Keywords idiopathic toe walking - pes cavus - toe walking family history - cause toe walking
- ITW
Introduction
The following is an exploratory retrospective study into possible strategies to investigate
the hypothesis that there is no link between idiopathic toe walking (ITW) and several
genetic variations in a gene panel linked to functions that have the potential to
affect gait. Before we present the study, we will provide a background discussion
on the term ITW and provide a rationale for the merits of investigating whether the
gait anomaly could have a genetic cause.
The term habitual toe walking or idiopathic toe walking is usually used as a diagnosis
of exclusion for healthy children who persist in walking on their toes after they
pass the age when they should normally have transitioned to a heel-toe gait.[1 ]
ITW was first described by Hall et al in 1967, they used the term “congenital short
tendon calcaneus,” by describing the anomaly as “congenital” they were already implying
a possibly hereditary cause for the condition.[2 ] Their diagnosis referred to otherwise healthy children who were displaying a toe
walking gait in the absence of a known neurological or orthopaedic cause. Since then,
various causal hypotheses and possible contributing factors have been put forward,
such as a possible underlying disorder of the sensory nervous system,[3 ]
[4 ] problems with isolated aspects of motor development,[5 ] or the excessive use of so-called “baby walkers.”[6 ] Finally, ITW has also been described as “habitual toe walking,” which suggests a
voluntary choice of walking pattern by the patient as the cause of the condition.
To date, the etiology of ITW remains unclear, despite the prevalence of the condition
among young people. A large study of 1,401 healthy Swedish children at the age of
approximately 5.5 years found that approximately 4.5% of those children displayed
ITW.[7 ]
When research on the potential causes of toe walking began, researchers were quick
to suspect underlying genetic disorders with autosomal inheritance, variable gene
expression, and heterogeneous etiology as a reason for the anomaly.[8 ]
[9 ] Levine described toe walking in five members of a family with short tendons as the
sole finding and noted that this condition caused some of those family members to
walk on their toes, but that they were otherwise healthy.[8 ] He concluded that the condition affecting this family could be dominantly inherited.
Similarly, Katz and Mubarak presented a case of dominantly inherited tendon Achilles
contracture in a patient leading to a minor impairment of gait.[9 ]
The theory of a hereditary cause for ITW is further supported by reports of a relatively
high prevalence of idiopathic toe walkers, who have at least one other relative who
currently is a toe walker or who had in the past displayed the gait anomaly. Engström
and Tedroff reported that 42 of 26 active idiopathic toe walkers and 38% of 37 inactive
idiopathic toe walkers (who had seized toe walking before the age of 5.5 years) had
a first- or second-degree relative who had also been a toe walker.[10 ] Other studies have reported a positive family history in 30 to 71% of patients.[11 ]
[12 ]
[13 ]
[14 ]
[15 ]
Multiple hereditary disorders are known to be associated with developmental delay.
There is evidence that concomitant developmental disorders or delays, affecting language,
speech, or motor development, are more frequent in ITW children. Engström and Tedroff
stated that “children with ITW as a group (n = 51) displayed more neuropsychiatric problems than a normative group of age matched
children (n = 385),” though significance was only reached in the items “Gross Motor Function”
and “General Learning” in the age group 9 to 12 years.[10 ] The same authors reported in 2018 that 10% out of 70 toe walking children had concomitant
neurodevelopmental problems such as autism spectrum disorder, unspecific delayed development,
or attention deficit/hyperactivity disorder.[7 ] Other groups noted a delay in language development in 27 to 33% of their toe walking
population, fine motor development, visuomotor or gross motor development.[12 ]
[16 ] Furthermore, studies by Barrow et al and Soto-Insuga et al found 20 to 21% of their
respective autism spectrum disorder and attention-deficit hyperactivity disorder population
demonstrated an accompanying persistent toe walking gait.[17 ]
[18 ]
There are also histopathological findings in some ITW patients suggesting underlying
neuromuscular pathologies. Eastwood et al completed a detailed examination of the
calf muscle fibers of 24 idiopathic toe walkers and discovered atrophic, angular fibers,
suggesting underlying neuropathic activities in 42% of patients.[19 ] Other studies focused on sensory and motor function, reporting poorer average function
in idiopathic toe walkers.[5 ]
[20 ]
[21 ]
[22 ]
There are many hereditary pathologies that can cause a toe walking gait alongside
other symptoms. The main group of diseases whose symptoms include toe walking are
neuromuscular diseases such as peripheral neuropathies (Charcot-Marie-Tooth disease),
congenital muscular dystrophies, and progressive muscular dystrophies.[23 ]
Charcot-Marie-Tooth disease is the most common form of an inherited polyneuropathy.[24 ] The disease is transmitted by both autosomal dominant and autosomal recessive inheritance.[25 ]
[26 ] In 2018, Haynes et al found in a retrospective study that 30% of 74 genetically
tested toe-walkers had identifiable gene mutations, five of them had Charcot-Marie-Tooth
disease type 1A, one had Angelman syndrome, one had Sjogren-Larsson syndrome, one
had x-linked syndromic mental retardation-14, and one had multiple synostoses syndrome.[27 ] While these children did not have ITW, but toe walking linked to a known condition,
the multitude of neurological and developmental disorders for which toe walking is
a symptom means that routine genetic testing of toe walking with an unknown cause
could help detect previously undetected conditions early. Engström and Tedroff noted
in a 2012 study that, “for children with a neuropsychiatric diagnosis or developmental
delay, the total prevalence for active or inactive toe-walking was 7 (41.2%) of 17.”[10 ] For this reason, many parents are concerned that persistent toe walking in their
children could be a sign of an undetected serious condition—genetic testing has the
potential of minimizing this worry.
Another pathology which has been linked to toe walking is Ullrich congenital muscular
dystrophy. Mutations in the collagen VI genes COL6A2 and COL6A3 are associated with
the development of either the severe phenotype Ullrich dystrophy or the mild-to-moderate
phenotype of a Bethlem myopathy.[28 ] Myotonia congenita, contributing 75% of nondystrophic myotonia, is caused by mutations
in the CLCN1 gene.[28 ]
To our knowledge, there are currently no studies examining the potential genetic causes
of toe walking in ITW patients (we searched the following databases: kofam.ch; basg.av.at;
drks.de; clinicaltrialsregister.eu; clinicaltrials.gov).
By performing this study, we want to address the much-discussed possibility of genetic
variants as a possible cause for the toe walking gait. We do this to investigate the
merits of further, more in-depth research to investigate specific genetic variants
that could be linked to toe walking and to describe a gene panel that could be used
to find any underlying pathologies linked to known genetic conditions early on. Since
toe walking is an important early symptom for a wide and growing range of motor developmental
and neurological disorders, we also hope to contribute to the development of strategies
to diagnose and treat such conditions from a young age. For the purposes of this study,
we put up the null hypothesis that variants in one or several of 49 distinct genes
related to myopathies and neuropathies, tested using a commercially available next-generation
sequencing (NGS) panel, cannot be brought in relation with the symptom “toe walking
gait” in any of the patients diagnosed with “idiopathic toe walking.” The aim of our
study is to confirm or rebut this hypothesis. Secondary endpoints are the detection
of possible areas for more complex future research into the possible significance
of future research projects and to postulate an improved diagnostic process for the
possible causes of toe walking in children with no clear indication for an underlying
neurological or orthopaedic cause.
Materials and Methods
We searched our inhouse database in our specialist practice for gait anomalies for
patients that have been diagnosed as “idiopathic toe walkers” by their assigned pediatrician.
The minimum age at the time of diagnosis for inclusion in this retrospective study
was 3 years. Underlying acquired or congenital pathologies such as cerebral palsy
or tethered cord syndrome were routinely tested for and ruled out prior to the diagnosis
of ITW being formulated in the specialist practice for gait anomalies. The retrospective
study excluded patients from the database, who experienced complications before, during
or immediately after their birth. Additionally, where an alteration of the monosynaptic
reflexes, pronounced muscular weakness in the triceps surae muscle, or an asymmetry
was detected during the initial clinical examination, patients were recommended for
further neurological assessment. If this additional examination and testing resulted
in the diagnosis of a neurological disorder, the relevant patients were excluded from
this study. No children with autism were included in the study. Lastly, patients who
displayed severe orthopaedic deformities, that is, limb length discrepancies, axis
deformities, scoliosis or severe foot deformities, were also excluded.
Patients suitable for inclusion had a reported toe walking gait (based on the time
spent walking barefoot or in socks; as estimated by the caregivers) during at least
50% of the time at their initial visit, as reported by their parent of guardian and
observed by the examiner.
Only patients who had undergone a genetic test using a specific NGS panel comprising
49 genes intended to detect any hereditary neuro- and myopathies with a potential
link to toe walking were eligible for inclusion. Children who had received other forms
of genetic testing such as exome sequencing were not selected for inclusion.
The genetic testing for any patients proposed for inclusion was routinely recommended
as part of their diagnostic process, and testing was facilitated using saliva samples,
collected by the individual patient's treating (neuro)pediatrician as part of the
routine diagnostic process. Written consent for the use of the results for the purpose
of scientific research was routinely obtained prior to testing and prior to inclusion
of the data in the database for all patients who were eligible for inclusion in the
proposed study. All data used for research was formally anonymized. Explanations of
the results of the laboratory analysis and any important implications of the test
results were routinely provided. The study was approved by the ethical board of LMU
Clinic in Munich, the project number is 22–0812. [Fig. 1 ].
Fig. 1 Retrospective recruitment process. NGS, next-generation sequencing.
The NGS panel that was used to test the hypothesis has been developed by a German
laboratory, using the HPO database (https://hpo.jax.org/app/ ). It comprises 49 genes that can be linked to several relevant neuro- and myopathies.
Genes exclusively associated with severe forms of neuro- or myopathies leading to
intrauterine fetal death or intrauterine onset of severe neurological symptoms are
not included in the panel.
The NGS panel is an Amplicon-based Customer Panel for the Ion Torrent Platform (Thermo
Fisher Scientific Headquarters, Waltham, Massachusetts, United States of America)
for genes that are clinically relevant for neuropathies. Sequencing of the coded exons
is inclusive of the exon-intron boundaries. Intronic regions are scored up to ± 10
base pairs from the exon boundary.
The panel analyzes the following genes: AIFM1 (NM_004208.3, MIM*300169), ALS2 (NM_020919.3,
MIM*606352), ATM (LRG_135t1, MIM*601556), ATXN1 (LRG_863t1, MIM*601556), ATXN2 (NM_002973.3,
MIM*601517), ATXN3 (NM_004993.5, MIM*607640), ATXN7 (NM_000333.3, MIM*607640), CACNA1A
(LRG_7t1, MIM*601011), CAV3 (LRG_329t1, MIM*601253), CHRNE (LRG_1254t1, MIM*100725),
CLCN1 (NM_000083.2, MIM*118425), COL6A2 (LRG_476t1, MIM* 120240), COL6A3 (LRG_473t1,
MIM*120250), CREBBP (NM_004380.3, MIM*600140), DHTKD1 (NM_018706.6, MIM*614984), EGR2
(LRG_234t1, MIM*129010), EPHB4 (NM_004444.4, MIM* 600011), FBLN5 (LRG_240t1, MIM*611104),
FGD4 (LRG_240t1, MIM*611104), FXN (NM_000144.4, MIM*606829), GARS1 (NM_002047.3, MIM*600287),
GDAP1 (LRG_244t1, MIM*606598), IQSEC2 (NM_001111125.2, MIM*300522), KCNC3 (NM_004977.2,
MIM*176264), KMT2C (NM_170606.2, MIM”606833), LITAF (LRG_253t1, MIM*603795), MED25
(LRG_368t1, MIM*6101970), MFN2 (LRG_255t1, MIM*608507), MORC2 (NM_001303256.2, MIM*616661),
MPZ (LRG_256t1, MIM* 159440), NAGLU (NM_000263.3, MIM*609701), NDRG1 (LRG_258t1, MIM*605262),
NEFL (LRG_259t1, MIM*162280), OPA1 (LRG_337t2, MIM*605290), PMP22 (LRG_263t1, MIM*601097),
POLG (LRG_765t1, MIM*174763), PRX (LRG_265t2,*605725), PYGM (NM_005609.3, MIM*608455),
RETREG1 (LRG_363t1, MIM*613114), SATB2 (NM_015265.3, MIM*608148), SBF1 (NM_002972.3,
MIM*603560), SBF2 (LRG_267t1, MIM*607697), SH3TC2 (LRG_371t1, *605713), TRPV4 (LRG_372t1,
MIM*605427), TTN (LRG_39111 It2, MIM*188840), TTR (LRG_416t1, MIM*176300), TRIO (NM_007118.3,
MIM*601893), ZFYVE26 (NM_015346.3, MIM*612012).
Data are analyzed using the SegNext module and using the SeqPilot software (version
5.0.0 build 508). The raw data has a sequence depth (coverage) of at least 30-fold
and variants with an allele read frequency of more than 20%.
Genetic variants were divided into five categories according to guidelines by Greenblatt
et al. Hum Mutat 29:1282ff: category 1 (benign), category 2 (likely benign), category
3 (variant with unclear significance), category 4 (likely pathogenic), and category
5 (pathogenic).[29 ] Variants that can be assigned to categories 1 and 2 according to this classification
were excluded during the process of bioinformatic analysis and are not usually reported
in the findings. However, they can be specified upon request. If required, in silico
analyses were performed, for example, using the programs Mutation Taster, PolyPhen2,
and/or Mutation Assessor. The following databases were used: HGMD professional (The
Human Gene Mutation Database (https://portal.biobase-international.com/hgmd/pr o/gene.ph p?), LOVD -IARC (Leiden Open Variation Database, http://grenada.lume.ni/LSDB_list/Isdbs ), dbSNP, ClinVar, as well as, when and as required, more specialized databases. Variants
outside the analyzed areas in the examined genes (for example in untranslated, regulatory
gene areas), in regions with multiple copies of high sequence homology, repeat variants
as well as copy number variants of single exons or when a complete gene cannot be
detected and thus cannot be excluded. In addition, mosaics with a low frequency component
cannot be excluded with certainty. Although unlikely, it is also possible that new
scientific knowledge could change the assessment of the pathogenicity of variants
at a later stage. The sensitivity for detection of clinically relevant variants for
the applied methods is more than 96%.
All anamnestic parameters of the toe walking patients were routinely recorded using
a standardized questionnaire. The parameters covered by the questionnaire include
a perinatal anamnesis, questions regarding the timing of milestones of motor development,
the onset and severity of toe walking, the occurrence of toe walking as an approximate
percentage of time per day, the social and speech development of the child according
to parental reports, their stamina and whether there was a higher propensity for toe
walking when the child seemed agitated, nervous, excited, etc. The questionnaire also
includes sections to record the results of the physical examination, including details
on any foot deformities and the mobility of the upper ankle joint. All patients who
would be included in the proposed study were examined using the standard process.
Dorsiflexion and plantarflexion of the upper ankle joint were tested in a straight
knee and a 90-degree bent knee position and measured using a hand-held goniometer.
The following clinical signs that would have arisen during the physical examination
were also eligible for inclusion in the database: tremor, cavus deformity of the foot,
reflex anomalies.
Results
Eighty-nine patients were included in the study. There were 66 (74.2%) boys and 23
(25.8%) girls. Mean age at testing was 7.7 years (range: 3–17 years). Forty-four patients
(49.4%) had been walking on their toes since they started walking. Twelve (13.5%)
patients developed a toe walking a few months after beginning to walk, 18 (20.2%)
started toe walking between the ages of 3 and 6, 7 (7.9%) patients were aged between
7 and 10 when they began walking on their toes, and one (1.1%) patient started walking
on their toes at a later age, namely after the age of 10. The onset of toe walking
was unknown in eight patients (9%).
All patients had a history of seeing different doctors before presenting for treatment
at our clinic. Mean dorsiflexion of the foot measured in a straight knee position
was 5 degrees (range: −10–10 degrees) and 8.5 degrees in the bent knee position (range:
−10–20 degrees).
Twenty-four patients (27%) had a positive family history for toe walking, where at
least one close relative was also reported to have the gait anomaly. Fifty-eight (65.2%)
patients showed a pes cavus deformity of the foot, three (3.4%) exhibited a funnel
chest, and 5 (5.6%) displayed a tremor during the initial clinical examination for
toe walkers. None of the children showed an indication for a mental developmental
disorder. Thirty-three (37.1%) patients had problems with their motor abilities when
speaking, causing mild speech impairments as observed by the parents and reported
by the examiner.
Of the 89 patients who were eligible for genetic testing using the genetic panel comprising
of 49 genes, 88 patients (98.9%) had at least one genetic variant in the 49 genes
that were tested. Fifteen of the 89 patients included in the study (16.9%) were found
to have at least one genetic variant characterized as likely pathogenic or pathogenic;
this group of patients had an additional 17 variants of uncertain significance ([Tables 1 ] and [2 ]).
Table 1
Clinical symptoms found in the study population
Patient group
Cavus deformity of the foot
Family history
Speech problems
Tremor
Total study population
n = 89
58
(65.5%)
24
(27%)
33
(37.1%)
5
(5.6%)
Patients with min. one variant of uncertain significance
n = 69
45
(65.2%)
20
(29%)
25
(36.2%)
3
(4.3%)
Patients with min. one likely pathogenic/pathogenic variant, n = 15
7
(46.7%)
2
(13.3%)
2
(13.3%)
1
(6.7%)
Table 2
Pathogenic and likely pathogenic variants found in the study population
Genetic variants by patient
Pathogenicity
Conditions linked to the gene
ATM c.8545C > T
Pathogenic
Ataxia-telangiectasia; mantle cell lymphoma; ataxia-telangiectasia; breast cancer
CACNA1A c.3787G > A
Likely pathogenic
Familial paroxysmal ataxia; familial or sporadic hemiplegic migraine; epileptic encephalopathy,
early infantile; benign paroxysmal torticollis of infancy; migraine, familial hemiplegic;
alternating hemiplegia of childhood; episodic ataxia, type 2; spinocerebellar ataxia
6; spinocerebellar ataxia type 6; Lennox-Gastaut syndrome; non-specific early-onset
epileptic encephalopathy
CHRNE c.346A > G
Likely pathogenic
Postsynaptic congenital myasthenic syndromes; myasthenic syndrome, congenital, 4c,
associated with acetylcholine receptor deficiency; myasthenic syndrome, congenital,
4a, slow-channel; myasthenic syndrome, congenital, 4b, fast-channel
CHRNE c.488C > T
Likely pathogenic
Postsynaptic congenital myasthenic syndromes; myasthenic syndrome, congenital, 4c,
associated with acetylcholine receptor deficiency; myasthenic syndrome, congenital,
4a, slow-channel; myasthenic syndrome, congenital, 4b, fast-channel
COL6A3 c.7174G > A
OPA1 c.113_130del,
Pathogenic
Pathogenic
Congenital muscular dystrophy, Ullrich type; dystonia 27; primary dystonia, dyt27
type; Bethlem myopathy; Bethlem myopathy 1; Ullrich congenital muscular dystrophy
1
Autosomal dominant optic atrophy plus syndrome; autosomal dominant optic atrophy,
classic form; optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia,
and neuropathy; mitochondrial DNA depletion syndrome 14 (encephalo-cardiomyopathic
Type); Behr syndrome; optic atrophy 1
PMP22 c.353C > T
Likely pathogenic
Roussy-Levy syndrome; Roussy-Levy hereditary areflexic dystasia; neuropathy, inflammatory
demyelinating. OMIM:118300; Charcot-Marie-Tooth disease and deafness; hypertrophic
neuropathy of Dejerine-Sottas; acute inflammatory demyelinating polyradiculoneuropathy;
hereditary neuropathy with liability to pressure palsies; neuropathy, hereditary,
with liability to pressure palsies; charcot-marie-tooth disease type 1a
PMP22 Complete Deletion of Exon 2
Pathogenic
Roussy-Levy syndrome; Roussy-Levy hereditary areflexic dystasia; neuropathy, inflammatory
demyelinating; Charcot-Marie-Tooth disease and deafness; hypertrophic neuropathy of
Dejerine-Sottas; acute inflammatory demyelinating polyradiculoneuropathy; hereditary
neuropathy with liability to pressure palsies; neuropathy, hereditary, with liability
to pressure palsies; Charcot-Marie-Tooth disease type 1a
PMP22 Gene Duplication
Pathogenic
Roussy-Levy syndrome; Roussy-Levy hereditary areflexic dystasia; neuropathy, inflammatory
demyelinating; Charcot-Marie-Tooth disease and deafness; hypertrophic neuropathy of
Dejerine-Sottas; acute inflammatory demyelinating polyradiculoneuropathy; hereditary
neuropathy with liability to pressure palsies; neuropathy, hereditary, with liability
to pressure palsies; Charcot-Marie-Tooth disease type 1a
POLG c.752C > T,
POLG c.1760C > T
Pathogenic
Pathogenic
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant
1; autosomal dominant progressive external ophthalmoplegia; recessive mitochondrial
ataxia syndrome; progressive external ophthalmoplegia with mitochondrial DNA deletions,
autosomal recessive; Alpers-Huttenlocher syndrome; mitochondrial DNA depletion syndrome
4a (Alpers type); sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome;
mitochondrial neurogastrointestinal encephalomyopathy; mitochondrial DNA depletion
syndrome 1; autosomal recessive progressive external ophthalmoplegia; mitochondrial
DNA depletion syndrome 4b; sensory ataxic neuropathy, dysarthria, and ophthalmoparesis
POLG c.926G > A
SATB2 c.1880G > T
Pathogenic
Likely pathogenic
SATB2-associated syndrome due to A chromosomal rearrangement progressive external
ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1; autosomal
dominant progressive external ophthalmoplegia; recessive mitochondrial ataxia syndrome;
progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive;
Alpers-Huttenlocher syndrome; mitochondrial DNA depletion syndrome 4a (Alpers type);
sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome; mitochondrial neurogastrointestinal
encephalomyopathy; mitochondrial DNA depletion syndrome 1 (MNGIE type); autosomal
recessive progressive external ophthalmoplegia; mitochondrial DNA depletion syndrome
4b; sensory ataxic neuropathy, dysarthria, and ophthalmoparesis
satb2-associated syndrome due to a chromosomal rearrangement
PYGM c.2056G > A
Pathogenic
Glycogen storage disease V; glycogen storage disease due to muscle glycogen phosphorylase
deficiency
PYGM c.660G > A
Likely pathogenic
Glycogen storage disease V; glycogen storage disease due to muscle glycogen phosphorylase
deficiency
SH3TC2 c.1402_1403delinsT
Likely pathogenic
Charcot-Marie-Tooth disease, type 4c; mononeuropathy of the median nerve, mild; Charcot-Marie-Tooth
disease type 4c
TTN c.16063G > A
Likely pathogenic
Myopathy, myofibrillar, 9, with early respiratory failure; autosomal recessive centronuclear
myopathy; Salih myopathy; tibial muscular dystrophy, tardive; tibial muscular dystrophy;
familial isolated dilated cardiomyopathy; hereditary myopathy with early respiratory
failure; classic multiminicore myopathy; muscular dystrophy, limb-girdle, autosomal
recessive 10; cardiomyopathy, familial hypertrophic, 9; cardiomyopathy, dilated, 1 g
TTN c.33742 + 1G > T
Pathogenic
Myopathy, myofibrillar, 9, with early respiratory failure; autosomal recessive centronuclear
myopathy; Salih myopathy; tibial muscular dystrophy, tardive; tibial muscular dystrophy;
familial isolated dilated cardiomyopathy; hereditary myopathy with early respiratory
failure; classic multiminicore myopathy; muscular dystrophy, limb-girdle, autosomal
recessive 10; cardiomyopathy, familial hypertrophic, 9; cardiomyopathy, dilated, 1 g
Descriptions of the genetic conditions currently known to be associated with variants
in the respective genes were compiled after consulting the omim.org database.
The interpretations were based on the available knowledge on the variants to date
and the results of the clinical examination of each individual patient, as interpreted
by the laboratory.
Discussion
To our knowledge, this retrospective study provides the only large-scale exploratory
genetic analysis whether there could be a link between ITW and genetic variants previously
not known to be associated with the conditions. The purpose of this study was to assess
the potential usefulness of future research in this area, which is why we present
our results despite the limitations of the sample size and the scope of genetic testing
targets. By performing this study, we found pathogenic or likely pathogenic variants
in 17% of our patients in one or several of 49 distinct genes related to myopathies
and neuropathies that could be brought in relation with the symptom “toe walking gait”
and we therefore reject our null hypothesis.
Secondary endpoints are the detection of possible areas for more complex future research
into the possible significance of future research projects and to postulate an improved
diagnostic process for the possible causes of toe walking in children with no clear
indication for an underlying neurological or orthopaedic cause. The presence of such
variants was interpreted as making a genetic cause for the gait anomaly more likely.
It was explicitly not interpreted as meaning that the patient has the condition the
variant is associated with. Furthermore, it does not indicate any specific mechanism
through which the variant could contribute to the gait anomaly. Many of the variants
and conditions are characterized by heterogeneity of symptoms in carriers. Consequently,
the results reported indicate initial findings and demonstrate the use of the diagnostic
method. We found an additional 129 variants of uncertain significance in a total of
69 patients, and we cannot exclude the possibility that some of these additional variants
could have contributed to the gait anomaly. Additionally, we found that 65.2% of patients
showed a pes cavus deformity and 27% of patients reportedly had at least one close
relative who also displayed the gait anomaly, while 37.1% had problems with their
speech development. We have considered these combined findings and reject our hypothesis
that there is no indication of a link between ITW and an underlying genetic cause.
We conclude that the result shows that further research into the genetic causes of
toe walking is justified—not least because such research could provide valuable insight
into the diagnosis of more serious diseases. There are some important arguments for
the use of genetic diagnostic methods outside the study results we have listed above.
Parents of children with ITW often worry that there could be a risk of a serious undetected
underlying condition and the treatment and interpretation of ITW are inconsistent.
Parents often seek out multiple options for diagnosis and treatment. An option for
routine genetic diagnosis which employs the diagnostic panel can offer them a pathway
that can provide increased clarity about the risk that the gait anomaly their child
is displaying could be associated with undetected underlying conditions.
In case of finding a genetic variant with a suspected pathological impact, treatment
can be tailored to the individual patient. Our previous research has shown that toe
walking can be a previously unknown initial symptom of a known genetic conditions.
We have to date published two case studies where we were able to diagnose patients
who had visited our practice for gait anomalies at a young age presenting with no
pronounced symptoms of a neurological or orthopaedic condition; their main symptom
at the time was toe walking. By using the NGS-panel, prior to this study, we were
able to identify an undetected spinocerebellar ataxia 13 in a boy and a Menke-Hennekam
syndrome in a girl.[30 ]
[31 ] Following both diagnoses, the gait anomaly could be treated alongside a recommendation
for treatment of the conditions and a clearer prognosis for the children's future
development. In this way, the further genetic testing could be used for the generation
of knowledge and as a novel method to detect progressive genetic conditions, with
the potential for more research to generate further insights.
Currently, many pediatricians do not pay particular attention to toe walking, often
considering it a temporary phenomenon. However, in persistent cases, the gait anomaly
may often require treatment to prevent progressive deformities and pain in later life,
even for children who are otherwise healthy. Furthermore, doctors should be wary of
toe walking as a possible early indicator of the presence of more serious hereditary
diseases. The use of the genetic testing helps parents and doctors have a greater
degree of clarity on the disease risks and possible resulting treatment risks. Often
testing provides reassurance and avoids overtreatment and mounting costs to families
and/or the health system as a result of attempts to establish the likelihood of a
child having a previously undetected hereditary condition linked to toe walking.
There are several limitations to the conclusions we can draw based on the data we
have discussed in this study. The sample size was limited given the large number of
genes included in the panel and the breadth of conditions variants could be associated
with. Second, due to the limited data available to date, we have little clarity on
if and, if yes, how each individual variant could be linked to the clinical symptoms
of toe walking. Our genetic testing targets were formulated very broadly, which means
our results should be primarily interpreted as an encouraging indicator for future
research on a larger scale or in-depth discussions of relevant case studies. The patients
were tested using panel diagnostics, meaning that they were tested for any mutations
in the 49 genes included in the panel only. However, there may have also been variants
with a possible link in other genes that were not covered by the testing in the panel.
Therefore, a lack of variants found as the result of the panel diagnosis does not
mean that there are no other mutations present outside the panel that could be causing
the gait anomaly. Because this study is merely taking initial steps to investigate
the significance of the genetic variants found in relation to toe walking, our findings
do not eliminate the possibility that a variant currently classified as being of uncertain
significance could be a cause for the gait anomaly. Our ongoing work indicates the
potential to reclassify some variants in the future. For example, many idiopathic
toe walkers with a variant of uncertain significance in its heterozygous form display
mild symptoms reminiscent of the more severe illnesses experienced by homozygous carriers
of the same variant. In addition to having a sample size and the broad scope of genetic
testing targets, we could not generate a control group of healthy, normal walking
children, as we used retrospective data for ethical reasons. Thus, the existence of
variants of relevance in the tested genes in healthy subjects remains unclear. Additionally,
the retrospective nature of the data affects the use of validated diagnostic tools
to report speech developmental problems and family history. Data on both indicators
were collected using our routine method during the anamnestic process, namely through
parental statements and examiner observation. For this reason, the aim of this study
was purposefully broad—it was an initial attempt to explore the merits of continued
research into the possibility of a link between genetic variations and the symptoms.
Conclusion
We conclude that our findings indicate a sufficient indication for a link between
ITW and genetic variants to encourage future research, despite the sample size and
the broad scope of our genetic testing targets. Beyond the potential to help us better
understand the genetic causes of toe walking, we stress that the panel could be developed
further to detect serious conditions early and to clarify treatment implications more
quickly. The known genetic disorders that have previously been linked to toe walking
are often characterized by a high degree of heterogenicity of symptoms and a variable
association between the genotype and the phenotype. We, therefore, think it is likely
that our continued research has the potential to identify ITW as a symptom for further
conditions, which it was not previously linked to. Despite its limitations, our study
shows the merit of continued genetic research into the genetic causes of toe walking.
In this way, researchers may eventually be able to move from discussing the possibility
of a hereditary cause for some instances of ITW to being able to precisely describe
the cause of the condition. Future research may lead to a change in the interpretation
of the significance of the variants found in this study.
