Background
Friedreich Ataxia (FRDA) is a neurological disease resulting in gait and balance abnormalities, sensory loss, weakness, loss of reflexes, and ataxia. A recessive disorder, FRDA can also result in scoliosis, urinary dysfunction, diabetes mellitus, optic atrophy, hearing loss, sleep apnea, and hypertrophic cardiomyopathy [1‐8]. The disease is caused by expanded guanine-adenine-adenine (GAA) repeats on both alleles of the FXN gene (FXN) in 98 % of patients. The remaining 2 % of individuals with FRDA have an expanded triplet repeat on one allele and a point mutation or deletion on the other. FRDA is a mitochondrial disease, as the deficient protein in FRDA (frataxin) is crucial for mitochondrial iron-sulfur cluster containing enzymes involved in oxidative phosphorylation and the Krebs cycle [9‐12]. There is currently no therapy for FRDA, though several clinical trials are ongoing [13, 14].
Although few manifestations outside of the typical features have been identified in FRDA, one previous report suggests an association of nephrotic syndrome (NS) with FRDA [15]. In addition, related ataxias with coenzyme Q deficiency are associated with NS as are other mitochondrial disorders [16, 17]. Here we report 2 more individuals with NS and FRDA, providing further evidence for a possible connection between the two diseases and focusing on the responsiveness of one individual to corticosteroid treatment, an effect not previously described in FRDA.
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Case Presentations
Patient 1: The patient is a 13 year old female of European descent (GAA repeat lengths = 650, 1000). She presented with gait and balance difficulties at age 4 and was diagnosed with FRDA at age 5. At age 7, she developed periorbital edema, abdominal swelling, problems with urination, and a weight gain of 10 lbs over 9 months. She was diagnosed with idiopathic NS after laboratory testing revealing a urine protein of 2854 mg/dl and albumin of 2.2 g/dL. Though renal biopsy was not performed, specific causes of secondary nephrotic syndrome were ruled out by clinical criteria and serological testing. She received prednisone pulse therapy at 30 mg daily, which was tapered after 4 weeks. Her NS responded rapidly and urine protein levels normalized. She had 5 relapses of NS over the next 5 years, characterized by urine protein levels >100 mg/dL, all treated with 30–60 mg daily of prednisone pulse therapy. Clinical manifestations and laboratory parameters (proteinuria) of NS resolved following steroid treatment; surprisingly, neurologic improvements were also noted by her caregiver and physical therapist. Specifically, after her first treatment with prednisolone, the patient’s physical therapist noted that she had maintained range of motion in her heel cords and hamstrings and retained her skill level in balance as related to single leg stance over the course of a year. In the year following a second steroid treatment, the patient demonstrated decreased balance, coordination and range of motion. Subjectively her sense of fatigue decreased and her endurance improved. Objectively, her gait improved with a narrower base and fewer falls.
The effect was most prominent in a worsening of her neurologic abilities following scoliosis surgery. Following surgery she again developed NS and became unable to walk. Corticosteroid treatment led to recovery of renal function as well as ambulation. However, as her steroids were tapered, she lost ambulatory ability. This improved with another pulse of steroid treatment in the absence of NS.
Patient 2: The patient is a 25 year old male of Indian descent with FRDA (GAA repeats lengths = 650, 850). At age 2, the patient presented with periorbital edema, lethargy, and abdominal swelling. Idiopathic NS was confirmed following urine protein testing. He developed gait difficulties at age 9 and was diagnosed with FRDA at age 10. He had been treated with chronic steroids from age 2 to age 10, with doses ranging from 15 mg every other day to 60 mg per day during episodic flares. In response to the onset of gait problems, the patient’s nephrologist switched him from steroid treatment to 100 mg of cyclophosphamide for 3 months. He has not had any relapses of NS since then. However, the patient’s ataxia worsened after the discontinuation of steroids.
Given the improvement of the first subject on corticosteroid treatment, we examined the records of the Children’s Hospital of Philadelphia (CHOP) and the Collaborative Clinical Research Network (CCRN) for other individuals reporting responses to corticosteroids prescribed for other indications in a retrospective review (Table 1) [18]. Nine people with FRDA experienced improved balance, gait or speech with corticosteroid or other immunomodulatory therapy, and no individuals were identified with significant steroid dependent worsening. One other patient treated with steroids showed improvement, although it is unclear whether improvement was due to corticosteroids or other medications initiated at the same time. All patients besides patients 1 and 2 described had normal kidney function.
Table 1
Patients with FRDA treated with steroids
Patient No. GAA repeats | Age of FRDA onset | Clinical course | Phenotypea
| Immunomodulator | Dose | Duration | Reason for steroid treatment | Response | Age of steroid treatment |
|---|---|---|---|---|---|---|---|---|---|
Patient 1 described 650, 1000 | 4 | Began using wheelchair at age 10; scoliosis surgery at age 13 | Ataxia, loss of balance, loss of sensation, leg cramps, tremors, hypertrophic cardiomyopathy, scoliosis, fatigue | Prednisolone, oral | 30 BID-50 QD | 26 months over 6 years | Nephrotic syndrome | Recurrent neurologic improvement coincident with steroid dosing | 8–14 |
Patient 2 described 650, 950 | 10 | Began using wheelchair at age 12 | Ataxia, loss of balance, loss of sensation, spasms, hypertrophic cardiomyopathy, arrhythmia, scoliosis | Prednisone, oral | unknown | 8 years | Nephrotic syndrome | Possible delay in presentation | 2–10 |
Patient 3 500, 570 | 15 | Began using cane at 23, wheelchair at 29 | Ataxia, loss of balance, loss of sensation, leg spasms, restless legs, scoliosis, sleep apnea | Prednisone and Medrol, oral | 8 QAM | 4–5 months | Chronic inflammatory demyelinating polyneuropathy (likely misdiagnosis) | Mild improvements in gait, eventual progression | 18 |
Patient 4 725, presumed point mutation | 7 | Began using wheelchair at 17 | Ataxia, loss of balance, loss of sensation, leg spasms, restless legs, sleep apnea, fatigue, hypertrophic cardiomyopathy, scoliosis | Prednisone, oral | 15–30 mg BID | 7 months | Chronic inflammatory demyelinating polyneuropathy (likely misdiagnosis) | Improvements in balance, eventual progression | 12 |
Patient 5 unknown | unknown | Unknown | Unknown | Prednisone | unknown | unknown | Rib fractures | Improvement in Gait | unknown |
Patient 6 1000, 1000 | 3 | Began using wheelchair at age 7 | Ataxia, loss of balance, loss of sensation, leg spasms, restless legs, increased tone, tremor, hypertrophic cardiomyopathy, scoliosis | Prednisolone | unknown | unknown | Chronic inflammatory demyelinating polyneuropathy (likely misdiagnosis) | Improvement in gait and strength, eventual progression | 3 |
Patient 7 1113, point mutation | 2 | Began using walker at age 5 | Ataxia, loss of balance, loss of sensation, leg spasms, sleep apnea, hypertrophic cardiomyopathy, scoliosis | Methylprednisolone, pulse therapy | 30 mg QD | 5 days | Pneumonitis | No change in gait, balance, improved energy | 6 |
Patient 8 766, 1000 | 7 | Able to walk without assistive device | Minimal ataxia, loss of balance, no scoliosis or cardiac screening | Solumedrol, oral | 5 mg TID | 5 months | Unclear | Sustained improvements in balance, eventual progression | 9 |
Patient 9 41, 696 | 43 | Began using a walker at age 58 | Ataxia, loss of balance, loss of sensation, leg spasms, increased tone | Depomedrone, injection | 80 mg QD | 7–9 years | Sciatic pain | Improvements in gait and speech | 49 |
Patient 10 966, 1099 | 2 | Able to walk without assistive device | Ataxia, loss of balance, loss of sensation, fatigue | Prednisolone, oral | 30 mg OPD | 3 days | Acute laryngotra-cheitis | Improvements in falling and fatigue | 8 |
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There are several limitations to this study. Improvement in the context of corticosteroid treatment often occurred in the context of significant clinical changes, such as NS in the case of the two cases presented and surgery or trauma in other FRDA patients treated with steroids. Furthermore, in two cases, steroid treatment was initiated following intravenous immunoglobulin G treatment prescribed for chronic inflammatory demyelinating polyneuropathy and Guillain-Barre syndrome, both likely misdiagnoses for Friedreich Ataxia. This raises the possibility that in these cases concomitant intravenous immunoglobulin G treatment was at least partially responsible for noted improvements.
Conclusions
We describe two patients with FRDA and NS, one of whom demonstrated significant improvement with corticosteroid treatment. An association between FRDA and NS was initially reported in a single family in association with myoclonic epilepsy. Epilepsy was not identified in our subject, thus dissociating such findings (as predicted previously). As NS and FRDA are both rare, the present association in multiple unrelated subjects is unlikely to be coincidental. Furthermore, nephrotic syndrome has been documented in a variety of mitochondrial cytopathies and mutations in the synthesis of Coenzyme Q10 cause a subset of steroid-resistant nephrotic syndrome cases [19, 20]. Mitochondrial dysfunction is central to the pathophysiology of Friedreich Ataxia [21]. Lack of frataxin disrupts the production of iron-sulfur clusters and increases levels of intracellular ROS in animal models,patient biopsies and FRDA fibroblasts, suggesting increased oxidative stress in FRDA cells [10, 22‐24]. Although the typical symptomatology of FRDA results from mitochondrial dysfunction in the spine, cerebellum and heart, we hypothesize that the cases of nephrotic syndrome in FRDA described result from mitochondrial involvement in renal cells.
Interestingly one of our subjects showed substantial neurological improvement following steroid treatment. No improvement in the non-neurological symptoms of FRDA were noted. Although this might represent a secondary event associated with improvement in her NS, we identified some degree of steroid responsiveness in her independent of NS and in other patients with FRDA. This could represent an anti-inflammatory effect (as two other patients responded transiently to intravenous immunoglobulin G) or could be the result of other effects of corticosteroids such as increased strength as a compensatory mechanism for balance dysfunction. The former possibility seems most likely, as a secondary inflammatory response in FRDA has been revealed in autopsy studies and in alterations of immune pathways in microarray analysis [11, 12]. This is felt to be the mechanism behind the well-documented response of Duchenne muscular dystrophy to corticosteroids [25, 26].
On the molecular level, it is possible that steroids modify the oxidative stress caused by frataxin deficiency and subsequent mitochondrial disease. This change in oxidative stress was hypothesized to be a cause for neurological improvement following steroid treatment in ataxia-telangiectasia [27]. The catabolic effect of steroids could provide a mechanism for the improvements seen in FRDA, as altered lipid metabolism has been documented in rat myocytes with diminished frataxin levels and in Drosophilia melanogaster [28, 29]. The present patient, taken with previous basic and scientific research, suggests the importance of pilot studies examining the efficacy of pulse steroid treatment as a potential therapy in FRDA.
Consent
Written informed consent was obtained from the patients for review of their records for publications. A copy of the written consent is available for review.
Acknowledgments
This work was supported by grants from the Friedreich Ataxia Research Alliance.
Funding
This study was sponsored by a grant from the Friedreich Ataxia Research Alliance. The funding body did not contribute to the design of the study; collection, analysis, and interpretation of data; or the writing of the manuscript.
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Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
JS compiled case series data and drafted manuscript; CI compiled case series data; SV provided physical therapy notes and interpretation; KS contributed to case series data and provided critical direction for the paper; DL contributed to manuscript and provided critical direction for the paper. All authors read and approved the final manuscript.
Authors’ information
DL is professor of Pediatrics and Neurology at the Perelman School of Medicine, University of Pennsylvania and founding physician in the Penn Medicine/CHOP Friedreich’s Ataxia Center of Excellence. KS is the nurse practitioner for the Friedreich’s Ataxia clinic at CHOP.