Alternative titles; symbols
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 4p16.3 | ?N-acetylaspartate deficiency | 614063 | Autosomal recessive | 3 | NAT8L | 610647 |
A number sign (#) is used with this entry because of evidence that N-acetylaspartate deficiency (NACED) is caused by homozygous mutation in the NAT8L gene (610647) on chromosome 4p16. One such patient has been reported.
The absence of brain N-acetylaspartate (NAA) was described in 1 patient with truncal ataxia, marked developmental delay, seizures, and secondary microcephaly. Martin et al. (2001) initially described a 3-year-old boy who was born at term as the second child of a 20-year-old woman of Eastern European descent. The child was brought to foster care and eventually adopted, so no additional information was available on family history or the pregnancy. At 3 years of age, he had developmental delay with slowing of milestones; vision and hearing appeared normal. Growth for height and weight followed the 25th percentile, whereas head circumference progressively fell below the 3rd percentile by the age of 19 months. At 3 years he was able to sit unaided and to walk a few steps with a broad-based gait. He vocalized sounds but no words and was able to follow simple commands. He was not dysmorphic. Electroencephalogram (EEG) was normal as were urine screening for amino acids, organic acids, and oligo- and mucopolysaccharides. Serum creatine kinase and lactate were normal. HIV and karyotype were normal. Cerebrospinal fluid (CSF) on testing was unremarkable for protein, glucose, cell count, biogenic amines, folate, and pterines. Proton magnetic resonance spectroscopy (MRS) showed complete absence of the NAA peak.
Boltshauser et al. (2004) reported a 5-year follow-up on the patient reported by Martin et al. (2001). At 8 years of age, the boy had profound neurologic dysfunction with truncal ataxia, no expressive speech, behavior abnormalities, secondary microcephaly, and cognitive level corresponding to less than 12 months of age. He developed generalized seizures at 5 years 9 months. Onset of seizures worsened his ataxia. He had a very short attention span. Boltshauser et al. (2004) suggested deficient L-aspartate N-acetyltransferase (ANAT; EC 2.3.1.17) activity as the cause of this disorder. Since N-acetyl-aspartyl-glutamate (NAAG) can be synthesized from NAA and glutamate by NAAG synthase (614054), Boltshauser et al. (2004) noted that the increased levels of NAAG in Canavan disease (271900), a disorder characterized by elevated levels of NAA, indicated that such an NAAG anabolic pathway may be activated. The decreased concentration of NAAG in the CSF of their patient suggested to Boltshauser et al. (2004) that NAAG could not be synthesized because insufficient NAA was available.
Burlina et al. (2006) also described the patient of Martin et al. (2001) at 8 years of age. Burlina et al. (2006) and Wiame et al. (2009) commented that this disorder is essentially the opposite of Canavan disease (271900) in terms of both the clinical phenotype, i.e., microcephaly versus macrocephaly in Canavan disease, and the biochemical phenotype, i.e., deficiency rather than excess of N-acetylaspartate.
Wiame et al. (2009) identified a homozygous 19-bp deletion in the NAT8L gene (610647.0001) in the patient described by Martin et al. (2001) with N-acetylaspartate deficiency.
Boltshauser, E., Schmitt, B., Wevers, R. A., Engelke, U., Burlina, A. B., Burlina, A. P. Follow-up of a child with hypoacetylaspartia. Neuropediatrics 35: 255-258, 2004. [PubMed: 15328569] [Full Text: https://doi.org/10.1055/s-2004-821036]
Burlina, A. P., Schmitt, B., Engelke, U., Wevers, R. A. Burlina, A. B.; Boltshauser, E.: Hypoacetylaspartia: clinical and biochemical follow-up of a patient. Adv. Exp. Med. Biol. 576: 283-287, 2006. [PubMed: 16802720] [Full Text: https://doi.org/10.1007/0-387-30172-0_20]
Martin, E., Capone, A., Schneider, J., Hennig, J., Thiel, T. Absence of N-acetylaspartate in the human brain: impact on neurospectroscopy? Ann. Neurol. 49: 518-521, 2001. [PubMed: 11310630]
Wiame, E., Tyteca, D., Pierrot, N., Collard, F., Amyere, M., Noel, G., Desmedt, J., Nassogne, M.-C., Vikkula, M., Octave, J.-N., Vincent, M.-F., Courtoy, P. J., Boltshauser, E., van Schaftingen, E. Molecular identification of aspartate N-acetyltransferase and its mutation in hypoacetylaspartia. Biochem. J. 425: 127-136, 2009. [PubMed: 19807691] [Full Text: https://doi.org/10.1042/BJ20091024]