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DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 39; DEE39

DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 39; DEE39

Alternative titles; symbolsEPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 39; EIEE39HYPOMYELINATION, GLOBAL CEREBRALASPARTATE-GLUTAMATE CARRIER 1 DEFICIENCYAGC1 DEFI...

Alternative titles; symbols

  • EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 39; EIEE39
  • HYPOMYELINATION, GLOBAL CEREBRAL
  • ASPARTATE-GLUTAMATE CARRIER 1 DEFICIENCY
  • AGC1 DEFICIENCY

▼ Description
Developmental and epileptic encephalopathy-39 (DEE39) is an autosomal recessive neurologic syndrome characterized clinically by global developmental delay apparent in early infancy, early-onset seizures, hypotonia with poor motor function, and hypomyelination on brain imaging. Other features include absent speech and inability to walk; spasticity and hyperreflexia has also been reported. Although there is significant hypomyelination on brain imaging, the disorder is not classified as a primary leukodystrophy. The myelination defect most likely stems from primary neuronal dysfunction due to impaired mitochondrial transport activity (summary by Wibom et al., 2009 and Falk et al., 2014).

For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

▼ Clinical Features
Wibom et al. (2009) reported a 3-year-old girl, born of distantly related Swedish parents, with severe psychomotor retardation, hypotonia, and hypomyelination of the central nervous system. After normal early development, she was first noted to have developmental delay at about 5 months of age. Seizures and episodic apnea began at age 7 months. She had poor head control, could not roll over or grasp objects, had poor eye contact, and was nonverbal. At age 3 years 8 months, she had essentially no psychomotor development and showed severe spasticity with hyperreflexia. Brain MRI showed global lack of myelination in the cerebral hemispheres and decreased supratentorial volume. The cerebellum, brainstem, and thalami were essentially normal. Focal lesions were not observed in gray matter. Serum lactate was increased, and MR spectroscopy showed decreased N-acetylaspartate (NAA). Skeletal muscle biopsy showed normal activities of mitochondrial respiratory enzyme complexes, but impaired ATP production under certain conditions. The findings suggested a mitochondrial disorder.

Wolf and van der Knapp (2009) commented that the patient described by Wibom et al. (2009) had a primary defect in the cortical gray matter, rather than a leukoencephalopathy. The reduced peak of NAA found on spectroscopy indicates neuronal degeneration, and impaired formation of myelin can result from neuronal dysfunction. In response, Kucinski et al. (2009) agreed that the primary defect in this condition is in the gray matter, and suggested that abnormal neuronal metabolism could result in disrupted crosstalk between neurons and oligodendrocytes, and defective myelination. However, neuronal dysfunction was not as apparent as the lack of normal myelin development in the imaging data.

Falk et al. (2014) reported 2 sibs, born of consanguineous Indian parents, with DEE39. The proband was a 6.7-year-old girl who had onset of focal and generalized seizures at 10 months of age, followed by delayed psychomotor development and profound mental retardation with absent speech, inability to sit or walk, profound hypotonia, and inability to follow commands. Brain imaging showed delayed myelination and cerebral volume loss. MR spectroscopy showed decreased NAA and increased choline and lactate. Extensive metabolic work-up and muscle biopsy did not show any etiology. Her brother presented with seizures at age 10 months and a similar neurologic disorder as his sister.

▼ Inheritance
The transmission pattern of DEE39 in the family reported by Falk et al. (2014) was consistent with autosomal recessive inheritance.

▼ Molecular Genetics
In a Swedish girl with global cerebral hypomyelination and severe psychomotor retardation, Wibom et al. (2009) identified a homozygous mutation in the SLC25A12 gene (603667.0001). In vitro functional expression studies showed impaired protein activity. Wibom et al. (2009) postulated that the disease pathogenesis did not result from impaired neuronal energy production, but rather from reduced mitochondrial aspartate efflux, which is necessary for NAA and myelin formation.

In 2 sibs, born of consanguineous Indian parents, with DEE39, Falk et al. (2014) identified a homozygous missense mutation in the SLC25A12 gene (R353Q; 603667.0002). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression studies in E. coli showed that the mutant protein had about 15% residual activity. Falk et al. (2014) suggested that the brain myelination defect in these patients stems primarily from neuronal loss attributable to the energy deficit caused by a lack of cellular reducing equivalents generated by the glutamate-aspartate shuttle, and that the brain insult may be compounded by a lack of neuronal-generated NAA that is required for myelin synthesis.

▼ Animal Model
Jalil et al. (2005) found that Slc25a12-null mice had no detectable malate-aspartate shuttle activity in skeletal muscle and brain mitochondria. Mutant mice showed retarded growth, generalized tremor, pronounced motor coordination defects, and decreased survival. Analysis of the central nervous system showed impaired myelination without a change in neuron number. Analysis of lipid components showed a marked decrease in the myelin lipid galactosyl cerebroside. Brain content of the myelin lipid precursor, N-acetylaspartate, and that of aspartate were drastically decreased. The findings showed that aralar plays an important role in myelin formation by providing aspartate for the synthesis of N-acetylaspartate in neuronal cells.

Tags: 2q31.1