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What is causing this 55-year-old woman to have distorted speech and balance problems when walking, and why have her symptoms worsened progressively since they came on 14 years ago? Those are the questions facing Mandar Jog, MD, and colleagues from the Movement Disorder Centre of the London Health Sciences Centre in Ontario, as they reported the case in .

The patient had a history of hypercholesterolemia and severe anxiety, and when she was referred due to worsening balance problems and fear of falling, she told clinicians she had been using a wheelchair for the past 4 years.

"Neurological examination showed gaze-evoked horizontal nystagmus in both directions along with slow saccades and gaze restriction in both vertical and horizontal planes," the authors wrote. In addition, her speech was notable for distortion of consonant sounds, which clinicians attributed to ataxic dysarthria.

Muscle tone and strength were normal in her arms and legs, although she had no stretch reflexes. Finger-to-nose and heel-knee-shin tests showed evidence of ataxia. Chorea was present in both legs. Her ankles were both turned inward and she had hammer toes on both feet.

Electromyography findings indicated neuronopathy, and brain MRI revealed diffuse cerebellar atrophy as well as T2 hyperintensities in bilateral middle cerebellar peduncles, cerebellar white matter, pons, and bilateral thalamus, the authors stated.

The patient was started on psychiatric treatment to manage her severe anxiety, but her debilitating fear of falling persisted. After considering various diagnoses, clinicians diagnosed the patient with mitochondrial ataxia.

Discussion

"Mitochondrial ataxia is an etiology worthy of consideration in patients with undiagnosed slowly progressive cerebellar ataxia," Jog and co-authors wrote. "The presence of ophthalmoplegia, peripheral neuropathy, deafness, retinitis pigmentosa, and history of seizure aid in the diagnosis."

Among the many mitochondrial syndromic disorders that can present with cerebellar ataxia are mitochondrial DNA polymerase gamma (POLG)–mediated disorders, which are the most common cause of mitochondrial ataxia.

"Sensory predominant , areflexia, and chronic progressive external ophthalmoplegia are the most commonly associated nonataxic features," possibly with associated dystonia, chorea, myoclonus, ptosis, myopathy, cognitive impairment, and seizures, the case authors said.

According to a of adults with biallelic polymerase gamma mutations, those with POLG-mediated ataxia (POLG-A) required walking aids after a median disease duration of 16 years and use of a wheelchair after 19 years. This constitutes a slightly faster progression of gait ataxia compared with about 24 years for patients with spinocerebellar ataxia type 6 and a slower progression than the approximately 12 years seen in Friedreich ataxia.

Brain MRI findings include T2/fluid attenuated inversion recovery hyperintensities, which mainly involve cerebellar white matter, middle cerebellar peduncles, and thalamus, with visible involvement of the brain stem and occipital frontal white matter. In suspected POLG-A, the case authors suggested either direct sequence analysis of the POLG gene or a next-generation sequencing panel for ataxia that includes POLG.

In this patient, mitochondrial genetic panel analysis showed compound heterozygous pathogenic mutation in the POLG gene, c.2243 G>C (p.W748S) in one allele, and c.1399 G>A (p.A467T) in the other allele.

Differential diagnoses to consider in this patient, the team said, included:

• Friedreich ataxia (FRDA)

• Fragile X-associated tremor/ataxia syndrome (FXTAS)

• Niemann-Pick disease type C (NPC).

"is one of the most common autosomal recessive cerebellar ataxias, caused by GAA trinucleotide repeat expansions in the frataxin (FXN) gene, with onset typically occurring in the second decade of life," the authors noted.

They added that FRDA is associated with peripheral neuropathy, dorsal root ganglionopathy, dorsal column involvement leading to loss of deep tendon reflexes, and early decline in the ability to perceive vibration in the hands and lower limbs. Eye movement abnormalities such as fixation instability and frequent square-wave jerks are also common in FRDA, and less frequently, patients may have gaze-evoked nystagmus.

Non-neurological systemic features of FRDA may include cardiomyopathy, diabetes, and musculoskeletal abnormalities like scoliosis, pes cavus, foot inversion, and hammer toes, the group explained. In general, late-onset disease (i.e., occurring after age 50) tends to present with "spastic ataxia with preserved or even brisk reflexes, without systemic manifestations." Brain MRI findings typically include spinal cord atrophy, although the cerebellar volume is preserved, the authors said.

While this patient had sensory neuronopathy and skeletal deformities affecting her feet, her disease presented when she was in her 30s -- with "absent reflexes, prominent gaze evoked nystagmus, slow saccades, gaze palsy, and diffuse cerebellar atrophy on MRI," the authors wrote. The patient did not test positive for FRDA genes, however.

is "an X-linked disease seen in premutation (55-200 CGG repeats) carriers of the fragile X mental retardation 1 (FMR1) gene," Jog and co-authors wrote, adding that the disease is characterized by onset intention/action tremor and cerebellar ataxia after age 50.

Other conditions commonly associated with FXTAS include cognitive problems such as frontal subcortical dementia with predominant executive dysfunction, psychiatric conditions such as anxiety, depression, and social avoidance, and Parkinson's-like symptoms. "Slow vertical saccade and impaired vertical optokinetic nystagmus can give rise to progressive supranuclear palsy phenotype," the team added. Motor symptoms are typically preceded by sensory axonal neuropathy and autonomic dysfunction.

FXTAS symptoms are usually less severe in females, although those affected are more likely to develop comorbid migraine, thyroid dysfunction, and fibromyalgia.

Classic x-ray findings include "bilateral T2/fluid attenuated inversion recovery hyperintensities of the middle cerebellar peduncles (middle cerebellar peduncles sign), diffuse cortical cerebellar atrophy, and hyperintensities involving periventricular, splenial, and pontocerebellar regions," the authors wrote.

They noted that although several of these features applied to this patient, including her being female and having anxiety, cerebellar ataxia, slow saccades, and hyperintensities of middle cerebellar peduncles and cerebellum, she tested negative for the FXTAS genes.

Another possible diagnosis the authors considered was , "an autosomal recessive neurovisceral lysosomal lipid storage disorder caused by mutation in the NPC1 or NPC2 genes," Jog and colleagues noted. Adult-onset NPC is usually associated with several movement disorders such as cerebellar ataxia, dystonia, and chorea, as well as vertical supranuclear gaze palsy and restricted downgaze.

NPC disease onset may be early or late, affecting people at any age, from newborns to older adults, the authors said. Enlargement of the liver and spleen generally precedes neurological manifestations.

Symptoms of early-onset and adult-onset NPC tend to differ, the case authors explained. For example, adult-onset NPC typically presents with psychosis, behavioral symptoms, and cognitive dysfunction, and may continue to be the only symptoms for several years. Early onset NPC in late infantile and juvenile forms, however, is more often associated with seizure, cataplexy, and demyelinating peripheral neuropathy. Brain MRI findings tend to be normal, or may show cerebellar, frontal, and midbrain atrophy in patients with disease progression.

The patient in the case report had generalized anxiety disorder and mild cognitive impairment, but no history of seizure. She had no organ enlargement, and gaze palsy was not supranuclear. Furthermore, she tested negative for NPC.

"This case highlights the value of screening for mitochondrial etiology when facing adult-onset slowly progressive cerebellar ataxia of unknown etiology," Jog and co-authors concluded.

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