490 Developmental Medicine & Child Neurology 2002, 44: 490–493 Benign paroxysmal torticollis of infancy: four new cases and linkage to CACNA1A mutation N J Giffin* MRCP, Clinical Research Registrar, Headache Group, Institute of Neurology; S Benton, Consultant Paediatric Neurologist, Department of Paediatric Neurology, Hospital for Sick Children, Great Ormond Street; P J Goadsby, Professor of Clinical Neurology, Headache Group, Institute of Neurology, Queen Square, London, UK. *Correspondence to first author at Headache Group, Institute of Neurology, Queen Square, London WC1N 3BG, UK. E-mail: n.giffi[email protected] Benign paroxysmal torticollis of infancy (BPTI) is a disorder characterized by recurrent episodes of head tilt secondary to cervical dystonia. Attacks are often accompanied by vomiting, pallor, and ataxia, settling spontaneously within hours or days. Episodes begin within the first 12 months of life and resolve by 5 years. We report four patients with BPTI. Symptoms started from 3 months of age, with head tilting lasting between 10 minutes and 2 months; the shorter episodes were followed by vomiting, apathy, and unsteadiness. Head tilt became less prominent after infancy, replaced by vertigo and eventually by migraine headaches. Two patients came from a kindred with familial hemiplegic migraine linked to CACNA1A mutation. BPTI may be regarded as a migraine aura equivalent. The syndrome poses interesting questions regarding varying phenotypic expression of calcium channelopathies at different stages of development. Benign paroxysmal torticollis of infancy (BPTI) is an under- recognized, self-limiting, benign disorder characterized by recurrent episodes of head tilt secondary to cervical dystonia (Snyder 1969). Attacks occur without warning and with no specific triggering factors, although often with remarkable regularity. Episodes settle spontaneously, usually within a few hours, but may last up to 7 days, only remitting in sleep (Balslev et al. 1998). Episodes usually begin within the first 12 months of life and resolve by 5 years, occurring between every 2 weeks and every 2 months. Infants may be hypotonic during an attack (Andermann et al. 1994) or have tortipelvis (Roulet and Deonna 1988), or an abnormal trunk posture (Sanner and Bergstrom 1979, Deonna and Martin 1981). BPTI is often accompanied by symptoms similar to some of the non-headache features of migraine including vomit- ing, ataxia, pallor, irritability, apathy, and drowsiness. As the child grows up the syndrome resolves spontaneously and may be replaced by benign paroxysmal vertigo of childhood (Dunn and Snyder 1976) and in later childhood by more migrainous features (Deonna and Martin 1981). A family history of a similar childhood syndrome is common (Sanner and Bergstrom 1979, Roulet and Deonna 1988) and a family history of migraine is usual (Deonna and Martin 1981). Neuroimaging should be performed to exclude a posterior fossa lesion (Balslev et al. 1998), but investigations have been otherwise unrevealing. Likewise, neurological exami- nation interictally is normal and children do not show any developmental delay (Angelini et al. 1988). We report four new cases of BPTI, two of which are from a kindred with familial hemiplegic migraine (FHM) with atax- ia and CACNA1A mutation. Case report 14698749, 2002, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1469-8749.2002.tb00311.x by Readcube (Labtiva Inc.), Wiley Online Library on [26/12/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Benign paroxysmal torticollis of infancy: four new cases and linkage to CACNA1A mutation
Dec 28, 2022
Benign paroxysmal torticollis of infancy (BPTI) is a disorder characterized by recurrent episodes of head tilt secondary to cervical dystonia. Attacks are often accompanied by vomiting, pallor, and ataxia, settling spontaneously within hours or days. Episodes begin within the first 12 months of life and resolve by 5 years. We report four patients with BPTI. Symptoms started from 3 months of age, with head tilting lasting between 10 minutes and 2 months; the shorter episodes were followed by vomiting, apathy, and unsteadiness. Head tilt became less prominent after infancy, replaced by vertigo and eventually by migraine headaches.
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BPTI is often accompanied by symptoms similar to some
of the non-headache features of migraine including vomiting, ataxia, pallor, irritability, apathy, and drowsiness. As the
child grows up the syndrome resolves spontaneously and
may be replaced by benign paroxysmal vertigo of childhood
(Dunn and Snyder 1976) and in later childhood by more
migrainous features (Deonna and Martin 1981). A family
history of a similar childhood syndrome is common (Sanner
and Bergstrom 1979, Roulet and Deonna 1988) and a family
history of migraine is usual (Deonna and Martin 1981).
Neuroimaging should be performed to exclude a posterior
fossa lesion (Balslev et al. 1998), but investigations have
been otherwise unrevealing. Likewise, neurological examination interictally is normal and children do not show any
developmental delay (Angelini et al. 1988).
Transcript
Benign paroxysmal torticollis of infancy: four new cases and linkage to CACNA1A mutation490 Developmental Medicine & Child Neurology 2002, 44: 490–493
Benign paroxysmal torticollis of infancy: four new cases and linkage to CACNA1A mutation
N J Giffin* MRCP, Clinical Research Registrar, Headache
Group, Institute of Neurology;
Ormond Street;
E-mail: [email protected]
cervical dystonia. Attacks are often accompanied by
vomiting, pallor, and ataxia, settling spontaneously within
hours or days. Episodes begin within the first 12 months of
life and resolve by 5 years. We report four patients with BPTI.
Symptoms started from 3 months of age, with head tilting
lasting between 10 minutes and 2 months; the shorter
episodes were followed by vomiting, apathy, and unsteadiness.
Head tilt became less prominent after infancy, replaced by
vertigo and eventually by migraine headaches. Two patients
came from a kindred with familial hemiplegic migraine linked
to CACNA1A mutation. BPTI may be regarded as a migraine
aura equivalent. The syndrome poses interesting questions
regarding varying phenotypic expression of calcium
channelopathies at different stages of development.
Benign paroxysmal torticollis of infancy (BPTI) is an under-
recognized, self-limiting, benign disorder characterized by
recurrent episodes of head tilt secondary to cervical dystonia
(Snyder 1969). Attacks occur without warning and with no
specific triggering factors, although often with remarkable
regularity. Episodes settle spontaneously, usually within a
few hours, but may last up to 7 days, only remitting in sleep
(Balslev et al. 1998). Episodes usually begin within the first
12 months of life and resolve by 5 years, occurring between
every 2 weeks and every 2 months. Infants may be hypotonic
during an attack (Andermann et al. 1994) or have tortipelvis
(Roulet and Deonna 1988), or an abnormal trunk posture
(Sanner and Bergstrom 1979, Deonna and Martin 1981).
BPTI is often accompanied by symptoms similar to some
of the non-headache features of migraine including vomit-
ing, ataxia, pallor, irritability, apathy, and drowsiness. As the
child grows up the syndrome resolves spontaneously and
may be replaced by benign paroxysmal vertigo of childhood
(Dunn and Snyder 1976) and in later childhood by more
migrainous features (Deonna and Martin 1981). A family
history of a similar childhood syndrome is common (Sanner
and Bergstrom 1979, Roulet and Deonna 1988) and a family
history of migraine is usual (Deonna and Martin 1981).
Neuroimaging should be performed to exclude a posterior
fossa lesion (Balslev et al. 1998), but investigations have
been otherwise unrevealing. Likewise, neurological exami-
nation interictally is normal and children do not show any
developmental delay (Angelini et al. 1988).
We report four new cases of BPTI, two of which are from a
kindred with familial hemiplegic migraine (FHM) with atax-
ia and CACNA1A mutation.
C a s e r e p o r t
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PATIENT 1
A 4-year-old female started to hold her head to the right or left
side at 4 months of age. Her head would click into position as
far on one side as possible, almost reaching the shoulder.
Straightening of her head caused discomfort. Initially this
occurred once a month but became more persistent between
the ages of 1 to 4 years with continuous episodes lasting up to
2 months (Fig. 1). The shorter episodes were associated with
general malaise, vomiting, and tugging at the ear on the affect-
ed side. With age, the child reported that the attacks were asso-
ciated with nausea, vomiting, headache, and vertigo. These
episodes gradually resolved but were replaced at the age of 4
years by episodes of dizziness and unsteadiness progressing to
headache, vomiting, and eventually sleep. These attacks lasted
a few hours and occurred unprovoked every two months. The
attacks reduced in frequency by the age of 5 years. Interictal
examination was normal. The child has two aunts with
migraine without aura but no family history of prolonged
aura. Brain MRI and interictal EEG were normal.
PATIENT 2
A 16-year-old male had episodes of head tilting between the
ages of 3 and 18 months. These occurred monthly and would
last a few hours, with head tilting either to the right or the
left. He would cry with the attacks and later in the attack
would vomit. The episodes resolved after infancy but at the
age of 2 years he developed episodes of vertigo, pallor, and
vomiting lasting 3 to 4 days, occurring every 8 to 11 weeks.
His mother had migraine without aura but there was no fam-
ily history of migraine with aura.
PATIENT 3
A 3-year-old male experienced attacks head tilting from the age
of 4 months. They started with tilting to the left for 15 to 30
minutes accompanied by aggressive behaviour. After this his
eyes would roll up, he vomited, and became unsteady. Since
the age of 2 years the head tilting has been less prominent but
the unsteadiness more marked with episodes occurring on a
weekly basis. He has mild interictal ataxia. He is from the
youngest generation of a kindred with FHM and ataxia linked
to a CACNA1A mutation. This mutation is in exon 37 of the
CACNA1A gene on chromosome 19, consisting of a C to G
change at position 5838 of the coding sequence, predicting a
premature stop codon. The gene product is located at the
beginning of the intracellular C-terminus of the α 1 2.1 subunit
of the calcium channel. Attacks have so far been unresponsive
to treatment with pizotifen, acetazolamide, or flunarizine.
The child had one sibling who was 6 months old at the
time of study and who had not manifested episodic ataxia
nor torticollis.
PATIENT 4
A 29-year-old male, the father of patient 3, whose mother
recalls that between 6 and 18 months he had episodes of
head tilting similar to his son, each lasting for 10 to 20 min-
utes before he developed irritability and vomiting. During
childhood he developed episodes of unsteadiness, slurred
speech, and headache, typical of migraine with prolonged
aura, which have persisted into adulthood.
Discussion
We have described four patients with the unusual syndrome
of BPTI and give further evidence that it may be considered
as a childhood migraine equivalent and may be associated
with a calcium channelopathy.
The clinical pattern of BPTI in most cases is for the syn-
drome to manifest in infancy, with or without other migrain-
ous features, progressing in early childhood to benign
paroxysmal vertigo of childhood (Dunn and Snyder 1976),
through to migraine with or without aura in adulthood. The
patients in our series have so far followed this overall pattern.
The International Headache Society (IHS; Headache
Classification Committee 1988) recognizes ‘childhood syn-
dromes that may be precursors to or associated with
migraine’. These include abdominal migraine, cyclic vomit-
ing syndrome, and benign paroxysmal vertigo. It is likely that
some of these disorders are related to migraine because of
complete recovery between attacks, a family history of a simi-
lar syndrome or of migraine, the presence of symptoms more
closely resembling migraine in the same or other attacks, and
the development of migraine at follow-up. As yet, BPTI is not
recognized among this classification, but the reported
patients largely fit the above description.
Case Report 491
Table I: Summary of clinical details
Patient Age at Age when Accompanying features Subsequent migraine Family history CACNA1A nr onset (mo) stopped of torticollis phenotype mutation
(y/mo)
1 4 4 y Miserable, vomiting, Paroxysmal vertigo, 2 aunts with ?
headache, vertigo headache and vomiting migraine
between 4 and 5 y
2 3 18 mo Crying, vomiting Paroxysmal vertigo, Mother ?
pallor, vomiting from migraine
age 2 y without aura
3 4 2 y Aggressive, eyes roll up, Episodic ataxia and Familial ataxic +
vomiting, unsteady dysarthria from 2 y migraine
4 6 18 mo Irritability, vomiting Episodic ataxia, vertigo, Familial ataxic +
dysarthria, and headache migraine
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trical discharge from the sternocleidomastoid in BPTI, con-
firming that the torticollis is dystonic (Kimura and Nezu
1998). The dystonia should be considered to be an atypical,
prolonged (when persisting for more than 1 hour) motor
aura. This can occur before, with, or without the other
migraine features (such as vomiting and pallor) within the
same individual in the same way that typical migraine aura
can occur before, with, or without headache. As the episodes
may occur with or without other migrainous features the tor-
ticollis cannot be an analgic reaction to a headache or a drug
reaction (Roulet and Deonna 1988).
The propensity for this atypical aura may be mediated by
calcium channel dysfunction. The father and son in our
series are part of a kindred with FHM with ataxia associated
with a recently described CACNA1A mutation (personal com-
munication, EE Kors 2001). Mutations in the α 1 2.1, pore
forming, subunit of the neuronal P/Q type calcium channel
gene (CACNA1A) have been found in over half of families
with FHM, including all those with cerebellar features
(Ducros et al. 2001). Spontaneous changes in the activation
state of the channel produced by these mutations may
account for the episodic nature of the disorder (Hans et al.
1999). Other family members with the same genotype did
not recall a history of BPTI. However, this may be ascertain-
ment bias and may underestimate the true occurrence of the
condition; when other parts of the attack are so florid, as in
FHM, intermittent torticollis for a few months in infancy may
easily be forgotten.
The other two children reported had neither a family his-
tory of BPTI nor migraine with atypical aura, although one
had a family history of migraine with aura. These two chil-
dren were not screened for CACNA1A mutations.
It is intriguing to speculate as to why a given mutation may
produce a spectrum of phenotypic manifestations at different
stages in life. The expression of the gene may be modulated
either by other genes (in particular genes coding for β [Escayg et al. 2000] and γ[Rousset et al. 2001] subunits of the
P/Q channel) that may be activated at different stages in
development, or biochemical/hormonal changes such as
cyclical hormonal profiles at menarche.
How could the CACNA1A mutation cause dystonia?
Dystonia is generally accepted to have a central mechanism
of pathogenesis. The most likely explanation for CACNA1A
mutations in the generation of dystonia involves the cerebel-
lum. The role of the cerebellum in dystonia in both humans
and animal models has been established by both functional
imaging and electrophysiological methods (Eidelberg et al.
1998, Kluge et al. 1998, LeDoux et al. 1998). It is of note that
one of the manifestations of the CACNA1A mutation
(CACNA1Atg) in the tottering mutant mouse is paroxysmal
dystonia. The cerebellar cortex, where the gene is abundant-
ly expressed, probably contributes to the expression of tot- tering mouse dystonic episodes (Campbell et al. 1999).
These dystonic episodes induce c-fos mRNA expression in
the cerebellar circuitry, including cerebellar granule and
Purkinje neurons, deep cerebellar nuclei, and the postsy-
naptic targets of the deep nuclei. Removal of Purkinje cells by
a Purkinje cell degeneration mutation completely abolishes
the dystonic episodes. P/Q type calcium channels may predom-
inantly mediate inhibitory GABA release onto Purkinje cells, at
least in the mouse (Stephens et al. 2001). A loss of function P/Q
mutation may episodically remove the GABAergic inhibition
and produce sustained over activity of motor pathways.
An alternative hypothesis for the generation of dystonia
may involve peripheral neurotransmitter release. It has also
been shown that there is increase of spontaneous acetyl-
choline release by approximately 100% and 40% at the neu-
romuscular junction in homozygous and heterozygous
tottering mice respectively, in addition to abnormal stimulat-
ed release of acetylcholine in homozygous mice (Plomp et al.
2000). However, this goes against the generally accepted
central mechanism of dystonia and does not explain the
specificity of the dystonia for the cervical region.
Clinical evidence for a role of the cerebellum in BPTI is sug-
gested by two case reports. The first, a child with frequent
intermittent dystonic posturing of the neck and arm in infancy,
showed decreased glucose metabolism in the cerebellar cor-
tex, as well as the basal ganglia and decreased perfusion in the
basal cortex and temporal cortex (John et al. 2000). The sec-
ond was a child who had alternating hemiplegia of childhood
associated with epilepsy and head and neck dystonia, and pro-
gressive cerebellar vermian atrophy on neuroimaging (Saito et
al. 1998). While there are no published studies of calcium
channelopathies in alternating hemiplegia of childhood, the
cerebellar atrophy is similar to that in CACNA1A mutations
(Elliott et al. 1996), suggesting a role for a calcium chan-
nelopathy in this syndrome (Saito et al. 1998).
A history of torticollis may not be apparent if the other man-
ifestations of the attack are more florid, and by itself it is often
not a cause for concern. However, the recognition of the
symptom at the start of the attack may increase the certainty of
a childhood migraine equivalent when there is diagnostic
uncertainty and direct appropriate antimigraine therapy.
Furthermore, it is at least appropriate to include this disorder
in the appendix of the new revision of the IHS classification
criteria to encourage further studies.
492 Developmental Medicine & Child Neurology 2002, 44: 490–493
Figure 1: Patient 1, showing head tilt to the right.
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Benign paroxysmal torticollis of infancy: four new cases and linkage to CACNA1A mutation
N J Giffin* MRCP, Clinical Research Registrar, Headache
Group, Institute of Neurology;
Ormond Street;
E-mail: [email protected]
cervical dystonia. Attacks are often accompanied by
vomiting, pallor, and ataxia, settling spontaneously within
hours or days. Episodes begin within the first 12 months of
life and resolve by 5 years. We report four patients with BPTI.
Symptoms started from 3 months of age, with head tilting
lasting between 10 minutes and 2 months; the shorter
episodes were followed by vomiting, apathy, and unsteadiness.
Head tilt became less prominent after infancy, replaced by
vertigo and eventually by migraine headaches. Two patients
came from a kindred with familial hemiplegic migraine linked
to CACNA1A mutation. BPTI may be regarded as a migraine
aura equivalent. The syndrome poses interesting questions
regarding varying phenotypic expression of calcium
channelopathies at different stages of development.
Benign paroxysmal torticollis of infancy (BPTI) is an under-
recognized, self-limiting, benign disorder characterized by
recurrent episodes of head tilt secondary to cervical dystonia
(Snyder 1969). Attacks occur without warning and with no
specific triggering factors, although often with remarkable
regularity. Episodes settle spontaneously, usually within a
few hours, but may last up to 7 days, only remitting in sleep
(Balslev et al. 1998). Episodes usually begin within the first
12 months of life and resolve by 5 years, occurring between
every 2 weeks and every 2 months. Infants may be hypotonic
during an attack (Andermann et al. 1994) or have tortipelvis
(Roulet and Deonna 1988), or an abnormal trunk posture
(Sanner and Bergstrom 1979, Deonna and Martin 1981).
BPTI is often accompanied by symptoms similar to some
of the non-headache features of migraine including vomit-
ing, ataxia, pallor, irritability, apathy, and drowsiness. As the
child grows up the syndrome resolves spontaneously and
may be replaced by benign paroxysmal vertigo of childhood
(Dunn and Snyder 1976) and in later childhood by more
migrainous features (Deonna and Martin 1981). A family
history of a similar childhood syndrome is common (Sanner
and Bergstrom 1979, Roulet and Deonna 1988) and a family
history of migraine is usual (Deonna and Martin 1981).
Neuroimaging should be performed to exclude a posterior
fossa lesion (Balslev et al. 1998), but investigations have
been otherwise unrevealing. Likewise, neurological exami-
nation interictally is normal and children do not show any
developmental delay (Angelini et al. 1988).
We report four new cases of BPTI, two of which are from a
kindred with familial hemiplegic migraine (FHM) with atax-
ia and CACNA1A mutation.
C a s e r e p o r t
14698749, 2002, 7, D ow
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reative C om
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PATIENT 1
A 4-year-old female started to hold her head to the right or left
side at 4 months of age. Her head would click into position as
far on one side as possible, almost reaching the shoulder.
Straightening of her head caused discomfort. Initially this
occurred once a month but became more persistent between
the ages of 1 to 4 years with continuous episodes lasting up to
2 months (Fig. 1). The shorter episodes were associated with
general malaise, vomiting, and tugging at the ear on the affect-
ed side. With age, the child reported that the attacks were asso-
ciated with nausea, vomiting, headache, and vertigo. These
episodes gradually resolved but were replaced at the age of 4
years by episodes of dizziness and unsteadiness progressing to
headache, vomiting, and eventually sleep. These attacks lasted
a few hours and occurred unprovoked every two months. The
attacks reduced in frequency by the age of 5 years. Interictal
examination was normal. The child has two aunts with
migraine without aura but no family history of prolonged
aura. Brain MRI and interictal EEG were normal.
PATIENT 2
A 16-year-old male had episodes of head tilting between the
ages of 3 and 18 months. These occurred monthly and would
last a few hours, with head tilting either to the right or the
left. He would cry with the attacks and later in the attack
would vomit. The episodes resolved after infancy but at the
age of 2 years he developed episodes of vertigo, pallor, and
vomiting lasting 3 to 4 days, occurring every 8 to 11 weeks.
His mother had migraine without aura but there was no fam-
ily history of migraine with aura.
PATIENT 3
A 3-year-old male experienced attacks head tilting from the age
of 4 months. They started with tilting to the left for 15 to 30
minutes accompanied by aggressive behaviour. After this his
eyes would roll up, he vomited, and became unsteady. Since
the age of 2 years the head tilting has been less prominent but
the unsteadiness more marked with episodes occurring on a
weekly basis. He has mild interictal ataxia. He is from the
youngest generation of a kindred with FHM and ataxia linked
to a CACNA1A mutation. This mutation is in exon 37 of the
CACNA1A gene on chromosome 19, consisting of a C to G
change at position 5838 of the coding sequence, predicting a
premature stop codon. The gene product is located at the
beginning of the intracellular C-terminus of the α 1 2.1 subunit
of the calcium channel. Attacks have so far been unresponsive
to treatment with pizotifen, acetazolamide, or flunarizine.
The child had one sibling who was 6 months old at the
time of study and who had not manifested episodic ataxia
nor torticollis.
PATIENT 4
A 29-year-old male, the father of patient 3, whose mother
recalls that between 6 and 18 months he had episodes of
head tilting similar to his son, each lasting for 10 to 20 min-
utes before he developed irritability and vomiting. During
childhood he developed episodes of unsteadiness, slurred
speech, and headache, typical of migraine with prolonged
aura, which have persisted into adulthood.
Discussion
We have described four patients with the unusual syndrome
of BPTI and give further evidence that it may be considered
as a childhood migraine equivalent and may be associated
with a calcium channelopathy.
The clinical pattern of BPTI in most cases is for the syn-
drome to manifest in infancy, with or without other migrain-
ous features, progressing in early childhood to benign
paroxysmal vertigo of childhood (Dunn and Snyder 1976),
through to migraine with or without aura in adulthood. The
patients in our series have so far followed this overall pattern.
The International Headache Society (IHS; Headache
Classification Committee 1988) recognizes ‘childhood syn-
dromes that may be precursors to or associated with
migraine’. These include abdominal migraine, cyclic vomit-
ing syndrome, and benign paroxysmal vertigo. It is likely that
some of these disorders are related to migraine because of
complete recovery between attacks, a family history of a simi-
lar syndrome or of migraine, the presence of symptoms more
closely resembling migraine in the same or other attacks, and
the development of migraine at follow-up. As yet, BPTI is not
recognized among this classification, but the reported
patients largely fit the above description.
Case Report 491
Table I: Summary of clinical details
Patient Age at Age when Accompanying features Subsequent migraine Family history CACNA1A nr onset (mo) stopped of torticollis phenotype mutation
(y/mo)
1 4 4 y Miserable, vomiting, Paroxysmal vertigo, 2 aunts with ?
headache, vertigo headache and vomiting migraine
between 4 and 5 y
2 3 18 mo Crying, vomiting Paroxysmal vertigo, Mother ?
pallor, vomiting from migraine
age 2 y without aura
3 4 2 y Aggressive, eyes roll up, Episodic ataxia and Familial ataxic +
vomiting, unsteady dysarthria from 2 y migraine
4 6 18 mo Irritability, vomiting Episodic ataxia, vertigo, Familial ataxic +
dysarthria, and headache migraine
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trical discharge from the sternocleidomastoid in BPTI, con-
firming that the torticollis is dystonic (Kimura and Nezu
1998). The dystonia should be considered to be an atypical,
prolonged (when persisting for more than 1 hour) motor
aura. This can occur before, with, or without the other
migraine features (such as vomiting and pallor) within the
same individual in the same way that typical migraine aura
can occur before, with, or without headache. As the episodes
may occur with or without other migrainous features the tor-
ticollis cannot be an analgic reaction to a headache or a drug
reaction (Roulet and Deonna 1988).
The propensity for this atypical aura may be mediated by
calcium channel dysfunction. The father and son in our
series are part of a kindred with FHM with ataxia associated
with a recently described CACNA1A mutation (personal com-
munication, EE Kors 2001). Mutations in the α 1 2.1, pore
forming, subunit of the neuronal P/Q type calcium channel
gene (CACNA1A) have been found in over half of families
with FHM, including all those with cerebellar features
(Ducros et al. 2001). Spontaneous changes in the activation
state of the channel produced by these mutations may
account for the episodic nature of the disorder (Hans et al.
1999). Other family members with the same genotype did
not recall a history of BPTI. However, this may be ascertain-
ment bias and may underestimate the true occurrence of the
condition; when other parts of the attack are so florid, as in
FHM, intermittent torticollis for a few months in infancy may
easily be forgotten.
The other two children reported had neither a family his-
tory of BPTI nor migraine with atypical aura, although one
had a family history of migraine with aura. These two chil-
dren were not screened for CACNA1A mutations.
It is intriguing to speculate as to why a given mutation may
produce a spectrum of phenotypic manifestations at different
stages in life. The expression of the gene may be modulated
either by other genes (in particular genes coding for β [Escayg et al. 2000] and γ[Rousset et al. 2001] subunits of the
P/Q channel) that may be activated at different stages in
development, or biochemical/hormonal changes such as
cyclical hormonal profiles at menarche.
How could the CACNA1A mutation cause dystonia?
Dystonia is generally accepted to have a central mechanism
of pathogenesis. The most likely explanation for CACNA1A
mutations in the generation of dystonia involves the cerebel-
lum. The role of the cerebellum in dystonia in both humans
and animal models has been established by both functional
imaging and electrophysiological methods (Eidelberg et al.
1998, Kluge et al. 1998, LeDoux et al. 1998). It is of note that
one of the manifestations of the CACNA1A mutation
(CACNA1Atg) in the tottering mutant mouse is paroxysmal
dystonia. The cerebellar cortex, where the gene is abundant-
ly expressed, probably contributes to the expression of tot- tering mouse dystonic episodes (Campbell et al. 1999).
These dystonic episodes induce c-fos mRNA expression in
the cerebellar circuitry, including cerebellar granule and
Purkinje neurons, deep cerebellar nuclei, and the postsy-
naptic targets of the deep nuclei. Removal of Purkinje cells by
a Purkinje cell degeneration mutation completely abolishes
the dystonic episodes. P/Q type calcium channels may predom-
inantly mediate inhibitory GABA release onto Purkinje cells, at
least in the mouse (Stephens et al. 2001). A loss of function P/Q
mutation may episodically remove the GABAergic inhibition
and produce sustained over activity of motor pathways.
An alternative hypothesis for the generation of dystonia
may involve peripheral neurotransmitter release. It has also
been shown that there is increase of spontaneous acetyl-
choline release by approximately 100% and 40% at the neu-
romuscular junction in homozygous and heterozygous
tottering mice respectively, in addition to abnormal stimulat-
ed release of acetylcholine in homozygous mice (Plomp et al.
2000). However, this goes against the generally accepted
central mechanism of dystonia and does not explain the
specificity of the dystonia for the cervical region.
Clinical evidence for a role of the cerebellum in BPTI is sug-
gested by two case reports. The first, a child with frequent
intermittent dystonic posturing of the neck and arm in infancy,
showed decreased glucose metabolism in the cerebellar cor-
tex, as well as the basal ganglia and decreased perfusion in the
basal cortex and temporal cortex (John et al. 2000). The sec-
ond was a child who had alternating hemiplegia of childhood
associated with epilepsy and head and neck dystonia, and pro-
gressive cerebellar vermian atrophy on neuroimaging (Saito et
al. 1998). While there are no published studies of calcium
channelopathies in alternating hemiplegia of childhood, the
cerebellar atrophy is similar to that in CACNA1A mutations
(Elliott et al. 1996), suggesting a role for a calcium chan-
nelopathy in this syndrome (Saito et al. 1998).
A history of torticollis may not be apparent if the other man-
ifestations of the attack are more florid, and by itself it is often
not a cause for concern. However, the recognition of the
symptom at the start of the attack may increase the certainty of
a childhood migraine equivalent when there is diagnostic
uncertainty and direct appropriate antimigraine therapy.
Furthermore, it is at least appropriate to include this disorder
in the appendix of the new revision of the IHS classification
criteria to encourage further studies.
492 Developmental Medicine & Child Neurology 2002, 44: 490–493
Figure 1: Patient 1, showing head tilt to the right.
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