Patient Presentation
A 12-year-old female came to clinic for her health supervision visit. She complained of new onset intoeing that had been occurring for more than 6 months. She had not seen a physician for more than 2 years and the family could provide few details about the history. She said that she was more “clumsy” over time and would trip and occasionally fall even when walking on even ground. She denied any pain, numbness, tingling, difficulty with walking distances or up stairs, or fine motor problems including writing, tieing shoes, brushing teeth or eating. She denied any visual problems. They weren’t sure if it was getting worse but the intoeing was obvious to other people. She denied any trauma or infectious diseases other than a cold. The travel and animal contact history was negative and she denied any anxiety or depressive symptoms. Her grades at school were the same and she had the same several friends. The family was moving to another state soon.
The past medical history showed her to be underimmuized, but she was fully immunized for varicella. The family history was negative for any neurological or orthopaedic problems including no intoeing or outtoeing as a younger child. The review of systems showed no fevers, nausea, emesis, changes in hair or skin, or dysuria.
The pertinent physical exam showed a well-appearing female with normal vital signs and growth parameters around the 50th percentile. HEENT showed pupils to be equal, round and reactive to light and accommodation and no nystagmus. Visual acuity was 20/30 bilaterally. Thyroid was normal size without masses. Lungs, heart, and abdomen were normal. She was Tanner 2 for breast. Her skin had a few open comedomes on her checks and nose. Neurologically her cranial nerves were intact. Her strength was normal in upper and lower extremities. She had +1/+2 deep tendon reflexes in the lower extremities and had positive Babinski reflexes. There was no clonus. Sensation and position sense were equivocal in the lower extremities because the patient didn’t seem to fully understand the questioning. She did not appear to have a direct sensory level though. She had normal deep tendon reflexes in the upper extremities. She appeared to have normal rapid alternating movements, but had some past pointing with finger-to-nose testing. She had had a positive Rhomberg test, but negative Gower maneuver. When walking she had intoeing bilaterally and a wider-based gait.
The diagnosis of a chronic, possibly progressive, neurological condition affecting mainly the lower extremities was made. The differential diagnoses included infection (which seemed unlikely), tumor affecting the spinal cord or cerebellum, or a underlying hereditary disease including ataxias. The patient’s clinical course showed that she was referred to a pediatric neurologist who felt her clinical examination was most consistent with a hereditary ataxia, most likely Friedreich ataxia. The family wanted minimal testing, so genetic testing was sent and was positive for Friedreich ataxia. The family moved to another state soon after the diagnosis.
Discussion
Friedreich ataxia (FRDA) was first extensively described in a series of papers from 1863-1877 by Nikolaus Friedreich at the University of Heidelberg, Germany. In 1996 the genetic mutation was described. It is an autosomal recessively inherited, homologous expansion of the GAA repeat in intron 1 of the frataxin gene on chromosome 9q13. It causes a transcription error leading to a decrease in frataxin which is a mitochondrial protein involved in iron metabolism and other cell functions. Frataxin is seen mainly in the central and peripheral nervous systems, heart, pancreas and skeleton. Frataxin is produced but in decreased amounts, and lack of frataxin causes in-utero lethality of the embryo.
FRDA is the most common cause of autosomal recessive ataxia. Point estimates are up to prevalence 3/100,000 and it is estimated that ~9000 patients in the United States with FRDA at any given time. Age of onset is in early teens with a mean of ~15 years with most cases developing by 25 years, although genetic testing has allowed more adult patients to be identified. FRDA is unfortunately progressive and patients’ have a decreased lifespan at 40 years (+/- 20 years). There is a correlation with the number of repeats with an increased number having increased disease severity. There is no generational anticipation where subsequent generations have increased severity or onset at earlier ages.
Unfortunately, FRDA is progressive and many treatments help to support the patients and decrease side effects to help with mobility and nursing care. Potential treatments being used include antioxidants, frataxin-inducing agents and gene therapy.
Learning Point
Patients with FRDA can have several presentations including neurological problems, scoliosis or pes planus, or sometimes cardiomyopathy. Neurological symptoms usually associated with FRDA include gait and limb ataxia, decreased tendon reflexes, positive Babinski reflex, loss of position and vibratory sense and dysarthria. Older individuals may have an atypical presentation with preservation of tendon reflexes or very slow progression.
Clinical symptoms of Friedreich ataxia include:
- Neurological
- Gait ataxia
- Distal extremity
- Dysmetria
- Atrophy and/or weakness
- Loss of vibratory and proprioception
- Sensory neuropathy – “stocking and glove”
- Loss of stretch muscle reflexes
- Babinski sign positive
- Head and Neck
- Nystagmus
- Head titubation
- Dysarthria
- Blindness (rare)
- Diminished speech perception
- Vestibular dysfunction
- Heart
- Cardiomyopathy – usually hypertropic but can be dilated
- Mural thrombi can occur and cause embolic strokes
- Skeletal
- Scoliosis – very common and progressive
- Pes cavus
- Endocrine
- Diabetes mellitus
Questions for Further Discussion
1. What causes ataxia in general? A review can be found here.
2. What causes hereditary ataxia?
3. What causes intoeing or outtoeing in younger age groups? A review can be found here.
Related Cases
- Disease: Friedreich’s Ataxia | Degenerative Nerve Diseases
- Symptom/Presentation: Ataxia, Dizziness, and Vertigo | Abnormal Gait
- Specialty: Genetics | Medical History | Neurology / Neurosurgery
- Age: Teenager
To Learn More
To view pediatric review articles on this topic from the past year check PubMed.
Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.
Information prescriptions for patients can be found at MedlinePlus for these topics: Friedreich Ataxia and Degenerative Nerve Diseases.
To view current news articles on this topic check Google News.
To view images related to this topic check Google Images.
To view videos related to this topic check YouTube Videos.
Koeppen AH. Friedreich’s ataxia: pathology, pathogenesis, and molecular genetics. J Neurol Sci. 2011 Apr 15;303(1-2):1-12.
Jayadev S, Bird TD. Hereditary ataxias: overview. Genet Med. 2013 Sep;15(9):673-83.
Aranca TV, Jones TM, Shaw JD, et.al.. Emerging therapies in Friedreich’s ataxia. Neurodegener Dis Manag. 2016;6(1):49-65.
OMIM. Friedreich Ataxia 1; FRDA. Available from the Internet at http://www.omim.org/entry/229300?search=FXN/frataxin&highlight=frataxin%20fxnfrataxin%20fxn (rev. 9/13/16, cited 2/6/17).
Author
Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa Children’s Hospital
Pediatric Education 