Johanna Fock

Reference values of maximum isometric muscle force obtained in 270 children aged 4-16 years by hand-held dynamometry

Since muscle force and functional ability are not related linearly; maximum force can be reduced while functional ability is still maintained. For diagnostic and therapeutic reasons loss of muscle force should be detected as early and accurately as possible. Because of growth factors, maximum muscle force in children varies with age, which makes detection of force loss difficult. The purpose of this study was to establish reference values for muscle force in children aged 4-16 years, obtained by hand-held dynamometry in 11 muscle groups. In boys muscle force was predicted best by weight whereas in girls weight and age were best predictors. At age 14 boys become significantly stronger for nearly all tested muscle groups. These age-related reference values can be used to quantify muscle weakness in individual muscle groups in children aged 4-16 years and to evaluate the effects of therapy.

Prognostic significance of amplitude-integrated EEG during the first 72 hours after birth in severely asphyxiated neonates

Amplitude-integrated EEG (aEEG) is used to select patients for neuroprotective therapy after perinatal asphyxia because of its prognostic accuracy within several hours after birth. We aimed to determine the natural course of aEEG patterns during the first 72 h of life, in relation to neurologic outcome, in a group of severely asphyxiated term infants. Thirty infants, admitted to our neonatal intensive care unit from October 1998 until February 2001, were studied retrospectively. The aEEG traces obtained during the first 72 h after birth were assessed by pattern recognition: continuous normal voltage (CNV), discontinuous normal voltage (DNV), burst suppression (BS), continuous low voltage, and flat trace. Epileptic activity was also determined. The course of aEEG patterns was examined in relation to neurologic findings at 24 mo. Initially, 17 of 30 infants had severely abnormal aEEG patterns (BS or worse), which changed spontaneously to normal voltage patterns (CNV, DNV) in 7 within 48 h. The sooner the abnormalities on aEEG disappeared, the better the prognosis. The likelihood ratio of BS or worse for adverse outcome was 2.7 (95% confidence interval 1.4–5.0) between 0 and 6 h and increased to a highest value of 19 (95% confidence interval 2.8–128) between 24 and 36 h; after 48 h, it was not significant. Normal voltage patterns (CNV and DNV) up to 48 h of life were predictive for normal neurologic outcomes (negative likelihood ratios < 0.3). Our findings indicate that the course of aEEG patterns adds to the prognostic value of aEEG monitoring in asphyxiated infants. Spontaneous recovery of severely abnormal aEEG patterns is not uncommon.

A novel defect of peroxisome division due to a homozygous non-sense mutation in the PEX11β gene

Background Peroxisomes are organelles that proliferate continuously and play an indispensable role in human metabolism. Consequently, peroxisomal gene defects can cause multiple, often severe disorders, including the peroxisome biogenesis disorders. Currently, 13 different PEX proteins have been implicated in various stages of peroxisome assembly and protein import. Defects in any of these proteins result in a peroxisome biogenesis disorder. The authors present here a novel genetic defect specifically affecting the division of peroxisomes. Methods The authors have studied biochemical and microscopical peroxisomal parameters in cultured patient fibroblasts, sequenced candidate PEX genes and determined the consequence of the identified PEX11β gene defect on peroxisome biogenesis in patient fibroblasts at different temperatures. Results The patient presented with congenital cataracts, mild intellectual disability, progressive hearing loss, sensory nerve involvement, gastrointestinal problems and recurrent migraine-like episodes. Although microscopical investigations of patient fibroblasts indicated a clear defect in peroxisome division, all biochemical parameters commonly used for diagnosing peroxisomal disorders were normal. After excluding mutations in all PEX genes previously implicated in peroxisome biogenesis disorders, it was found that the defect was caused by a homozygous non-sense mutation in the PEX11β gene. The peroxisome division defect was exacerbated when the patients fibroblasts were cultured at 40°C, which correlated with a marked decrease in the expression of PEX11γ. Conclusions This novel isolated defect in peroxisome division expands the clinical and genetic spectrum of peroxisomal disorders and indicates that peroxisomal defects exist, which cannot be diagnosed by standard laboratory investigations.

Kinematic characteristics of reaching movements in preterm children with cerebral palsy

Kinematic characteristics of reaching movements of the dominant arm were assessed in 51 sitting preterm children who were aged 2–11 y and had cerebral palsy (CP), including 33 with spastic hemiplegia and 18 with bilateral CP (Bi-CP). Reference data of 29 typically developing children were present. The results indicated that the quality of reaching movements from the dominant arm of children with CP was significantly worse than that of typically developing children. This held true in particular for the children with Bi-CP. For example, reaching movements of children with CP took more time and consisted less often of one movement unit. The quality of reaching was related to the severity of lesion present on the neonatal ultrasound scan of the brain, the severity of motor disorder, the degree of spasticity, and the ability to perform activities of daily life. The last indicates that movements of the dominant arm in children with spastic hemiplegia and Bi-CP deserve clinical attention.

Mutations in RARS Cause Hypomyelination

Hypomyelinating disorders of the central nervous system are still a diagnostic challenge, as many patients remain without genetic diagnosis. Using magnetic resonance imaging (MRI) pattern recognition and whole exome sequencing, we could ascertain compound heterozygous mutations in RARS in 4 patients with hypomyelination. Clinical features included severe spasticity and nystagmus. RARS encodes the cytoplasmic arginyl‐tRNA synthetase, an enzyme essential for RNA translation. This protein is among the subunits of the multisynthetase complex, which emerges as a key player in myelination. Ann Neurol 2014;76:134–139

Kinematic characteristics of postural control during reaching in preterm children with cerebral palsy

The relationships between kinematic characteristics of sitting posture during reaching movements of the dominant arm and 1) the kinematics of the reaching movement itself and 2) functional performance during daily life activities (PEDI) were assessed in 51 sitting preterm children with cerebral palsy (CP). The children were 2–11 y, 33 had spastic hemiplegia (SH) and 18 bilateral CP (Bi-CP). The data were compared with those of 26 typically developing children (TD). Sitting posture before the onset of reaching of children with CP differed from that of TD children: they sat with a more reclined pelvis and a more collapsed trunk. The more reclined pelvic position was associated with a better quality of reaching movements. The different sitting postures of pelvis and trunk were not related to functional performance during daily life activities. Displacement of the head, trunk, and pelvis of the children with CP did not differ from that of the TD children. Nevertheless, in the children with CP a more stable head, a more mobile trunk, and a more stable pelvis were related to better functional performance and/or a better quality of reaching. This suggests that physiotherapeutic guidance of children with CP should focus rather on the latter postural parameters than on the different sitting posture of pelvis and trunk.

Effect of Seat Surface Inclination on Postural Control During Reaching in Preterm Children With Cerebral Palsy

Background and Purpose Because it is debatable whether seat surface inclination improves motor function in children with cerebral palsy (CP), the effect of seat surface tilting on postural control and quality of reaching was studied. Subjects The subjects were 58 children with CP aged 2 to 11 years (34 with unilateral spastic CP, 24 with bilateral spastic CP). Methods During the task of reaching movements, surface electromyographic and kinematic data were recorded for posture and reaching with the dominant arm in 3 sitting conditions: horizontal seat surface, seat surface tilted forward 15 degrees, and seat surface tilted backward 15 degrees. Results In the children with unilateral spastic CP, forward tilting improved postural efficiency and quality of reaching. In the children with bilateral spastic CP, both forward and backward tilting of the seat surface was associated with more postural instability and did not affect the quality of reaching. Discussion and Conclusion The results suggest that, in terms of postural control and quality of reaching, children with unilateral spastic CP benefit from a forward-tilted position and children with bilateral spastic CP benefit from a horizontal sitting position.

Mild hypothermia for refractory focal status epilepticus in an infant with hemimegalencephaly

Hypothermia can reduce seizure frequency in animal models of status epilepticus, and its effectiveness in human status epilepticus has been reported occasionally. We report an infant with hemimegalencephaly who presented with generalized status epilepticus. After high dose intravenous drug therapy, this converted to focal status epilepticus in the right occipital region. A sudden cessation of all seizure activity was found to coincide with accidental hypothermia. After application of mild continuous hypothermia, a marked reduction of seizure frequency occurred, which allowed reduction of intravenous drug doses and discharge from the IC unit. Ultimately, hemispherectomy was needed to achieve long term seizure control. The therapeutic effect of hypothermia should be further investigated in patients with refractory status epilepticus. When used in combination with anti-epileptic drugs, seizure control may be achieved at lower doses. Hypothermia may obviate the need for potentially dangerous barbiturate therapy. This case demonstrates that even a mild degree of hypothermia (+/-36 degrees C) can be remarkably effective.

Variants in SLC18A3, vesicular acetylcholine transporter, cause congenital myasthenic syndrome

Objective: To describe the clinical and genetic characteristics of presynaptic congenital myasthenic syndrome secondary to biallelic variants in SLC18A3. Methods: Individuals from 2 families were identified with biallelic variants in SLC18A3, the gene encoding the vesicular acetylcholine transporter (VAChT), through whole-exome sequencing. Results: The patients demonstrated features seen in presynaptic congenital myasthenic syndrome, including ptosis, ophthalmoplegia, fatigable weakness, apneic crises, and deterioration of symptoms in cold water for patient 1. Both patients demonstrated moderate clinical improvement on pyridostigmine. Patient 1 had a broader phenotype, including learning difficulties and left ventricular dysfunction. Electrophysiologic studies were typical for a presynaptic defect. Both patients showed profound electrodecrement on low-frequency repetitive stimulation followed by a prolonged period of postactivation exhaustion. In patient 1, this was unmasked only after isometric contraction, a recognized feature of presynaptic disease, emphasizing the importance of activation procedures. Conclusions: VAChT is responsible for uptake of acetylcholine into presynaptic vesicles. The clinical and electrographic characteristics of the patients described are consistent with previously reported mouse models of VAChT deficiency. These findings make it very likely that defects in VAChT due to variants in SLC18A3 are a cause of congenital myasthenic syndrome in humans.

Quantitative assessment of calf circumference in Duchenne muscular dystrophy patients

Duchenne muscular dystrophy is clinically characterised by progressive muscle weakness and a gradual increase in the size of some affected muscles, especially calf muscles. The extent of calf enlargement is usually determined by subjective visual assessment. The purpose of this study was to determine the extent of calf muscle enlargement in Duchenne muscular dystrophy (DMD) patients compared with healthy age matched boys by quantifying calf circumference. Calf circumference in the group of DMD patients is significantly increased. However, in individual patients calf enlargement can be feigned by a discrepancy between calf circumference and circumference of the upper leg and arm muscles as part of a general muscle atrophy.