Importance of an echocardiogram in the evaluation of ataxia

Abstract

We present the case of a boy in his middle childhood with gait ataxia and loss of reflexes with a 1-year onset. He had a background of an autism spectrum disorder but was otherwise healthy. A paediatric cardiology assessment was requested to investigate possible cardiac involvement associated to his neurological symptoms. Even though he had no cardiac symptoms and a normal electrocardiography, the echocardiogram revealed severe asymmetric left ventricle hypertrophy consistent with hypertrophic cardiomyopathy. This prompted genetic testing and the diagnosis of Friedreich’s ataxia was confirmed.

Background

Friedreich’s ataxia (FRDA) is a neurodegenerative, autosomal recessive, movement disorder with a prevalence of about 1:40 000.^{1 2} It is the most common ataxia in Europe. Most cases are caused by a pathological expansion in the FXN gene that leads to a reduced expression of a mitochondrial protein called frataxin.³

A high suspicion is required for the diagnosis of FRDA, especially in the presence of other neurological/neuropediatric conditions namely autism spectrum disorders which can lead to symptom misinterpretation and delay the diagnosis.

Cardiac evaluation can support the diagnosis and is routinely required since the most common cause of death is cardiomyopathy. Although treatment is supportive it should be initiated in an early stage. Even though some advances have been made through the years, many questions have remained unsolved and the prediction of disease progression is still unknown.

This case report highlights the importance of a careful clinical history and the need for a multidisciplinary evaluation. For example, the trained eye of a paediatric neurologist allowed a timely referral to paediatric cardiology and subsequent genetic diagnosis of a rare and underdiagnosed disease.

Case presentation

We present the case of a boy in his middle childhood with gait ataxia, dysarthria and loss of lower limb reflexes. He had a normal neurodevelopment until the age of 2 when he started with social isolation and a speech disorder, being diagnosed with an autism spectrum disorder by the age of 3½. He was later diagnosed with an intellectual development disorder. He started toe walking at 13 months old with an evolution to a clumsy gait with frequent falls. These findings were interpreted as being a part of the autism spectrum disorder and were not found to be relevant at the time. There was no family history of neurological diseases and the parents were non-consanguineous. By the age of 7 he had presented with changes in his regular walk pattern but he had an otherwise normal examination. At 8 years of age gait ataxia and loss of neuron reflexes was noted. This prompted further investigation and he was referred to paediatric cardiology to investigate cardiac involvement associated to his neurological symptoms. He had no cardiovascular complaints and his physical examination was normal apart from the neurological signs.

Investigations

An electromyography was performed which revealed sensitive axonal polyneuropathy. Additionally, a brain MRI was performed that was reported as normal.

In terms of cardiological investigation, the ECG was normal for his age but the transthoracic echocardiogram revealed a severe left ventricle asymmetric hypertrophy (posterior wall z-score of +5.29 and interventricular septum z-score of +2.35) (figures 1 and 2). Heart function was normal and there was no obstruction to the left ventricular outflow tract. This prompted setting up a cardiac MRI which corroborated the echocardiogram findings and confirmed the diagnosis of hypertrophic cardiomyopathy. There was no late enhancement.

Figure 1.

Parasternal short axis view demonstrating the marked left ventricular hypertrophy. White arrows indicate septal hypertrophy. *Posterior wall hypertrophy. LA, left atrium; LV, left ventricle; RV, right ventricle.

Figure 2.

Parasternal long axis view showing the marked left ventricular hypertrophy. White arrows indicate septal hypertrophy. *Posterior wall hypertrophy. LA, left atrium; LV, left ventricle; RV, right ventricle.

Arterial hypertension was excluded after a normal ambulatory blood pressure monitoring. Additionally, a 24-hour Holter monitoring was performed for risk stratification, which was normal.

With the diagnosis of hypertrophic cardiomyopathy, genetic testing was requested and confirmed the diagnosis of FRDA due to a mutation in the FXN gene.

Differential diagnosis

Ataxias can exist in many forms. They can be acute, chronic, hereditary or non-hereditary. Some other causes of ataxia can be present in children other than FRDA, such as Charcot Marie Tooth disease and ataxia-telangiectasia.

Progressive and chronic ataxias presenting in the paediatric patient are challenging to diagnose, especially when there is a coexisting diagnosis of autism spectrum disorder.

Diagnostic criteria for FRDA have been proposed and reformed since 1976, but there is a consensus that FRDA should be suspected in individuals that present a combination of clinical features and positive family history (consistent with autosomal recessive inheritance). However, a negative family history does not preclude the diagnosis.⁴ The most common symptoms are progressive ataxia of gait and limbs, dysarthria, decrease or loss of position sense and/or vibration sense in lower limbs, pyramidal weakness of the legs and extensor plantar responses, muscle weakness, scoliosis, pes cavus, hypertrophic non-obstructive cardiomyopathy, glucose intolerance, diabetes mellitus, optic atrophy and deafness.

In this case, the first diagnostic tool used was the brain MRI which excluded any possible brain structural changes. More specifically, brain MRI allowed to exclude cerebellar alterations (such as those present in ataxia-telangiectasia, ataxia with ocular apraxia or Niemann Pick type C disease) and more generalised brain changes (such as those present in leukodystrophy, mitochondrial diseases) since in FRDA the brain MRI is normal.⁵

Hypertrophic cardiomyopathy can be secondary to hypertensive heart disease, neuromuscular diseases, metabolic disorders (eg, Pompea (glycogen storage disease type II)), malformation syndromes (eg, Noonan syndrome) or valvular disease. Besides the concentric hypertrophy pattern, a sparkling granular texture may be seen in FRDA patients that can be compared with what is seen in cardiac amyloidosis.⁶ Therefore the echocardiogram plays an essential role in diagnosing cardiomyopathy and excluding valvular disease. Ambulatory blood pressure monitoring to exclude arterial hypertension is also important. Cardiac MRI can confirm the diagnosis of hypertrophic cardiomyopathy with the added benefit of prognostic and risk stratification, as the presence of late gadolinium enhancement is associated with more severe disease and worst outcomes.

The association of hypertrophic cardiomyopathy and ataxia is characteristic of FRDA, and it should prompt genetic diagnosis.

Cardiomyopathy can also be present in ataxia with vitamin E deficiency, but it is much more uncommon.⁵

The diagnosis of FRDA is established by a genetic test that detects pathogenic variants in FXN, most commonly an abnormally expanded GAA repeat in intron q of FXN.^{1 7–9}

Treatment

After the genetic confirmation, the patient started therapy with idebenone and a beta blocker.

He maintained his multidisciplinary follow-up, including physiotherapy and clinical psychology.

Outcome and follow-up

Currently, at his 1-year follow-up he remains clinically stable and his imaging did not show any improvement or worsening after the beginning of treatment.

Discussion

In FRDA the deficiency of the frataxin protein has been linked to a decreased activity of enzymes containing an iron-sulphuric cluster and an abnormal mitochondrial iron homeostasis. This then causes high levels of free iron and increases the burden of oxidative stress. These changes lead to progressive cell toxicity and death, affecting the heart, nervous system and pancreatic beta cells.¹⁰

The symptoms and clinical findings are progressive and multisystemic. Even though they are not the most common inaugural feature, cardiac symptoms can be the initial presentation of the disease.⁷ FRDA is usually accompanied of altered cardiac structure and function.^{1 3} It is well known that heart disease (especially hypertrophic cardiomyopathy) may develop in over half of the patients with FRDA, and many of them die because of cardiomyopathy. A study has shown that the mean age at the diagnosis of hypertrophic cardiomyopathy on FRDA patients was of 10.9 (±3.1) years.¹¹

Some recommendations have been made for the cardiac follow-up of FRDA patients. It has been suggested that there should be regular testing with ECG and echocardiography and in case of cardiac symptoms, such as palpitations or syncope, a 24-hour Holter monitoring should be done.³ Hypertrophic cardiomyopathy is the most frequent cardiac phenotype, but its clinical and electrocardiograph abnormalities are variable.¹² Global systolic function is preserved in most patients and only when they achieve end stage disease do they develop reduced ejection fraction with global hypokinesia and a slightly dilated left ventricle.⁶ Typically the pattern is of a concentric left ventricle with an end-diastolic thickness of less than 15 mm and no outflow tract obstruction.³ The ECG usually has a normal QRS amplitude and duration, even when significant hypertrophy is present.⁶

The difficulty in the diagnosis of this disease is its initial recognition, a problem common to almost all rare diseases. Sometimes cardiac disease leads to a suspicion of FRDA and the genetic test is requested.⁷

The treatment options are limited and new approaches to treatment are being investigated targeting the underlying pathophysiology in FRDA. For now, treatment options are limited to antioxidants such as idebenone, and iron chelation such as deferiprone. Some patients may need symptomatic treatment for heart failure such as salt restriction and diuretic therapy.^{6 8} More investigation is needed for this disorder.

To avoid the misdiagnosis or delay in diagnosis of FRDA, patients with symptoms related to autism spectrum disorder may need further evaluation of neurological disease at their initial evaluation.

Learning points.

• High suspicion is required for the diagnosis of Friedreich’s ataxia and genetic study is the gold-standard for diagnosis.

• When evaluating children with a history of autism, special care should be taken as some symptoms might be misinterpreted and delay the diagnosis of more serious, neuromuscular diseases.

• The presence of ataxia and neurological abnormalities in a child/adolescent should prompt a cardiology evaluation.

• Although treatment is merely supportive it should be initiated sooner, rather than later, in an attempt to reduce the oxidative stress injury.

• The most common cause of death is cardiomyopathy and follow-up should include a multidisciplinary team with risk stratification.

Ethics statements

Patient consent for publication

Consent obtained from parent(s)/guardian(s).