Neurodevelopmental Disorder With Microcephaly, Epilepsy, And Hypomyelination

A number sign (#) is used with this entry because of evidence that neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination (NEDMEHM) is caused by compound heterozygous mutation in the MTHFS gene (604197) on chromosome 15q25.

Clinical Features

Rodan et al. (2018) reported 2 unrelated patients, aged 8 and 11 years, with a similar neurodevelopmental disorder. The patients presented at birth or in early infancy with microcephaly, short stature, exaggerated startle response, poor feeding, and global developmental delay with delayed walking and spasticity. Both patients developed seizures around 2 to 3 years of age. Patient 1 had well-controlled seizures, spastic quadriparesis managed with a baclofen pump, a feeding tube, and cortical visual impairment. Patient 2 had refractory seizures and recurrent episodes of hyperthermia that responded to lamotrigine. He walked at age 4 and could speak, but had limited vocabulary and articulation difficulties. Serial brain imaging in both patients showed delayed myelination, hypomyelination, enlarged ventricles, and cerebellar atrophy. Both patients had low-normal levels of 5-methyl-tetrahydrofolate (5-MTHF) in the CSF, but other laboratory values were normal.

Clinical Management

Rodan et al. (2018) reported that treatment with folinic and folic acid in a patient with low-normal 5-methyl-tetrahydrofolate (5-MTHF) levels in the CSF was unsuccessful. Treatment with oral levomefolic acid (L-5-methyltetrahydrofolate), a usable reduced form of folate, and methylcobalamin resulted in subjective improvement and increased CSF 5-MTHF.

Inheritance

The transmission pattern of NEDMEHM in the families reported by Rodan et al. (2018) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 unrelated boys with NEDMEHM, Rodan et al. (2018) identified compound heterozygous mutations in the MTHFS gene (604197.0001-604197.0003). The mutations, which were found by exome sequencing, segregated with the disorder in the families. Fibroblasts derived from patient 1 showed no MTHFS enzymatic activity, and there was a 30-fold increase in the MTHFS substrate 5-formyl-THF (folinic acid). Rodan et al. (2018) concluded that accumulation of folinic acid may act as a toxic metabolite, but also noted that the phenotype, particularly abnormal myelination, was consistent with cerebral folate deficiency syndromes.