Table 1.
Clinical features of patients with KDM6B variants.
| Features | Patient 1 * | Patient 2 | Patient 3 ** | Patient 4 *** | Patient 5 |
|---|---|---|---|---|---|
| Gender | F | M | F | F | F |
| Age (years at evaluation) | ¼ | 5 ½ | 4 | 11 ½ | 11 |
| KDM6B gene variant | c.C2282G p.T761S; c.G3047A p.R1016Q |
c.C2722T p.R908C |
c.C2722T p.R908C |
c.C2477A p.S826Y |
c.C1991T p.P664L |
| Pregnancy | Epilepsy, treated with VPA b + FA c |
normal | normal | N/A a | Pre-eclampsia |
| Growth parameters Height Weight Head circumference |
75–90th 75th 50–70th |
3rd 3rd 3rd |
25th 25th <3rd |
3rd <3rd <3rd |
N/A N/A 50th |
| Dysmorphic features | none | none | none | Coarse facial features | Facial; Pulmonary valve stenosis |
| Neurological features ° Unrest, insomnia ° Decelerating head growth ° Psychomotor delay and Regression ° Hypotonia and ataxia ° Pyramidal dysfunction ° Dyskinesias (chorea, athetosis) ° Epilepsy |
+ - + - + - - - |
+ + + + + + - + |
- + - + - - + At 9 months ** Epileptic status and liver failure |
+ + + - - - - + |
+ N/A + + - - - + |
| Cognitive functions ° Language delays ° Intellectual disability |
- - |
+ + |
+ + |
+ + |
+ + |
| Autism spectrum disorder | + | - | - | - | + |
| Neuro-imaging | Normal | LTBL d; partial recovery of white matter changes |
Progressive cortical/cerebellar atrophy | Subcortical white matter lesions | N/A |
| Spinal fluid folate (nmol/L) | 14 | 24 | 38 | 30 | 34 |
| % of bottom reference CSF | 22.2% | 58.5% | 60.3% | 73.2% | 83% |
| Serum FRα antibodies | + | + | - | + | + |
| Start folinic acid treatment | 2 ½ months | 5 years | 3 ½ years | 11 ½ months | None |
* Patient 1. In the patient, her brother and mother a mutation of the NFκB1 gene was found. ** Patient 3 (younger sister of patient 2) had normal development until 9 months, but then suffered from severe epileptic status with transient liver failure, hypoglycemia and lactic acidosis. Seizures have been treated with clonazepam, valproic acid and phenobarbitone. Since this episode she developed irritability, had a deceleration of head growth, choreatic movements and cognitive decline. MRI showed progressive cerebellar and cortical atrophy. Alpers disease could be excluded with normal POLG1 gene findings. *** Patient 4 was found to carry a duplication at chromosome 7q31.32-q32.3. ° CSF 5-methyltetrahydrofolate levels were low in all patients. Reference range for healthy controls aged between 0–4 years: 63–111 nmol/L; age 5–16 years: 41–117 nmol/L. Patient 1–4 received folinic acid treatment, whereas a repeat spinal tap for patient 5 showed normal CSF folate. Abbreviations: a N/A data not available. b VPA valproic acid. c FA folic acid. d LTBL leukoencephalopathy with thalamus and brainstem involvement and high lactate.