Ataxia is a neurological manifestation characterized by the loss of truncal balance
and incoordination of limbs. Among various neurological diseases presenting with ataxia
as the main symptom, neurodegenerative diseases comprise the majority, which are usually
classified as sporadic and hereditary ataxias from the viewpoint of genetics. Hereditary
ataxias are further classified on the basis of the mode of inheritance into diseases
with autosomal dominant, autosomal recessive, and X-linked inheritances. Hereditary
spastic paraplegias (HSPs) are occasionally included in hereditary ataxias owing to
some overlaps of ataxia as part of the clinical presentations of HSPs.[1] In addition to sporadic and hereditary ataxias, various diseases may also present
with ataxias, which include mitochondrial diseases, congenital diseases, metabolic
diseases, autoimmune diseases, remote effects of malignancies, infectious diseases,
and intoxications.
With recent remarkable advances in molecular genetics studies, many causative genes
have been discovered in hereditary ataxias. Although these advances no doubt contribute
to a better understanding of hereditary ataxias, we are now facing the difficulty
in conducting comprehensive genetic tests to establish the molecular diagnosis of
patients with hereditary ataxias, because they are costly.[2] Through the genetic tests of hereditary ataxias, we have learned that the molecular
epidemiology of hereditary ataxias varies considerably among populations.[1] For example, while Friedreich's ataxia is the most common hereditary ataxia with
autosomal recessive inheritance in European descent populations, we have never encountered
a single case of Friedreich's ataxia in the Japanese population. In contrast, spinocerebellar
ataxia type 3 (SAC3), also called Machado–Joseph disease (MJD), is the most common
form of hereditary ataxia with autosomal dominant inheritance worldwide, despite the
historical background that families with MJD were originally described in those originated
from Azores, Portugal. Thus, neurologists need to consider not only the clinical presentations
of individual hereditary ataxias but also the molecular epidemiology of hereditary
ataxias to consider the algorithm of genetic tests for hereditary ataxias. The selection
of appropriate diagnostic tests is important to save costs for genetic tests. To accomplish
this, we need to have sufficient knowledge of the clinical presentations and epidemiology
of individual diseases.
To facilitate diagnostic approaches, detailed epidemiological data of not only hereditary
ataxias but also other diseases should be taken into consideration. Although many
molecular epidemiological studies focusing on hereditary ataxias have been reported,
only a limited number of comprehensive epidemiological studies focusing on diseases
other than hereditary ataxias, including sporadic ataxias and other various forms
of ataxias as described below, have been published to date.
As described in the paper published in this journal, Massuyama et al.[3] conducted a large-scale cross-sectional analysis of 1,332 patients with various
forms of ataxias evaluated over 17 years at a single ataxia center, the Ataxia Unit
at the Hospital São Paulo, in São Paulo, Brazil. They successfully established the
diagnosis of 744 patients (55.9%), including 101 sporadic ataxia, 326 spinocerebellar
ataxias (SCAs) (ataxias with autosomal dominant inheritance), 186 ARCAs (ataxias with
autosomal recessive inheritance), 6 X-linked ataxias, and 51 HSPs. Among the hereditary
ataxias with autosomal dominant inheritance, MJD/SCA3 is the most common type as similarly
observed worldwide in previous studies.[1] Of interest, among the 17 patients with SCA6, 15 were Japanese descendants, raising
the possibility that this relatively higher prevalence of SCA6 reflects the historical
background that the city of São Paulo has been the main immigration destination of
Japanese people. In contrast, the paper describes only a limited number of patients
with SCA31 or those with dentatorubral-pallidoluysian atrophy (DRPLA), which are also
relatively common types of hereditary ataxia with autosomal dominant inheritance in
the Japanese population. Thus, we may need to further investigate the details of the
Japanese immigration in relation to the original regions of the Japanese immigrants
in Japan. Note that even in the Japanese population, the molecular epidemiology of
hereditary ataxias shows considerably different regional differences.[4]
[5] In the ataxias with autosomal recessive inheritance identified in this study, Friedreich's
ataxia was the most common type, as it has been observed similarly in European descent
populations.
With regard to the sporadic ataxia group, the most common diagnosis was multiple system
atrophy (MSA) (n = 51). MSA is a devastating neurological disease presenting with various combinations
of autonomic symptoms, ataxia, and parkinsonism. The accurate diagnosis of MSA is
often difficult, especially at the early stage. Special attention should be paid to
the epidemiology of MSA since the relative frequencies of MSA-C (a subtype of MSA
mainly presenting with ataxia) and MSA-P (a subtype mainly presenting with parkinsonism)
differ between European descent populations and East Asian populations.[6]
[7] The relative frequencies of MSA-C and MSA-P in the Brazilian population would be
helpful in the investigation of the epidemiology of MSA in Brazil. Since patients
with MSA-P may not have been referred to the ataxia center, epidemiological investigation
of MSA should be further broadened to include patients with MSA-P.
Importantly, the study by Massuyama et al. further identified patients with other
ataxias, which include cerebellar alcohol degeneration (n = 12), anti-glutamic acid decarboxylase (GAD; n = 4), Chiari malformation type 1 (n = 4), HIV (n = 3), infections (n = 3), stroke (n = 3), and vitamin B12 deficiency (n = 3). Of note, there were 8 immune-mediated cerebellar ataxias, including the Sjogren
syndrome (n = 2), as well as those with the neuronal antigens anti-GAD (n = 4), anti-Hu (n = 1), and anti-Yo (n = 1). These observations strongly emphasize the necessity to include various forms
of ataxias in the differential diagnosis of ataxias in clinical practice. In particular,
it should be emphasized that treatable diseases are included in this group.
As described by the authors, the diagnosis was not established in 588 (44.1%) of the
1,332 patients with various forms of ataxias. Thus, further investigations based on
broad research disciplines are encouraged to better understand the diseases with ataxias.
In the field of molecular genetics, investigations focusing on dynamic aspects of
the human genome, including expanded tandem repeats, imprinting, de novo mutations, mosaicisms, and epigenetic changes, should be explored.[8]
[9]
[10] The development of highly effective therapies based on the elucidated disease mechanisms
is the ultimate goal of these molecular genetics research studies.
Bibliographical Record
Shoji Tsuji. Ataxias in Brazil. Arq Neuropsiquiatr 2024; 82: s00441788782.
DOI: 10.1055/s-0044-1788782
