EFNS guidelines on the molecular diagnosis of channelopathies, epilepsies, migraine, stroke, and dementias.

Abstract

These EFNS guidelines on the molecular diagnosis of channelopathies, including epilepsy and migraine, as well as stroke, and dementia are designed to summarize the possibilities and limitations of molecular genetic techniques and to provide diagnostic criteria for deciding when a molecular diagnostic work-up is indicated.
To collect data about planning, conditions, and performance of molecular diagnosis of these disorders, a literature search in various electronic databases was carried out and original papers, meta-analyses, review papers, and guideline recommendations were reviewed.
The best level of evidence for genetic testing recommendation (B) can be found for a small number of syndromes, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, severe myoclonic epilepsy of infancy, familial recurrent hemorrhages, familial Alzheimer's disease, and frontotemporal lobar degeneration. Good practice points can be formulated for a number of other disorders.
These guidelines are provisional, and the future availability of molecular genetic epidemiological data about the neurogenetic disorders under discussion in our article will allow improved recommendation with an increased level of evidence.

Full text

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EFNS GUIDELINES/CME ARTICLE
EFNS guidelines on the molecular diagnosis of channelopathies,
epilepsies, migraine, stroke, and dementias
J-M. Burgundera, J. Finstererb, Z. Szolnokic, B. Fontained, J. Baetse,f,g, C. Van Broeckhovenf,g, S.
Di Donatoh, P. De Jonghee,f,g, T. Lynchi, C. Mariottij, L. Scho ¨lsk, A. Spinazzolal, S. J. Tabrizim, C.
Tallaksenn,o, M. Zevianil, H. F. Harbooand T. Gasserp
aDepartment of Neurology, University of Bern, Bern, Switzerland;bKA Rudolfstiftung, Vienna and Danube University Krems, Austria;
cDepartment of Neurology and Cerebrovascular Diseases, Pandy County Hospital, Gyula, Hungary;dAssistance Publique-Ho ˆpitaux de Paris,
Centre de re´fe´rence des canalopathies musculaires, Groupe Hospitalier Pitie´-Salpeˆtrie`re, Paris, France;eDepartment of Neurology, University
Hospital of Antwerp;fDepartment of Molecular Genetics, VIB;gLaboratory of Neurogenetics, Institute Born-Bunge, and University of
Antwerp, Antwerpen, Belgium;hFondazione-IRCCS, Istituto Neurologico Carlo Besta, Milan, Italy;iThe Dublin Neurological Institute,
Mater Misericordiae University, Beaumont & Mater Private Hospitals, Dublin, Ireland;jUnit of Genetic of Neurodegenerative and Metabolic
Diseases, IRCCS Foundation, Neurological Institute Carlo Besta, Milan, Italy;kClinical Neurogenetics, Center of Neurology and Hertie-
Institute for Clinical Brain Research, University of Tu ¨bingen, Tu ¨bingen, Germany;lDivision of Molecular Neurogenetics, IRCCS Foundation
Neurological Institute Carlo Besta, Milan, Italy;mDepartment of Neurodegenerative Disease, Institute of Neurology and National Hospital
for Neurology and Neurosurgery, Queen Square, London, UK;nDepartment of Neurology, Ulleva ˚l University Hospital;oDepartment of
Neurology, Oslo University Hospital, Ulleva ˚l, Oslo, Norway; andpDepartment of Neurodegenerative Diseases, Hertie-Institute for Clinical
Brain Research, University of Tu ¨bingen and German Center for Neurodegenerative Diseases (DZNE), Tu ¨bingen, Germany
Keywords:
channelopathies, EFNS
task force, migraine,
molecular diagnosis,
neurogenetic, stroke
Received 22 August 2009
Accepted 20 January 2010
Objectives: These EFNS guidelines on the molecular diagnosis of channelopathies,
including epilepsy and migraine, as well as stroke, and dementia are designed to sum-
marize the possibilities and limitations of molecular genetic techniques and to provide
diagnostic criteria for deciding when a molecular diagnostic work-up is indicated.
Search strategy: To collect data about planning, conditions, and performance of
molecular diagnosis of these disorders, a literature search in various electronic data-
bases was carried out and original papers, meta-analyses, review papers, and guideline
recommendations were reviewed.
Results: The best level of evidence for genetic testing recommendation (B) can be
found for a small number of syndromes, cerebral autosomal dominant arteriopathy
with subcortical infarcts and leukoencephalopathy, severe myoclonic epilepsy of
infancy, familial recurrent hemorrhages, familial Alzheimer?s disease, and fronto-
temporal lobar degeneration. Good practice points can be formulated for a number of
other disorders.
Conclusion: These guidelines are provisional, and the future availability of molecular
genetic epidemiological data about the neurogenetic disorders under discussion in our
article will allow improved recommendation with an increased level of evidence.
Introduction
Since the publication of the first EFNS guidelines on
the molecular diagnosis of inherited neurological dis-
eases in 2001 [1,2], rapid progress has been made in this
field, necessitating the creation of an updated version of
these guidelines, which follows the EFNS Scientific
Committee recommendations for guideline papers [3].
Objectives: These EFNS guidelines on the molecular
diagnosis of channelopathies, including epilepsy and
migraine, as well as stroke, and dementia are designed
to summarize the possibilities and limitations of
molecular genetic techniques and to provide diagnostic
criteria for deciding when a molecular diagnostic work-
up is indicated in adults.
Search strategy: To collect data about planning,
conditions, and performance of molecular diagnosis of
Correspondence: J.-M. Burgunder MD, Department of Neurology,
University of Bern, Inselspital, CH-3010 Bern, Switzerland
(tel.: +41 31 352 20 70; fax: +41 31 351 80 70; e-mail: Jean-marc.
burgunder@dkf.unibe.ch).
This is a Continuing Medical Education article, and can be found with
corresponding questions on the Internet at http://www.efns.org/
EFNSContinuing-Medical-Education-online.301.0.html. Certificates
for correctly answering the questions will be issued by the EFNS.
? 2010 The Author(s)
Journal compilation ? 2010 EFNS
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these disorders, a literature search in various electronic
databases, such as Cochrane library, MEDLINE,
OMIM, GENETEST, or Embase was carried out and
original papers, meta-analyses, review papers, and
guideline recommendations were reviewed.
Method for reaching consensus: Consensus about the
recommendationswasreached
approach. First, task force members met at the EFNS
congresses in 2007 and 2008 to discuss the prepara-
tions of the guidelines. In a second step, experts in
genetics of the disorders mentioned previously wrote a
guideline proposal. In a third step, these recommen-
dations were distributed and discussed in detail among
all task force members until a final consensus had been
reached.
Results and recommendations: Recommendations
follow the criteria established by the EFNS [3], with
some modifications to account for the specific nature
of genetic tests. As genetic testing is by definition the
gold standard to diagnose a genetically defined dis-
ease, its diagnostic accuracy cannot be tested against
another diagnostic method. Therefore, the level of
recommendations was based on the quality of avail-
able studies [3], and the proportion of cases of a
clinically defined group of patients that are explained
by a specific molecular diagnostic test was estimated.
As nearly all of these studies have a retrospective
design and look for a specific mutation in a previously
ascertained and clinically diagnosed cohort of patients,
the highest achievable recommendation level was B [3].
If only small case-series studying genotype–phenotype
correlations were available, the level of recommenda-
tion was C. If only case reports could be found, but
byastep-wise
experts still felt that they could give a recommenda-
tion, the level of recommendation was assessed as
?good practice point.?
Channelopathies
Ion channels are trans-membrane proteins, which allow
fluxes between the intra- and extracellular spaces with
specific conductance for different ions, including
sodium, calcium, chloride, and other. Voltage-gated
activation modulates membrane excitability, allowing
intercellular communication and impulse propagation.
Ion channel gene mutations have been found in neu-
rological disorders, which have in common episodic or
paroxysmal clinical manifestations. Muscle channelop-
athies include periodic paralysis, non-dystrophic myo-
tonia, Andersen–Tawilsyndrome,
myasthenia. Disorders affecting the central nervous
system comprise episodic ataxia, migraine, and epi-
lepsy. Molecular diagnosis is now available for many
neurological channelopathies (Table 1).
andcongenital
Muscular channelopathies
Hypokalemic periodic paralysis is an autosomal domi-
nant hereditary disease [4] characterized by episodic
muscle paralysis concomitant with a decrease in blood
potassium levels and facilitated by muscle exercise or
sugar ingestion. Between attacks, muscle examination is
normal. The disease may be caused by specific muta-
tions either in the calcium channel a1S-subunit (CAC-
NA1S) gene, localized on chromosome 1, or in the
sodium channel a1-subunit (SCN4A) on chromosome
Table 1 Neurological channelopathies
Disease Gene
Mode of
inheritance
Gene
locus Mutated protein OMIM
Hypokalemic periodic paralysis (HOKPP)CACNA1S
SCN4A
SCN4A
AD
AD
AD
1q32
17q23
17q23
Calcium channel a1S subunit type 1
Sodium channel a-subunit type 4
Sodium channel a-subunit type 4
170400
170400
170500
168300
608390
Hyperkalemic periodic paralysis (HYPP)
Paramyotonia congenita (PMC)
Sodium channel myotonia or
potassium-aggravated myotonia
Myotonia congenitaCLCN1 AD (Thomsen)
AR (Becker)
AD
AD
AD
AD
AD
AD
AD
AD
AR
AR
7q35
7q35
17q23
17q23
20q13
8q24
2q24
19q13
2q24
2q24
3q26
3q26
Chloride channel type 1160800
255700
170390
603967
121200
121201
607745
604233
Andersen–Tawil syndrome (ATS)
Congenital myasthenic syndrome (CMS)
Benign neonatal epilepsy (BNE1, 2)
KCNJ2
SCN4A
KCNQ2
KCNQ3
SCN2A
SCN1B
SCN1A
SCN1A
CLCN2
CLCN2
Potassium channel subfamily J member 2
Sodium channel a-subunit type 4
Potassium channel subfamily Q member 2
Potassium channel subfamily Q member 3
Sodium channel a-subunit type 2
Sodium channel b-subunit type 1
Sodium channel a-subunit type 1
Sodium channel a-subunit type 1
Chloride channel type 2
Chloride channel type 2
Benign familial neonatal–infantile seizures
Generalized epilepsy with febrile
seizure-plus (GEFS+)
Severe myoclonic epilepsy of infancy (SMEI)
Juvenile myoclonic epilepsy
Childhood absence epilepsy
607208
606904
607682
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17. Mutations in CACNA1S, found in 70–90% of pa-
tients from different ethnic backgrounds, are the most
frequent. Patients with SCN4A mutations tend to have
muscle aches and drug-induced symptom aggravation
[5]. In vitro expression of mutated channels suggests a
loss-of-function mechanism and an increased ?leakiness?
of the channels [6]. Mechanisms underlying blood
potassium level changes are still not well understood.
Electromyography following sensitization by a long
exercise test allows diagnosis of periodic paralysis even
between attacks and may predict channel type mutation
[7]. Treatment relies on the avoidance of provocative
factors and the use of chloride potassium salts and
acetazolamide.
Hyperkalemicperiodic
congenita, and sodium channel myotonia have in
common to be caused by distinct mutations of the
sodium channel gene SCN4A on chromosome 17 [8–
10]. Overlapping syndromes with different degrees of
paralysis and myotonia occur depending on the
mutation. Hyperkalemic periodic paralysis is charac-
terized by episodic attacks of muscle weakness con-
comitantwith increased
Provocation factors include muscle exercise, cold,
alcohol, potassium-richfood,
Paramyotonia congenita is characterized by prolonged
muscle contraction aggravated by exercise (paradoxi-
cal myotonia) and cold. Distinct patterns of sponta-
neous activity, possibly related to the mutation type,
may be recorded on needle electromyography [11]. All
these disorders are transmitted with an autosomal
dominant mode of inheritance and are caused by
mutations in SCN4A distinct from the ones impli-
cated in hypokalemic periodic paralysis. Although
there may be variations between and within families,
there is a good genotype–phenotype correlation.
In vitro expression of mutated channels has revealed
that they may activate early or inactivate late or
incompletely resulting in increased excitability of the
cell membrane. A slight increase in excitability will
result in an increased number of action potentials and
thus myotonia. Treatment is based on the avoidance
of provoking factors, mild exercise at onset of an
attack, or intake of carbohydrates. Acetazolamide
may prevent the attacks of muscle weakness. Blockers
of the open states of the sodium channel (mexiletine,
carbamazepine, and diphenylhydantoin) can alleviate
myotonia [12].
paralysis,paramyotonia
bloodpotassiumlevels.
stress,or steroids.
Neuronal channelopathies
Neuronal channelopathies comprise a variety of dis-
orders including episodic ataxias, migraine, and some
forms of epilepsy [13]. Ataxias are discussed in another
study of this series and migraine later. Rare inherited
forms of epilepsy are increasingly recognized as
channelopathies. Benign infantile neonatal epilepsy
(EBN1, EBN2) is an autosomal dominant condition,
in which newborns develop tonic-clonic seizures within
the first days of life. Neurological development is
normal, and the seizures are easily controlled by
antiepileptic medication. The disease is caused by loss-
of-function mutations in either the potassium channel
gene KCNQ2 or KCNQ3 (Table 1). In autosomal
dominant benign familial neonatal–infantile seizures,
mutations have been found in the gene encoding the
neuronal sodium channel a-subunit (SCN2A) on
chromosome 2. Generalized epilepsy with febrile sei-
zures-plus (GEFS+) is an autosomal dominant con-
dition with different types of seizures (febrile seizures,
generalized seizures, and partial seizures). Mutations
were found in the genes encoding the b1-subunit of the
sodium channel (SCN1B), the a1-subunit of the neu-
ronal sodium channel (SCN1A), and in the GABRG2
gene. In severe myoclonic epilepsy of infancy (SMEI),
seizures are refractory to medication, and patients
develop neurological deterioration because of de novo
mutations in the gene encoding the a1-subunit of the
neuronal sodium channel SCN1A on chromosome 2.
Juvenile myoclonic epilepsy has an onset in adoles-
cence with a combination of myoclonic, generalized,
and absence seizures. Mutations were found in the
gene encoding the chloride channel CLCN2 on chro-
mosome 3. Mutations in CLCN2 have also been
linked to childhood absence epilepsy, a condition of
good prognosis characterized by multiple absences
beginning in mid-childhood with generalized 3Hz
spike-and-wave complexes.
Recommendations
There is good evidence to suggest that a thorough
clinical and electrophysiological investigation may lead
to the choice of the gene to be tested in patients with
periodic paralysis (level B). In myotonic disorders, it is
recommended to first search for myotonic dystrophy
and use clinical and electrophysiological phenotype
characterization to guide for molecular genetic testing
(level B).
Molecular investigations are possible and may help in
some cases to diagnose the condition but cannot be
considered as a routine procedure with regard to the
large number of different mutations in different genes.
Furthermore, diagnosis can be made more easily by
clinical and physiological investigations (good practice
point). One exception of note is the diagnosis of SMEI,
in which mutations are found in SCN1A in 80% of the
patients (level B).
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Cerebrovascular diseases
CADASIL
The main clinical features of cerebral autosomal dom-
inant arteriopathy with subcortical infarcts and leu-
kencephalopathy (CADASIL) include migraine with
aura in the third decade of life, recurrent ischaemic
stroke or transitory ischaemic attacks 10 years later,
followed by dementia 20 years after onset. The disorder
results from mutations in the gene coding for Notch3
located on chromosome 19q12 (Table 2). Mutations are
localized in coding regions for epidermal growth factor
(EGF)-like repeat domains. Most of the mutations
(70%) are clustered within exons 3 and 4. Direct
sequencing of these two exons is suggested as a first step
if clinical suspicion is high. Multiple small subcortical
infarcts with leukoaraiosis are typically found in the
frontal poles [14]. The diagnosis may also be supported
by skin biopsy showing typical osmiophilic granula.
Amyloid angiopathies
Cerebral amyloid angiopathy (CAA), Dutch type is
caused by a point mutation within the amyloid pre-
cursor protein (APP) gene (guanine-to-cytosine at
nucleotide 1852), resulting in a substitution of gluta-
mine for glutamic acid at position 693 (Table 2). Sev-
eral other APP mutations in Alzheimer disease (AD)
are associated with a strong microvascular amyloid
involvement [15]. The Icelandic type CAA results from
a point mutation within the cystatin C gene with a
change of leucine in position 68 to glutamine. CAA
should be considered in patients with early onset of
recurrent cerebral hemorrhages in association with
prominent white matter changes.
Cavernous malformations
Cerebral cavernous malformations (CCM) are vascular
malformations causinghemorrhagic
strokes. Approximately half of the cases are inherited as
an autosomal dominant trait with incomplete pene-
trance. Most of the CCM cases result from mutations in
the KRIT1 gene (Table 2), localized on chromosome
7q21–22 (CCM1) [16]. Mutations seem to be distributed
over the entire coding sequence. Mutational analysis
can be considered in patients with multiple cavernomas
or a family history of cerebral hemorrhages. However,
at-risk individuals may also be identified by MR-scan-
ning. Two additional loci CCM2 (OMIM 603 284) and
CCM3 (OMIM 603 285) have been localized to chro-
mosomes 7p13–15 and 3q25.2–27, respectively.
or ischaemic
Fabry?s disease
Fabry?s disease is an X-linked systematic disorder
resulting from deficiency of the lysosomal enzyme al-
pha-galactosidase A. Early clinical features such as
angiokeratoma, hypohidrosis typically occur in child-
Table 2 Main genetic causes of stroke and migraine
DiseaseGene product MutationPosition
Mode of
transmissionOMIM
Cerebral autosomal dominant arteriopathy
with subcortical infarcts and
leukoencephalopathy (CADASIL)
Cerebral amyloid angiopathy
(CAA, Dutch Type)
Cerebral amyloid angiopathy
(CAA, Icelandic Type)
Cerebral cavernous malformations
Notch3Point mutations 19q12 AD 125 310
Amyloid Precursor
Protein
Cystatin C
Point mutations21q21 AD 104 760
L68Q mutation20p11.2 AD105 150
CCM1 Point mutations
deletions
Point mutations
deletions
Point mutations
deletions
Point mutations,
Point mutations
7q21–22AD (incomplete
penetrance)
AD (incomplete
penetrance)
AD (incomplete
penetrance)
AD
AR
116 860
Cerebral cavernous malformations CCM27p13–15603 284
Cerebral cavernous malformations CCM3 3q25.2 ± 27603 285
Familial hemiplegic migraine (FHM)
Elevated level of serum homocysteine
CACNA1A
Methylenetetrahydrofolate
reductase enzyme
(MTHFR)
Cystatione b-synthetase
enzyme (CBS)
19p13
1p36.3
141 500
607 093
Elevated level of serum homocysteine Missense, nonsense,
splicing,
deletion, insertion
mutations
21q22.3 AR236 200
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hood. Kidney, heart, and brain involvement may
develop in mid-adulthood. Cerebrovascular involve-
ment includes both large-vessel and small-vessel disease
resulting in ischaemic lesions or vascular demyelization
of the white matter. Diagnosis may be confirmed by
measuring alpha-galactosidase A activity or by screen-
ing for mutations. Because of X-linked inheritance, in
women, mutation screening may be required.
Homocystinuria
Homocystinuria results from a group of mostly auto-
somal recessive enzyme deficiencies, which are associ-
ated with a highly or mildly elevated level of serum
homocysteine (>15 lM). The majority of the patients
with a highly elevated serum homocysteine level have a
thrombembolic stroke or stroke-like episodes, if they
are not treated. Screening for mutations in the cystati-
one
b-synthetaseand
reductase gene is available. Correlation between muta-
tions, homocysteine serum level, and clinical phenotype
is influenced by several biochemical conditions such as
folic acid and B vitamin daily uptake.
The cystatione b-synthetase enzyme deficiency has
been associated with several missense, nonsense, splic-
ing, deletion, or insertion mutations. A permanent or
temporary (thermo-sensitive) decrease in the activity of
the methylenetetrahydrofolate reductase enzyme can
also result from C677T or A1298C mutations. The
above relatively frequent mutations are associated with
mostly autosomal recessive enzyme deficiencies.
methylenetetrahydrofolate
Ehlers-Danlos syndrome
Ehlers-Danlos syndrome type IV is an autosomal
dominant disorder caused by mutations in COL3A1
gene. The main clinical features are easy bruising,
hyperextensibility of joints, thin skin with visible veins,
and rupture of arteries, uterus, or intestines. Arterial
dissection in large- and medium-sized arteries can
account for ischaemic stroke.
Recommendations
Direct sequencing of exons 3 and 4 in the Notch3 gene
is suggested as a first step if clinical suspicion for
CADASIL is high (level B). CCA should be considered
in patients with early-onset, recurrent cerebral hemor-
rhages in association with prominent white matter
lesions without classic clinical risk factors. In such
cases, the KRIT1 gene should be screened for causative
mutations (level B). Genetic tests for Fabry?s disease are
suggested in the case of neuropathic pain, hypohydro-
sis, acroparesthesia, corneal opacities, cataract, renal
failure, cardiac failure, ischaemic stroke, or TIAs (level
B). Mutation screening in Ehlers-Danlos syndrome can
be performed in case of clinical implications (easy
bruising, hyperextensibility of joints, thin skin with
visible veins, rupture of arteries, uterus or intestines,
and arterial dissection) (good practice point). In the
event of a stroke attack with elevated level of serum
homocysteine (>15 lM), screening for mutations in
cystatione beta-synthetase and methylenetetrahydrofo-
late reductase is suggested (level B).
Migraine
Familial hemiplegic migraine
FHM is inherited in an autosomal dominant way. Most
of the cases are linked to a locus on chromosome 19p13,
and in some instances, point mutations have been
described in the alpha1 subunit of the calcium channel
gene (CACNA1A). Point mutations in the same gene
cause episodic ataxia type 2 (EA2), and the expansion
of a CAG-repeat is responsible for spinocerebellar
ataxia type 6 (SCA6). Clinical presentation and genetic
findings overlap between all three conditions. A
minority of affected families is linked to a second locus
on chromosome 1q23 (ATP1A2), and a mutation in the
neuronal voltage-gated sodium channel gene (SCN1A)
has recently been described (Table 2).
Recommendations
The diagnosis of familial hemiplegic migraine can be
confirmed with sequencing the hot spots of the most
often affected gene (CACNA1A) (good practice point).
Inherited dementias
The majority of degenerative dementias occur with an
autosomal dominant inheritance pattern and similar
phenotypes to sporadic disease. The proportion of
familial occurrence varies between 2% and 50%,
depending on the dementia subtype. In dementing
disorders, it is particularly important to ensure ade-
quate genetic counseling and obtain consent from the
patient and/or family caregiver prior to any attempt of
molecular genetic diagnosis [17]. It also needs to be
pointed out that a postmortem diagnosis of the cause of
a familial degenerative dementia can provide critically
important information for future counseling of the
family and should be discussed. In most instances,
molecular genetic diagnosis will only be feasible in
patients with a clear family history that is indicative of a
monogenic form of the disease or in sporadic occur-
rences with an unusually early age of onset. Because of
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reduced penetrance, however, some known dominant
mutations can also cause seemingly sporadic late-onset
disease in some populations even in a surprisingly high
proportion of cases.
Alzheimer?s disease
Alzheimer?s disease is the most common type of pri-
mary degenerative dementia. Clinical features include a
slow, progressive amnesic syndrome and variable
combinations of other cortical cognitive deficits but
also include behavioral changes and affective symp-
toms. Mutations in three genes have been found to
cause an autosomal dominant form of the disease
(sometimes referred to as AD type 1, 3, and 4) [18], and
together these account for <5% of all cases (Table 3)
(http://www.molgen.ua.ac.be/ADMutations).
them, AD3, which is caused by mutations in the
presenilin 1 gene (PSEN1) on chromosome 14, is the
most common. In contrast, AD1, due to mutations in
the gene for the amyloid precursor protein (APP,
OMIM 104760, chromosome 21), and AD4 with
mutations in the presenilin 2 gene (PSEN2, OMIM
600759, chromosome 1) are rare [19]. APP encodes a
transmembrane protein that gives rise, after proteolytic
cleavage, to Aß-fragments that pathologically aggregate
in amyloid plaques thought to be at the centre of the
pathogenic cascade in AD [20]. Point mutations in
coding regions as well as whole gene duplications and
promoter mutations increasing transcriptional activity
have been shown to lead to AD [15,21]. The presenilins
are part of the proteolytic complex known as the
c-secretase that cleaves APP and releases the Aß-frag-
ment. PSEN1 mutations are probably pathogenic
because of the fact that they increase the relative ratio
of the more amyloidogenic Aß1–42fragment to Aß1–40.
An earlier onset age between 30 and 60 years is com-
mon in monogenic forms, although PSEN1 mutations
Among
have also been detected in patients with onset at ages
over 60–70 years. When accompanied by a positive
family history, molecular genetic testing should be
considered. Several specialized laboratories across
Europe provide such testing. Here, the probability of
identifying a mutation in one of the three AD genes is
approximately 10%, in case the patient has a clear
autosomal dominant inheritance, the chance increases
to 20%. Mutation screening can also be offered to
apparently sporadic patients with a diagnosis age below
70, with a chance of approximately 5% to find a
mutation. In addition to the mutations mentioned
previously that can cause AD with high penetrance, a
common variant of the apolipoprotein E gene (APOE)
known as the ?4-allele has been clearly established as a
risk factor for early and late-onset AD (AD2). As the
APOE ?4-allele is neither necessary nor sufficient to
cause AD, there is a wide consensus that at present
there is no clear benefit in APOE genotyping to assist
with diagnosis [22] or pre-symptomatic risk assessment.
One exception involves APOE genotyping in individu-
als carrying a causal mutation in PSEN1, APP, or
PSEN2, because the APOE ?4-allele can lower the age
of onset by approximately 5 years in mutation carriers.
A growing number of other loci (AD5–15 in the
?OMIM?-catalogue) and genes have been suggested.
Most of these were identified through association
studies, but none is currently relevant for genetic testing
in clinical practice (AlzGene Database http://www.
alzforum.org/res/com/gen/alzgene/default.asp).
Frontotemporal lobar degeneration
The heterogeneous group of frontotemporal lobar
degeneration (FTLD) disorders are characterized by
predominantly frontotemporal distribution of cortical
cerebral atrophy and a clinical picture of prominent
behavioral changes, frontal deficits, and/or speech dis-
Table 3 Genetics of hereditary dementias
DisorderAbbreviation
Mode of
inheritance
Gene
locus Mutated proteinType of mutationOMIM
Familial Alzheimer?s
disease
AD1AD 21q21Amyloid Precursor
Protein
ApoE
Presenilin 1
Presenilin 2
MAPTau
Pm, Dupl 104760
AD2
AD3
AD4
FTPD-17
AD
AD
AD
AD
19q13.2
14q24.3
1q31–q42
17q21
CV
Pm, exonic deletions
Pm
Pm, Del, Ins
104310
104311
600759
601630Frontotemporal dementia
with parkinsonism
Frontotemporal dementia
with ubiquitinated lesions
Fam. Creutzfeld–Jakob disease
FTD-UAD17q21 Progranulin Pm, genomic Del607485
PRNPAD 20pter-p12Prion proteinPm, Ins123400
AD, autosomal dominant; Pm, point mutation; Del, deletion; Ins, insertion; CV, common variant; MAPTau, microtubule-associated protein tau.
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turbances. Consensus criteria have been published and
are widely accepted to distinguish three clinical vari-
ants. The behavioral variant (bvFTLD or FTD) is also
called frontal variant with prominent behavioral dis-
turbances. The two variants with prominent language
disorders include semantic dementia (SD, characterized
mainly by a fluent dysphasic syndrome) and primary
non-fluent aphasia (PNFA). In all of these variants,
however, other signs and symptoms of an atypical
parkinsonian syndrome (often in the form of a corti-
cobasal syndrome, CBS, or of a syndrome resembling
progressive supranuclear palsy, PSP) or motor neuron
degeneration (MND) might occur and may even dom-
inate the clinical picture. The most common presenta-
tion is an early change in personality, social behavior,
and language dysfunction, with relative preservation
of memory functions. Historically, at least a subset of
these patients had been subsumed under the heading of
Pick?s disease. Today, the term FTLD is suggested as an
umbrella term.
Pathologically, the majority of patients with FTLD
show ubiquitinated deposits of the protein TDP-43 (this
form has been designated FTLD-TPD). In a substantial
proportion of patients, however, deposition of the
microtubule-associated protein tau (MAPT) is found;
in these patients, the disease is called FTLD-Tau.
Further, in a small subset of patients with FTLD-U
pathology, the ubiquitinated inclusions are negative for
TDP-43 and Tau and consist of an as yet elusive protein
composition. A wide spectrum of loss-of-function
mutations (haploinsufficiency), often small deletions or
insertions leading to a pre-mature stop codon in the
progranulin gene (PGRN) [23,24], have been found in
FTLD-TDP. In contrast, missense or splice-site muta-
tions MAPT have been recognized as a cause of FTLD-
tau (Table 3).
The relationship between genotype, pathology, and
clinical phenotype in FTLD is complex. Clinical fea-
tures associated with a particular genetic cause or
pathology vary widely, even within families. As a gen-
eral rule, prominent extrapyramidal symptoms are
somewhat more likely to predict a tauopathy, whereas
behavioral problems and semantic dementia are more
likely to predict a TDP-43 proteinopathy [25]. On the
other hand, however, parkinsonism was found in 30%
of patients with PGRN mutations in a large series [26].
The fact that approximately 30–50% of patients with
FTLD, depending on the clinical subtype, have a
positive family history, suggests autosomal dominant
inheritance. The proportion is highest in those with
FTD-ALS and lowest in semantic dementia [27].
Mutations in the MAPT gene can be found in 10–43%
of patients with a positive family history of FTLD but
only about 3% of all patients with FTLD. PGRN
mutations account for 13–26% of familial and 1–11%
of all FTLD cases (3.2% in apparently sporadic cases)
[28]. Therefore, genetic screening of the PGRN and
MAPT genes is clearly indicated and useful for genetic
counseling in patients with autosomal dominant FTLD.
It can also be considered in sporadic cases, although
mutations are found only in <10%. Other genes
associated with familial forms of FTLD include the
CHMP2B gene on chromosome 3 and the gene for the
valosin-containing protein on chromosome 9. In the
latter, FTLD is often found in conjunction with an
inclusion body myopathy and early-onset Paget?s dis-
ease. Both of these forms of familial FTLD are very
rare.
Prion diseases
Prion
humans usually known as Creutzfeld–Jakob disease,
CJD) are a group of usually rapidly progressive
dementias manifesting as idiopathic, acquired, or
inherited disorders. A clearly positive family history of
a dominant inheritance is found in 10–20% of cases.
Numerous different mutations in the prion protein gene
on chromosome 20 have been identified in these families
(Table 3). Complete sequencing of the prion protein
gene is provided by several centers and can be offered,
given the appropriate counseling, in cases with a strong
clinical suspicion of familial CJD.
diseases(spongiform encephalopathies, in
Clinical heterogeneity
Occasionally, mutations in genes typically implicated in
one neurodegenerative disorder can be identified in
patients clinically presenting with another neurode-
generative disorder. Examples include the MAPT
Arg406Trp mutation associated with Alzheimer?s dis-
ease phenotype and PSEN1 Gly183Val in a patient with
pathologically confirmed Pick disease. Patients with
PGRN loss-of-function mutations also display a broad
phenotypic spectrum. Thus, in a case of negative
mutation screening of known genes but a strong indi-
cation of familial inheritance, it is recommended to
extend the mutation screening to genes implicated in
other neurodegenerative diseases.
Recommendations
In the setting of a clinical diagnosis of AD, mutational
screening first in PSEN1, then in APP, and finally (if
negative) in PSEN2 can be useful for genetic counseling
in cases of early-onset autosomal dominant AD (level
B). Genetic screening in sporadic cases with early onset
can be considered (good practice point). If the clinical
EFNS guidelines on the molecular diagnosis
647
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Journal compilation ? 2010 EFNS European Journal of Neurology 17, 641–648

Page 8

diagnosis is that of a frontotemporal dementia, genetic
testing for mutations in PGRN and MAPT is clearly
indicated and useful for genetic counseling in patients
with autosomal dominant FTLD (level B), regardless of
the presence or severity of extrapyramidal features.
Testing can also be considered in familial and sporadic
cases, although mutations are found only in <5%
(good practice point).
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