Lysine Restriction and Pyridoxal Phosphate Administration in a NADK2 Patient
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Lysine Restriction and Pyridoxal Phosphate Administration in a NADK2 Patient Frederic Tort, PhD,a Olatz Ugarteburu, MSc,a Maria Angeles Torres, MD,b Judit García- Villoria, PhD, a Marisa Girós, PhD,a Angeles Ruiz, MD, b Antonia Ribes, PhDa We report the case of a 10-year-old Spanish girl with mutations in NADK2. abstract Prenatal central nervous system abnormalities showed ventriculomegaly, colpocephaly, and hypoplasia of the corpus callosum. At birth, axial hypotonia, uncoordinated movements, microcephaly, and generalized a Secció d’Errors Congènits del Metabolisme–IBC, Servei de cerebellar atrophy were detected. Metabolic investigations revealed high Bioquímica i Genètica Molecular, Hospital Clínic, IDIBAPS, lysine, lactate, and pipecolic acid levels in blood and cerebrospinal fluid. CIBERER, Barcelona, Spain; and bHospital Universitario Son Pyruvate carboxylase and pyruvate dehydrogenase activity in fibroblasts Espases, Palma de Mallorca, Spain were normal. Beginning at birth she received biotin, thiamine, and Dr Tort designed the study, analyzed exome carnitine supplementation. A lysine-restricted diet was started when she sequencing, performed and analyzed molecular data, and wrote the initial manuscript; was 1 month old. Because pipecolic acid was high, pyridoxine was added Ms Ugarteburu performed genetic and molecular to treatment. At 3 years old, astatic myoclonic epilepsy appeared, with no studies and drafted the initial manuscript; response to levetiracetam. We switched pyridoxine to pyridoxal phosphate, Dr Torres supervised data collection, helped with the with electroclinical improvement. Because the activity of mitochondrial follow-up of the patient, and critically reviewed the manuscript; Drs García-Villoria and Girós performed respiratory chain complexes III and IV was slightly low in muscle, other biochemical studies and critically reviewed the cofactors such as ubidecarenone, idebenone, vitamin E, and creatine manuscript; Drs Ruiz and Ribes designed the were added to the treatment. At 8 years old, plasma acylcarnitine testing study, coordinated and supervised data collection, performed the follow-up of the reported patient, was performed, and high levels of 2-trans, 4-cis-decadienoylcarnitine and wrote the initial manuscript; and all authors were found. Whole exome sequencing identified a homozygous splice site approved the fi nal manuscript as submitted. mutation in NADK2 (c.956+6T>C; p.Trp319Cysfs*21). This substitution DOI: 10.1542/peds.2015-4534 generates exon skipping, leading to a truncated protein. In fact, NADK2 Accepted for publication Jul 26, 2016 messenger RNA and the corresponding protein were almost absent. Now, Address correspondence to Antonia Ribes, Secció at 10 years of age she presents with ataxia and incoordination. She has d’Errors Congènits del Metabolisme–IBC, Servei de oromotor dysphasia but is able to understand fluid language and is a very Bioquímica i Genètica Molecular, Hospital Clínic, IDIBAPS, CIBERER, C/Mejía Lequerica s/n, Edifi ci friendly girl. We hypothesize that the patient’s clinical improvement could Helios III, Planta Baixa, 08028 Barcelona, Spain. be due to her lysine-restricted diet together with cofactors and pyridoxal E-mail: [email protected] phosphate administration. PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2016 by the American Academy of Familial hyperlysinemia is a rare inborn errors of metabolism such Pediatrics autosomal recessive disorder caused as urea cycle disorders, pyruvate FINANCIAL DISCLOSURE: The authors have indicated they have no fi nancial relationships by mutations in AASS, encoding for carboxylase deficiency, and organic 3 relevant to this article to disclose. the first enzyme in the main lysine acid disorders. FUNDING: Supported by the Instituto de Salud degradation pathway, which takes Using next-generation sequencing, Carlos III (FIS PI12/01138) and the Centro de place in the mitochondria. 1, 2 Investigación Biomédica en Red de Enfermedades a recent study identified disease- The impairment of this catabolic causing mutations in NADK2 in a pathway leads to the accumulation child presenting with hyperlysinemia, To cite: Tort F, Ugarteburu O, Torres MA, et al. of lysine in both plasma and urine. hyperlysinuria, elevated 2-trans, Lysine Restriction and Pyridoxal Phosphate Ad- High levels of lysine in body fluids 4-cis-decadienoylcarnitine (C10: ministration in a NADK2 Patient. Pediatrics. 2016; 138(5):e20154534 are often concomitant of many 2- carnitine), and 2, 4-dienoyl-CoA Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 138 , number 5 , November 2016 :e 20154534 CASE REPORT ( Fig 1). Toxoplasmosis, syphilis, varicella-zoster, parvovirus B19, rubella, cytomegalovirus, and herpes infections were ruled out. Biochemical investigations revealed high levels of lysine in plasma, urine, and cerebrospinal fluid (CSF). Pipecolic acid and lactate were also high in blood and CSF. Plasma acylcarnitine analysis showed high C10: 2- carnitine ( Table 1), but no abnormalities were detected in FIGURE 1 the organic acid profile in urine Brain MRI studies. At (A) 6 years and (B) 9 years of age no alteration in myelin was found, but a performed in several occasions. progressive global cerebellar atrophy and a high peak of lactate was observed in WM/BG, especially Other metabolic investigations in CSF (intraventricular), with a relative decrease of the 3 main metabolites (N-acetylaspartate, creatine, and choline). BG, basal ganglia; WM, white matter. such as coenzyme Q10, biotinidase, sialotransferrins, very long-chain reductase deficiency. 4 NADK2 PATIENT PRESENTATION fatty acids, and phytanic and encodes for the mitochondrial pristanic acids in plasma, as well Written consent was obtained from nicotinamide adenine dinucleotide as creatine, guanidinoacetate, and the parents of the patient for whole α kinase, which is considered the only -aminoadipic semialdehyde were exome sequencing analysis and biosynthetic source of mitochondrial normal. publication of this case report. nicotinamide adenine dinucleotide Beginning at birth she presented phosphate (NADP), a cofactor We report on a 10-year-old girl born with anorexia, feeding refusal, and necessary for the activity of enzymes from non consanguineous healthy frequent vomiting. Because plasma implicated in a large variety of Spanish parents. Prenatal scan at and CSF lactate were slightly high, biochemical pathways involved in the 34 and 37 weeks’ gestational age a disturbance of mitochondrial mitochondrial function. 5, 6 showed CNS abnormalities with energy metabolism was suspected. grade I to II ventriculomegaly, Therefore, biotin (10 mg per day), Here, we report a patient with colpocephaly, and hypoplasia of thiamine (300 mg per day), and prenatal central nervous system the corpus callosum. The patient carnitine (30 mg/kg per day) were (CNS) dysgenesia, microcephaly, was born at 40 weeks’ gestational empirically supplemented. At 1 delayed myelinization, progressive age by elective cesarean delivery. and a half months of age, lysine cerebellar atrophy, psychomotor She presented with asymmetric restriction (45 mg/kg per day) intrauterine growth retardation was started, maintaining the total retardation, and astatic myoclonic and low birth weight (2400 g, protein intake at 2.7 g/kg per day epilepsy, associated with third percentile) and height with hypercaloric supplements. This hyperlysinemia, high levels of lactate (45 cm, third percentile). Head diet resulted of great benefit for and pipecolic acid in body fluids, circumference was 34 cm (50th anorexia and vomiting resolution, and deficiency of the mitochondrial percentile). Examination at birth and plasma lysine decreased respiratory chain complexes III showed central hypotonia along with drastically, ranging from 40 to and IV. The use of whole exome uncoordinated movements with 257 μmol/L (control values [CV] sequencing has allowed us to identify no seizure activity, lack of sucking 52–196 μmol/L). At 3 months of age a new homozygous mutation in reflex, abnormal neonatal reflexes, high levels of pipecolic acid in plasma NADK2, leading to a premature stop and generalized hyperreflexia. The and CSF were found ( Table 1). Despite codon and absence of protein. This anterior fontanelle was bulging, normal α-aminoadipic semialdehyde is the second reported patient with and she showed downward eye in urine, pyridoxine (50 mg per mutations in this gene. Treatment deviation to the vertical side. During day) was added empirically to with a low-lysine diet and a cocktail the first 10 days of life she had treatment. At 3 years of age she of cofactors, including pyridoxal persistent signs of hypertensive developed epileptic seizures with phosphate (PLP), improved hydrocephalus that resolved myoclonic astatic absences. EEG considerably the clinical course spontaneously but progressed to changes showed a generalized spike of the disease compared with the a persistent microcephaly with wave of 2 to 2.5 per second with previously reported patient. 4 generalized cerebellar atrophy no clinical or electrical response to Downloaded from www.aappublications.org/news by guest on September 26, 2021 e2 TORT et al TABLE 1 Biochemical and Clinical Data Patient, This Report Houten et al 2014 4 Roe et al 1990 7 Biochemical data Metabolites Lysine Plasma (CV: 52–196 μmol/L) 617–1506 135–831 908–1.052 Urine (CV: 22–171 mmol/mol creatinine) 544–6976 1779 (CV: 81–213) CSF (CV: 9.0–51.0 μmol/L) 204 226 Pipecolic