History and Physical
A 15-year-old boy visited the clinic due to a progressively abnormal gait that started 3 years prior. Initially, he experienced an unsteady gait, which gradually worsened and became wide-based and staggering. He presented with difficulties while taking steps, climbing stairs, and running. Additionally, he developed slurred speech and clumsiness in his hands, resulting in deteriorated handwriting. Over the past year, he also developed a head tremor and sensory disturbances in his lower limbs. The pregnancy and birth history were unremarkable, and there was no family history of neurological disorders or other diseases. There was no parental consanguinity.
Prior to the onset of symptoms, his school performance was normal. After the symptoms appeared, he began experiencing difficulties with his writing.
The boy’s weight was measured at 56 kg (50%), height 168 cm (50–75%), and head circumference 54 cm (50%). He exhibited normal cognitive function and had no vision or hearing problems. Oculomotor movements were normal. However, an unusual cadence in speech and subtle head tremor were observed. Furthermore, bilateral dysmetria was noted during the nose-finger test. He displayed a wide-based ataxic gait and was unable to walk in tandem. Motor and sensory examinations revealed diffuse areflexia and bilateral Babinski signs. Distal joint position and vibration sense were also affected.
The Scale for the Assessment and Rating of Ataxia (SARA) score was determined to be 12, with the following scores: gait 2.0, stance 2.0, sitting 0.0, speech 2.0, finger chase 1.0 (left 1, right 1), nose-finger test 2.0 (left 2, right 2), fast alternating hand movements 1.0 (left 1, right 1), and heel-shin slide 2.0 (left 2, right 2).
Diagnostic Workup
Initial laboratory investigations, including a complete blood count, glucose, liver and kidney function tests, celiac antibodies, fasting lipids, thyroid function tests, copper and ceruloplasmin levels, vitamin B 12 , creatinine kinase, alpha-fetoprotein, and immunoglobulins, were normal.
Brain and spinal cord MRIs revealed mild cerebellar atrophy (CA) ( Fig. 77.1 ) and cervical cord thinning with posterior column hyperintensity ( Fig. 77.2 ).
Ataxia with vitamin E deficiency. Brain MRI, (A) sagittal and (B) coronal T2 show mild cerebral and cerebellar atrophy with enlarged interfolial spaces ( arrow ).
Ataxia with vitamin E deficiency. Cervical spine MRI, sagittal T2 shows mild spinal degenerative changes and gracile cord with faint posterior hyperintensity.
Electrocardiography and echocardiography were normal.
Ophthalmologic examination was significant for myopia.
Friedreich ataxia was ruled out through triplet primed repeat PCR. A comprehensive metabolic profile was normal.
Vitamin E level was low at 3.7 mg/dl (normal range: 6–10 mg/dl). Genetic testing showed two compound heterozygous pathogenic variants in the TTPA gene, leading to a loss of α‐TTP activity. The variants identified were c.661C>T (p.Arg221Trp) and c.744delA (p.Glu249Asnfster15). The child was put on high doses (1000 mg/day) of oral vitamin E.
Clinical Differential Diagnoses
Ataxia is a common clinical sign characterized by impaired coordination of movement and balance, resulting in a lack of muscle control during voluntary activity. It is primarily caused by dysfunction in the circuitry that connects the cerebellum, basal ganglia, and cerebral cortex, known as “cerebellar ataxia.”
Acute cerebellar syndromes typically arise as acquired, nongenetic conditions that require prompt medical attention. It is crucial to consider various conditions including posterior fossa tumors, drug intoxication, postinfectious cerebellitis, meningitis or cerebellar abscess, cerebellar stroke, and inherited metabolic disorders such as nonketotic hyperglycinemia and pyruvate dehydrogenase deficiency.
Chronic cerebellar ataxia can manifest as either nonprogressive or progressive. Nonprogressive ataxia is often associated with cerebral damage, such as hypoxic- ischemic or vascular damage. It can also be linked to brain malformations, such as Arnold-Chiari malformation or Dandy-Walker syndrome.
Progressive ataxia encompasses a heterogeneous group of clinically and genetically diverse neurodegenerative disorders with various inheritance patterns. Among pediatric populations, the most common form is the autosomal recessive type, with Friedreich ataxia being the most prevalent.
Progressive cerebellar ataxia can also be related to inborn errors of metabolism, including ataxia with vitamin E deficiency (AVED), abetalipoproteinemia, Refsum disease, cerebrotendinous xanthomatosis, type 2 gangliosidosis, Niemann-Pick disease type C, and disorders of coenzyme Q10 biosynthesis, among others.
Systemic causes of ataxia and vitamin E deficiency include hypothyroidism, celiac disease, immune disorders such as ataxia-telangiectasia, chronic fat malabsorption, and deficiency of plasma lipoproteins. Abetalipoproteinemia can also cause hereditary vitamin E deficiency due to abnormal absorption of fat-soluble vitamins, including vitamin E, in the distal ileum. In AVED, defective alpha-tocopherol transfer protein (ATTP) results in abnormal incorporation of alpha-tocopherol into lipoproteins secreted by the liver. Vitamin E is involved in many physiological processes. In the neurological and immune systems, it has a role as an antioxidant, protecting molecules and tissues against the deleterious effects of free radicals. It also contributes to the stabilization of membranes and regulates many enzymes involved in gene expression and apoptosis. These findings suggest that primary or secondary vitamin E deficiency has an important role in neurodegeneration.
Imaging Differential Diagnoses
Combining neuroimaging findings with clinical information is essential when investigating pediatric cerebellar ataxia. Brain MRI can identify cerebellar abnormalities such as atrophy or hypoplasia of the cerebellar hemispheres and/or vermis, as well as signal changes and extracerebellar structures.
On neuroimaging, CA is defined as a cerebellum with normal morphology but enlarged fissures (interfolial spaces) ( Fig. 77.3 ). This pattern implies loss of cerebellar parenchyma caused by a progressive disease or a single severe insult such as an infection or toxic exposure.
