Primary Intracranial Atypical Teratoid/Rhabdoid Tumor in a Child with Canavan Disease

Canavan's disease (CD) is a fatal, hereditary disorder of CNS development that has been linked to mutations in the gene for the enzyme aspartoacylase (ASPA) (EC 3.5.1.15). ASPA acts to hydrolyze N-acetylaspartate (NAA) into L-aspartate and acetate, but the connection between ASPA deficiency and the failure of proper CNS development is unclear. We hypothesize that one function of ASPA is to provide acetate for the increased lipid synthesis that occurs during postnatal CNS myelination. The gene encoding ASPA has been inactivated in the mouse model of CD, and here we show significant decreases in the synthesis of six classes of myelinassociated lipids, as well as reduced acetate levels, in the brains of these mice at the time of peak postnatal CNS myelination. Analysis of the lipid content of white matter from a human CD patient showed decreased cerebroside and sulfatide relative to normal white matter. These results demonstrate that myelin lipid synthesis is significantly compromised in CD and provide direct evidence that defective myelin synthesis, resulting from a deficiency of NAAderived acetate, is involved in the pathogenesis of CD.acetyl CoA ͉ leukodystrophy ͉ oligodendrocytes ͉ aspartoacylase N -acetylaspartate (NAA) attains one of the highest concentrations of any molecule in the human CNS (1), yet the functions it serves remain controversial. NAA is synthesized from L-aspartate and acetyl CoA in neuronal mitochondria by the enzyme aspartate N-acetyltransferase (Asp-NAT) (EC 2.3.1.17) (2, 3). NAA is found predominantly in neurons, (4) but the catabolic enzyme aspartoacylase (ASPA) is present primarily in oligodendrocytes in the CNS (5). The high concentration of NAA in the CNS and its characteristic peak in water-suppressed proton magnetic resonance spectroscopy (MRS) permits noninvasive determinations of NAA concentrations in the human brain. MRS determinations of NAA levels are commonly used for evaluating the integrity of neurons in a number of neurological disorders, and this method has emerged as a preferred technique for following the clinical course of several CNS pathologies (6-8). MRS studies operate on the assumptions that NAA is synthesized by and accumulated in neurons and that the steady-state NAA levels in the brain can be interpreted as indicating overall neuronal health or integrity (9, 10).Canavan's disease (CD) is a fatal, hereditary leukodystrophy that compromises normal CNS development and is caused by mutations in the gene for the enzyme ASPA (11, 12). ASPA currently is thought to function exclusively to hydrolyze NAA, a neuron-specific amino acid derivative, into L-aspartate and free acetate. However, ASPA is strongly expressed in other tissues, such as kidney, even though the only known substrate, NAA, is present predominantly in the nervous system (13). Despite the established connection between mutations in the gene for ASPA in CD and the lost capacity to deacetylate NAA, the specific connection between ASPA deficiency and the failure of proper CNS development is unclear (14). Furt...

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“…This child was described by Manhoff et al (30). She was a 4.75-year-old girl who had developmental delay and macrocephaly during infancy.…”

Section: Methodsmentioning

confidence: 91%

Defective N-acetylaspartate catabolism reduces brain acetate levels and myelin lipid synthesis in Canavan's disease

Madhavarao

Arun

Moffett

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

173

153

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“…Although there has been no previous review of the coexistence of metabolic diseases with central nervous system tumors, there have been two case reports: an atypical teratoid/rhabdoid tumor in a child of 4 years and 9 months [17]and an ependymoma in the posterior fossa in a 19-month-old patient with mucopolysaccharidosis I [18]. Barbot et al [15]presented clinical and biochemical findings and cranial MRI data of six pediatric patients with LHGA.…”

Section: Discussionmentioning

confidence: 99%

Medulloblastoma in a Child with the Metabolic Disease <i>L</i>-2-Hydroxyglutaric Aciduria

Özişik¹,

Akalan²,

Palaoğlu³

et al. 2002

Pediatr Neurosurg

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L-2-Hydroxyglutaric aciduria (LHGA) is a rare autosomal recessively inherited neurodegenerative disorder. It is characterized by psychomotor retardation, progressive ataxia and typical magnetic resonance imaging findings, and presents in early infancy. On the other hand, medulloblastomas are very common solid tumors of childhood and infancy. We present a 3-year-old boy with LHGA who developed a medulloblastoma during the course of the disease. There has been no previous report of the coexistence of medulloblastomas with LHGA. Central nervous system tumors are encountered in children with other metabolic neurodegenerative disorders. The aim of this paper is to focus on the difficulties in the diagnosis and treatment of an intracranial tumor in a child already neurologically impaired due to metabolic neurodegenerative disease.

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“…30 One focus of chondroidlike tissue was found in one tumor. One tumor, however, was predominantly mesenchymal and was characterized by a dense growth of tumor cells resembling a fibrosarcoma, with the rhabdoid, PNET, and epithelial fields much less conspicuous.…”

Section: Routine Light Microscopic Featuresmentioning

confidence: 98%

Central nervous system atypical teratoid/rhabdoid tumors of infancy and childhood: definition of an entity

Rorke¹,

Packer²,

Biegel³

1996

Journal of Neurosurgery

717

696

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Clinical and pathological features of 52 infants and children with atypical teratoid/rhabdoid tumor (ATT/RhT) of the central nervous system are defined. This tumor is typically misdiagnosed as a primitive neuroectodermal tumor (PNET) primarily because 70% of ATT/RhTs contain fields indistinguishable from classic PNETs. Separation of these two tumor types is crucial because the prognosis for ATT/RhT is given even when treatment includes surgery with or without radio and/or chemotherapy. These tumors are most common in infants less than 2 years of age. The cases described in this study arose in intracranially in all but one instance, although one-third had already spread throughout the subarachnoid space at presentation. Clinical signs and symptoms and radiological features do not distinguish ATT/RhTs from PNETs. The tumors are composed entirely (13%) or partly (77%) or rhabdoid cells. Seventy percent contains fields of typical PNET alone or in combinations with mesenchymal and/r epithelial elements. The immunohistochemical profile is unique: epithelial membrane antigen, vimentin, and smooth-muscle actin are positive in the majority of tumors and markers for germ-cell tumors are consistently negative. Abnormalities of chromosome 22 distinguish ATT/RhTs from PNETs, which typically display an i(17q) abnormality.

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Primary Intracranial Atypical Teratoid/Rhabdoid Tumor in a Child with Canavan Disease

Cited by 21 publications

References 14 publications

Defective N-acetylaspartate catabolism reduces brain acetate levels and myelin lipid synthesis in Canavan's disease

Defective N-acetylaspartate catabolism reduces brain acetate levels and myelin lipid synthesis in Canavan's disease

Medulloblastoma in a Child with the Metabolic Disease <i>L</i>-2-Hydroxyglutaric Aciduria

Central nervous system atypical teratoid/rhabdoid tumors of infancy and childhood: definition of an entity

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