Vestibular Pathology as Early Finding of Friedreich’s Ataxia in a 16 Years Old Woman

Abstract

Friedreich’s ataxia is degenerative disease frequently starting around puberty and it’s characterized by a progressive gait ataxia, limb weakness, apparition of Babinsky sign, loss of deep tendon reflex, dysarthria and skeletal deformities. The development of vestibular pathology is common but not completely understood. A 16 years old woman with early vestibular defects in relation to a latter Friedreich’s ataxia diagnosis is reported.

Introduction

Friedreich ataxia is the most frequent form of inherited ataxias [1–5] with an estimated carrier frequency of 1/50 − 1/100 in the general population and a disease incidence between 1/20000 and 1/250000 [1]. Friedreich ataxia is an autosomal recessive degenerative disease frequently starting around puberty and it’s characterized by a progressive gait ataxia, limb weakness, apparition of Babinsky sing, loss of deep tendon reflex, dysarthria, and skeletal deformities [1–4]. In addition, hypertrophic cardiomyopathy is found in almost all patients, diabetes mellitus in about 12% and carbohydrate intolerance in 49% [1, 4]. The natural history is a slow progression over decades with increasing dependence for daily activities [1, 5].

Some studies on Friedreich ataxia patients report abnormal vestibular functions that suggest the impairment of the vestibular system [1]. Hearing tends to be normal, but some patients frequently report speech perception problems [1]. Oculomotor abnormalities are common in these patients too. These defects include saccadic dysmetria, impaired smooth pursuit, gaze instability and gaze nystagmus with ocular flutter or square wave jerks [1, 5].

The most common cause of death is complications of cardiomyopathy. The average time from onset to death is about 36 years [2–4].

Case Report

A 16 years old woman complains about instability after COVID 19 infection 4 months ago. There is not episodic oscillopsia, hearing loss, loss of strength or problems in speech perception. The only symptom is the mentioned instability for walking. Before the COVID infection there were no problems.

As medical precedents, pes cavus and scoliosis should be mentioned. Both of them are followed by traumatologists.

With the first exploration, a bilateral impaired vestibulo-ocular reflex (VOR) is identified, but not spontaneous nystagmus, impaired smooth pursuit or other alterations in cerebellar and vestibular systems.

Video head impulse test (V-HIT) and caloric test are made (Figs. 1 and 2). Both of the lateral semicircular canals are impaired in gain in V-HIT and there are few ocular movements when the caloric test is made, but no criteria for hypofunction in the last test (more than 12º/s).There are some square wave jerks in saccades test, but these saccades are accurate. The smooth pursuit is normal in morphology and gain.

Fig. 1.

Video head impulse test results (VHIT), where a reduced gain exists in both of the lateral semicircular canals

Fig. 2.

Caloric test results through Freyss’ graphic, where there are few ocular movements when the ears are stimulated, but there are not criteria for hypofunction

The audition threshold is normal in both of the ears (by tonal audiometry).

Vestibular rehab is offered and made, but there is no profit. In addition, the patient starts feeling loss of sensibility in legs and a neurophysiological study from a private centre shows axonal sensory neuropathy.

The patient is now evaluated by neurology, stablishing a differential diagnosis with some types of spinocerebellar ataxia and CANVAS syndrome.

Some genetic studies are made, and there is a mutation in the frataxin gene, with more than 120 GAA repeats in both copies of the gene.

There is a significant thickening of the myocardial walls typical in hypertrophic cardiomyopathy by echocardiography. There are no complications in this moment due to this pathology.

After exhaustive neurological exploration (with ataxia, absence of tendon reflexes, loss of distal sensitivity and bilateral Babinski sign) and the receipt of the genetic test results, the diagnosis of Friedreich’s ataxia is stablished.

A biannual follow up is made. Two years after the diagnosis, there are not complications due to the myocardial pathology. The instability doesn’t change. The patient can walk, but she refers progressively more difficult for doing it.

Discussion

Friedreich ataxia is the most frequent form of inherited ataxias with a disease incidence between 1/20000 and 1/250000 [1–3]. It is an autosomal recessive neurodegenerative disease frequently starting around puberty [1, 4, 5] with an average age of onset of 10–15 years old [2, 3, 5], and is characterized by a progressive gait ataxia, limb weakness, apparition of Babinski sign, loss of deep tendon reflex, dysarthria and skeletal deformities [1]. In addition, hypertrophic cardiomyopathy is found in almost all patients, diabetes mellitus in about 12% and carbohydrate intolerance in 49% [1].

The natural history is a slow progression of the symptoms over decades with increasing dependence for daily activities [1, 2, 5].

Lifespan is marked reduced with the average time from onset to death being 36 years [2, 3]. The most common cause of death is complications of cardiomiopathy [2], as congestive heart failure or arrythmia [3].

This pathology is due to a mutation of the FXN gene on chromosome 9. In most patients the anomaly is an unstable GAA triplet repeat expansion within intron 1 of FXN [1–3, 5]. Where normal chromosomes contain 7–22 units, chromosomes in Friedreich ataxia can carry 100 to 1300 triplets in both copies of the gene. The intronic GAA expansion silences the FXN gene, resulting in pathologically suppressed levels of the frataxin protein [1, 3], which is essential for an adequate mitochondrial function [1]. A deficiency leads to progressive central and peripheral nervous system damage [1]. Phenotypic variability correlates with the size of expanded triplets [1]. Shorter expansions are often associated with late onset of the disease, slower progression and absence or mild cardiomyopathy and diabetes [1–3].

Previous studies report abnormal vestibular functions by abnormal vestibulo-ocular reflexes (VOR) [1]. Maudoux et al. reported a vestibular dysfunction in the patients of their study. The majority of them present vestibular impairment of canal function for high (by video head impulse test) and middle head velocities (by earth vertical axis rotation) with mostly normal low head velocities canal function (bithermal caloric test) [1]. They also have severe impairment of otolith vestibulospinal function (by cVEMP) [1].

The time constant of earth vertical axis rotation (EVAR) responses is greatly reduced. Shorter time constant can therefore be linked to alteration in the cerebellum [1], but peripheral vestibular lesions can also produce shorter time constant [1].

Other cause that involves the vestibular system in the VOR impairment is the reduced gain in V-HIT (reflex between semicircular canals and oculomotor muscles), due to the absence of central control in the VOR at high head velocity [1].

All the subjects except one could perfectly inhibit the vestibulo-ocular reflex with fixation, and this fact does not support the hypothesis of cerebellar responsibility of VOR anomalies due to the fact of neurons important in VOR suppression are located in the cerebellar flocculus y paraflocculus [1]. The ability to perform a VOR suppression by fixation differentiates Friedreich ataxia from other kinds of cerebellar ataxia [1]. Zeigelboim et al. reported the suppression of the vestibulo-ocular reflex in all the patients of their study too [4].

Responses to otolithic stimulation are abnormal in almost all subjects with absent or high threshold cVEMPs responses. However, when a response is observed, the latencies were normal in almost all subjects. This fact is related with a peripherical vestibular impairment (central pathologies usually present long latencies) [1]. Observation of signs of fatigability of the CVEMP responses could be an argument for neuropathy at the level of the vestibulospinal tract [1].

The vestibular failure limited to middle and high velocities but respecting low head velocities responses and the histopathological findings of no hair cells lesions but gliosis in the vestibular nucleus and abnormalities of the spiral ganglion and vestibular nerve in Friedreich ataxia patients could support the possibility of a vestibular neuropathy with central extension to the vestibular nuclei [1, 5].

Clinically differentiating the different types of cerebellar ataxia can be difficult, and there is often an overlap in neurological signs and symptoms. Although the diagnosis oh inherited ataxias is ultimately genetic, Luis et al. suggest the use of video head impulse test to differentiate them by some features of the study (Table 1) [6].

Table 1

FEATURES	FA	SCA1	SCA2	SCA3
VOR LATENCY	INCREASED	NORMAL	NORMAL	INCREASED
VOR GAIN	LOW	LOW/NORMAL	NORMAL	LOW
COVERT SACCADES	ABSENT	ABSENT	ABSENT	PRESENT
OVERT SACCADES	PRESENT	PRESENT	PRESENT	PRESENT

FA (Friedreich ataxia), SCA1 (Spinocerebellar ataxia type 1), SCA2 (Spinocerebellar ataxia type 2). SCA3 (Spinocerebellar ataxia type 3)

Hearing loss is uncommon in these patients, and the majority of them present normal hearing thesholds [1]. However, they frequently report speech perception problems that could be linked to disorders in the central auditory tracts [1, 5]. In the literature, the incidence of abnormal auditory brainstem responses varies from 30–100% [1].

In addition, oculomotor abnormalities that could be found in Friedreich ataxia patients are fixation instability, dysmetric saccades and saccadic pursuit [1].

Conclusion

Friedreich ataxia is a neurodegenerative disease where vestibular defects could be present. In early cases, vestibular impairment could appear before gait ataxia or others symptoms so, in these cases, to differentiate between this pathology and some kind of vestibulopathy could be difficult. It is recommendable the follow up in patients with some vestibulopathy specially when they are teenagers and to think in this pathology when other symptoms as gait ataxia or loss of distal sensitivity appear.

Funding

There is no funding for preparing this paper.

Declarations

Compliance with Ethical Standards

The author is in accordance with the Code of Ethics of the World Medical Association (Helsinki Declaration).

Ethical Approval

It is not necessary an ethical approval due the absence of investigation with patients.

Conflict of Interest

There are no conflicts of interest or supports for writing and preparing this paper.

Informed Consent

Parents‘ patient have given their consent for preparing and publishing this paper.