cerebellar ataxia - spastic paraparesis - genetics - magnetic resonance imaging -
ophthalmology
ataxia cerebelar - paraparesia espástica - genética - imagem por ressonância magnética
- oftalmologia
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) was initially reported
in the Charlevoix-Saguenay region of northeastern Quebec, Canada, in 1978, as an early-onset,
neurodegenerative disorder[1],[2]. The ARSACS is caused by bi-allelic mutations in SACS (chromosome 13q12.12) that encode sacsin; a protein highly expressed in large neurons,
including cerebellar Purkinje cells. Sacsin contains a DNAJ motif, two domains similar
to the N-terminal of the HSP90 class of heat-shock protein and a ubiquitin-like domain,
that is probably involved in the ubiquitin-proteasome system and chaperone-mediated
protein folding[3],[4],[5],[6].
In Quebec, ARSACS was described as a homogenous syndrome with childhood onset, between
12 and 18 months of age, typically characterized by slowly progressive signs such
as spastic-ataxia of upper and lower limbs, dysarthria, slurred and dysrhythmic speech,
distal amyotrophy and absence of ankle reflexes after 25 years of age. Furthermore,
early non-progressive signs were also reported, including generalized hyperreflexia,
Babinski sign, broken-up ocular smooth pursuit and retinal hypermyelination[2]. Now, ARSACS has been described worldwide; however, the clinical picture of patients
born outside Quebec is often different, including atypical findings such as later
onset, cognitive impairment, ophthalmoplegia and absence of spasticity and retinal
hypermyelination[7],[8],[9],[10],[11],[12],[13],[14],[15]. Nerve conduction studies generally demonstrate signs of progressive axonal-demyelinating
peripheral neuropathy and magnetic resonance imaging (MRI) shows predominant superior
cerebellar vermis atrophy[2] and T2-fluid-attenuated inversion recovery (FLAIR) pontine linear hypointensities[16],[17].
We aimed to report clinical, imaging and molecular findings of a Brazilian family
in which two cousins presented with a similar phenotype to ARSACS families from Quebec.
METHODS
Case report study
Two cousins were referred to a neurogenetics outpatient service to investigate a clinical
picture of ataxia. They were included in an ataxia screening panel from the Brazilian
institution, after a written informed consent form was obtained. The present work
was approved by the Ethics Committee from the institution at which the work was performed
– Comissão de Ética em Pesquisa do Hospital de Clínicas de Porto Alegre, which follows
the Code of Ethics of the World Medical Association (Declaration of Helsinki) and
the standards established by the author’s Institutional Review Board and granting
agency.
After excluding other causes of hereditary ataxia, the coding region and exon–intron
boundaries of the nine coding exons of SACS (NM_014363.5) were sequenced (Molecular Medicine-Neurogenetics, Pisa, Italy), amplified
by polymerase chain reaction. Amplicons were sequenced in both directions using a
standard Sanger sequencing approach on an ABI3130xl automatic sequencer.
All patients and their parents gave written informed consent to publish this report
and its media files.
Patient description
Both cousins were born to consanguineous parents ([Figure 1]) and reported multiple other consanguineous marriages in the family. The surname
related to consanguinity was of Germanic background. The family lives in the countryside
of Camaquã, a city with 63,000 inhabitants, located in Rio Grande do Sul, the southernmost
state of Brazil, with mainly Azorean, Germanic and Polish colonization. No other similar
cases were reported in their family.
Figure 1 Simplified pedigree and genotypes.
Case 1
Patient 1 was a 28-year-old woman presenting with an early-onset slowly progressive
spastic-ataxic disorder. Disease onset was probably in the first or second year of
life, since she achieved independent walking at 20 months of age and never acquired
a steady gait. Slurred speech started at the age of 10 and dysphagia was also reported
in the following years. On current neurological examination, she presented with a
spastic-ataxic gait; abnormal balance; moderate lower limb spasticity; general hyperreflexia,
except for absent Achilles reflexes; bilateral Babinski sign; and mild limb ataxia.
Other findings were broken-up smooth pursuit and gaze-evoked nystagmus, dysarthria,
pes cavus and hammertoes. No cognitive deficit was observed.
An MRI showed cerebellar vermis atrophy and T2-FLAIR central pontine linear hypointensities
([Figure 2]), raising the suspicion of an ARSACS diagnosis. Fundoscopy and optical coherence
tomography showed thickening of the nerve fiber retinal layer, compatible with hypermyelination
([Figure 3]). The electroretinogram was normal and pattern reversal visual evoked potentials
were prolonged bilaterally. Nerve conduction studies revealed a length-dependent,
predominantly sensory, axonal-demyelinating sensorimotor polyneuropathy. Both upper
and lower limb cortical somatosensory evoked potentials were absent.
Figure 2 Brain MRI of ARSACS patients. Brain MRI of patient 1 (A-D) and patient 2 (E-F). A)
Axial T2-weighted image showing mild parietal lobe atrophy (black arrowhead); B) sagittal
T1-weighted image showing superior cerebellar vermian atrophy (white arrow); C) axial
T2-FLAIR weighted image showing linear hypointensities in the pons (black arrows)
and hyperintensities of the lateral pons merging into the middle cerebellar peduncles
(white arrowhead); D) coronal T2-weighted image showing hyperintensities of the lateral
pons merging into the middle cerebellar peduncles (white arrowhead); E) sagittal T1-weighted
image showing superior cerebellar vermian atrophy (white arrow); F) axial T2-FLAIR
weighted image showing linear hypointensities in the pons (black arrows) and hyperintensities
of the lateral pons merging into the middle cerebellar peduncles (white arrowhead).
FLAIR, fluid-attenuated inversion recovery.
Figure 3 Fundoscopy and optical coherence tomography of ARSACS patients. Ophthalmological
evaluation of patient 1 (A-B) and patient 2 (C-D). A) and C) striated whitish aspect
of the peripapillar retina suggestive of nerve fiber retinal layer hypermyelination
on fundoscopy (white arrow); B) and D) increased thickness and reflectance of the
nerve fiber retinal layer (black arrow) on optical coherence tomography.
Case 2
Patient 2 was a 30-year-old woman also presenting with an early-onset, slowly progressive,
spastic-ataxic disorder. She started independent walking at 13 months of age; frequent
falls and gait difficulties were noticed at two years of age with progressive worsening
thereafter. Progressive distal weakness in her lower limbs started at 15 years of
age, resulting in foot drop. Neither significant dysphagia nor slurred speech were
reported. A clinical picture very similar to Patient 1 was seen on neurological examination,
with the addition of foot drop. Cognitive function was preserved.
An MRI showed similar findings to Patient 1 ([Figure 2]). Additionally, tractography with diffusion tensor imaging showed thick and displaced
transverse pontine fibers with compressed corticospinal tracts in the pons ([Figure 4]).
Figure 4 Diffusion tensor imaging tractography in ARSACS. Fractional anisotropy images show
the difference between a healthy individual (A-C) and patient 2 with ARSACS (D-F).
While the healthy patient (A) has normal sized corticospinal (blue) and pontine transverse
(red) tracts, patient 2 (D) has abnormally thickend pontine transverse tracts, leading
to displaced and reduced corticospinal tract thickness. Tractography of the corticospinal
tract (red and blue) and transverse pontine fibers (yellow) are shown in images B,
C, E and F.
Fundoscopy and optical coherence tomography showed thickening of the nerve fiber retinal
layer ([Figure 3]). Electroretinogram and pattern-reversal visual evoked potentials were normal bilaterally.
Nerve conduction studies revealed a length-dependent, predominantly sensory, axonal-demyelinating
sensorimotor polyneuropathy. Cortical somatosensory evoked potentials were prolonged
in upper, and absent in lower, limbs.
Diagnostic work-up
An extensive diagnostic work-up for autosomal recessive and dominant ataxic disorders
was performed for both cousins. Molecular analysis for Friedreich’s ataxia, spinocerebellar
ataxias type 1, 2, 3, 6, 7, 10, 12, 17, and dentatorubral-pallidoluysian atrophy were
normal. Normal blood levels of vitamin E, LDL and HDL cholesterols, triglycerides,
alpha-fetoprotein, lactate, ceruloplasmin and immunoglobulins A, E, G and M; and normal
leukocytes activities of arylsulfatase A, hexosaminidase A, galactocerebrosidase,
beta-galactosidase and chitotriosidase, were found.
Their clinical pictures were highly suggestive of an autosomal recessive condition.
Posterior fossa MRI and ophthalmological findings suggested an ARSACS diagnosis. The
SACS sequencing revealed that Patients 1 and 2 were homozygous for the novel frameshift
variant c.5151_5152insA, and that both pairs of parents were heterozygous for the
variant ([Figure 1]). This DNA variant was absent from the Exome Aggregation Consortium and from 1000
genomes project databases, and it was classified as pathogenic according to the 2015
American College of Medical Genetics and Genomics criteria[18], confirming the diagnosis of ARSACS.
DISCUSSION
Autosomal recessive spastic ataxia of Charlevoix-Saguenay was first described in Quebec
province, Canada. The incidence at birth of the disease in the Charlevoix-Saguenay
region of Quebec is around 50/100,000 live born infants with a carrier prevalence
estimated to be 1/22[7],[19], but it is largely unknown in other countries. Since the identification of several
mutations in many populations, it is now recognized that ARSACS is not only limited
to this region, but occurs worldwide[8]
-
[15]. More than 100 SACS mutations have been described to date. The majority of Quebecois harbor a homozygous
single nucleotide deletion (c.8844delT) due to a founder effect, whereas about 4%
of the total carrier frequency harbor the nonsense c.7504C > T, and additional mutations
(including four recurrent alleles) are less common[20]. In a few compound heterozygous patients, this mutation was associated with (5254C
> T) nonsense mutation[3].
The presence of certain brain MRI, retinal and nerve conduction abnormalities in ataxic
or spastic individuals might raise suspicion of an ARSACS diagnosis17,21,22,23,24,25.
Neuroimaging
At least three case series (64 patients in total) have evaluated qualitative brain
MRI findings in ARSACS patients born outside Quebec[17],[24],[25]. The MRI findings with greater sensitivity for ARSACS diagnosis were predominant
superior cerebellar vermis atrophy (range: 88–100%), T2-FLAIR pontine linear hypointensities
(range: 46–100%), enlargement of middle cerebellar peduncles (range: 22–100%) and
T2-FLAIR hyperintensities of the lateral pons (range: 17–100%). As these studies only
reported MRI abnormalities in ARSACS patients, it was not possible to estimate the
specificity of the findings. However, considering that T2-FLAIR pontine linear hypointensities
were rarely described for other diseases, this is probably the most specific MRI sign
of ARSACS.
Ophthalmological findings
Case series and reports have depicted low sensitivity (17-19%) of prominent myelinated
retinal nerve fibers for an ARSACS diagnosis in patients born outside Quebec[21],[24],[25], except for a recent Italian study that reported 4/5 ARSACS patients with this finding[22]. Specificity of retinal abnormalities for an ARSACS diagnosis, however, seems to
be high, although not adequately addressed up to now. Importantly, some authors point
out that ARSACS might be underdiagnosed due to erroneous fundoscopy interpretation
as persistent myelination of the retina (present in 1–2% of normal population) and
that optical coherence tomography might help to differentiate this pattern from thickening
of peripapillar retinal fibers typical of ARSACS[23].
Nerve conduction studies
At least two case series (46 patients evaluated with nerve conduction studies) evaluated
peripheral nervous system abnormalities in ARSACS patients born outside Quebec[24],[25]. Sensitivity of sensorimotor polyneuropathy ranged from 88-97%, with axonal involvement
in 25%, demyelinating in 53% and both axonal and demyelinating in 14% of patients[25]. Therefore, peripheral neuropathy is another sensitive marker for an ARSACS diagnosis.
A demyelinating component of the sensorimotor peripheral neuropathy (present in 67–88%
of cases) might help to distinguish ARSACS from other common recessive ataxias like
Friedreich’s ataxia, POLG or ataxia with oculomotor apraxia type 2[24].
ARSACS frequency worldwide, and in Brazil
Autosomal recessive spastic ataxia of Charlevoix-Saguenay has rarely been addressed
in population studies outside Quebec, in the context of autosomal recessive ataxias,
spastic ataxias and hereditary spastic paraplegias. The relative frequency of ARSACS
varied from 0.3% of hereditary spastic paraplegia patients to 5% of early onset ataxia
patients from Germany[24],[26]; and to 8% of spastic ataxia or congenital ataxia patients from multiple origins[25]. The ARSACS frequency among ataxic or hereditary spastic paraplegia families from
Brazil is unknown.
The two individuals in the present report presented with clinical, neuroimaging, electrophysiological
and ophthalmological findings resembling the characteristics of the Quebec patients,
which led to the suspicion of ARSACS. Before them, three Brazilian siblings presenting
with a clinical diagnosis of typical ARSACS, without molecular confirmation, were
reported[27]. Therefore, there is reason to expect other cases, typical or atypical, in our population.
In conclusion, ARSACS is a spastic ataxic disorder, with worldwide distribution, being
the second or third most common cause of autosomal recessive ataxias in some series
outside Quebec[24]. Brain MRI is a mandatory complementary investigation for ataxic disorders of unknown
diagnosis[28] and ARSACS is one of the diseases where a specific MRI pattern may give rise to
a correct diagnosis. Both ophthalmological evaluation and nerve conduction studies
should be routinely ordered for patients with ataxia for a better phenotypic characterization.
The suspicion of persistent myelination of the retina in an ataxic patient should
be confirmed by optical coherence tomography; prominent myelinated retinal nerve fibers
on fundoscopy should lead to SACS sequencing. A demyelinating or axonal-demyelinating sensorimotor polyneuropathy in
an ataxic patient should also raise ARSACS suspicion. Finally, atypical ARSACS cases
with Charcot-Marie-Tooth-like, or other complex phenotypes, might lack both MRI and
fundoscopy abnormalities. Their diagnosis may be made with a next-generation sequencing
panel or whole exome sequencing analysis[24],[25].
