Available online 10 November 2022

Abstract

During recent years an increasing number of neurologic disorders due to expanded tri-, tetra-, penta-, or hexa-nucleotide repeat motifs in introns of various genes have been described (neurologic intronic repeat disorders (NIRDs)). The repeat may be pathogenic in the heterozygous or homozygous form. Repeat lengths vary considerably and can be stable or unstable during transmission to the next generation. The most well-known NIRDs are Friedreich ataxia, spinocerebellar ataxia types-10, -31, and -36, CANVAS, C9Orf72 familial amyotrophic lateral sclerosis (fALS), and myotonic dystrophy-2 (MD2). Phenotypically, NIRDs manifest as mono-organ (e.g. spinocerebellar ataxia type 31) or multi-organ disease (e.g. Friedreich ataxia, myotonic dystrophy-2). A number of other more rare NIRDs have been recently detected. This review aims at summarising and discussing previous findings and recent advances concerning the etiology, pathophysiology, clinical presentation, and therapeutic management of the most common NIRDs.

Introduction

An increasing number of neurological and non-neurological disorders are due to a tri-, tetra-, penta-, or hexa-nucleotide DNA repeat expansions of variable size, which either occur in exons or in introns [1]. Among the neurologic intronic repeat disorders (NIRDs) currently nine are known. First discovered were trinucleotide repeat disorders, which are also the most common NIRDs [2]. Since this discovery an increasing number of different NIRDs has been detected, often only in a single family or a few families. This review aims at summarising and discussing previous findings and recent advances concerning the etiology, pathophysiology, clinical presentation, and therapeutic management of NIRDs (Table 1).

Section snippetsMethods

A literature review in the databases PubMed and Google Scholar using the search terms “intronic repeat disorder”, “tri-nucleotide disorders”, “tetra-nucleotide”, “penta-nucleotide”, “hexa-nucleotide”, and “neurologic”, in combination with “intron”, “expansion”, “retraction” and all known names of genes associated with intronic repeat expansion disorders has been conducted. Inclusion criteria were neurological disorder due to an intronic repeat, known gene, and known pathologic expansion size.

Results

The number of NIRDs described as per the end of May 2021 is 9. The phenotype varies considerably between the disorders but also between families and individuals carrying the same repeat in the same gene. Some of the NIRDs are multisystem disorders, affecting not only the brain, peripheral nerves and the muscles but potentially all other organs as well, whereas others only affect the brain. Though there are similarities of the pathophysiolgy between the different NIRDs, knowledge about the

Conclusions

This review demonstrates that NIRDs are an increasingly recognised group of disorders which present with either an early or late onset. They may occur sporadically or are inherited. Inherited NIRDs follow an autosomal dominant or autosomal recessive trait of inheritance. Diagnosing NIRDs requires not only phenotypic information but confirmation of the underlying genetic defect. Therapy of NIRDs is symptomatic and aims at maximising function and reduce complications. Despite efficient treatment,

Funding

No funding was received.

Author contribution

JF: design, literature search, discussion, first draft, critical comments.

Disclosure of interest

The author declares that he has no competing interest.

Informed consent

Was obtained.

Ethics approval

The study was approved by the institutional review board.

Data availability

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

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