Download PDF
Journal of Pediatric Neurology
DOI: 10.1055/s-0041-1728686
Review Article

ALDH7A1 Gene and Its Related Pyridoxine-Dependent Epilepsy

Flavia Maria Consuelo La Mendola
1   Unit of Pediatrics, Caltanissetta Hospital, Caltanissetta, Italy
,
Tiziana Timpanaro
2   Pediatrics Postgraduate Residency Program, Section of Pediatrics and Child Neuropsychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
,
Daniela Caruso
2   Pediatrics Postgraduate Residency Program, Section of Pediatrics and Child Neuropsychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
,
Maria Teresa Garozzo
3   Unit of Pediatric and Pediatric Emergency, Hospital “Cannizzaro,” Catania, Italy
,
Santiago Presti
2   Pediatrics Postgraduate Residency Program, Section of Pediatrics and Child Neuropsychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
,
Catia Romano
4   Italian Blind Union, Catania section, Catania, Italy
,
Elena R. Praticò
5   Unit of Pediatrics, Carpi Hospital, Carpi, Italy
,
Giulia Lombardo
2   Pediatrics Postgraduate Residency Program, Section of Pediatrics and Child Neuropsychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
,
Antonio Zanghì
6   Department of Medical and Surgical Sciences and Advanced Technology “G.F. Ingrassia,” University of Catania, Catania, Italy
,
Raffaele Falsaperla
7   Unit of Pediatrics and Pediatric Emergency, University Hospital “Policlinico Rodolico-San Marco,” Catania, Italy
8   Unit of Neonatal Intensive Care and Neonatology, University Hospital “Policlinico Rodolico-San Marco,” Catania, Italy
› Author Affiliations Funding None.
› Further Information
    Permissions and Reprints

Abstract

Despite being classically reported as caused by mutations in solute carriers genes (SLC2A1), it has been recently shown that also mutations in ALDH7A1 can cause pyridoxine-dependent epilepsy (PDE). ALDH7A1 is a gene encoding for the antiquitin, an enzyme that catalyzes the nicotinamide adenine dinucleotide-dependent dehydrogenation of L-α-aminoadipic semialdehyde/L-Δ1-piperideine 6-carboxylate. It is a highly treatable disorder, but nevertheless it is still not certain when to consider this diagnosis and how to test for it. It is possible to identify a classical form and an atypical one of PDE associated with more than 70 mutations of ALDH7A1 gene. The typical form is characterized by the onset of seizures within the first month of life and can be treated with pyridoxine in monotherapy, as they are not responsive to traditional anticonvulsant therapy. The atypical forms are equally pyridoxine-dependent, but are characterized by a later onset of seizures, sometimes up to the age of 3 years. Several brain abnormalities have been associated with ALDH7A1 mutations. Seizure control is achieved by the administration of high-dose pyridoxine, which must be started in the patient as soon as possible. However, it has been observed that pyridoxine therapy does not prevent developmental delay in most cases; in these cases, it can be recommended and useful to supplement arginine with pyridoxine therapy associated with a dietary restriction of lysine.

Keywords

ALDH7A1 - pyridoxine - epilepsy - childhood


Publication History

Received: 21 September 2020

Accepted: 24 February 2021

Article published online:
21 May 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Mills PB, Footitt EJ, Mills KA. et al. Genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy (ALDH7A1 deficiency). Brain 2010; 133 (Pt 7): 2148-2159
    CrossrefPubMedGoogle Scholar
  • 2 Haidar Z, Jalkh N, Corbani S, Fawaz A, Chouery E, Mégarbané A. Atypical pyridoxine dependent epilepsy resulting from a new homozygous missense mutation, in ALDH7A1. Seizure 2018; 57: 32-33
    CrossrefPubMedGoogle Scholar
  • 3 Toldo I, Bonardi CM, Bettella E. et al. Brain malformations associated to Aldh7a1 gene mutations: report of a novel homozygous mutation and literature review. Eur J Paediatr Neurol 2018; 22 (06) 1042-1053
    CrossrefPubMedGoogle Scholar
  • 4 Ruggieri M, Polizzi A, Pavone L, Musumeci S. Thalamic syndrome in children with measles infection and selective, reversible thalamic involvement. Pediatrics 1998; 101 (1 Pt 1): 112-119
    CrossrefPubMedGoogle Scholar
  • 5 Salpietro V, Polizzi A, Di Rosa G. et al. Adrenal disorders and the paediatric brain: pathophysiological considerations and clinical implications. Int J Endocrinol 2014; 2014: 282489
    CrossrefPubMedGoogle Scholar
  • 6 Pavone P, Praticò AD, Vitaliti G. et al. Hydranencephaly: cerebral spinal fluid instead of cerebral mantles. Ital J Pediatr 2014; 40: 79
    CrossrefPubMedGoogle Scholar
  • 7 Pavone P, Briuglia S, Falsaperla R. et al. Wide spectrum of congenital anomalies including choanal atresia, malformed extremities, and brain and spinal malformations in a girl with a de novo 5.6-Mb deletion of 13q12.11-13q12.13. Am J Med Genet A 2014; 164A (07) 1734-1743
    CrossrefPubMedGoogle Scholar
  • 8 Mercimek-Mahmutoglu S, Cordeiro D, Cruz V. et al. Novel therapy for pyridoxine dependent epilepsy due to ALDH7A1 genetic defect: L-arginine supplementation alternative to lysine-restricted diet. Eur J Paediatr Neurol 2014; 18 (06) 741-746
    CrossrefPubMedGoogle Scholar
  • 9 Pena IA, Roussel Y, Daniel K. et al. Pyridoxine-dependent epilepsy in zebrafish caused by ALDH7A1 deficiency. Genetics 2017; 207 (04) 1501-1518
    CrossrefPubMedGoogle Scholar
  • 10 Mills PB, Struys E, Jakobs C. et al. Mutations in antiquitin in individuals with pyridoxine-dependent seizures. Nat Med 2006; 12 (03) 307-309
    CrossrefPubMedGoogle Scholar
  • 11 Falsaperla R, Perciavalle V, Pavone P. et al. Unilateral eye blinking arising from the ictal ipsilateral occipital area. Clin EEG Neurosci 2016; 47 (03) 243-246
    CrossrefPubMedGoogle Scholar
  • 12 Striano P, Battaglia S, Giordano L. et al. Two novel ALDH7A1 (antiquitin) splicing mutations associated with pyridoxine-dependent seizures. Epilepsia 2009; 50 (04) 933-936
    CrossrefPubMedGoogle Scholar
  • 13 Ruggieri M, Rizzo R, Pavone P, Baieli S, Sorge G, Happle R. Temporal triangular alopecia in association with mental retardation and epilepsy in a mother and daughter. Arch Dermatol 2000; 136 (03) 426-427
    CrossrefPubMedGoogle Scholar
  • 14 Ruggieri M, Iannetti P, Clementi M. et al. Neurofibromatosis type 1 and infantile spasms. Childs Nerv Syst 2009; 25 (02) 211-216
    CrossrefPubMedGoogle Scholar
  • 15 Ruggieri M, Praticò AD, Serra A. et al. Childhood neurofibromatosis type 2 (NF2) and related disorders: from bench to bedside and biologically targeted therapies. Acta Otorhinolaryngol Ital 2016; 36 (05) 345-367
    CrossrefPubMedGoogle Scholar
  • 16 Pavone P, Falsaperla R, Ruggieri M, Praticò AD, Pavone L. West syndrome treatment: new roads for an old syndrome. Front Neurol 2013; 4: 113
    CrossrefPubMedGoogle Scholar
  • 17 Pavone P, Praticò AD, Ruggieri M. et al. Acquired peripheral neuropathy: a report on 20 children. Int J Immunopathol Pharmacol 2012; 25 (02) 513-517
    CrossrefPubMedGoogle Scholar
  • 18 Scharer G, Brocker C, Vasiliou V. et al. The genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy due to mutations in ALDH7A1. J Inherit Metab Dis 2010; 33 (05) 571-581
    CrossrefPubMedGoogle Scholar
  • 19 Yeghiazaryan NS, Zara F, Capovilla G, Brigati G, Falsaperla R, Striano P. Pyridoxine-dependent epilepsy: an under-recognised cause of intractable seizures. J Paediatr Child Health 2012; 48 (03) E113-E115
    CrossrefPubMedGoogle Scholar
  • 20 Coughlin II CR, Swanson MA, Spector E. et al. The genotypic spectrum of ALDH7A1 mutations resulting in pyridoxine dependent epilepsy: a common epileptic encephalopathy. J Inherit Metab Dis 2019; 42 (02) 353-361
    CrossrefPubMedGoogle Scholar
  • 21 Stockler S, Plecko B, Gospe Jr SM. et al. Pyridoxine dependent epilepsy and antiquitin deficiency: clinical and molecular characteristics and recommendations for diagnosis, treatment and follow-up. Mol Genet Metab 2011; 104 (1-2): 48-60
    CrossrefPubMedGoogle Scholar
  • 22 Pratico AD, Longo L, Mansueto S. et al. Off-label use of drugs and adverse drug reactions in pediatric units: a prospective, multicenter study. Curr Drug Saf 2018; 13 (03) 200-207
    CrossrefPubMedGoogle Scholar
  • 23 Incorpora G, Pavone P, Castellano-Chiodo D, Praticò AD, Ruggieri M, Pavone L. Gelastic seizures due to hypothalamic hamartoma: rapid resolution after endoscopic tumor disconnection. Neurocase 2013; 19 (05) 458-461
    CrossrefPubMedGoogle Scholar
  • 24 Ruggieri M, Pavone V, De Luca D, Franzò A, Tiné A, Pavone L. Congenital bone malformations in patients with neurofibromatosis type 1 (Nf1). J Pediatr Orthop 1999; 19 (03) 301-305
    CrossrefPubMedGoogle Scholar
  • 25 Ruggieri M, Iannetti P, Pavone L. Delineation of a newly recognized neurocutaneous malformation syndrome with “cutis tricolor”. Am J Med Genet A 2003; 120A (01) 110-116
    CrossrefPubMedGoogle Scholar
  • 26 van Karnebeek CD, Tiebout SA, Niermeijer J. et al. Pyridoxine-dependent epilepsy: an expanding clinical spectrum. Pediatr Neurol 2016; 59: 6-12
    CrossrefPubMedGoogle Scholar
  • 27 Sorge G, Ruggieri M, Polizzi A, Scuderi A, Di Pietro M. SHORT syndrome: a new case with probable autosomal dominant inheritance. Am J Med Genet 1996; 61 (02) 178-181
    CrossrefPubMedGoogle Scholar
  • 28 Ruggieri M, Milone P, Pavone P. et al. Nevus vascularis mixtus (cutaneous vascular twin nevi) associated with intracranial vascular malformation of the Dyke-Davidoff-Masson type in two patients. Am J Med Genet A 2012; 158A (11) 2870-2880
    CrossrefPubMedGoogle Scholar
  • 29 Wilson MP, Plecko B, Mills PB, Clayton PT. Disorders affecting vitamin B6 metabolism. J Inherit Metab Dis 2019; 42 (04) 629-646
    CrossrefPubMedGoogle Scholar
  • 30 Kaczorowska M, Kmiec T, Jakobs C. et al. Pyridoxine-dependent seizures caused by alpha amino adipic semialdehyde dehydrogenase deficiency: the first polish case with confirmed biochemical and molecular pathology. J Child Neurol 2008; 23 (12) 1455-1459
    CrossrefPubMedGoogle Scholar
  • 31 Pratico AD, Ruggieri M, Falsaperla R, Pavone P. A probable topiramate-induced limbs paraesthesia and rigid fingers flexion. Curr Drug Saf 2018; 13 (02) 131-136
    CrossrefPubMedGoogle Scholar
  • 32 Praticò AD, Polizzi A, Salafia R. et al. Megalencephaly capillary malformation syndrome. J Pediatr Neurol 2018; 16: 328-337
    Article in Thieme ConnectPubMedGoogle Scholar
  • 33 Mefford HC, Zemel M, Geraghty E. et al. Intragenic deletions of ALDH7A1 in pyridoxine-dependent epilepsy caused by Alu-Alu recombination. Neurology 2015; 85 (09) 756-762
    CrossrefPubMedGoogle Scholar
  • 34 Bennett CL, Chen Y, Hahn S, Glass IA, Gospe Jr SM. Prevalence of ALDH7A1 mutations in 18 North American pyridoxine-dependent seizure (PDS) patients. Epilepsia 2009; 50 (05) 1167-1175
    CrossrefPubMedGoogle Scholar
  • 35 Plecko B, Paul K, Paschke E. et al. Biochemical and molecular characterization of 18 patients with pyridoxine-dependent epilepsy and mutations of the antiquitin (ALDH7A1) gene. Hum Mutat 2007; 28 (01) 19-26
    CrossrefPubMedGoogle Scholar
  • 36 Hortopan GA, Dinday MT, Baraban SC. Spontaneous seizures and altered gene expression in GABA signaling pathways in a mind bomb mutant zebrafish. J Neurosci 2010; 30 (41) 13718-13728
    CrossrefPubMedGoogle Scholar
  • 37 Salpietro V, Mankad K, Kinali M. et al. Pediatric idiopathic intracranial hypertension and the underlying endocrine-metabolic dysfunction: a pilot study. J Pediatr Endocrinol Metab 2014; 27 (1-2): 107-115
    CrossrefPubMedGoogle Scholar
  • 38 Lionetti E, Leonardi S, Franzonello C, Mancardi M, Ruggieri M, Catassi C. Gluten psychosis: confirmation of a new clinical entity. Nutrients 2015; 7 (07) 5532-5539
    CrossrefPubMedGoogle Scholar
  • 39 Yang Z, Yang X, Wu Y. et al. Clinical diagnosis, treatment, and ALDH7A1 mutations in pyridoxine-dependent epilepsy in three Chinese infants. PLoS One 2014; 9 (03) e92803
    CrossrefPubMedGoogle Scholar