Review article
Huntington's disease-like disorders in Latin America and the Caribbean

https://doi.org/10.1016/j.parkreldis.2018.05.021Get rights and content

Highlights

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    Resources for genetic diagnosis are limited in Latin America and the Caribbean and require significant improvement.

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    International collaborations play a critical role in developing these resources.

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    A number of patients affected by rare choreas have been reported.

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    Genetic, ethnic, and socio-cultural factors play roles in the appearance of these disorders.

Abstract

Diseases with a choreic phenotype can be due to a variety of genetic etiologies. As testing for Huntington's disease (HD) becomes more available in previously resource-limited regions, it is becoming apparent that there are patients in these areas with other rare genetic conditions which cause an HD-like phenotype. Documentation of the presence of these conditions is important in order to provide appropriate diagnostic and clinical care for these populations. Information for this article was gathered in two ways; the literature was surveyed for publications reporting a variety of genetic choreic disorders, and movement disorders specialists from countries in Latin America and the Caribbean were contacted regarding their experiences with chorea of genetic etiology. Here we discuss the availability of molecular diagnostics for HD and for other choreic disorders, along with a summary of the published reports of affected subjects, and authors' personal experiences from the regions. While rare, patients affected by non-HD genetic choreas are evidently present in Latin America and the Caribbean. HD-like 2 is particularly prevalent in countries where the population has African ancestry. The incidence of other conditions is likely determined by other variations in ethnic background and settlement patterns. As genetic resources and awareness of these disorders improve, more patients are likely to be identified, and have the potential to benefit from education, support, and ultimately molecular therapies.

Introduction

As access to testing for Huntington's disease (HD) increases worldwide, it is becoming apparent that a number of patients with an HD-like phenotype test negative for this disease [1,2]. Patients with “HD-like” disorders, which include HD-like 2 (HDL2), the inherited ataxias, c9orf72 disease, chorea-acanthocytosis (ChAc), McLeod syndrome, and others [3,4], are rare, however the gradual improvement of genetic testing resources means that these patients are increasingly being identified. The aim of this article is to summarize the situation regarding patients with an HD-like phenotype, who test negative for HD, in Latin America and the Caribbean.

A systematic survey of the prevalence of HD and genetic testing resources in Latin America and the Caribbean is beyond the scope of this article; however, some general information is documented regarding these data from a number of different countries in this region.

Section snippets

Methods

The information reported here reflects a survey of the published literature, augmented by the experiences of experts from various countries, gathered in an informal manner. The PubMed database was searched in May 2017 using the term “chorea” in combination with each of the countries of the region. Authors who were likely to have informative experience in this area were identified by colleagues and contacted by email. These authors provided details of their patients who had HD-like disorders

A brief overview of HD in Latin America and the Caribbean

The presence of patients affected by HD is well-documented in Latin America and the Caribbean, although this disease is still likely underdiagnosed [5]. Estimation of prevalence with any degree of accuracy is challenging, however, reported prevalence ranges from 0.5/100,000 (Venezuela) - 4/100,000 (Mexico City) (compared with 4–7/100,000 in the US) [5]. It is worth noting that studies of patients from the community devastatingly affected by HD at Lake Maracaibo in Venezuela were critical in

The availability of HD genetic testing

The identification of HD-like disorders requires the exclusion of HD, which is not yet readily available in a number of countries. For example, in a middle-income country such as Argentina, despite the development of a genetic diagnosis program at the national level since 2008, genetic testing for HD and other genetic disorders is not uniformly available. There are gaps in the interactions between services, with duplication and inefficiencies, and the absence of a national system for genetics

Huntington's disease-like 2 (Fig. 1; video 1)

HDL2 was first described in an African-American family presenting in the 3rd or 4th decade with chorea, dystonia or parkinsonism, and progressive cognitive deficits [34]. Similar to HD, HDL2 is inherited in an autosomal dominant manner and is due to a CTG trinucleotide repeat expansion [35,36]. The prevalence of HDL2 depends very much upon the ethnic make-up of the population studied - all HDL2 patients reported to date have been of African ancestry [2,34,35,[37], [38], [39]], likely due to an

Benign hereditary chorea

Two families with autosomal dominant benign hereditary chorea due to mutations of NKX2-1 have been reported from Brazil [106,107].

Autosomal recessive disorders

Autosomal recessive diseases are likely to be relatively common in Latin America and the Caribbean, due to the patterns of settlement and the tendency of communities to remain geographically isolated, with a high rate of consanguineous marriages.

Aceruloplasminemia

Two siblings with aceruloplasminemia (autosomal recessive) have been reported from Brazil [109]; the proband presented with psychiatric symptoms and neither patient was reported to have significant neurological abnormalities.

McLeod syndrome (Fig. 3)

Similar to ChAc, McLeod syndrome can present with a wide range of neurologic phenotypes including chorea, tics, dystonia, parkinsonism, seizures, peripheral neuropathy, and psychiatric symptoms [79,99]. The phenotype is more variable in severity than ChAc, and very mild neurological phenotypes have been reported. McLeod syndrome typically affects middle-aged males [99]. Due to its extreme rarity it is difficult to estimate the prevalence of this condition, however, it may be approximately

Discussion

While HD is clearly documented to be present in many Latin American and Caribbean countries, patients are also diagnosed with the rarer HD-like diseases when resources are available (Table 1). A comparison of the numbers of patients diagnosed with the sizes of the populations, and indeed, the absence of identified cases from a number of countries, indicates that these disorders are likely to be present and underdiagnosed, or at least under-reported. This is likely due to a variety of factors,

Conclusions

In addition to HD, a number of HD-like disorders have been identified in Latin America and the Caribbean. Many patients are likely undiagnosed for a number of reasons, including lack of access to medical specialists, lack of awareness of these conditions amongst physicians, and limited diagnostic resources.

As molecular therapies for genetic disorders become possible, it becomes more important to improve access to diagnostic tests in order to make these therapies available to all affected

Financial disclosures

EMG has received honoraria from Genzyme –Sanofi and served as external advisor for Glaxo Smith Klein, Tuteur, Bago, and Allergan.

OBP has received honoraria from Boehringer, Biopas, and Medtronic.

LMB has no disclosures.

FC has received honoraria from Roche and Teva, and for serving on the advisory board of Zambon.

RMC has no disclosures.

PC has no disclosures.

MC-O has no disclosures.

IEB has received honoraria from UCB, Boehringer, Sanfer, and Medtronic.

RL-Ca has no disclosures.

RL-Co has no

Financial disclosure/conflict of interest

None of the authors have any financial disclosures or conflicts of interest relevant to this work.

Funding

None.

Acknowledgements

Illustrations by Christopher M. Smith, CMI, and Jill Gregory CMI. Thanks to Dr. Adrian Danek for providing information regarding the distribution of patients with chorea-acanthocytosis. The work reported here is unfunded.

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