A number sign (#) is used with this entry because of evidence that Bachmann-Bupp syndrome (BABS) is caused by heterozygous mutation in the ornithine decarboxylase-1 gene (ODC1; 165640) on chromosome 2p25.

Bachmann-Bupp syndrome (BABS) is a neurometabolic disorder associated with global developmental delay, ectodermal abnormalities including alopecia, absolute or relative macrocephaly, dysmorphic features, and characteristic neuroimaging features (summary by Rodan et al., 2018).

Rodan et al. (2018) described 4 unrelated patients with a similar neurometabolic disorder. Patient 1 was a 7-year-old boy whose prenatal history was significant for polyhydramnios and decreased fetal movement. He was noted to be hypotonic at birth and had global developmental delay. He had behavioral issues including attention deficit-hyperactivity disorder (ADHD) and episodic aggression. Dysmorphic features included relative macrocephaly, bilateral ptosis, hypertelorism, deep-set eyes, retrognathia, large ears, bulbous nasal tip, and fifth finger clinodactyly. He had absent eyebrows and sparse hair. An EEG showed electrical status epilepticus during sleep. Brain MRI at 6 years of age showed bilateral germinolytic cysts, peritrigonal white matter volume loss, and a mildly dysmorphic cerebellar vermis. Patient 2 was a 16-year-old girl whose prenatal history was significant for polyhydramnios and macrosomia. She had global developmental delay since birth and behavioral issues including ADHD and aggression. On examination at age 16 years, she had dysmorphic features including macrocephaly, a broad forehead, hypertelorism, deep-set eyes, and blepharophimosis. Scalp and extremity hair was sparse. Brain MRI at 8 years of age showed a thick and short corpus callosum and dilated perivascular spaces. Patient 3 was an 8-year-old boy with global developmental delay since birth. There were no behavioral concerns. Dysmorphic features included high forehead, hypertelorism, ptosis, downslanting palpebral fissures, large ears, and bulbous nasal tip. He had sparse eyebrows and scalp hair as well as hypoplastic nails. Brain MRI at 4 years of age showed periventricular cysts, prominent perivascular spaces and multifocal white matter hyperintensities. Patient 4 was a male who was stillborn at 34 weeks' gestation. A third trimester ultrasound showed a fetal brain cyst and an increased biparietal diameter. Fetal MRI at 34 weeks' gestation showed multiple periventricular cysts, some of which were surrounded by T2-weighted hyperintensities suggestive of calcification. There were also cortical irregularities consistent with polymicrogyria in the left insula and prominent perivascular spaces. Postnatal features included hypertelorism and sparse eyebrows and eyelashes.

Bupp et al. (2018) reported a 32-month-old girl who was born to a pregnancy complicated by polyhydramnios and decreased fetal movements. She required neonatal intensive care for hypotonia, hypoglycemia, feeding difficulties, and hyperbilirubinemia. She was found to have right-sided sensorineural hearing loss. She was born with silver-blonde hair, which fell out during the first month of life. She had absent eyebrows, sparse eyelashes, macrocephaly, a high-arched palate, and cupped ears. At 11 months of age, she had developmental delay and developed spasticity in the lower extremities. Brain MRI at 2 days of life showed prominent cystic changes in the periventricular region. Brain MRI at age 15 months showed resolution of the periventricular cystic abnormality but progression of white matter volume loss in both cerebral hemispheres.

The heterozygous mutations in the ODC1 gene that were identified in patients with NEDABA by Rodan et al. (2018) and Bupp et al. (2018) occurred de novo.

Rodan et al. (2018) and Bupp et al. (2018) hypothesized that pharmacologic reduction of putrescine levels with DFMO, an irreversible ODC1 inhibitor, may be a potential therapy for NEDABA. Rodan et al. (2018) further suggested that putrescine levels could be reduced with initiation of a low putrescine diet or antibiotic therapy to reduce synthesis of polyamines from gastrointestinal flora.

In 4 unrelated patients with BABS, Rodan et al. (2018) identified de novo heterozygous mutations in the ODC1 gene (165640.0002-165640.0005). All of the mutations were identified by trio exome sequencing. The resultant proteins were predicted to escape nonsense-mediated decay and to have a truncated C terminus, leading to decreased protein degradation and a net increase in enzyme activity.

Bupp et al. (2018) identified a de novo heterozygous nonsense mutation in the ODC1 gene (K448X; 165640.0006) in a 32-month-old girl with BABS. The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. Molecular modeling suggested that due to lack of a C terminus in the mutant protein, antizyme binding does not induce ODC degradation, leading to accumulation of active protein.