Download PDF
Journal of Pediatric Neurology 2016; 14(02): 078-081
DOI: 10.1055/s-0036-1583275
Case Report
Georg Thieme Verlag KG Stuttgart · New York

Secondary Cerebral Folate Deficiency Comorbidity in Neuronal Ceroid Lipofuscinosis

Yvonne Yijuan Lim
1   Division of Paediatric Neurology, Khoo Teck Puat-National University Children's Medical Institute, National University Health Systems, Singapore
,
Sarah Jane Corpuz Tapawan
2   Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
,
Aileen Yu-Wen Pang
1   Division of Paediatric Neurology, Khoo Teck Puat-National University Children's Medical Institute, National University Health Systems, Singapore
,
Keith Hyland
3   Medical Neurogenetics, Atlanta, Georgia, United States
,
Stacey Kiat-Hong Tay
1   Division of Paediatric Neurology, Khoo Teck Puat-National University Children's Medical Institute, National University Health Systems, Singapore
2   Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
› Author Affiliations
Further Information

Publication History

20 April 2014

30 April 2015

Publication Date:
04 May 2016 (online)

Also available at
    Permissions and Reprints

Abstract

Secondary cerebral folate deficiency (CFD) has been described in various neurodegenerative diseases, for example, Aicardi–Goutieres syndrome, Kearns–Sayre syndrome, and other mitochondriopathies. The importance of associated CFD lies in the possibility that treatment with folinic acid may improve the outcome of these diseases, or its presence may affect the course of the disease. We describe a patient with neuronal ceroid lipofuscinosis (NCL) type 2 due to tripeptidyl-peptidase I (TPP1) deficiency with an atypical presentation of chorea and dystonia. She was subsequently found to have low cerebrospinal fluid (CSF) 5-methyltetrahydrofolate (5-MTHF). TPP1 level in skin fibroblast cultures was < 0.1 nmol/min/mg protein (normal range: 0.7–2.2 nmol/min/mg protein), confirming the diagnosis of NCL. CSF 5-MTHF was 36 nmol/L (normal range: 40–150 nmol/L) while red blood cell folate was slightly elevated at 1,902 nmol/L (normal range: 776–1,784 nmol/L). Oral folinic acid was administered with no clear amelioration of the movement disorder. This is the first documented case of low CSF folate levels in NCL. Given the unusual clinical presentation of dyskinesia, it is possible that low CSF 5-MTHF levels may have contributed to this. It is important to evaluate CSF 5-MTHF levels in patients with NCL as low cerebral folate levels may aggravate the neurodegenerative process.

Keywords

neuronal ceroid lipofuscinosis - methyltetrahydrofolate - folate deficiency
 

  • References

  • 1 Hyland K, Shoffner J, Heales SJ. Cerebral folate deficiency. J Inherit Metab Dis 2010; 33 (5) 563-570
    CrossrefPubMedGoogle Scholar
  • 2 Wevers RA, Hansen SI, van Hellenberg Hubar JL, Holm J, Høier-Madsen M, Jongen PJ. Folate deficiency in cerebrospinal fluid associated with a defect in folate binding protein in the central nervous system. J Neurol Neurosurg Psychiatry 1994; 57 (2) 223-226
    CrossrefPubMedGoogle Scholar
  • 3 Ramaekers VT, Blau N. Cerebral folate deficiency. Dev Med Child Neurol 2004; 46 (12) 843-851
    PubMedGoogle Scholar
  • 4 Garcia-Cazorla A, Quadros EV, Nascimento A , et al. Mitochondrial diseases associated with cerebral folate deficiency. Neurology 2008; 70 (16) 1360-1362
    CrossrefPubMedGoogle Scholar
  • 5 Pérez-Dueñas B, Ormazábal A, Toma C , et al. Cerebral folate deficiency syndromes in childhood: clinical, analytical, and etiologic aspects. Arch Neurol 2011; 68 (5) 615-621
    PubMedGoogle Scholar
  • 6 Pezzini F, Gismondi F, Tessa A , et al. Involvement of the mitochondrial compartment in human NCL fibroblasts. Biochem Biophys Res Commun 2011; 416 (1–2) 159-164
    CrossrefPubMedGoogle Scholar
  • 7 Wei H, Kim SJ, Zhang Z, Tsai PC, Wisniewski KE, Mukherjee AB. ER and oxidative stresses are common mediators of apoptosis in both neurodegenerative and non-neurodegenerative lysosomal storage disorders and are alleviated by chemical chaperones. Hum Mol Genet 2008; 17 (4) 469-477
    CrossrefPubMedGoogle Scholar
  • 8 Kang S, Seo JH, Heo TH, Kim SJ. Batten disease is linked to altered expression of mitochondria-related metabolic molecules. Neurochem Int 2013; 62 (7) 931-935
    CrossrefPubMedGoogle Scholar
  • 9 Simonati A, Santorum E, Tessa A , et al. A CLN2 gene nonsense mutation is associated with severe caudate atrophy and dystonia in LINCL. Neuropediatrics 2000; 31 (4) 199-201
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Van Beersel G, Tihon E, Demine S, Hamer I, Jadot M, Arnould T. Different molecular mechanisms involved in spontaneous and oxidative stress-induced mitochondrial fragmentation in tripeptidyl peptidase-1 (TPP-1)-deficient fibroblasts. Biosci Rep 2013; 33 (2) e00023
    PubMedGoogle Scholar
  • 11 Ramaekers VT, Hansen SI, Holm J , et al. Reduced folate transport to the CNS in female Rett patients. Neurology 2003; 61 (4) 506-515
    CrossrefPubMedGoogle Scholar
  • 12 Sequeira JM, Ramaekers VT, Quadros EV. The diagnostic utility of folate receptor autoantibodies in blood. Clin Chem Lab Med 2013; 51 (3) 545-554
    PubMedGoogle Scholar
  • 13 Hansen FJ, Blau N. Cerebral folate deficiency: life-changing supplementation with folinic acid. Mol Genet Metab 2005; 84 (4) 371-373
    CrossrefPubMedGoogle Scholar
  • 14 Moretti P, Sahoo T, Hyland K , et al. Cerebral folate deficiency with developmental delay, autism, and response to folinic acid. Neurology 2005; 64 (6) 1088-1090
    CrossrefPubMedGoogle Scholar
  • 15 Pineda M, Ormazábal A, López-Gallardo E , et al. Cerebral folate deficiency and leukoencephalopathy caused by a mitochondrial DNA deletion. Ann Neurol 2006; 59 (2) 394-398
    CrossrefPubMedGoogle Scholar