Ataxia in Neurometabolic Disorders: History
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Contributor:
Konrad Kaminiów
,
Izabella Ryguła
,
Justyna Paprocka

Ataxia is a movement disorder that manifests during the execution of purposeful movements. It results from damage to the structures of the cerebellum and its connections or the posterior cords of the spinal cord. It should be noted that, in addition to occurring as part of many diseases, pediatric ataxia is a common symptom in neurometabolic diseases. 

  • ataxia
  • neurometabolic disorders
  • neurometabolism
  • movement disorders

1. How to Recognize Ataxia

1.1. Clinical Investigation

Clinical symptoms in patients with cerebellar ataxia are associated with impaired localization [1][2]. Dysfunction of the cerebellar vermis manifests as trunk imbalance, nystagmus, and head waddling, while impairment of the cerebellar hemispheres results in a gait that veers toward the affected side, with asymmetry of the ipsilateral extremities and a high-stepping gait [1][2][3]. The involvement of afferent/sensory ataxia manifests with a walking gait and sensory damage of the extremities. In addition, ataxia is also characterized by intention tremors and speech-forming difficulties [1].
As in any other disease, obtaining a medical history and conducting a physical examination are important and invaluable diagnostic steps. They make it possible to recognize motor abnormalities and distinguish cerebellar involvement from other affected areas of the nervous system [1][3].
The first step in the clinical evaluation of a patient with cerebellar ataxia is the diagnosis of gait imbalance, which is usually the first symptom in patients with ataxia [3][4]. Patients often struggle to climb and descend stairs; they usually have to use a handrail [1][3][5]. Other symptoms the patient may report include difficulty running, as well as leaning to one side [1]. Over time, falls are often added to this clinical picture [3][5]. In the early stages, patients may experience double vision when turning their heads quickly [1][3][5][6]. Blurred vision is also a common symptom, resulting from transient and mild double vision [1][3][5][6]. Slurred speech may occur, making it difficult to understand some words [1][3]. Patients also sometimes report loss of hand dexterity, resulting in illegible handwriting and difficulty in performing manual activities [3].
The following factors may prompt physicians to include hereditary metabolic disorders in the differential diagnosis: obtaining information in the medical history from the patient or relatives regarding the presence of recurrent episodes of lethargy or even coma during comorbidities; a history of protein aversion or lack of growth; hearing loss or significant deterioration of hearing; progressive loss of skills; hair growth abnormalities, global developmental delay (GDD), and behavioral problems [2][7]. In addition, a family history involving other family members (usually first-degree relatives) of GDD, psychiatric disorders, and cognitive impairment, as well as recurrent miscarriages in women, sudden infant death syndrome (SIDS), or congenital malformations in close family members may also be important clues to include hereditary metabolic disorders in the diagnostic process [2][7]. Although the diagnosis of ataxia is a significant first step, the symptoms associated with ataxia can often suggest a possible diagnosis [1][3]. Therefore, evaluating the patient for signs of peripheral neuropathy, autonomic symptoms, and seizures is also an important part of the clinical management of the patient [1][3]. In addition, sometimes it is also worthwhile to broaden the patient’s history by assessing their exposure to toxins and drugs, which can also prove helpful in identifying the cause [1][6][8][9][10].

1.2. Neurological Examination

The neurological examination of patients with ataxia can be divided into several parts: eyes, speech, hands, legs and gait, and typical symptoms and specific maneuvers can be very helpful in revealing pediatric ataxia [1][3][7]. The patient can be evaluated in different positions: sitting, in which the affected child manifests loss of trunk control, and walking, in which the patient demonstrates a tandem gait or deviation toward the affected side [1].
The diagnosis of ataxia is especially difficult in early childhood. The most common cerebellar symptom among children is gait instability [1]. The child stands with feet wide apart and quickly loses balance. When attempting to walk, the child sways and stops, and may also walk backwards. Some patients may have a lack of coordination of their eye movements. After the age of three, the semiology of ataxia is similar to that seen in adulthood [1].
Various abnormalities of eye movements can be associated with different types of ataxia [3]. However, it is important to note that genotypically different ataxias may have a similar clinical picture, and patients with the same genotype may have different oculomotor abnormalities. In addition, the clinical picture changes with the severity of the disease. The main anomalies include [3][11][12][13]:
  • hyper- or hypometric saccades (observed in many types of ataxia);
  • vertical or horizontal nystagmus (observed in many types of ataxia);
  • saccadic intrusion in fixed gaze (i.e., square-wave jerks);
  • breakdown of smooth pursuit;
  • slow saccades;
  • ophthalmoplegia/ophthalmoparesis, (observed in sensory ataxic neuropathy, dysarthria and ophthalmoparesis (SANDO));
  • ptosis (observed in SANDO and ataxia associated with mitochondrial genome mutations).
Symptoms of cerebellar involvement include slurred speech, poor expression, and scarring [1][2][3][5]. Scanning speech can be common in patients with ataxia. It is characterized by a disruption of normal speech patterns and words are broken into separate syllables [1][2][3][5]. Speech speed may become slow and speech volume may be variable [1][3][5].
Maneuvers commonly used to test hand ataxia and coordination include:
  • The finger–nose test (the patient repeatedly uses the index finger to touch the tip of their nose with their eyes open and then closed);
  • The finger–nose test (the patient points with their index finger from the nose to the physician’s finger);
  • The finger-chase test (the patient’s index finger follows the physician’s moving index finger as closely as possible);
  • Rapid alternating movements (the patient performs cycles of repeated alternating pronation and supination of the hand on the thigh).
Patients with ataxia may show excessive acceleration in the finger-chase test and variable rhythm and speed in alternating movements, as well as intention tremors in the finger–nose–finger test [1][3]. This is because the tremor becomes more prominent when the fingers are closer to the target [1][3]. Another neurological test used to evaluate patients with ataxia is the heel–knee test. In this test, patients are asked to straighten one leg and use the heel of the other leg to smoothly and precisely slide the shin off the knee. Patients with ataxia will experience difficulty keeping the heel on the shin. Dysmetria observed through errors in determining the correct distance (too long or too short) can also be of diagnostic value.
Then, the patient is asked to stand in a neutral position so that the physician can observe any swaying of the trunk. Later, the patient stands with his or her feet together in tandem, on both feet, or hops on both feet. These maneuvers can highlight subtle imbalances associated with cerebellar dysfunction [1][3]. In clinical practice, the patient is often asked to close his or her eyes while performing these maneuvers. If there is a significant deterioration of balance in this situation, it indicates the involvement of sensory neuropathy [1][3][5]. During gait testing, attention should be paid to variability in the stride length and direction. It is important to remember that the features of ataxic gait can change at different stages of the disease. In mild ataxia, the gait may be narrow, but twisting in one direction and abnormal steps are often observed [1][3][5]. In moderate ataxia, the gait becomes wide to compensate for imbalance [1][3][5]; meanwhile, if the patient has more advanced ataxia, in addition to a wide-base gait, step length may be shortened to allow for further compensation [1][3][5]. For patients who have difficulty walking up stairs and on level, horizontal ground or running, the observation of their performance in such tasks will usually provide additional information for diagnosis.
Among the maneuvers used to reveal ataxia in children are the Romberg test, which is characterized by a tendency to fall down with eyes closed in the holding position, as well as the test of holding a full glass of water in the hand without spilling it [1][14].
In the Romberg test, the patient stands with feet together and arms straight, extended in front of him (elbow joints should be straight and the forearms should remain in supination), with his eyes open and then also closed. The patient should stand in this position for 30 s. It is worth noting that, when performing the Romberg test, a patient who has his eyes closed should be belayed, in order to avoid falling and suffering injury. The ability to maintain balance and the possible direction of falling are assessed: the patient falls toward the injured cerebellar hemisphere or backward in the situation of cerebellar vermis injury [1][14].
Once the presence of ataxia has been established through neurological examination, other accompanying symptoms may be key to indicating a specific diagnosis. Special attention should be paid to signs of parkinsonism, myoclonus, dystonia, tremor, hyperreflexia, sensory neuropathy and extensor reflexes [3][7]. Sensory–tactile, pain, thermal, and prosodic assessments should be recorded, and any abnormalities should be carefully checked [1].

2. Diagnosis of the Neurometabolic Causes of Ataxia and Their Specific Treatment

Inherited neurometabolic disorders should be included in the differential diagnosis of all children with ataxia, even if there are only a few signs and symptoms that might indicate that they could be the cause [7][15][16]. Clinicians should be particularly concerned when the causes of ataxia remain unexplained after the most common etiologies, such as drug side effects, infections, and focal brain lesions, have been ruled out [17][18][19]. Then, neurometabolic diseases should always be suspected [17][18][19].
Due to the fact that modern science is moving away from providing information in the comprehensive form of a coherent text, neurometabolic disorders that can manifest as ataxia and the characteristics that are necessary for diagnosing clinicians are presented in the form of a table. In authors' opinion, this is an easier to analyze, more readable source of all the information needed by the clinician to begin to suspect a neurometabolic disorder, make a diagnosis, and initiate appropriate treatment (if available).
Among this group of neurometabolic disorders are those that have their own characteristic clinical or neurological features. In such a situation, appropriate disease-targeted metabolic tests can be performed to provide preliminary support for the suspected diagnosis. The source of material for testing may be serum, cerebrospinal fluid (CSF), or urine. One test that is used to confirm the diagnosis of neurometabolic disorders is targeted direct Sanger sequencing [2][3]. In some cases, the patient has no specific features when they undergo clinical examination, biochemical tests, or neuroimaging. In this situation, non-targeted genetic testing, including a targeted next-generation sequencing panel, whole exome, or mitochondrial genome sequencing is used to establish the diagnosis [2][3].

This entry is adapted from the peer-reviewed paper 10.3390/metabo13010047

References

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  2. Silver, G.; Mercimek-Andrews, S. Inherited Metabolic Disorders Presenting with Ataxia. Int. J. Mol. Sci. 2020, 21, 5519.
  3. Kuo, S.H. Ataxia. Contin. Lifelong Learn. Neurol. 2019, 25, 1036–1054.
  4. Luo, L.; Wang, J.; Lo, R.Y.; Figueroa, K.P.; Pulst, S.M.; Kuo, P.H.; Perlman, S.; Wilmot, G.; Gomez, C.M.; Schmahmann, J.; et al. The Initial Symptom and Motor Progression in Spinocerebellar Ataxias. Cerebellum 2017, 16, 615–622.
  5. Ismail, F.Y.; Mitoma, H.; Fatemi, A. Metabolic ataxias. Handb. Clin. Neurol. 2018, 155, 117–127.
  6. Vedolin, L.; Gonzalez, G.; Souza, C.F.; Lourenço, C.; Barkovich, A.J. Inherited cerebellar ataxia in childhood: A pattern-recognition approach using brain MRI. Am. J. Neuroradiol 2013, 34 (Suppl. S1–S2), 925–934.
  7. Ortigoza-Escobar, J.D. A Proposed Diagnostic Algorithm for Inborn Errors of Metabolism Presenting with Movements Disorders. Front. Neurol. 2020, 11, 582160.
  8. Akbar, U.; Ashizawa, T. Ataxia. Neurol. Clin. 2015, 33, 225–248.
  9. van Gaalen, J.; Kerstens, F.G.; Maas, R.P.; Härmark, L.; van de Warrenburg, B.P. Drug-induced cerebellar ataxia: A systematic review. CNS Drugs 2014, 28, 1139–1153.
  10. Manto, M. Toxic agents causing cerebellar ataxias. Handb. Clin. Neurol. 2012, 103, 201–213.
  11. Anheim, M.; Tranchant, C.; Koenig, M. The autosomal recessive cerebellar ataxias. N. Engl. J. Med. 2012, 366, 636–646.
  12. Moscovich, M.; Okun, M.S.; Favilla, C.; Figueroa, K.P.; Pulst, S.M.; Perlman, S.; Wilmot, G.; Gomez, C.; Schmahmann, J.; Paulson, H.; et al. Clinical evaluation of eye movements in spinocerebellar ataxias: A prospective multicenter study. J. Neuro Ophthalmol. 2015, 35, 16–21.
  13. Kuo, P.H.; Lo, R.Y.; Tanji, K.; Kuo, S.H. Clinical Reasoning: A 58-year-old man with progressive ptosis and walking difficulty. Neurology 2017, 89, e1–e5.
  14. Kruer, M.C. Pediatric movement disorders. Pediatr. Rev. 2015, 36, 104–129.
  15. Ebrahimi-Fakhari, D.; van Karnebeek, C.; Münchau, A. Movement disorders in treatable inborn errors of metabolism. Mov. Disord. 2019, 34, 598–613.
  16. Cordeiro, D.; Bullivant, G.; Siriwardena, K.; Evans, A.; Kobayashi, J.; Cohn, R.D.; Mercimek-Andrews, S. Genetic landscape of pediatric movement disorders and management implications. Neurol. Genet. 2018, 4, e265.
  17. Ferreira, C.R.; Hoffmann, G.F.; Blau, N. Clinical and biochemical footprints of inherited metabolic diseases. I. Movement disorders. Mol. Genet. Metab. 2019, 127, 28–30.
  18. Sedel, F.; Saudubray, J.M.; Roze, E.; Agid, Y.; Vidailhet, M. Movement disorders and inborn errors of metabolism in adults: A diagnostic approach. J. Inherit. Metab. Dis. 2008, 31, 308–318.
  19. García-Cazorla, A.; Ortez, C.; Pérez-Dueñas, B.; Serrano, M.; Pineda, M.; Campistol, J.; Fernández-Álvarez, E. Hypokinetic-rigid syndrome in children and inborn errors of metabolism. Eur. J. Paediatr. Neurol. 2011, 15, 295–302.
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