title: Lysine Restriction and Pyridoxal Phosphate Administration in a NADK2 Patient.
abstract: We report the case of a 10-year-old Spanish girl with mutations in NADK2 Prenatal central nervous system abnormalities showed ventriculomegaly, colpocephaly, and hypoplasia of the corpus callosum. At birth, axial hypotonia, uncoordinated movements, microcephaly, and generalized cerebellar atrophy were detected. Metabolic investigations revealed high lysine, lactate, and pipecolic acid levels in blood and cerebrospinal fluid. Pyruvate carboxylase and pyruvate dehydrogenase activity in fibroblasts were normal. Beginning at birth she received biotin, thiamine, and carnitine supplementation. A lysine-restricted diet was started when she was 1 month old. Because pipecolic acid was high, pyridoxine was added to treatment. At 3 years old, astatic myoclonic epilepsy appeared, with no response to levetiracetam. We switched pyridoxine to pyridoxal phosphate, with electroclinical improvement. Because the activity of mitochondrial respiratory chain complexes III and IV was slightly low in muscle, other cofactors such as ubidecarenone, idebenone, vitamin E, and creatine were added to the treatment. At 8 years old, plasma acylcarnitine testing was performed, and high levels of 2-trans, 4-cis-decadienoylcarnitine were found. Whole exome sequencing identified a homozygous splice site mutation in NADK2 (c.956+6T>C; p.Trp319Cysfs*21). This substitution generates exon skipping, leading to a truncated protein. In fact, NADK2 messenger RNA and the corresponding protein were almost absent. Now, at 10 years of age she presents with ataxia and incoordination. She has oromotor dysphasia but is able to understand fluid language and is a very friendly girl. We hypothesize that the patient's clinical improvement could be due to her lysine-restricted diet together with cofactors and pyridoxal phosphate administration.
authors.affiliation: Secció d'Errors Congènits del Metabolisme-IBC, Servei de Bioquímica i Genètica Molecular, Hospital Clínic, IDIBAPS, CIBERER, Barcelona, Spain; and.
authors.forename: Frederic
authors.initials: F
authors.lastname: Tort
authors.affiliation: Secció d'Errors Congènits del Metabolisme-IBC, Servei de Bioquímica i Genètica Molecular, Hospital Clínic, IDIBAPS, CIBERER, Barcelona, Spain; and.
authors.forename: Olatz
authors.initials: O
authors.lastname: Ugarteburu
authors.affiliation: Hospital Universitario Son Espases, Palma de Mallorca, Spain.
authors.forename: Maria Angeles
authors.initials: MA
authors.lastname: Torres
authors.affiliation: Secció d'Errors Congènits del Metabolisme-IBC, Servei de Bioquímica i Genètica Molecular, Hospital Clínic, IDIBAPS, CIBERER, Barcelona, Spain; and.
authors.forename: Judit
authors.initials: J
authors.lastname: García-Villoria
authors.affiliation: Secció d'Errors Congènits del Metabolisme-IBC, Servei de Bioquímica i Genètica Molecular, Hospital Clínic, IDIBAPS, CIBERER, Barcelona, Spain; and.
authors.forename: Marisa
authors.initials: M
authors.lastname: Girós
authors.affiliation: Hospital Universitario Son Espases, Palma de Mallorca, Spain.
authors.forename: Angeles
authors.initials: A
authors.lastname: Ruiz
authors.affiliation: Secció d'Errors Congènits del Metabolisme-IBC, Servei de Bioquímica i Genètica Molecular, Hospital Clínic, IDIBAPS, CIBERER, Barcelona, Spain; and aribes@clinic.ub.es.
authors.forename: Antonia
authors.initials: A
authors.lastname: Ribes
mesh_terms: D002648:Child; D004032:Diet; D004831:Epilepsies, Myoclonic / Q000235:genetics / Q000628:therapy; D005260:Female; D006720:Homozygote; D006801:Humans; D020167:Hyperlysinemias / Q000235:genetics*; D019344:Lactic Acid / Q000097:blood / Q000134:cerebrospinal fluid; D008239:Lysine / Q000008:administration & dosage* / Q000097:blood / Q000134:cerebrospinal fluid; D028361:Mitochondrial Diseases / Q000235:genetics; D024101:Mitochondrial Proteins / Q000235:genetics*; D009154:Mutation; D009421:Nervous System Malformations / Q000235:genetics; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics*; D010875:Pipecolic Acids / Q000097:blood / Q000134:cerebrospinal fluid; D011732:Pyridoxal Phosphate / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D014803:Vitamin B Complex / Q000627:therapeutic use*
chemical_list: D024101:Mitochondrial Proteins; D010875:Pipecolic Acids; D012333:RNA, Messenger; D014803:Vitamin B Complex; D019344:Lactic Acid; D011732:Pyridoxal Phosphate; C581562:NADK2 protein, human; D017853:Phosphotransferases (Alcohol Group Acceptor); C031345:pipecolic acid; D008239:Lysine