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Friedreich Ataxia and nephrotic syndrome: a series of two patients

  • Julianna E. Shinnick1,
  • Charles J. Isaacs1,
  • Sharon Vivaldi2,
  • Kimberly Schadt1 and
  • David R. Lynch1, 3Email author
BMC Neurology201616:3

https://doi.org/10.1186/s12883-016-0526-2

Received: 17 September 2015

Accepted: 5 January 2016

Published: 12 January 2016

Abstract

Background

Friedreich Ataxia (FRDA) is a neurodegenerative disorder characterized by gait and balance abnormalities, sensory loss, weakness, loss of reflexes, and ataxia. Previously, two cases of FRDA and Nephrotic Syndrome (NS) have been reported. Here we report two additional individuals with NS and FRDA, providing further evidence for a possible connection between the two diseases and focusing on the neuromuscular responsiveness of one individual to corticosteroid treatment, an effect not previously described in FRDA.

Case presentations

We describe two patients with FRDA also presenting with NS. The first patient was diagnosed with FRDA at age 5 and NS at age 7 following the development of periorbital edema, abdominal swelling, problems with urination, and weight gain. The second patient was diagnosed with NS at age 2 after presenting with periorbital edema, lethargy, and abdominal swelling. He was diagnosed with FRDA at age 10. Nephrotic syndrome was confirmed by laboratory testing in both cases and both individuals were treated with corticosteroids.

Conclusions

Nephrotic syndrome may occur in individuals with FRDA, but was not associated with myoclonic epilepsy in our patients as previously described. It is unlikely that this association is coincidental given the rarity of both conditions and the association of NS with mitochondrial disease in model systems, though coincidental coexistence is possible. One patient showed neurological improvement following steroid treatment. Although neurological improvement could be attributed to the treatment of NS, we also identified some degree of steroid responsiveness in a series of patients with FRDA but without NS.

Keywords

Friedreich Ataxia Nephrotic Syndrome Steroid

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 [18]. 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 [912]. 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.

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

aPhenotype at closest exam to steroid use

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, 2224]. 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.

Abbreviations

FRDA: 

Friedreich’s Ataxia

GAA: 

Guanine-Adenine-Adenine

NS: 

Nephrotic Syndrome

CHOP: 

Children’s Hospital of Philadelphia

CCRN: 

Collaborative Clinical Research Network

Declarations

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.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Departments of Pediatrics and Neurology, Children’s Hospital of Philadelphia
(2)
Department of Physical Therapy, Department of Rehabilitation, Children’s Hospital of Philadelphia, King of Prussia Specialty Care and Surgery Center
(3)
Perelman School of Medicine, University of Pennsylvania

References

  1. Delatycki MB, Corben LA. Clinical features of Fredreich Ataxia. J Child Neurol. 2012;27(9):1133–7.PubMedPubMed CentralView ArticleGoogle Scholar
  2. Corben LA, Ho M, Copland J, Tai G, Delatycki MB. Increased prevalence of sleep-disordered breathing in Friedreich ataxia. Neurology. 2013;81(1):46–51.PubMedView ArticleGoogle Scholar
  3. Seyer LA, Galetta K, Wilson J, Sakai R, Perlman S, Mathews K, et al. Analysis of the visual system in Friedreich ataxia. J Neurol. 2013;260(9):2362–9.PubMedView ArticleGoogle Scholar
  4. Delatycki MB, Paris DB, Gardner RJ, Nicholson GA, Nassif N, Storey E, et al. Clinical and genetic study of Friedreich ataxia in an Australian population. Am J Med Genet. 1999;87(2):168–74.PubMedView ArticleGoogle Scholar
  5. Greeley NR, Regner S, Willi S, Lynch DR. Cross-sectional analysis of glucose metabolism in Friedreich ataxia. J Neurol Sci. 2014;342(1–2):29–35.PubMedView ArticleGoogle Scholar
  6. Rance G, Corben L, Barker E, Carew P, Chisari D, Rogers M, et al. Auditory perception in individuals with Friedreich’s ataxia. Audiol Neurooto. 2010;15(4):229–40.View ArticleGoogle Scholar
  7. Lynch DR, Regner SR, Schadt KA, Friedman LS, Lin KY, St John Sutton MG. Management and therapy for cardiomyopathy in Fridreich’s ataxia. Expert Rev Cardiovasc Ther. 2012;10(6):767–77.PubMedView ArticleGoogle Scholar
  8. Parkinson MH, Boesch S, Nachbauer W, Mariotti C, Giunti P. Features of Friedreich’s ataxia: clinical and atypical phenotypes. J Neurochem. 2013;126(S1):103–17.PubMedView ArticleGoogle Scholar
  9. Puccio H, Kœnig M. Recent advances in the molecular pathogenesis of Friedreich ataxia. Hum Mol Genet. 2000;9(6):887–92.PubMedView ArticleGoogle Scholar
  10. García-Giménez J, Gimeno A, Gonzalez-Cabo P, Dasí F, Bolinches-Amorós A, Mollá B. Differential expression of PGC-1alpha and metabolic sensors suggest age-dependent induction of mitochondrial biogenesis in Friedreich ataxia fibroblasts. PLoS One. 2011;6(6):e20666.PubMedPubMed CentralView ArticleGoogle Scholar
  11. Michael S, Petrocine SV, Qian J, Lamarche JB, Knutson MD, Garrick MD, et al. Iron and iron-responsive proteins in the cardiomyopathy of Friedreich’s ataxia. Cerebellum. 2006;5(4):257–67.PubMedView ArticleGoogle Scholar
  12. Koeppen AH, Ramirez RL, Becker AB, Bjork ST, Levi S, Santambrogio P, et al. The pathogenesis of cardiomyopathy in Friedreich ataxia. PLoS. 2006;10(3):e0116396.View ArticleGoogle Scholar
  13. Strawser CJ, Schadt KA, Lynch DR. Therapeutic approaches for the treatment of Friedreich’s ataxia. Expert Rev Neurother. 2014;14(8):947–55.View ArticleGoogle Scholar
  14. Seyer L, Greeley N, Foerster D, Strawser C, Gelbard S, Dong Y, et al. Open-label pilot study of interferon gamma-1b in Friedreich ataxia. Acta Neurol Scand. 2015;132(1):7–15.PubMedView ArticleGoogle Scholar
  15. Watters GV, Zlotkin SH, Kaplan BS, Humphreys P, Drummond KN. Friedreich’s ataxia with nephrotic syndrome and convulsive disorder: clinical and neurophysiological studies with renal and nerve biopsies and an autopsy. Can J Neurol Sci. 1981;8(1):55–60.PubMedGoogle Scholar
  16. Quinzii CM, Hirano M. Coenzyme Q and mitochondrial disease. Dev Disabil Res Rev. 2010;16(2):183–8.PubMedPubMed CentralView ArticleGoogle Scholar
  17. Martín-Hernández E, García-Silva MT, Vara J, Campos Y, Cabello A, Muley R, et al. Renal pathology in children with mitochondrial diseases. Pediatr Nephrol. 2005;20(9):183–8.View ArticleGoogle Scholar
  18. Regner SR, Wilcox NS, Friedman LS, Seyer LA, Schadt KA, Brigatti KW, et al. Friedreich ataxia clinical outcome measures: natural history evaluation in 410 participants. J Child Neurol. 2012;27(9):1152–8.PubMedPubMed CentralView ArticleGoogle Scholar
  19. Emma F, Bertini E, Salviati L, Montini G. Renal involvement in mitochondrial cytopathies. Pediatr Nephrol. 2012;27(4):539–50.PubMedPubMed CentralView ArticleGoogle Scholar
  20. Ashraf S, Gee HY, Woerner S, Xie LX, Vega-Warner V, Lovric S, et al. ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ10 biosynthesis disruption. J Clin Invest. 2013;123(12):5179.PubMedPubMed CentralView ArticleGoogle Scholar
  21. González‐Cabo P, Palau F. Mitochondrial pathophysiology in Friedreich’s ataxia. J Neurochem. 2013;126(s1):53–64.PubMedView ArticleGoogle Scholar
  22. Babcock M, de Silva D, Oaks R, Davis-Kaplan S, Jiralerspong S, Montermini L, et al. Regulation of mitochondrial iron accumulation by Yfh1p, a putative homolog of frataxin. Science. 1997;276(5319):1709–12.PubMedView ArticleGoogle Scholar
  23. Puccio H, Simon S, Cossée M, Criqui-Filipe P, Tiziano F, Melki J. Mouse models for Friedreich ataxia exhibit cardiomyopathy, sensory nerve defect and Fe-S enzyme deficiency followed by intramitochondrial iron deposits. Nat Genet. 2001;27(2):181–6.PubMedView ArticleGoogle Scholar
  24. Rotig A, de Lonlay P, Chretien D, Foury F, Koenig M, Sidi D. Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia. Nat Genet. 1997;17(2):215–7.PubMedView ArticleGoogle Scholar
  25. Pane M, Fanelli L, Mazzone ES, Olivieri G, D’Amico A, Messina S, et al. Benefits of glucocorticoids in non-ambulant boys/men with Duchenne muscular dystrophy: A multicentric longitudinal study using the Performance of Upper Limb test. Neuromuscul Disord. 2015. doi:10.1016/j.nmd.2015.07.009.PubMed CentralGoogle Scholar
  26. Reeves EK, Rayavarapu S, Damsker JM, Nagaraju K. Glucocorticoid analogues: potential therapeutic alternatives for treating inflammatory muscle diseases. Endocr Metab Immune Disord Drug Targets. 2012;12(1):95–103.PubMedView ArticleGoogle Scholar
  27. Broccoletti T, Del Giudice E, Cirillo E, Vigliano I, Giardino G, Ginocchio VM, et al. Efficacy of very-low-dose betamethasone on neurological symptoms in ataxia-telangiectasia. Eur J Neurol. 2011;18(4):564–70.PubMedView ArticleGoogle Scholar
  28. Obis E, Irazusta V, Sanchis D, Ros J, Tamarit J. Frataxin deficiency in neonatal rat ventricular myocytes targets mitochondria and lipid metabolism. Free Radic Biol Med. 2014;73:21–33.PubMedView ArticleGoogle Scholar
  29. Navarro JA, Ohmann E, Sanchez D, Botella JA, Liebisch G, Moltó MD, et al. Altered lipid metabolism in a Drosophila model of Friedreich’s ataxia. Hum Mol Genet. 2010;19(14):2828–40.PubMedView ArticleGoogle Scholar

Copyright

© Shinnick et al. 2016

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