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161
REVIEW ARTICLE
Current and Promising Therapies in Autosomal Recessive Ataxias
Vincent Picher-Martel1,2,* and Nicolas Dupré2,*
1Research Centre of Institut Universitaire en Santé Mentale de Québec and Department of Psychiatry and Neuroscience,
Laval University, 2601 Chemin de la Canardière, Québec, QC, G1J 2G3, Canada; 2Department of Medicine, Faculty of
Medicine, Laval University and CHU de Québec-Laval University, Axe Neurosciences, 1401, 18th Street, Québec, QC,
Canada, G1J 1Z4
A R T I C L E H I S T O R Y
Received: May 30, 2 017
Revised: December 18, 20 17
Accepted: April 01, 2018
DOI:
10.2174/1871527317666180419115029
Abstrac t: Background & Objective: Ataxia is clinically characterized by unsteady gait and imbal-
ance. Cerebellar disorders may arise from many causes such as metabolic diseases, stroke or genetic
mutations. The genetic causes are classified by mode of inheritance and include autosomal dominant,
X-linked and autosomal recessive ataxias. Many years have passed since the description of the Frie-
dreich’s ataxia, the most common autosomal recessive ataxia, and mutations in many other genes h ave
now been described. The genetic mutations mostly result in the accumulation of toxic metabolites
which causes Purkinje neuron lost and eventual cerebellar dysfunction. Unfortunately, the recessive
ataxias remain a poorly known group of diseases and most of them are yet untreatable.
Conclusion: The aim of this review is to provide a comprehensive clinical profile and to review the
currently available therapies. We overview the physiopathology, neurological features and diagnostic
approach of the common recessive ataxias. The emphasis is also made on potential drugs currently or
soon-to-be in clinical trials. For instance, p romising gene therapies raise the possibility of tr eating dif-
ferently Friedreich’s ataxia, Ataxia-t elangiectasia, Wilson’s disease and Niemann-Pick disease in the
next few years.
Keywords: Recessive ataxia, friedreich’s ataxia, ataxia-telangiectasia, ataxia with v itamin E deficiency, refsum’s disease, wil-
son’s disease, cerebrotendinous xantomatosis, niemann-pick disease type C, ataxia with oculomotor apraxia, autosomal reces-
sive spastic ataxia of charlevoix-saguenay.
1. INTRODUCTION
Symptoms of ataxia are common complaints among pa-
tients in neurology clinics. The term ataxia is generally used
to designate the neurologic conditions affecting the cerebel-
lum, which is implicated in movement coordination. Its dys-
function can cause a variety of symptoms including loss of
hand coordination and difficulty with fine motor tasks, nys-
tagmus, tremor, dysarthria, walking and balance difficulties.
Many etiologies account for this group of diseases. Although
an acute onset of cerebellar dysfunction is often caused by
infarction or hemorrhage, the differential diagnosis of
chronic degeneration is wide and contains, for instance, ge-
netic disorders, metabolic disorders, auto-immune diseases,
infections and drug-induced toxicity [1].
*Address correspondence to these authors at the Research Centre of Institut
Universitaire en Santé Mentale de Québec and Department of Psychiatry
and Neuroscience, Laval University, 2601 Chemin de la Canardière, Qué-
bec, QC, G1J 2G3, Canada; Tel: 418-455-0982;
E-mail: vince nt.picher-martel.1@ulaval.ca and Department of Medicine,
Faculty of Medicine, Laval University and CHU de Québec- Laval Univer-
sity, Axe neurosciences, 1401, 18th Street, Québec, QC, Canada, G1J 1Z4;
Tel: 418-649-0252 (63177); Fax: 418-649-5915;
E-mail: nicolas.dupre.cha@ssss.gouv.qc.ca
Hereditary conditions are frequent and numerous genes
are linked to ataxic syndromes. It is useful to classify the
hereditary ataxia by mode of inheritance. The autosomal
dominant ataxias, also referred to spinocerebellar ataxias, ar e
caused by CAG expansions into more than 35 different
genes. The clinical spectrum of sy mptoms usually appears on
average after 30 years of age and a family history of ataxic
syndrome is generally noted [2]. If the mode of inheritance
suggests an X-linked inheritance, the clinician should con-
sider the possibility of X-associated tremor-ataxia syndrome
or adrenomyeloneuropathy. On the other hand, autosomal
recessive ataxias should be considered in cases of affected
siblings and in consanguine families with healthy parents.
However, sporadic cases remain th e most common pr esenta-
tion in western countries.
Autosomal recessive cerebellar ataxias (ARCA) are a
heterogeneous group of diseases. ARCAs generally manifest
before the age of 30 with a progressive disorder of gait and
balance. The number of the identified causative gene has
grown in the past years with the advanced technologies in
genetic screening. The prevalence of all ARCAs is estimated
to be 3.3/100 000 inhabitants worldwide. However, the
prevalence varies between countries and some ARCAs are
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162 CNS & Neurological Disorders - Drug Targets, 2018, Vol. 1 7, No. 3 Picher-Marte l and Dup ré
particularly restricted to isolated regions [3]. Compared to
other causes of cerebellar dysfunction, systemic manifesta-
tions are peculiar findings in most ARCAs and are useful to
establishing the diagnosis. Once the diagnosis of ARCA is
suspected, the clinician should perform a magnetic resonance
imaging (MRI) to determine the presence or the absence of
cerebellar atrophy and perform electromyography (EMG) to
characterize an associated neuropathy. ARCAs can be cate-
gorized according to the presence of a pure sensory neuropa-
thy, a sensorimotor neuropathy or the absence of a neuropa-
thy [4]. Finally, the diagnosis of ARCA is generally con-
firmed by gene sequencing.
The aim of this review is to highlight novel therapies for
common recessive ataxias. An emerging number of studies
have been published in the last decade. The present paper is an
updated version of a previous review written by Martineau L,
Moreau N, and Dupre N in 2014 [5]. We reviewed advances
in treatments for Friedreich’s ataxia, Ataxia-telangiectasia,
Ataxia with vitamin E deficiency, Refsum’s disease, Wilson’s
disease, Cerebrotendinous xantomatosis, Niemann-Pick dis-
ease type C, Ataxia with oculomotor apraxia and Autosomal
Recessive Spastic Ataxia of Charlevoix-S aguenay. Emphasis
is made on therapies with promising results in clinical stud-
ies and we discussed of few pre-clinical studies where the
results are highly optimistic. Although we only stated about
the medical approach, it is important to mention that patients
with ARCA certainly benefit from physiotherapy and occu-
pational therapy. Recently, a systemic review of rehabilita-
tion highlighted the effectiveness of balance exercises and
gait training [6]. The young patients also benefit from a
multidisciplinary team that includes pediatrician, neuro logist,
physiotherapist, nurses and other medical specialists.
2. AUTOSOMAL RECESSIVE CEREBELLAR ATA-
XIAS
2.1. Friedreich’s Ataxia
Friedreich’s ataxia (FRDA) was described in 1863 by
Nikolaus Friedreich and is the most common autosomal re-
cessive ataxia. Guanine-adenine-adenine (GAA) trinucleo-
tide repeat expansion in the frataxin (FXN) gene, located on
chromosome 9q13, accounts for the majority of FRDA cases
[7]. Frataxin is a mitochondrial protein implicated in iron
metabolism, oxidative stress, energy metabolism and other
mitochondrial functions [8]. Defects in the frataxin protein
result in a neurodegenerative disease affecting both the cen-
tral and the peripheral nervous systems (Fig. 1). Indeed, th e
symptoms originate from a spinocerebellar degeneration, a
cerebellar pathology and a peripheral sensory neuropathy
[7]. Most of the cases exhibit progressive limb and gait
ataxias, dysarthria and lower limb areflexia. Other features
such as dysphagia, optic atrophy, weakness, positive Babin-
ski’s sign, loss of position and vibration sense are also com-
monly found [9]. The age at onset is generally 10-12 years of
age and patients usually die between 30 to 40 years of age.
Non-neurological features such as diabetes, scoliosis and
cardiomyopathies are frequent in FRDA (Table 1). The diag-
nosis is based on clinical suspicion and genetic testing.
There is currently no therapy for Friedreich’s ataxia. Cur-
rent therapeutic concepts can be separated into three strate-
gies. The first proposed strategy is grounded on increasing
the mitochondrial function to substitute from the normal
FXN function, whereas the second and the third strategies are
based on enhancing the FXN gene expression with small
molecules or with the use of gene therapy. As a mitochon-
drial function enhancer, the antioxidant combination of vi-
tamin E with coenzyme Q10 showed some improvement in
the International Cooperative Ataxia Rating Scale (ICARS)
in two studies. The first study, a 4-years follow-up on 10
patients showed an improvement in the ICARS scores when
compared to cross-sectional data from 77 FRDA patients but
failed to demonstrated any positive effect on posture, gait
and hand dexterity [10]. The second study, a double-blind
multiple-dose study, demonstrated better than expected IC-
ARS scores in 49% of patients [11]. However, no placebo
group was used for comparison. Besides, idebenone, a struc-
tural analog of coenzyme Q10, have been widely studying in
FRDA but the results were conflicting and this compound is
not recommended. Essentially, some studies demonstrated an
improvement in cardiac structure and function but without
any improvement in neurological outcomes [12-14]. Two
open-label trials found either a significant reduction in the
ICARS scores or a stabilization of neurological symptoms in
both the pediatric and the adult populations [15, 16].
Though, these results were not reproduced in additional dou-
ble-blinded, placebo-controlled trials [17, 18].
There is evidence of iron accumulation in mitochondria
of FRDA patients but the detailed pathological mechanisms
are still unclear [19]. Therefore, the iron chelator deferiprone
have been studied in FRDA but the results were also con-
flicting and this treatment is not recommended either. Using
apparent transverse relaxation rate on MRI, a group demon-
strated a reduced iron accumulation but no significant neuro-
logical amelioration in patients treated with deferiprone [20].
Following this study, a multicentre randomized placebo-
controlled trial tested three different doses of deferiprone
(20, 40 and 60 mg/kg/day). Deterioration of ataxia symptoms
was observed in patients treated with 40 and 60 mg/kg/day
and inconclusive results were observed with the lowest dose
[19]. Besides, a combined therapy of deferiprone and idebe-
none demonstrated a slight improvement in cardiac hyper-
trophy, a progress in kinetic functions but a worsening of
gait and posture scores [21]. A triple therapy with darbepo-
etin alfa, idebenone and riboflavin showed a reduction in
disease evolution with a stability in cardiac hypertrophy dur-
ing the first two years of treatment [22] (Table 2).
Recent studies have tried to understand the effect of in-
creased frataxin protein expression levels in animal models
and in human patients. Erythropoietin was shown to have a
positive effect on frataxin expression in primary culture of
patients lymphocytes [23]. However, clinical studies failed to
demonstrate any improvement of neurological symptoms
[24-26]. Interferon-gamma (IFNγ), a cytokine implicated in
iron metabolism, increased frataxin level in cell lines and in
a mouse model of FRDA. Therefore, the sensorimotor per-
formance was strongly upgraded in these mice [27]. Follow-
ing the pre-clinical studies, an open-label trial tested subcu -
taneous injection of IFNγ during 12 weeks on 12 children
with FRDA. IFNγ was well tolerated and improved the Frie-
dreich Ataxia Rating Scale (FARS) scores [28]. A small in-
crease of the frataxin protein level was measured in the
Current and Promising Therapies in Autosomal Recessive Ataxias CNS & Neurological Disorders - Drug Targets, 2018, Vol. 17, No. 3 163
Fig. (1). Pathological mechanisms of autosomal recessive cerebellar ataxias. A) In healthy individuals, iron is transferred from cytosol to
mitochondria and iron-sulfur clusters (ISC) are formed. GAA repeats in Frataxin (FXN) gene and FXN deficiency imp airs ISC fo rmation in
the mitochondria and leads to iron responsive element binding protein 1 (IRP1) activation and causes an increased cellular iron uptake by
transferrin receptor protein 1 (TfR1). FXN deficiency also interferes with Heme synthesis. Finally, iron accumulation into mitochondria leads
to oxidative damage and Purkinje cells death. B) Ataxia-telangiectasia mutated (ATM) is implicated in coordination of reparation in DNA
double-strain breaks. Reduced ATM protein levels increase sensitivity to DNA breaks and lead to tumors, telangiectasia, ataxia and more. C)
Mutations in Phytanoyl-CoA Hydroxylase (PHYH) or peroxisomal targeting signal 2 (PTS2) genes lead to phytanic acid (PA) accumulation,
normally degraded by PhyH. PA accumulates in membranes and causes mitochondrial defects. D) Mutation in α-tocopherol transfer protein
(TTPA) gene causes a reduction of vitamin E incorporation into low density lipoproteins (LDL) in the liver. This results in reduced vitamin E
in tissue and oxidative damage in Purkinje neurons. E) Mutation in copper-transporting P-type ATPase (ATP7B) gene reduces copper clear-
ance into bile and increases copper accumulation into tissues. F) Mitochondrial sterol 27-hydroxylase is implicated in oxidation of cholesterol
into-27-hydroxycholesterol, which is subsequently needed for bile acids formation. Accumulation of cholesterol in brain can affects myelin
formation and disrupts blood-brain barrier (BBB). G) Cholesterol particles are normally trafficked from endosomal vesicles to Golgi and
endoplasmic reticulum (ER) apparatus. Niemann-Pick Type 1 and 2 (NPC1-2) mutations inhibit this trafficking and cause an accumulation in
intracellular compartments.
blood. More recently, GIFT-1, a phase IIa clinical trial, tested
the efficacy of IFNγ on 9 adult patients. Unfortunately, the
study failed to demonstrate any significant variations in the
frataxin level and in the neurological scores [29]. A phase III
clinical trial is currently ongoing.
Research in animal models proposed that nicotinamide
(vitamin B3) could increase frataxin level. It could act by
histone acetylation near the GAA repeat which leads to in-
creased wild-type frataxin expression [30]. An open-label
study from the United Kingdom evaluated escalating dose of
nicotinamide (2-8g) on 10 eligible patients. A sustained and
significant upregulation of frataxin level was observed with a
daily dose of 3 to 6 g but no significant changes on clinical
scales were observed [31].
Such as in other neurodegenerative disorders, gene ther-
apy is a promising approach in FRDA. This approach is not
yet tested in human but has demonstrated interesting results
in animal models. Interestingly, an increased expression of
FXN gene in drosophila caused a harmful effect on the fly
phenotype and suggested that level of frataxin must be care-
fully controlled in gene therapy approaches [32]. Inversely,
AAV-mediated specific cardiac expression of human frataxin
164 CNS & Neurological Disorders - Drug Targets, 2018, Vol. 1 7, No. 3 Picher-Marte l and Dup ré
Table 1. Clinical features of the recessive ataxias.
Recessive Ataxias Gene (Protein) Age at Onset
(Years of Age) Special Features Laboratory and Ima ging
Findings
Friedreich’s ataxia FXN (Frataxin) 10-12 Areflexia, dysphagia, optic atrophy, weakness,
Babinski sign, peripheral neuropathy, cardiomyopa-
thy, diabetes, scoliosis
No cerebellar atrophy
Spinal cord atrophy
Ataxia with vitamin E
deficiency
TTPA (α-tocopherol
transfer protein)
5-15 Loss of proprioception, areflexia, Babinski sign,
decrease visual acuity, head tremor, intellectual
decline, dystonia, retinitis pigmentosa, sensory
disturbances
Decreased serum Vit E level
No cerebellar atrophy
Spinal cord atrophy
Wilson’s disease ATP7B (copper-
transporting P-type
ATPase)
20-40 Dystonia, parkinsonism, flapping tremor, altered
cognition, seizure, personality changes, abnormal
behaviour, anxiety, depression
Reduced serum copper and ceru-
loplasmin
Elevated hepatic transaminase
Aminoaciduria
Increased copper urinary excretion
Tectal plate hyperintensity and face
of giant panda sign in MRI
Ataxia-telangiectasia ATM (ataxia
telangiectasia,
mutated)
1-2A Dysphagia, involuntary movements, abnormal eye
movement, oculocutaneous telangiectasia, cancer,
immune deficiency, pulmonary diseases, radiation
sensibility
Elevated alpha-fetoprotein
Igg deficiency
Cerebellar atrophy
Refsum’s disease PHYH (Phytanoyl-
CoA Hydroxylase)B
0-50 Infantile: early onset, hepatic and cerebral dysfunc-
tion, dysmorphia, developmental abnormalities and
infancy death
Classical: retinitis pigmentosa, anosmia, polyneuropa-
thy, deafness, cardiac arrhythmias, ichthyosis
Elevated serum phytanic acid
No cerebellar atrophy
Cerebrotendinous
xantomatosis
CYP27A1 (sterol 27-
hydroxylase)
10-50C Parkinsonism, UMN weakness, epilepsy, intellectual
disability, d ementia, psychiatric symptoms, dysto-
nia, peripheral neuropathy, cataracts, xanthomas,
hypothyroidism, cardiovascular disease, infantile
diarrhea, neonatal cholestatic jaundice
Elevated serum cholestenol
Variable cerebellar atrophy
Cerebellar of cerebral leukodystro-
phy
Niemann-Pic k Dis-
ease
NPC1/2 (intracellular
cholesterol transpor-
ter 1/2)
6-15D Movement disorder, dysphagia, supranuclear
ophtalmoplegia, cataplexy, learning and writing
difficulty, psychiatric symptoms and dementia
Variable cerebellar of brain atrophy
Ataxia with oculomo-
tor apraxia
APTX (aprataxin) 2-10 AOA1: Early and severe oculomotor apraxia,
marked dystonia, severe neuropathy, AOA2: Mild
oculomotor apraxia, low dystonia, low neuropathy,
AOA3: Severe oculomotor apraxia, severe neuropa-
thy, no dystonia, AOA4: Severe oculomotor apraxia,
marked dystonia, severe neuropa thy, cognitive
impairment
Elevated serum LDL (AOA1) low
albumin (AOA1)
Elevated serum alpha-fetoprotein
(AOA2)
Cerebellar atrophy (AOA1-2)
ARSACS ARSACS (sacsin) 1-2 Progressive spasticity, distal muscle atrophy, myeli-
nated fibers in optic disk, brisk refle x, bilateral
Babinski sign
Anterior superior cerebellar atro-
phy, variable T2 liner hypo-
densities in pons
AAtaxia appears when children begin to walk, but is highly variable between affected children; B 90% of cases are caused by mutation PHYH and 10% are caused by mutation in PTS2
Receptor (PEX7) gene; CAverage age at onset is 19 years; DJuvenile presentation is the most common; UMN upper motor neuron; ARSACS autosomal recessive spastic ataxia of
Charlevoix-Saguenay; Igg immunoglobulin.
gene in an FRDA mouse model completely prevented car-
diac disease and managed to reverse cardiomyopathy when
injected after the onset [33]. Similarly, lentiviral FXN ex-
pression in human FRDA fibroblasts improved cell viability
and ameliorated DNA damage-repair capacity [34].
2.2. Ataxia with Vitamin E Deficiency
Ataxia with vitamin E deficiency (AVED) is an infre-
quent autosomal recessive ataxia and one the rare treatable
ataxias [35]. AVED is caused by mutations in the α-
tocopherol transfer protein gene (TTPA) on chromosome
8q13.1 [36]. This protein normally supports the production
of low density lipoproteins in the liver by incorporations of
α-tocopherol (vitamin E). The resulting vitamin E deficiency
leads to Purkinje neurons defect in cerebellum [37]. Abe-
talipoproteinemia and neuroacanthocytosis syndromes, char-
acterized by mutations in the microsomal triglyceride trans-
fer protein gene (MTTP), lead to irregularity in the fat ab-
sorption and are also a source of AVED [38-40].
Current and Promising Therapies in Autosomal Recessive Ataxias CNS & Neurological Disorders - Drug Targets, 2018, Vol. 17, No. 3 165
Table 2. Treatments in recessive ataxias.
Recessive Ataxias Approved and Supportive Potential
Friedreich’s ataxia - Vitamin E with Coenzyme Q10
Inteferon gamma
Gene therapy
Ataxia with vitamin E deficiency Vitamin E -
Wilson’s disease D-penicillamine
Trientine
Zinc
Tetrathiomolybdate
Gene therapy
Ataxia-telangiectasia Physical, occupational and speech therapies,
Dopamine agonist, anticholinergics, SSRI
Betamethasone/Dexamethasone
Gene therapy
Refsum’s disease 1. Dietary restrictions
2. Plasmapheresis
3. Lipid apharesis
Liver transplantation
Cerebrotendinous xantomatosis Chenodeoxycholic acid
Ursodeoxycholic acid
Cholic acid
Taurocholic acid
-
Niemann-Pick disease Miglustat Cyclodextrin
Histone deacetylase inhibitors
Gene therapy
Ataxia with oculomotor apraxia - -
ARSACS Baclofen -
SSRI selective serotonin reuptake inhibitors; ARSACS autosomal recessive spastic ataxia o f Charlevoix-Saguenay.
AVED patients have a clinical syndrome with many fea-
tures resembling FRDA. They exhibit a progressive ataxia
with dysarthria, areflexia, cardiomyopathy and peripheral
neuropathy. However, the patients usually have retinitis
pigmentosa and head tremor which help to distinguish from
the clinical presentation of FRDA [41, 42]. Abetalipopro-
teinemia also specifically includes a vitamin A deficiency-
associated progressive retinal degeneration, acanthocytosis,
low serum triglycerides/total cholesterol and an absence of
serum beta-lipoproteins [40, 43]. Diagnosis of AVED is
based on clinical findings, low plasma level of vitamin E and
genetic testing for a mutation in TTPA [44]. Neurological
features in all forms of AVED can be improved with high
doses of vitamin E and other fat-soluble vitamins supple-
mentation [44].
2.3. Wilson’s Disease
Samuel Alexander Kinnier Wilson first described the
familial nervous system disease with cirrhosis in 1912 [45].
Wilson’s disease (WD) is characterized by reduced biliary
excretion of copper which initiates a copper accumulation in
the brain and in the liver, such as other organs. It is caused
by mutations in ATP7B gene which encode a copper-
transporting P-type ATPase [46-48]. The resulting copper
accumulation leads to mitochondrial dysfunctions with oxi-
dative stress and free radical formation [49]. An untreated
WD will occasion liver cirrhosis accompanying with a se-
vere neurologic disorder and ultimately death. WD generally
presents in young adult but is also well described in infants
and adults over 70 years of age. The typical neurological
features include dystonia, parkinsonism, dysarthria and flap-
ping tremor. Though, ataxia is rarely the primary complaint.
In addition, almost every patient with neurologic features
have Kayser-Fleischer rings and psychiatric symptoms can
be present, along with abnormal behaviours, personality
changes and cognitive impairment [49].
Wilson’s disease is one of the rare treatable recessive
ataxias but treatment must be lifelong. Treatment can be
achieved by removing the accumulated copper in the acute
phase and by preventing the subsequent accumulation with a
maintenance drug. The copper chelators D-penicillamine and
trientine are the first-line therapies for copper removing.
They act by binding copper in blood and tissues and drive its
urinary excretion. Zinc salt is an alternative treatment wh ich
inhibits the intestinal absorption of copper. It is particularly
effective to prevent subsequent tissue accumulation but has
low de-coppering capacity [49]. While the hepatic symptoms
are usually improved by copper chelators, the outcomes on
neurological symptoms are less notable. A recent study sug-
gested that only 55% of patients noticed an improvement in
166 CNS & Neurological Disorders - Drug Targets, 2018, Vol. 1 7, No. 3 Picher-Marte l and Dup ré
their symptoms after 4 years of treatment [50]. It is also im-
portant to note that worsening of neurological symptoms can
be reported after introduction of D-penicillamine in ap-
proximately 10% of patients [51]. Indeed, it has been sug-
gested that initial copper removing from tissues raises the
copper blood level which is toxic to the brain [52]. Another
copper chelator, tetrathiomolubdate (TTM) appeared to be a
promising alternative but is not yet approved. TTM had the
advantages of fast acting, since it can restore copper level in
few weeks instead of months, and have a superior capacity of
reducing the free blood copper [53]. Finally, in addition to
pharmacological treatment, it is also recommended to adopt
a low copper diet.
The only curative treatment for WD is liver transplanta-
tion and it is considered only for liver failure or decompen-
sated cirrhosis. However, there are not enough evidences to
support the liver transplantation for patients with predomi-
nant neurologic features [54, 55]. This lack of curative
treatment for neurologic WD opens the gate for new auspi-
cious therapies such as gene therapy or hepatocyte transplan-
tation. Several groups have tried these approaches but failed
to demonstrate any long-term positive effect on animal mod-
els [56, 57]. However, AAV has recently been used for the
expression of ATP7B gene in a WD mouse model and shown
promising results. The authors observed a long-term restora-
tion of physiological copper excretion, a decreased copper
accumulation and a reduction in liver injury in mice treated
with AAV-ATP7B [58].
2.4. Ataxia-telangiectasia
Ataxia-telangiectasia (A-T) is a multisystem disorder
caused by mutations in the ataxia-telangiectasia mutated
gene (ATM) on chromosome 11q22.3 [59]. The ATM protein
is mostly implicated in the coordination of cellular responses
to DNA double-strain breaks and in oxidative stress [60].
The clinical spectrum of symptoms is wide and highly vari-
able between patients. The first neurological symptom is
progressive ataxia beginning when the children start to walk
and they eventually reach the requirement for a wheelchair in
their teenage [61]. The patients also develop involuntary
movements (choreathetosis, dystonia and tremors), abnormal
eye movements, oculocutaneous telangiectasia, dysphagia
and immune deficiency. The patients are also at higher risk
of developing pulmonary diseases, cancers, diabetes mellitus
and are particularly sensitive to radiations [61]. The early
diagnosis can be hard to make since the disorder is rare and
the telangiectasia appears only in the later phase. However,
the typical clinical presentation associated with elevated se-
rum α-fetoprotein makes the diagnosis very probable for A-
T. The confirmed diagnosis can be made with cultured cells
or by the identification of a pathological mutation in the
ATM gene.
There is currently no therapy that modifies the progres-
sion of A-T, though it is possible to reduce some of the neu-
rological symptoms. Clinicians have observed an improve-
ment of involuntary movements with dopamine agonists and
anticholinergics. Some ataxia symptoms, such as loss of bal-
ance, may respond to the selective serotonin reuptake inhibi-
tors (SSRI) fluoxetine or to the anxiolytic buspirone [62]. A
case series proposed that betamethasone could reduce symp-
toms of ataxia [63]. To test this hypothesis, a randomized
controlled trial was conducted on 13 A-T patients from 3 to 8
years of age. A reduction of 13 (-19 to -5.5) points in the
ICARS score was observed in the betamethasone group
compared to placebo group after 31 days of treatment [64].
However, the long-term safety of betamethasone remains to
be tested. Following this trial, a single-arm, open-label Phase
II trial, was conducted with a new delivery method [65]. The
encapsulation of dexamethasone into autologous erythro-
cytes allowed a one month sustained low infusion and re-
duced the side effects normally seen with long-term corticos-
teroids. After 6 months of monthly injection on 22 A-T pa-
tients, the authors observed a reduction of 4 points (-7.1 to -
0.9) in the ICARS scores. These studies suggest that corticos-
teroids may be beneficial for A-T patients but more works
remain to be performed to clarify the treatment posology.
A recen t study proposed that the beneficial effects of
corticosteroids may come from their antioxidant properties
[66]. Indeed, the antioxidant therapy approach with different
drugs has been tested in many pre-clinical studies in the last
decade [67-69]. Lavin MF et al. previously reviewed ongo-
ing clinical trials on antioxidan t or combined therapies [62].
Unfortunately, none of these trials are available in the cur-
rent literature, suggesting inconclusive or negative results on
neurological outcomes. Finally, gene therapy approaches,
using herpes simplex virus and AAV, have demonstrated
interesting results in animal models but have not yet been
tested in humans [70, 71].
2.5. Refsum’s Disease
First described in 1946, Refsum’s disease (RD) is caused
by mutations in either Phytanoyl-CoA Hydroxylase (PHYH),
also called PAHX, or PTS2 Receptor (PEX7) genes [72, 73].
It is characterized by the accumulation of phytanic acid (PA)
which is normally degraded by the phytanoyl-CoA hydroxy-
lase. The pathogenesis is not well understood but a mem-
brane distortion caused by the excessive incorporation of PA
has been suggested [74]. We can classify RD into classical,
adult or infantile forms. The infantile RD is distinguishable
by the early onset, hepatic and cerebral dysfunction with
dysmorphia, developmental abnormalities and death in in-
fancy. The classical form of RD starts in teenage and the
patients exhibit retinitis pigmentosa, anosmia, polyneuropa-
thy, deafness, ataxia, cardiac arrhythmias and ichthyosis. The
diagnosis requires elevated plasma level of PA over 200
μmol/L with either genetic testing or enzyme analysis. A n
increased level of cerebrospinal fluid proteins can also sup-
port the diagnosis [75].
The handling of RD is separated into the chronic mainte-
nance and into the treatment of the acute presentation. The
maintenance is based on dietary restrictions of PA-containing
meals. PA is mostly present in dairy products, animal fats and
green vegetables. The average consumption of PA is esti-
mated to be around 50-100 mg/day and the treatment aim is
to reduce the intake to less than 10 mg per day. A retrospec-
tive study on 13 patients succeeds to demonstrate a reduction
of 89±11% of plasma PA with dietary restriction only [76].
The reduction of plasmatic PA level was generally sufficient
to stop the progression of neurological symptoms but did not
entirely resolve them [75]. To assure the appropriate intake
Current and Promising Therapies in Autosomal Recessive Ataxias CNS & Neurological Disorders - Drug Targets, 2018, Vol. 17, No. 3 167
of micronutrients with the low-PA diet, the fat-soluble vita-
mins, vitamin B12, copper and selenium have to be periodi-
cally monitored. However, no regular supplementation is
recommended [77]. In addition to low-PA diet, patients are
advised to avoid rapid weight loss and fasting which can
stimulate lipolysis and increase PA level. The acute presenta-
tion can be controlled by plasmapheresis or lipid apheresis.
A case series of 4 patients has also suggested that lipid
apheresis can be a long-term treatment since this method is
well tolerated and efficient [78]. Liver transplantation has
been tried for infantile Refsum’s Disease and has managed to
significantly improve the neurological outcomes of these
young patients [79, 80].
2.6. Cerebrotendinous Xantomatosis
Cerebrotendinous xantomatosis (CTX) is a rare disorder
of bile metabolism caused by mutations in CYP27A1 gene on
chromosome 2q33. This gene encodes for the mitochondrial
sterol 27-hydroxylase implicated in the oxidation of choles-
terol into 27-hydroxycholesterol, which is subsequently
needed for bile acid formation [81]. The enzyme dysfunction
leads to an accumulation of cholesterol and cholestenol in
almost all tissues. The mechanisms underlying neurodegen-
eration are not well described but it is suggested that accu-
mulation of cholestenol in the brain can affect myelin forma-
tion or disrupt the blood-brain barrier [82]. The mean age at
onset is 19 years of age (10-50) but the delay in diagnosis
can easily reach 20 years [83]. Neurological features are of-
ten the initial symptoms and include ataxia, parkinsonism,
upper motor neuron weakness, epilepsy, intellectual disabil-
ity, dementia, psychiatric symptoms, dystonia and peripheral
neuropathy. The systemic non-neurological symptoms are
composed of premature cataracts, xanthomas, hypothyroid-
ism, atherosclerosis and cardiovascular disease. Infantile
diarrhea and neonatal cholestatic jaundice precede the onset
of symptoms by many years [84]. Although the confirmed
diagnosis is made with genetic analysis, typical neuroimag-
ing and laboratory findings strongly suggest the diagnosis.
An elevated blood cholestanol concentration and an in-
creased bile alcohol concentration in urine and plasma also
suggest the diagnosis. Magnetic resonance imaging can re-
veal cerebellar atrophy and bilateral cerebellar lesions in
dentate nuclei [84].
Rep lacement therapy is the treatment of choice for CTX.
A supplementation of bile acids is thought to reduced chole-
stanol concentration by activating the bile acid negative
feedback. Chenodeoxycholic acid (CDCA), ursodeoxycholic
acid (UDCA), cholic acid and taurocholic acid are currently
available for treatment of CTX [85, 86]. An important reduc-
tion in neurological symptoms and an improvement of elec-
troencephalograms and imaging was observed in a clinical
trial on 17 patients treated with CDCA [87]. CDCA is the
therapy of choice to reduced neurological symptoms whereas
cholic acid is particu larly efficient for non-neurological
symptoms. CDCA treatment must be started during the early
phase for efficient prevention of neurological deterioration
[88]. The recommended posology is 750 mg/day divided into
three doses and 15 mg/kg per day for children. However, a
recent case report suggested that 15mg/kg was hepatoxic in
infants and a maximum of 5 mg/kg/day was non-toxic and
efficient [89].
2.7. Niemann-Pick Disease Type C
Niemann-Pick disease (NP) is a group of lipid storage
disorders grounded on the description of Albert Niemman
and Ludwig Pick in the 1920s. NP type A and B are charac-
terized by a defect in sphingomyelinase acid production
while a defect in intracellular lipid trafficking is involved in
the pathogenesis of NP type C (NP-C) and leads to the ac-
cumulation of cholesterol and glycosphingolipids in tissues
[90]. NP-C is caused by mutations in NPC1 (90%) or NPC2
(4%) [91, 92] genes, both encoding for intracellular choles-
terol transporters which function together. The age at onset
can vary from the prenatal period to the late adult age and
the patients with early manifestations are normally dying
between 10 and 25 years of age [90].
The symptoms of NP-C are dependant on the age at on-
set. In prenatal and neonatal periods, the features include
hydrops fetalis, fetal ascites, jaundice and cholestatic hepa-
topathy. The infants also develop hepatosplenomegaly as a
major manifestation. However, the most common form of
NP-C begins between 6 and 15 years of age and is mostly
characterized by neurological manifestations. An ataxic syn-
drome accompanied by movement disorders, dysphagia, ver-
tical supranuclear ophthalmoplegia and cataplexy is typical
of the juvenile presentation. While the young also develop
behavioral problems accompanied by learning and writing
difficulty, the adults can develop psychiatric symptoms and
dementia. A suspicion index (SI) has been created to help the
diagnosis of NP-C [93]. The index attributes determined
points to each NP-C manifestation and separates the diagno-
sis between high, moderate and low probability. A high sus-
picion index should be referred for genetic analysis.
Miglustat, an inhibitor of glucosylceramide synthase, the
enzyme that catalyzes glycosphingolipids synthesis, is th e
only approved treatment with recognised efficacy in reduc-
ing neurological symptoms [94]. A randomized-controlled
12-months duration trial of 29 patients showed an improve-
ment in horizontal saccadic eye movement velocity, ambula-
tion, cognition and dysphagia [95]. A long-term extension
trial and a retrospective observational study also confirmed
these findings and suggested that disease progression can be
delayed with miglustat [96, 97]. The treatment regimen for
adults (≥12 years of age) is 200 mg three times a day and the
dose is calculated per body surface area under the age of 12
[95].
Cyclodextrin, a cholesterol chelator, has been shown to
be effective in mice models [98, 99]. Two patients were
treated with cyclodextrin in an initial clinical study [100].
The drug was partially effective in reducing hepatosple-
nomegaly but no effect on neurological outcomes was noted,
probably because of its incapacity to cross the blood-brain
barrier. To overcome this difficulty, the authors have per-
formed intrathecal injection of cyclodextrin in one patient
with the use of an Ommaya reservoir. The neurological
symptoms remained stable over a two years period [101].
Finally, the quest for a curative treatment is still ongoing
and promising therapies are drawing attention into the litera-
ture. Histone deacetylase inhibitors have shown some effec-
tiveness in reducing cholesterol storage in fibroblasts and in
reducing neurological symptoms in mouse models [102-
168 CNS & Neurological Disorders - Drug Targets, 2018, Vol. 1 7, No. 3 Picher-Marte l and Dup ré
105]. A phase III clinical trial is currently ongoing but the
results ar e not yet available. Recently, intracardiac injection
of AAV9-NPC1 gene in mice resulted in longer Purkinje cell
survival, increased lifespan and improved locomotor activity
[106].
2.8. Ataxias with Oculomotor Apraxia
Ataxias with oculomotor apraxia are a group of 4 reces-
sive ataxias with associated gene mutations: type 1 (AOA1)
is caused by mutations in APTX, type 2 (AOA2) by muta-
tions in SETX, type 3 (AOA3) by mutations in PIK3R5 and
type 4 (AOA4) by mutations in PNKP. All four types can be
differentiated by age at onset and variable degrees of symp-
toms. AOA1, the most severe AOA and the second most
common ARCA in Japan and Portugal, is characterized by
the onset of cerebellar ataxia and severe oculomotor aprax ia
at 4 (2-10) years of age. Patients with oculomotor apraxia
have difficulty with object fixation and have limited and
slow gaze. The other neurological findings include an axonal
peripheral neuropathy, as well as areflexia, dystonia, chorea
and cognitive deficits. Peculiar findings for each AOA are
shown in Table 1. The diagnosis is suggested by cerebellar
atrophy in cerebral imaging, axonal neuropathy on EMG and
genetic analysis. The treatment is mainly symptomatic and a
wheelchair is often necessary by 15-20 years of age.
2.9. Autosomal Recessive Spastic Ataxia of Charlevoix-
Saguenay
First described in the 70’ in the Charlevoix-Saguenay
region of Quebec, the autosomal recessive spastic ataxia of
Charlevoix-Saguenay (ARSACS) is now described world-
wide [107, 108]. It is caused by mutations in the ARSACS
gene on chromosome 13q12.12 which encodes the sacsin
protein [109]. The exact role of sacsin is not well described
but it seems to have a chaperone activity together with
Hsp70, which is implicated in aggregates clearing in many
neurodegenerative diseases [110]. Progressive spasticity is
the initial symptom observed in infants with ARSACS. They
also developed dysarthria, cerebellar ataxia with distal mus-
cle atrophy and nystagmus. Two findings can help distin-
guish ARSACS from the other recessive ataxias. Abnormal
myelination process may cause myelinated fibers radiating
from the optic disk on fundoscopy examination. It is also
possible to observe brisk reflexes in the middle stage of the
disease as compared to most recessive ataxias where the re-
flexes are usually decreased. Babinski’s sign is present in
almost of all cases. The diagnosis is suggested by the combi-
nation of a typical neurological examination with MRI imag-
ing which demonstrates atrophy mostly in the cerebellar
vermis. Abnormal fundoscopy and signs of a severe axonal
neuropathy confirmed on nerve conduction studies are elec-
tromyography can also improve diagnostic accuracy [108].
The diagnosis is confirmed with genetic analysis. Unfortu-
nately, there is no effective treatment for ARSACS. Baclofen
can be useful to reduce spasticity and prevent joint contrac-
tures in the early phases of the disease.
CONCLUSION
The differential diagnosis of ARCA is not easy to per-
form with clinical findings since the peculiar features are not
always present in early phases of the diseases. The accessi-
bility of the gen etic tests has completely changed the clinical
approach. It is now easier to perform the precise diagnosis
and includ e patients into the appropriate clinical trials. Hope-
fully, this will increase the number of patients in clinical
trials and these will eventually result in potential therapies.
Gene therapy approach is one of the potential treatments in
many ARCAs since most of them result from a lost-of-
function mechanism and replacement of that mutated protein
could correct the metabolic dysfunction. This approach has
been clinically tested in other neurological diseases such as
amyotrophic lateral sclerosis and gave promising results with
advanced delivering technologies [111]. Successfully, this
approach recently led to the first medical therapy for spinal
muscular atrophy [112]. Although few recessive ataxias are
treatable, more research must be performed for most ARCAs
if we are to improve patient care over the next decade.
LIST OF ABBREVIATIONS
AAV = Adeno-associated Viral
AOA = Ataxia with Oculomotor Apraxia
ARCA = Autosomal Recessive Cerebellar Ataxias
ARSACS = Autosomal Recessive Spastic Ataxia of Char-
levoix-Saguenay
A-T = Ataxia-telangiectasia
ATM = Ataxia-telangiectasia Mutated
AVED = Ataxia with Vitamin E Deficiency
CDCA = Chenodeoxycholic Acid
CTX = Cerebrotendinous Xantomatosis
EMG = Electromyography
FARS = Friedreich Ataxia Rating Scale
FRDA = Friedreich’s Ataxia
FXN = Frataxin
GAA = Guanine-adenine-adenine
ICARS = International Cooperative Ataxia Rating Scale
IFNγ = Inteferon Gamma
MRI = Magnetic Resonance Imaging
MTTP = Microsomal Triglyceride Transfer Protein
NP = Niemann-Pick Disease
NP-C = Niemann-Pick Disease Type C
PA = Phytanic Acid
PHYH = Phytanoyl-CoA Hydroxylase (PAHX)
PTS2 = Peroxisomal Targeting Signal Receptor
(PEX7)
RD = Refsum’s Disease
SSRI = Selective Serotonin Reuptake Inhibitors
TTM = Tetrathiomolubdate
TTPA = α-tocopherol Transfer Protein
UDCA = Ursodeoxycholic Acid
WD = Wilson’s Disease
Current and Promising Therapies in Autosomal Recessive Ataxias CNS & Neurological Disorders - Drug Targets, 2018, Vol. 17, No. 3 169
CONSENT FOR PUBLICATION
Not applicable.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or
otherwise.
ACKNOWLEDGEMENTS
V.P-M. MD is a neurology resident and PhD student who
holds a Frederick Banting and Charles Best doctoral scholar-
ship from Canadian Institutes of Health Research (CIHR).
N.D. MD-MSc. is funded by CIHR and by Canadian Consor-
tium on Neurodegeneration in Aging (CCNA). V.P-M. per-
formed the review of the literature, wrote the paper and pre-
pared the tables and the figure. N.D. reviewed the paper and
supervised the project.
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PMID: 29676235
