The ubiquitin fold modifier 1 (UFM1) cascade is a recently identified evolutionarily conserved ubiquitin-like modification system whose function and link to human disease have remained largely uncharacterized. By using exome sequencing in Finnish individuals with severe epileptic syndromes, we identified pathogenic compound heterozygous variants in UBA5, encoding an activating enzyme for UFM1, in two unrelated families. Two additional individuals with biallelic UBA5 variants were identified from the UK-based Deciphering Developmental Disorders study and one from the Northern Finland Intellectual Disability cohort. The affected individuals (n = 9) presented in early infancy with severe irritability, followed by dystonia and stagnation of development. Furthermore, the majority of individuals display postnatal microcephaly and epilepsy and develop spasticity. The affected individuals were compound heterozygous for a missense substitution, c.1111G>A (p.Ala371Thr; allele frequency of 0.28% in Europeans), and a nonsense variant or c.164G>A that encodes an amino acid substitution p.Arg55His, but also affects splicing by facilitating exon 2 skipping, thus also being in effect a loss-of-function allele. Using an in vitro thioester formation assay and cellular analyses, we show that the p.Ala371Thr variant is hypomorphic with attenuated ability to transfer the activated UFM1 to UFC1. Finally, we show that the CNS-specific knockout of Ufm1 in mice causes neonatal death accompanied by microcephaly and apoptosis in specific neurons, further suggesting that the UFM1 system is essential for CNS development and function. Taken together, our data imply that the combination of a hypomorphic p.Ala371Thr variant in trans with a loss-of-function allele in UBA5 underlies a severe infantile-onset encephalopathy.

A population-based survey was conducted among 152,732 Finnish children and adolescents aged under 16 years and living in northern Finland. Diagnoses and associated medical conditions were derived from the hospital and institutional records of this area. One hundred and eighty-seven children with DSM-IV autistic disorder were identified. Associated medical disorders or associated disorders of known or suspected genetic origin were found in 12.3 percent, including tuberous sclerosis, Down syndrome, fragile X syndrome, Klinefelter syndrome, XYY syndrome, chromosome 17 deletion, chromosome 46, XX, dup(8) (p) and mitochondriopathy. Other associated medical disorders identified were epilepsy, hydrocephalus, foetal alcohol syndrome and cerebral palsy. Hearing impairments were found in 8.6 percent and severe impairment of vision in 3.7 percent of the individuals with autistic disorder. Medical disorders seem to have a special impact on the genesis of autistic disorder and need to be thoroughly examined in each child with autistic disorder.

Signal intensity changes in fMRI during rest caused by vasomotor fluctuations were investigated in this work. Resting‐state baseline fluctuations were evaluated in 12 children anesthetized with thiopental. Five subjects had fluctuations related to subvoxel motion. In seven subjects without significant motion, slow signal fluctuation at 0.025–0.041 Hz near one or more primary sensory cortices was observed. In each subject the amplitude and frequency of the fluctuations were stable. It is hypothesized that thiopental, which reduces blood pressure and flow in the cortex, alters the feedback in neurovascular coupling leading to an increase in the magnitude and a reduction in the frequency of these fluctuations. The use of anesthesia in fMRI may provide new insight into neural connectivity and the coupling of blood flow and neural metabolism. Magn Reson Med 44:373–378, 2000. © 2000 Wiley‐Liss, Inc.

Summary: Purpose: To analyze the occurrence, outcome, and prognostic factors of infantile spasms (IS) and the LennoxGastaut syndrome (LGS) in a defined population.Methods: All children treated because of IS and LGS in the Department of Pediatrics, University of Oulu, from January 1, 1976, until December 31, 1993, who came from the primary catchment area of the hospital were included. Detailed information concerning their individual pre-, peri-, and postnatal medical histories and medical and laboratory examinations were compiled.Results: Thirty-seven children (1 8 boys) had IS, and 25 (14 boys) had LGS. The occurrence of IS of 0.41/1,000 live births [95% confidence interval (CI), 0.29-0.57/1,000] did not differ significantly from that of LGS, which was 0.28/1,000 live births (95% CI, 0.18-0.41/1,000). Ten (27%) of the 37 patients with IS evolved to LGS, which was 40% of the LGS cases. All the 10 children with both IS and LGS had symptomatic epilepsy, were mentally retarded, and had active epilepsy at the end of -10 years' follow-up. Twenty-six (87%) of the 30 symptomatic IS cases and all the 17 symptomatic LGS cases were due to either congenital or genetic etiologies. The outcome in cryptogenic IS cases was favorable; the risk for a poor neurologic and mental outcome was extremely low; odds ratio, 0.015 (95% CI, 0.001-0.196). as it was for therapy-resistant epilepsy; odds ratio, 0.013 (95% CI, 0.001-0.166). In LGS patients, cryptogenic etiology did not decrease the risk for a poor outcome.Conclusions: Cryptogenic etiology is associated with a very low risk for a poor outcome in IS patients, but not in LGS patients. The outcome of IS children and the relation of IS to LGS are determined by the underlying brain disease, not by the epilepsy itself.