SB939 We report on four affected
We report on four affected children from two unrelated consanguineous SB939 with moderate to severe ID associated with epilepsy and variable neuropsychiatric features. Using whole-exome sequencing, we identified homozygous missense variants in SLC45A1 (OMIM: 605763), which codes for a neuronal glucose transporter that is predominantly expressed in the developing and adult brain. Functional studies indicate that the identified variants reduce the activity of the protein, thus implicating SLC45A1 dysfunction in the etiology of ID and epilepsy. SLC45A1 could thus represent the second cerebral glucose transporter, along with GLUT1, to be involved in neurodevelopmental disability. Individuals A.II-2 and A.II-3 from family A are Palestinian sisters whose parents are first-degree cousins (Figure 1A). Individual A.II-2 is currently 22 years old. She was born after an uncomplicated pregnancy and delivery. Her birth weight was 3,750 g (75th percentile), and her length was 50 cm (50th percentile). She had a patent ductus arteriosus (PDA) repair during infancy. Gross motor development was normal, but language development was delayed. She has moderate ID and has always attended special schools. She can read and write simple sentences. She is able to take the bus independently and hold a simple job. She developed focal seizures with impaired awareness at the age of 4.5 years. These seizures were characterized by epigastric discomfort followed by staring and eye blinking lasting less than 1 min. Electroencephalography (EEG) demonstrated focal epileptic activity mainly over the left fronto-temporal region but also at times over the right fronto-temporal region. Background activity was normal. Her seizures were well controlled on a combination of carbamazepine and clobazam. At the age of 9 years, she developed a 45 min secondarily generalized tonic-clonic status epilepticus in the context of fever, 3 months after her antiepileptic medications were discontinued. She was restarted on clobazam and carbamazepine, which she continues to take, and hasn’t had any seizure recurrence. She is very anxious and has some obsessive-compulsive tendencies, such as compulsively cleaning or eating, although this behavior has not significantly interfered with her daily activities. On her last examination at the age of 19 years, her weight was 72.5 kg (80th percentile), her height was 157 cm (20th percentile), and head circumference was 54 cm (40th percentile). She has downslanting eyes, a smooth philtrum, and a thin upper lip. Her neurological examination was unremarkable except for slowness during finger-to-nose testing and rapid-alternating-movement testing. Brain MRI and karyotype (450 bands) were normal. Subject A.II-3 is currently 20 years old. She was born after an uneventful pregnancy and delivery. She attained early milestones appropriately but had significant difficulties at school and was diagnosed with moderate ID. She is able to walk, speak in sentences, and understand complex commands. She can read and write and has always attended special classes for children with ID. At the age of 11 years, she developed focal seizures accompanied by impaired awareness consisting of staring episodes, epigastric discomfort, fumbling with her clothes, chewing, and right facial twitches lasting 30–60 s. She has had occasional secondarily generalized seizures. EEG video telemetry during ictal events captured focal spike-and-wave epileptic activity over the right fronto-temporal region. Seizures originating from the left temporal lobe were also recorded. Seizures were initially poorly controlled despite the trial of multiple anticonvulsants. She has had no seizure recurrence since the age of 17 years on a combination of carbamazepine and clobazam, which she continues to take. This individual has significant neuropsychiatric and behavioral issues. She has important difficulties with social integration, obsessive-compulsive disorder with repetitive behaviors (e.g., repeatedly saying the same thing, repeating the same action, and echolalia), and tangential speech that seems to worsen with age. She was treated by a psychiatrist, who diagnosed her with autism spectrum disorder. She has had multiple neuropsychological assessments (at the ages of 11, 12, 16, and 19 years), which have not documented any cognitive decline. She cannot live independently, nor can she hold a simple job. At the age of 16 years, she developed tics such as eye blinking, eye deviation, and throat clearing. She has scoliosis. At the age of 16 years, this individual was started on the modified Atkins diet in an attempt to improve her behavior; she was having focal seizures with impaired awareness every 2–3 months. The diet consisted of a 2:1 ketogenic ratio (grams of fat to combined carbohydrates and protein) and a net carbohydrate total of 10 g per day. It was discontinued after 6 months because she had difficulties with adhering to the diet and showed no clear improvements in either behavior or seizure frequency. On physical examination at the age of 16 years, her weight was 52.5 kg (45th percentile), height was 149 cm (2nd percentile), and head circumference was 53.5 cm (25th percentile). Her facial features (downslanting eyes, a smooth philtrum, and a thin upper lip) are similar to those of her sister. Neurological examination was normal except for bilateral tight heel cords, normal reflexes, and slowness during rapid-alternating-movements and finger-to-nose testing. Brain MRI, chromosomal microarray, serum amino acids, urine organic acids, very-long-chain fatty acids, lactate, blood gas (including pCO2), and ammonia were normal. Amino acids and lactate in the cerebrospinal fluid (CSF) were normal. The CSF glucose was normal (60 mg/dL; age-related cutoff = 48.7 mg/dL), and the ratio of CSF to blood glucose was in the normal range (0.70; age-related cutoff = 0.57; non-fasting blood glucose: 85 mg/dL).