Infantile onset carnitine palmitoyltransferase 2 deficiency: Cortical polymicrogyria, schizencephaly, and gray matter heterotopias in an adolescent with normal development

Abstract

Objective: To report an adolescent with infantile-onset carnitine palmitoyltransferase 2 (CPT2) deficiency and cerebral malformations and to review the occurrence of brain malformations in CPT2 deficiency. The patient presented clinically at age 5 months with dehydration and hepatomegaly. He also has an unrelated condition, X-linked nephrogenic diabetes insipidus. He had recurrent rhabdomyolysis but normal psychomotor development. At age 17 years, he developed spontaneous focal seizures. Cerebral magnetic resonance imaging revealed extensive left temporo-parieto-occipital polymicrogyria, white matter heterotopias, and schizencephaly. Neuronal migration defects were previously reported in lethal neonatal CPT2 deficiency but not in later-onset forms.

Design and methods: We searched PubMed, Google Scholar, and the bibliographies of the articles found by these searches, for cerebral malformations in CPT2 deficiency. All antenatal, neonatal, infantile, and adult-onset cases were included. Exclusion criteria included insufficient information about age of clinical onset and lack of confirmation of CPT2 deficiency by enzymatic assay or genetic testing. For each report, we noted the presence of cerebral malformations on brain imaging or pathological examination.

Results: Of 26 neonatal-onset CPT2-deficient patients who met the inclusion criteria, brain malformations were reported in 16 (61.5%). In 19 infantile-onset cases, brain malformations were not reported, but only 3 of the 19 reports (15.8%) include brain imaging or neuropathology data. In 276 adult-onset cases, no brain malformations were reported.

Conclusion: To the best of our knowledge, this is the first report of cerebral malformations in an infantile onset CPT2-deficient patient. Brain imaging should be considered in patients with CPTII deficiency and neurological manifestations, even in those with later clinical onset.

Keywords: CPT2; carnitine; cerebral; heterotopias; infantile; malformation; palmitoyltransferase; polymicrogyria.

FIGURE 1

Cerebral magnetic resonance imaging at age 17 years in the carnitine palmitoyltransferase 2 (CPT2)‐deficient patient. Coronal,A, and sagittal, B, 1 mm reformat from a 3D T1 volume acquisition. A, Extensive polymicrogyria, closed lip schizencephaly, and heteropia. B, Extensive heterotopia and abnormal hippocampal formation. The yellow arrows indicate the edge of the malformation

FIGURE 2

Metabolic proximity of carnitine palmitoyltransferase 2 (CPT2) deficiency (CPT2‐D) and glutaric aciduria type 2 (GA2, OMIM 231680), inborn errors with similar malformations. Long‐chain fatty acids (LCFA) are esterified to LCFA‐CoA in the cytoplasm (not shown), then shuttled into mitochondria. First, LCFA‐carnitines are synthesized near the outer mitochondrial membrane (dotted rectangle) by CPT1. Transport of the LCFA‐carnitine into the mitochondrial matrix is mediated by carnitine‐acylcarnitine translocase (CACT). CPT2 catalyzes reesterification to coenzyme A, forming a LCFA‐CoA for oxidation by very long‐chain acyl‐CoA dehydrogenase (VLCAD). GA2 results either from deficiency of electron transfer flavoprotein (ETF) or of ETF dehydrogenase (ETFDH). GA2 causes the deficiency of multiple flavin‐bound acyl‐CoA dehydrogenases (FAD‐DH) including VLCAD. These enzymes covalently bind flavin adenine dinucleotide (FAD). During catalysis, FAD is reduced to FADH, which must be oxidized in order to restore enzymatic activity. This oxidation is carried out by ETFDH and is coupled to the reduction of ETF to ETFH. ETFH moves to donate an electron to coenzyme Q in the respiratory chain (RC), providing an important fraction of cellular energy supply. Neuronal migration defects and renal cysts can occur both in CPT2 deficiency and in GA2. Both conditions increase LCFA‐carnitines in the mitochondrial matrix, with corresponding increases of plasma LCFA‐carnitines. The mechanistic link, if any, between these metabolic abnormalities and brain and kidney malformations is currently unknown