Neurodevelopmental Disorder With Cerebellar Atrophy And With Or Without Seizures

A number sign (#) is used with this entry because of evidence that neurodevelopmental disorder with cerebellar atrophy and with or without seizures (NEDCAS) is caused by compound heterozygous mutations in the BRAT1 gene (614506) on chromosome 7p22.

Biallelic mutations in the BRAT1 gene can also cause lethal neonatal rigidity and multifocal seizure syndrome (RMFSL; 614498), a more severe disorder with overlapping features.

Clinical Features

Hanes et al. (2015) reported a girl, born of unrelated patients, with a neurodevelopmental disorder. After a normal neonatal period, she was noted to have delayed psychomotor development, poor eye fixation, nystagmus, stiffness, hand fisting, and staring spells. She sat at age 15 months, but never gained more advanced motor milestones and had no language. She had a small head, but no dysmorphic features. Examination showed horizontal nystagmus, difficulty swallowing, axial hypotonia with appendicular hypertonia, and ankle clonus. EEG was normal, but her spells were consistent with focal dyscognitive seizures. At age 2.5 years, she developed episodes of pallor, hyperthermia, and decreased responsiveness. She gained few new developmental milestones, but showed no regression. Brain imaging showed progressive generalized cerebellar atrophy and associated atrophy of the brainstem, as well as dysmyelination. She was alive at 3 years, 8 months, but functioned at a 6-month-old level.

Srivastava et al. (2016) reported 2 sisters (patients 1 and 2), born of unrelated parents, with a similar neurodevelopmental disorder. After a normal neonatal course, the girls presented in infancy with delayed psychomotor development, delayed walking (3 to 5 years of age), and delayed language acquisition. The patients were able to speak several words, point to body parts, and say the letters of the alphabet around 3 to 5 years of age. The older sister could write her name at age 7. Both developed disruptive, angry, and defiant behaviors around 5 years of age. They had axial hypotonia that improved with age and no evidence of rigidity; cerebellar signs included ataxic gait, truncal titubation, tremor, dysmetria, and nystagmus. Brain imaging showed cerebellar atrophy. The older sister did not have any seizure-like episodes, whereas the younger sister developed staring spells associated with normal EEG at age 6. Both also had dysmorphic features, including epicanthal folds, slightly high-arched palate, tented upper lip, and fifth finger clinodactyly. An unrelated girl (patient 3) had a similar disorder with delayed psychomotor development and language delay. She had dyspraxia with fine motor skills, rigid and wide-based gait with no arm swing, and could walk, but not run. Additional features included staring spells associated with autonomic changes of pallor and perioral cyanosis, small head circumference, mild optic nerve hypoplasia with impaired vision, and moderate appendicular rigidity. She had a flat facial profile and fifth finger clinodactyly. At age 4 years, she was very social and visually interactive and could follow simple commands. Brain imaging showed cerebellar atrophy and mild myelination delay.

Mundy et al. (2016) reported a 6-year-old girl with onset of intractable seizures at 3 months of age. She had axial and peripheral hypertonia with hyperreflexia, a small head circumference, and dysmorphic features, including brachycephaly, long grooved philtrum, and thin lips. She developed apneic episodes at age 10 months. Developmental progress was delayed: she sat at age 15 months, babbled at age 17 months, and could stand with support at age 6 years, but could not walk. She had both hypotonia and hypertonia and developed apneic episodes at age 10 months. Brain MRI showed decreased myelination, thin corpus callosum, and cerebellar hypoplasia. Mundy et al. (2016) noted that the patient had a severe phenotype with severe intellectual disability and intractable seizures, but was still alive, unlike patients with RMFSL.

Inheritance

The transmission pattern of NEDCAS in the families reported by Srivastava et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In a girl with NEDCAS, Hanes et al. (2015) identified compound heterozygous mutations in the BRAT1 gene (614506.0006 and 614506.0007). The mutations, which were found through a next-generation sequencing panel for neurologic disorders, segregated with the disorder in the family. Functional studies of the variants and studies of patients cells were not performed. Hanes et al. (2015) postulated that patients with compound heterozygous BRAT1 mutations may have a less severe phenotype than patients with homozygous mutations.

In 3 patients from 2 unrelated families with NEDCAS, Srivastava et al. (2016) identified compound heterozygous mutations in the BRAT1 gene (614506.0001 and 614506.0008-614506.0009). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the families. Functional studies of the variants and studies of patient cells were not performed.

In a 6-year-old girl with NEDCAS, Mundy et al. (2016) identified compound heterozygous mutations in the BRAT1 gene (c.294dupA, 614506.0006 and A642E, 614506.0011). Functional studies of the variants and studies of patient cells were not performed.