Limited environmental oxygen might one day help Friedreich’s ataxia patients

a–e Sagittal and axial reconstructed (along the yellow line in a, c) T1 weighted images in a control (a, b) and a FRDA patient ( d) showing that the lower medulla cross-sectional area at the obex is smaller in the FRDA patient (d) as compared to the control subject (b). Anatomic drawing (e) shows the gracilis and cuneatus nuclei (sky)

Friedreich’s ataxia (FRDA) is a rare, inherited disorder that causes progressive damage to the nervous system.

In 1863, Friedreich first described an inherited early onset ataxia associated with kyphoscoliosis and fatty degeneration of the heart in six members from two families associated with degeneration of the dorsal columns and dorsal roots [1].

Friedreich interpreted the disorder as a developmental defect of the medulla oblongata.

In analogy to tabes dorsalis, he considered the spinal lesions as mainly inflammatory.

Friedreich’s work gained little attention during his lifetime.

Only 30 years after Friedreich’s original description, Pierre Marie realized the scientific impact of Nikolaus Friedreich’s work by discriminating FA from dominant ataxias [2].

The core syndrome is an early onset, slowly progressive ataxia associated with areflexia.

Ataxia arises from combined afferent (peripheral sensory neuropathy plus spinal degeneration), cerebellar and sometimes also vestibular dysfunction.

In addition to ataxia of stance and gait, patients develop appendicular and truncal ataxia.

Dysarthria is another cerebellar feature present in 70% with abnormal pitch variation, loudness maintenance, breath support for speech, hypernasality and consonant imprecision due to laryngeal or velopharyngeal dysfunction [11].

Loss of deep tendon reflexes due to degeneration of dorsal root ganglia and peripheral neuropathy is an early and robust feature of FA.

However, preserved reflexes do not exclude FA.

Plantar responses are extensor in 70 to 90%.

If spasticity is not masked by peripheral involvement, it should be treated to prevent contractures and painful spasms.

Muscular weakness and wasting – usually more pronounced in the lower limbs – can complicate advanced cases.

Proprioceptive deficits with abnormal position and vibration sense are present in virtually all FA subjects. 

Nerve conduction studies reveal signs of an axonal sensory neuropathy with reduced or absent nerve action potentials typically first present in the sural nerve.

Cortical potentials of somatosensory evoked potentials are delayed or absent [3].

Square wave jerks (SWJ) represent a typical, though not pathognomonic eye movement abnormality of FA.

They are usually horizontal and can be observed in primary position and during smooth pursuit.

Twenty to 60% of patients show gaze evoked nystagmus mainly on lateral gaze.

Saccades are dysmetric, but of normal velocity.

Ptosis is present in about 10% of patients [12].

Involvement of the visual system is complex.

Vision is impaired in about one fifth of patients with optic atrophy on fundoscopy in about one third.

FA may even lead to complete blindness in late stages.

This is usually reflected by abnormal visually evoked potentials [313].

Variable perimetric deficits, impaired contrast letter acuity, reduced retinal fiber layer thickness and optic radiation abnormalities have also been described [41314].

Hearing problems are common and worsen over time [15].

Single patients may even suffer from combined blindness and deafness.

Deficits mainly affect central auditory pathways with abnormal auditory evoked brainstem potentials while peripheral components are usually preserved [5].

There is electro-physiological evidence for dyssynchrony of central auditory pathway components resulting in impaired discriminative hearing and verbal communication.

Autonomic dysfunction such as vasomotor abnormalities or dyshidrosis are most prevalent in the lower limbs.

Dysphagia may complicate advanced disease requiring percutaneous endoscopic gastrostomy (PEG) to avoid aspiration.

Micturition is only mildly affected with urgency and detrusor hypoactivity being the most frequent symptoms.

In a series of FA patients, there was evidence for dilatation of the upper urinary tract without creatinine increase in 14% [16].

Systematic assessment of bowel function has not been published to date.

Affective disorders affect almost all patients with severe depression in almost 10% [17].

Dementia is not part of the FA phenotype but systematic neuropsychological studies revealed wide-spread abnormalities of information processing, visuoconstructive and visuospatial capacity, verbal fluency, motor and mental reaction times, concept formation, sustained volitional attention, working memory as well as concrete thinking [1821].

Cognitive deficits have been attributed to primary prefrontal dysfunction, disruption of cerebello-prefrontal connections or cerebro-ponto-cerebello-thalamo-cerebral circuits as well as parieto-temporal dysfunction [1821].

However, the deficits do not significantly interfere with education or social life.

Many patients successfully pursue academic careers.

MRI usually shows spinal atrophy. Cerebellar shrinkage is considered less common [3436].

Volume loss of the medulla oblongata may be seen in advanced cases [37].

Volumetric studies demonstrated a close relationship between atrophic changes of infratentorial brain structures and disease duration and severity [3839].

Recent MRI studies also gave evidence for reduced cortical thickness especially in the premotor and supplementary motor areas, disrupted fronto-cerebellar networks as well as volume loss of extrapyramidal structures [4042].

FRDA is caused by low levels of the mitochondrial protein frataxin, which helps synthesize essential iron-sulfur clusters.

Although it is rare, FRDA is the most common form of hereditary ataxia in the United States, afflicting roughly 1 in every 50,000 people.

“Friedreich’s ataxia is a debilitating and crippling disease, and we have no proven therapies,” said Vamsi Mootha, an institute member and co-director of the Metabolism Program at the Broad Institute.

Iron-sulfur cluster formation, which is disrupted in FRDA, is essential to many biochemical reactions in the body.

Iron-sulfur clusters first formed spontaneously more than 2.5 billion years ago when Earth’s atmosphere had little oxygen.

The evolutionary origins of the clusters made Mootha and his team wonder if environmental oxygen might play a key role in FRDA.

Along with postdoctoral fellows Tslil Ast and Joshua Meisel, Mootha led a recent effort to grow frataxin-depleted yeast, human cells, and nematodes in extremely low oxygen levels (1 percent ambient O2).

They found that these frataxin-depleted cells and organisms thrive in hypoxia.

Featured in Cell, the work showed that hypoxia restores iron-sulfur cluster levels and normalizes FRDA-associated signaling events.

In a mouse model of FRDA, breathing low oxygen slowed progression of ataxia, while higher oxygen levels did the reverse.

“While these results suggest that breathing thin air could one day have therapeutic potential in treating FRDA, no one should yet use hypoxia as an improvised therapy,” said Mootha, who is also a professor of systems biology and medicine at Harvard Medical School and Massachusetts General Hospital.

“Oxygen is essential for life and hypoxia can be extremely dangerous.

While these initial, basic results are promising, we need to do more research before applying this in any clinical context.”

More information: Tslil Ast et al. Hypoxia Rescues Frataxin Loss by Restoring Iron Sulfur Cluster Biogenesis, Cell (2019). DOI: 10.1016/j.cell.2019.03.045
Journal information: Cell
Provided by Broad Institute of MIT and Harvard


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