in elderly subjects. The most
prominent risk factors are age and essential hypertension, followed
by the remaining classical cardiovascular risk factors . WML
may also be detected in younger adults without typical risk factors
and are occasionally associated with inflammatory, and, in
particular, demyelinating diseases . However, despite extensive
diagnostic efforts, the underlying etiology often remains elusive in
Fabry disease (FD; Online mendelian inheritance in man
(OMIM) #301500) is a X-linked (Xq22.1) inborn error of
glycosphingolipid catabolism resulting from deficient a-galacto-
sidase A activity (GLA; OMIM #300644) due to mutations in
the GLA coding region, leading to the systemic accumulation of
globotriaoslyceramide (Gb3 or GL-3) in the plasma and cellular
lysosomes of vessels, nerves, tissues, and organs . Without
enzyme replacement therapy (ERT), life span in FD patients is
dramatically shortened, generally due to heart failure, renal
dysfunction and cerebrovascular disease. Ischemic strokes and
WML are characteristic neurological complications of FD .
Although mono-organic manifestations (e. g. an atypical ‘cardiac
variant’) have been described , a disease manifestation that is
limited to WML has not yet been reported.
The first identified missense mutation leading to a so-called
pseudo-deficient allele was GLA D313Y (Exon 6; c.937G.T),
which results in decreased enzyme activity in plasma, but nearly
normal activity in leukocytes [7–9]. Although controversially
discussed, the D313Y mutation is considered as non-pathogenic
by most authors and, thus, D313Y carriers are not treated with
ERT . In the current work, we identified an index patient
with significant WML carrying D313Y. After thorough exclu-
sion of other diseases, biochemical and molecular studies, and
recruitment of 7 more affected family members, we exclusively
identified D313Y potentially causing manifest WML as cerebral
manifestations of FD. We, consequently, evaluated the differen-
PLOS ONE | www.plosone.org1 February 2013 | Volume 8 | Issue 2 | e55565
tial impact of D313Y on clinical manifestations and concluded
that D313Y might broaden the spectrum of hereditary small
artery diseases of the brain which preferably occur ,45 years of
age and should be more specifically taken into account in
patients with multifocal WML in the absence of classical risk
Materials and Methods
All investigations were performed after approval of the Medical
Association of Westfalian-Lippe and the Ethical Committee of the
Medical Faculty of the University of Muenster (project-no.: 2011-
347-f, date of report: 07.07.2011) and written informed consent of
the patients for molecular analysis and publication.
Biochemical and Molecular Studies
Genomic DNA was isolated from leukocytes with subsequent
sequencing of GLA exons, 30–50 bp of adjacent introns and
a 700 bp genomic fragment of the regulatory GLA 59-sequence.
RNA extraction from leukocytes for expression analysis was
done by NucleoSpin RNA Blood-Kit (Macherey-Nagel, Dueren,
GER). cDNA synthesis was accomplished with SuperScript II
Reverse Transcriptase Kit (Invitrogen, Darmstadt, GER). Sub-
sequent semi-quantitative PCR was performed with oligonucleo-
tides for glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and GLA
amplifying fragments of 93 bp and 118 bp. Western blot analysis
was performed with primary anti-GLA antibody (Shire, Berlin,
GER) and secondary anti-mouse HRP-coupled antibody (GE
Healthcare, Little Chalfont, UK).
GLA sequencing, GLA activity measurements in leukocytes and
determination of lyso-Gb3 contents were performed at the
Figure 1. Pedigree and positions of D313Y and W349X in the GLA coding region. (A) Pedigree. (B) Representative chromatograms showing
nucleotide substitution at position +937 (G.T) in the GLA coding region. (C) Schematic overview of the GLA transcript including localizations of
D313Y and W349X. The pedigree shows the complete family of index patient II.7. Black arrow in A labels index patient. Squares indicate males, circles
indicate females. Diagonal lines indicate deceased family members. Dark grey, light grey, and white color in squares and circles indicates W349X,
D313Y, and non-carriers, respectively. Scattered circles represent not sequenced patients. Red flags indicate patients with white matter lesions (WML)
seen in magnetic resonance imaging (MRI), green flags indicate control patients without WML. Patient’s age at MRI is given in years. D313Y results in
single amino acid substitution at position +313, leading to a conversion of aspartate (Asp) to tyrosine (Tyr). W349X results in a c-terminal truncated
GLA protein, due to a conversion of tryptophan (Trp) to a stop-codon. A: Adenine; C: Cytosine; G: Guanine; T: Thymine; TLS: translational start side;
WT: wild-type GLA without any coding mutations.
White Matter Lesions Due to GLA D313Y
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University Hospital of Rostock (A. Rolfs). GLA activity in plasma
was determined using 4-methlyumbelliferyl-a-D-galactopyrano-
side (Santa Cruz Biotechnology, Santa Cruz, USA), as described
previously . N-acetylgalactosamine (Santa Cruz Biotechnolo-
gy, Santa Cruz, USA) was used as specific inhibitor of endogenous
a-Galactosidase B activity. GLA enzyme activity was measured as
nanomoles (nmol) of substrate hydrolyzed per hour (h) per mg
protein or ml plasma.
MRI Data Analysis
Lesion load on axial FLAIR sequences was determined semi-
automatically by outlining the peripheral borders of WML.
Lesions were marked and borders were set by local thresholding
using a custom-tailored software based on Analyse-software (Brain
Imaging Resource, Mayo Clinic, Rochester, MI, USA). By
multiplying with the interslice distance, total volume of WML is
established. Intra- and interobserver reliability was high with
a weighted kappa of 0.98 and 0.93, respectively.
Patient Characteristics and Clinical Features
Index patient II.7 specifically reported burning pain and
paraesthesia in hands and feet for several years. The patient
presented to our hospital for possible diagnosis of FD, as two
brothers (II.1 and II.2) already developed classical FD phenotypes
(Figure 1). Subject II.1 died at 38 years of age from myocardial
infarction, subject II.2 at the age of 53 from renal failure. Both
brothers were hemizygous carriers of the W349X mutation and
showed typical FD manifestations. We screened the family and
identified at least 10 members with the D313Y mutation (Figure 1).
In contrast to W349X, which leads to a truncated inactive GLA
protein and severe FD manifestations, D313Y only resulted in
decreased plasma GLA activities (Figure 1 B+C). However, FD-
typical clinical symptoms of subject II.7 prompted us to perform
appropriate diagnostic procedures including biochemical and
The neurological examination on admission was normal. Nerve
conduction velocity and somatosensory, visual and motor evoked
potentials showed normal latencies. MRI of the brain revealed
multiple, disseminated, T2 hyperintense, partly confluent lesions
from periventricular to subcortical without gadolinium enhance-
ment (Figure 2). Spinal cord MRI was unrevealing. Two
cerebrospinal fluid (CSF) analyses (4 and 7 month after first
symptoms) including immunotyping by flow cytometry and
biomarkers for dementia (beta-amyloid(1–42), total tau, and
hyperphosphorylated tau) were normal, CSF-specific oligoclonal
bands were absent (Table 1). Manual CSF cytology did not reveal
any malignant cells. DNA polymerase chain reactions in CSF for
herpes simplex virus type 1 and 2, varicella zoster virus, JC virus,
as well as mycobacterium tuberculosis complex and Tropheryma
whipplei were negative. Antibody titers against measles and
herpesviridae were not elevated. We observed a moderate CD4
(462/ml; normal range 500–1200/ml) lymphopaenia, while the
remaining blood count (including total leukocyte count) was
unsuspicious. Renal and liver function tests as well as homo-
cysteine level were normal. Serological testing for borreliosis,
syphilis and HIV-1/2 infection were unrevealing. Angiotensin-
converting enzyme in serum was normal (42 U/l; normal range
15–80 U/l). Serum antibodies against the aquaporin-4 water
channel, thyroid peroxidase, thyreoglobulin, glutamic acid dec-
arboxylase, GQ1b and onconeural antibodies (anti-amphiphysin,
anti-Ri, anti-Yo, anti-Hu, anti-CV2/CRMP5, anti-Ma2/Ta, anti-
NMDA, LGI-1, GAD) as well as anti-cardiolipin immunoglobulin
were all negative. A screen for antibodies against extractable
nuclear and anti-nuclear antigens was negative. Three long-term
blood pressure measurements were normal (,130/80 mmHg)
with nocturnal dipping. Arylsulfatase A activity and serum very
long-chain free fatty acid levels were within normal ranges.
Analysis of Notch3 mutations, consistent with cerebral autosomal
dominant arteriopathy with subcortical infarcts and leukoence-
phalopathy (CADASIL), was negative. Cerebral MR- and catheter
angiography was normal with no evidence for vasculitis. Although
no angiokeratomas were found, a skin biopsy was done that
showed a normal lipid content. However, intraepidermal nerve
fiber (IENF) density was reduced (index patient: 6 IENF/mm;
normal: .9 IENF/mm; Supporting Information S1), and along
with the typical clinical presentation a small-fiber neuropathy was
diagnosed. Transesophageal echocardiogram, renal ultrasound
and urine analysis as well as ophthalmological and dermatological
examination did not show other typical organ manifestations of
FD. In conclusion, the diagnostic work-up provided no indication
of inflammatory, neoplastic, metabolic, degenerative or congenital
diseases. Of note, no classical risk factors of WML were present.
Patients II.3, II.4, II.6, III.7, III.8, III.11 and III.14, all of which
carried GLA D313Y, also underwent detailed clinical examina-
tions (Table 2). Subjects II.3 and II.7 presented with unspecific
‘‘cardiac dysfunction’’. Only patient II.3 had mild cardiovascular
risk factors (well-treated arterial hypertension and well-treated
hyperlipidemia). To exclude cerebral manifestations, brain MRI
were performed in subjects II.3, II.4, II.6, II.7, III.8, III.11 and
III.14. Although no FD-specific organ manifestations were found,
all patients showed different extents (lesion volumes ranged from
8.1 ml to 42.9 ml; mean 23.4 ml 612.9 ml) of multifocal WML
(Figure 3). Localisation of WML were primarily subcortical with
punctuate lesions (patient II.6), but showed also confluent,
periventricular involvement (patient II.3). MR images of patient
II.3 showed a severe leukoencephalopathy with confluent cortical
and subcortical lesions and large lesion load (42.9 ml). Overall,
lesion loads were age-related, but WML were already present in
young family members without any vascular risk factor (III.8 [49
y], III.11 [34 y], and III.14 [41 y]). Brain MRI was also performed
in two family members that do not carry the GLA D313Y
mutation. These controls (III.16 [25 y], III.17 [32 y]) showed no
WMLs (Figure 4). Gadolinium enhancement was not seen in any
of the cases.
Genetic and Biochemical Analysis
Re-sequencing of all seven GLA exons and adjacent 59- and 39-
exon-intron-boundaries confirmed the exclusive presence of
D313Y in exon 6 in all affected subjects (Figure 1, Table 2).
GLA enzyme activities in leukocytes were in the normal range, or
at the lower limit, but GLA activities in plasma were decreased
(Table 2). Measurements of lyso-Gb3 content in blood plasma, as
an additional marker for FD, were in the normal range (Table 2).
To check whether GLA expression is affected by mutations within
the 59-regulatory region of GLA, we resequenced 700 bp of the
upstream regulatory sequence, including the 59-flanking UTR and
did not detect any genetic variation. To exclude that low plasma
GLA activity might result from decreased mRNA expression level
or absent GLA enzyme in plasma, we performed PCR and
western blot analysis (Supporting Information S1). All tested
subjects showed considerable GLA mRNA expression in leuko-
cytes and GLA protein in plasma (Table 2). Interestingly, even
when CSF analyses were normal in index patient II.7, CSF-GLA
activities were increased (215 pmol MU6h216ml21) compared
to a healthy control group (mean: 151622 pmol MU 6 h216
ml21; P-value: 0.03).
White Matter Lesions Due to GLA D313Y
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Figure 2. FLAIR- (A), T2- (B) and T1- (C) MR images of index patient II.7 showed widespread, punctuated (arrows) and confluent
(yellow circles) WML from periventricular (yellow) to subcortical (red) without gadolinium enhancement. Lesions were associated with
‘‘black holes’’ in T1-weigthed images (C) as a surrogate of severe demyelination and axonal injury. MR-angiography (D) showed no signs of cerebral
vasculitis or intracranial arteriosclerosis.
Table 1. Exclusion of risk factors and elicitors for white matter lesions in index patient II.7.
Neurologic cerebrospinal fluid beta-amyloid(1–42), total tau, hyperphosphorylated tau, malignant cells,
antibodies against: herpes simplex virus type 1 and 2, varicella zoster
virus, epstein barr virus, treponema pallidum, JC virus, borrelia
burgdorferi, mycobacterium tuberculosis, tropheryma whipplei, measles
PCR: herpes viridae, JC virus, mycobacterium tuberculosis
blood borrelia burgdorferi, treponema pallidum, HIV-1/2, aquaporin-4 water
channel, thyroid peroxidase, thyreoglobulin, glutamatic acid decarboxylase,
GQ1b, anti-cardiolipin immunoglobulin, angiotensin-converting enzyme
onco-neural antibodies: anti-amphiphysin, anti-Ri, anti-Yo, anti-Hu,
anti-CV2/CRMP5, anti-Ma2/Ta, anti-NMDA, LGI-1, GAD
CADASIL* (Notch3 sequencing)
arylsulfatase A activity, very long chain fatty acid levels
MR-angiography, catheter angiographycerebral vasculitisnormal
skin biopsy small-fiber neuropathy
Cardiac 24 h-blood pressure monitoring, PWV#,
fatty acid metabolism, ECG##
arterial hypertension, arteriosclerosis, hyperlipidemianormal
Renal serumeGFR++, proteinuria/albuminuria,normal
ultrasonography renal morphologynormal
*cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy;
+intraepidermal nerve fiber;
#pulse wave velocity;
++estimated glomerular filtration rate (Modification of Diet in Renal Disease [MDRD] formula; Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formula).
Two cerebrospinal fluid (CSF) analyses after 4 and 7 months after first symptoms were performed.
White Matter Lesions Due to GLA D313Y
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The widespread availability of MRI has resulted in an increased
recognition that WML are common incidental findings in elderly
individuals .65 years of age (up to 97%), but have rarely be seen
as early as in the third and fourth life decades . Although the
clinical relevance of such MRI findings primarily depends on the
respective etiology, even incidentally discovered WML are
frequently reported to be associated with various neurological
symptoms, e.g. progressive cognitive and neurobehavioral deficits,
gait and balance disturbances, epileptic seizures, or depression
[13–16]. In general, WML show a strong correlation with a wide
range of neurodegenerative and neuropsychiatric disorders, in-
dependent of other risk factors . Specific treatment is available
for some of the underlying causes, which effectively could modify
symptoms and prognosis, e.g. some metabolic and inflammatory
disorders. Furthermore, the cerebral lesions are often irreversible,
and thus the underlying etiology is particularly important to
consider. However, in clinical practice, uncovering the underlying
etiology of WML in adults without cardiovascular risk factors
remains dissatisfying in most of the cases. There are many different
causes of WML, which can occur at all ages, be progressive or
static, and be genetically determined or acquired. The diagnostic
workup is complicated as many different analyses have to be
performed, at high financial costs as well as emotional stress and
often with disappointing results .
With more widespread use of neuroimaging, neurologists will
increasingly be confronted with WML in younger adults. In recent
years, a considerable number of new sporadic or hereditary small
artery diseases of the brain have been detected which preferably
occur ,45 years of age . FD is one of those hereditary diseases
that can cause cerebral vasculopathy. Apart from macroangio-
pathic changes, FD is frequently associated with early micro-
angiopathic brain alterations with progressive WML . Howev-
er,the typicalFD symptom
manifestations such as cornea verticillata or angiokeratoma, renal
or cardiac manifestations, strokes and peripheral neuropathy .
Of note, strokes are highly important for Fabry diagnosis, because
they often occur before FD is readily diagnosed and in absence of
other clinical events . Although most patients present with the
classical phenotype, ‘‘variant’’ forms with prominent cardiac or
renal manifestations have been described . Whether these
mono- or oligo-organic phenotypes are associated with specific
mutations remains unclear. In fact, efforts to associate genotype
with clinical phenotype have been largely unsuccessful .
In the current study, we report on a family carrying the GLA
D313Y mutation and being affected by a potentially exclusive
neurologic manifestation of the CNS with multifocal WML, in the
absence of other FD-specific symptoms. The diagnosis was further
supported by the reduced intraepidermal nerve fiber density in the
index patient (small-fiber neuropathy), which is also known as
GLA enzyme activities in leukocytes and severely decreased
activities in plasma. There is still an ongoing discussion whether
deficiency’’. Recent case series or studies reported an association of
D313Y with other typical FD manifestations, e.g. peripheral
neuropathy, hypertrophic cardiomyopathy, renal failure, or stroke
non-causal. Thus, as a consequence, to date almost all D313Y-
carriers are not treated with ERT . Other studies support our
patients carrying GLA D313Y. In this respect, a recent prospective
and 55 reported that GLA D313Y was associated with cryptogenic
stroke . Recent reports point to an association of particular
mutations with a’’ late-onset’’ or ‘‘intermediate’’ type of FD, e.g.
N215S, A143T or F113C [26–28]. In this regard, the authors
as ‘‘predisposing polymorphisms’’ (e.g. R118C or E66Q). In view of
the D313Y mutation causing a CNS involvement. It should,
however, be noted that our findings could still represent a clinical
coincidence. Thus, further studies are necessary to confirm a causal
relationship between the D313Y mutation and cerebral manifesta-
Figure 3. Punctuated (arrows) and confluent (yellow circles) WML were present on MR images (axial and sagittal FLAIR- and T2-
sequences) of all six examined family members, all carrying D313Y. Only patient II.3 had mild cardiovascular risk factors (treated arterial
hypertension). Extent and lesion load were age-related, but WML were already present in young family members without any vascular risk factor
(patient III.8, III.11 and III.14; 49, 34 and 41 years of age, respectively).
White Matter Lesions Due to GLA D313Y
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The significant difference of enzymatic activity in leukocytes
and plasma caused by the change of aspartic acid to threonine at
position 313 is most likely due to a functional intolerance to blood
plasma neutral pH conditions. This obviously results in a profound
decrease of enzymatic GLA activity in plasma . Additionally,
this effect seems to be irreversible. Once in contact with a neutral
or basic pH environment D313Y remains inactive, even if
transferred to optimal pH (unpublished data). The GLA substrate
Figure 4. MR images of family members that were negative for D313Y did not show any white matter changes. Upper row: Sagittal
FLAIR-sequence; median and lower row: Axial T2-weighted sequences of subject III.16 and III.17.
White Matter Lesions Due to GLA D313Y
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Gb3, also known as CD77, has been shown to act as a cell surface
receptor in apoptotic signaling triggered not only by Shiga toxin
and Shiga-like toxins (vero toxin), but also by Gb3/CD77
If extracellular GLA activity is involved in inactivation of CD77
or its removal from the cellular surface, then a decrease of
extracellular GLA activity could lead to an increased initiation of
apoptosis. If so, the occurrence of abundant WML and the mild
FD symptoms in D313Y carriers points to a higher susceptibility of
neural tissues to this possible pathomechanism. To strengthen the
hypothesis, GLA should be further analyzed in appropriate studies
as a potential extracellular regulator of CD77.
From the clinical point of view, the most appropriate time to
start evaluating and follow-up the neurological manifestations of
D313Y carriers, or whether and when starting treatment with
ERT, remains to be investigated and should be based on more
clinical data. We, therefore, decided to perform a follow-up MRI
within 6 months and started a symptomatic treatment of the
neuropathic pain of the index patient with pregabaline. If the
neuropathic pain does not respond to appropriate medication,
ERT should be suggested, in particular with regard to the
excellent ERT response on neuropathic pain in appropriate
studies [30–32]. In case of a significant increase of WML an
effective anti-platelet agent such as clopidogrel should be
considered as an appropriate therapeutic option.
In conclusion, our results provide evidence that GLA D313Y
could be involved in neural damage with consecutive WML,
demonstrating the necessity of evaluating patients carrying D313Y
more thoroughly. D313Y might broaden the spectrum of
hereditary small artery diseases of the brain which preferably
occur in young adults. In view of the existing causal therapy
regime (ERT), D313Y should be more specifically taken into
account in patients with multifocal WML in the absence of
classical risk factors.
Supporting Information S1
methods and three supporting figures. Figure S1: Skin biopsy of
index patient II.7. Lipid content was normal and intraepidermal
nerve fiber density was slightly reduced. Subepidermal and
intraepidermal (arrow) PGP 9.5 positive cutaneous nerve fibers.
Magnification 400-fold. Figure S2: GLA expression in patients’
leukocytes. Semi-quantitative PCR was performed with RNA
samples extracted from leukocytes. GPDH was used as loading
control. All tested patients showed GLA mRNA expression in
leukocytes. Figure S3: GLA protein expression in plasma.
Western-blot analysis was performed with 20 mg of total plasma
protein. All tested patients showed GLA protein expression in
plasma. GLA protein size: 53 kDa.
The file contains supplemental
We thank the family whose participation make this work possible. The
technical assistance of Samira Schiwek and Birgit Orlowski is gratefully
Conceived and designed the experiments: ML TD SMB EB. Performed
the experiments: ML TD MS SS AR EB. Analyzed the data: ML TD BS
SS SMB EB. Contributed reagents/materials/analysis tools: TD SS AR
SMB EB. Wrote the paper: ML TD BS SMB EB.
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Table 2. Summary of investigated parameters and abnormalities as typical for FD.
Laboratory FD parameters
FD typical abnormalities
Enzyme activity in
in plasma Renal CardiacNeurologic
II.3m 71 D313Y 2.3978 0.83yesyes nono WML
II.4f 74 D313Y5.67 830.41 yes yesno no WML
II.6f 76 D313Y0.60161 0.82yes yesnono WML
II.7f 58 D313Y 3.2138 0.61 yesyesno noWML
III.7f38 D313Y4.89551.26 n.d. yes nonon.d.
III.8f49 D313Y5.83n.d n.d.yes yesnonoWML
III.14f41D313Y0.10 790.75yesyes no noWML
III.16f 25no9.14 57n.d.yes yesno nono
III.17f31 no 10.164 n.d.yesyes no no No
Renal parameters: ultrasonography, albumin/creatinine ratio, determination of eGFR. Cardiac parameters: echocardiography, cardiac magnetic resonance imaging (MRI)
and electrocardiogram. Neural/cerebral parameters: MRI, neurography and neuropsychologic diagnostics. Reference values: plasma activity .8.0 nmol MU/h/ml;
leukocyte activity .33 nmol MU/h/mg protein; lyso-Gb3,1.84 ng/ml. n.d.: not determined; WML: white matter lesions. Abnormal findings are highlighted in bold.
White Matter Lesions Due to GLA D313Y
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White Matter Lesions Due to GLA D313Y
PLOS ONE | www.plosone.org8 February 2013 | Volume 8 | Issue 2 | e55565