Eli Shahar

Mitochondrial Hsp60 Chaperonopathy Causes an Autosomal-Recessive Neurodegenerative Disorder Linked to Brain Hypomyelination and Leukodystrophy

Hypomyelinating leukodystrophies (HMLs) are disorders involving aberrant myelin formation. The prototype of primary HMLs is the X-linked Pelizaeus-Merzbacher disease (PMD) caused by mutations in PLP1. Recently, homozygous mutations in GJA12 encoding connexin 47 were found in patients with autosomal-recessive Pelizaeus-Merzbacher-like disease (PMLD). However, many patients of both genders with PMLD carry neither PLP1 nor GJA12 mutations. We report a consanguineous Israeli Bedouin kindred with clinical and radiological findings compatible with PMLD, in which linkage to PLP1 and GJA12 was excluded. Using homozygosity mapping and mutation analysis, we have identified a homozygous missense mutation (D29G) not previously described in HSPD1, encoding the mitochondrial heat-shock protein 60 (Hsp60) in all affected individuals. The D29G mutation completely segregates with the disease-associated phenotype. The pathogenic effect of D29G on Hsp60-chaperonin activity was verified by an in vivo E. coli complementation assay, which demonstrated compromised ability of the D29G-Hsp60 mutant protein to support E. coli survival, especially at high temperatures. The disorder, which we have termed MitCHAP-60 disease, can be distinguished from spastic paraplegia 13 (SPG13), another Hsp60-associated autosomal-dominant neurodegenerative disorder, by its autosomal-recessive inheritance pattern, as well as by its early-onset, profound cerebral involvement and lethality. Our findings suggest that Hsp60 defects can cause neurodegenerative pathologies of varying severity, not previously suspected on the basis of the SPG13 phenotype. These findings should help to clarify the important role of Hsp60 in myelinogenesis and neurodegeneration.

Melatonin improves sleep-wake patterns in psychomotor retarded children

Five children with severe psychomotor retardation (mean age 8.2+/-3.6 years) and irregular sleep-wake patterns underwent 1 week of wrist actigraphic monitoring before and after treatment with 3 mg melatonin. Three underwent multiple measurements of urinary sulfatoxymelatonin levels. Urine sulfatoxymelatonin levels were abnormally low, without any significant day/night differences. Melatonin treatment increased nighttime sleep from 5.9+/-0.8 to 7.3+/-0.5 hours (paired t test, P<0.01) and sleep efficiency from 69.3%+/-6.2% to 88.3%+/-2.3% (P<0.01). Daytime sleep decreased from 3.2+/- 1.2 to 1.7+/-1.2 hours (P<0.05). Thus, no change in 24-hour total sleep time (9.1+/-1.5 vs. 9.0+/-1.6 hours) occurred. Administration of 3 mg melatonin to five severely psychomotor retarded children resulted in a significant improvement in their sleep-wake patterns.

Outcome of Severe Encephalomyelitis in Children Effect of High-Dose Methylprednisolone and Immunoglobulins

Acute encephalomyelitis in children refers to an insult of cortical white matter leading to acute disseminated encephalomyelitis, insult of the spinal cord leading to multifocal myelopathy, or a combined form of encephalomyelitis. We report here the clinical presentations and outcome of 16 children with severe acute encephalomyelitis analyzing the effect of high-dose methylprednisolone or intravenous immunoglobulins, administered separately or in combination. Five children developed acute disseminated encephalomyelitis alone, eight developed severe multifocal myelopathy accompanied in two of them by radiculoneuropathy, and three developed the most severe form of combined encephalomyeloradiculoneuropathy. The indications for treatment with either high-dose methylprednisolone, intravenous immunoglobulin, or a combination of the two were severe acute disseminated encephalomyelitis, visual loss, or severe flaccid weakness accompanied by bladder and bowel incontinence. Overall, 10 children had remarkably responded to high-dose methylprednisolone alone and recovered within 10 days. One patient with severe myelopathy, developing paraplegia, who failed oral corticosteroids completely recovered following intravenous immunoglobulin. Of the isolated acute disseminated encephalomyelitis group, all patients were initially treated with high-dose intravenous methylprednisolone and recovered within 10 days, including visual remission in the child with severe optic neuritis. All six children with solitary severe multifocal myelopathy were treated with high-dose methylprednisolone alone and recovered within the first week. Two patients had severe myeloradiculoneuropathy and were therefore treated with combined high-dose methylprednisolone and intravenous immunoglobulin: one remains paraplegic, whereas the second was ventilated for 3 weeks and recovered after 2 months. The three children with the most severe form of encephalomyeloradiculoneuropathy were treated with combined high-dose methylprednisolone and intravenous immunoglobulin; two remain severely handicapped, of whom one is paraplegic, and the third unexpectedly recovered within 3 months. Therefore, our experience indicates that either high-dose methylprednisolone or intravenous immunoglobulin, given separately or combined, may be efficacious in severe debilitating pediatric-onset acute encephalomyelitis. In children with the most severe form of encephalomyeloradiculoneuropathy, we suggest initially administering high-dose methylprednisolone and intravenous immunoglobulin combined, given the poorer outcome of our patients with combined severe central and peripheral demyelination. (J Child Neurol 2002; 17: 810—814).

Prevalence and risk of sleep disturbances in adolescents after minor head injury.

Sleep disturbances were reported in patients during the acute stage after minor head injury, and for some of these patients, the disturbances may become chronic. The purpose of the present study was to assess the prevalence and risk factors of the long-term sleep disturbances in adolescents after minor head injury. Unselected adolescents (98) who had experienced a minor head injury 0.5-6 years before the institution of the study and 80 matched control subjects were interviewed and completed a detailed questionnaire. The prevalence of sleep disturbances was significantly larger among adolescents who experienced minor head injury compared with the control subjects (28% versus 11%, P < 0.05). Within the study group, those who developed long-term sleep disturbances manifested a greater body mass index (20.8 +/- 4.0 vs 18.4 +/- 2.8 kg/m(2), P = 0.005) and poorer parental education (fathers 11.0 +/- 4.0 vs 13.4 +/- 3.0 years, mothers 11.8 +/- 3.3 vs 13.2 +/- 2.9 years, P < 0.05 for both), compared with those who did not develop sleep disturbances. Our data indicate that subjective sleep disturbances may be evident in a fairly high percentage of adolescents after minor head injury, up to 28%, suggesting that minor head injury may not be as benign as previously estimated. Risk factors include heavier body mass and poorer parental education.

Rapid recovery from transverse myelopathy in children treated with methylprednisolone

Acute transverse myelopathy is an uncommon disease that manifests with gradually developing weakness of the lower extremities associated with bladder or bowel dysfunction, sensory deficits, and pain localized in the back, legs, or abdomen. There are controversies in the literature regarding the role of steroids in the treatment of acute transverse myelopathy. Recently, a pilot open study of five children with acute transverse myelopathy treated with high-dose methylprednisolone demonstrated significant shortening of motor recovery when compared with an historic control group receiving either no treatment or low-dose steroids. The authors add their experience of 10 children with acute transverse myelopathy treated with high-dose methylprednisolone as soon as the diagnosis was confirmed. The median time of motor recovery in the present series was 5.5 compared with 23 days in the other study. No significant side effects were observed after treatment. This study provides further support that this treatment modality is safe and efficient and should be suggested for all children with acute transverse myelopathy after establishing the diagnosis.

Neonatal Guillain-Barré syndrome

A term female infant had the clinical manifestations and accompanying electrophysiologic studies to fulfill the criteria of Guillain-Barré syndrome. At birth, she presented with generalized hypotonia, paucity of lower limb movements, and diminished muscle stretch reflexes. At 3 weeks of age, motor nerve conduction studies demonstrated evidence of demyelination and axonal involvement. Progressive clinical improvement was observed beginning at the age of 2 weeks with subsequent normalization of clinical examinations and nerve conduction studies. To our knowledge, this patient is the youngest reported with Guillain-Barré syndrome.

Benign childhood epilepsy with centrotemporal spikes: clinical characteristics and identification of patients at risk for multiple seizures.

This study aimed to characterize patients diagnosed as having benign childhood epilepsy with centrotemporal spikes and few seizures and compare them with patients with benign childhood epilepsy with centrotemporal spikes with multiple seizures. The medical files of 87 consecutive patients with benign childhood epilepsy with centrotemporal spikes were reviewed and data on gender, age at disease onset, duration of the disease, number of seizures, seizure semiology, and electroencephalographic and neuroimaging findings were analyzed. The mean age at disease onset was 8 years. The mean duration of the disease was 2 years. Eighteen percent of the patients had more than 20 seizures each, whereas 24% had 1 to 3 seizures each. The only predictor for a disease course with multiple seizures was an onset prior to 3 years of age. (J Child Neurol 2002;17:17-19).

Absence Seizures Aggravated by Valproic Acid

Summary:  Purpose: To report on pediatric patients with absence epilepsy who experienced absence seizure aggravation while receiving valproic acid (VPA).

Kindergarten Children's Failure to Qualify for First Grade Could Result From Sleep Disturbances

Every year, 7% to 15% of preschool children are found to be underqualified for first grade. We examined whether sleep disturbances are factors in school readiness and their association with neurocognitive skills and behavior. The population included 148 kindergarten students. The study group consisted of 50 students who were assessed by the educational authority as unready for first grade. Children who were scheduled to attend first grade (n = 98) were in the control group. All children/parents filled in a sleep questionnaire and underwent a week of actigraphic sleep/wake study as well as cognitive and behavioral assessments. Children in the study group had significantly shorter total sleep time, reduced sleep efficiency, and increased number of nighttime awakenings. There were significant correlations between sleep variables, and cognitive and behavioral scores. In conclusion, children who fail to qualify for first grade have significantly inferior sleep patterns. Sleep disturbances were associated with cognitive and emotional immaturity.

Parkinsonian Syndrome Complicating Systemic Lupus Erythematosus

Two girls with florid extrapyramidal parkinsonism complicating systemic lupus erythematosus (SLE) are reported. One patient (15 years old) presented with extreme rigidity, irritability, and mutism initially diagnosed as acute psychosis. Examination revealed severe extrapyramidal akinetic mutism, along with marked restlessness. CT and MRI imaging of the brain were unremarkable. EEG revealed moderate generalized disturbance of background activity. 99mTc-HmPAO SPECT cerebral scanning detected decreased regional cerebral blood flow at the basal ganglia. Dopamine-agonist drugs led to complete recovery after 3 months, along with normalization of EEG and SPECT alterations. The second patient (16 years old) was assessed for progressive bradykinesia and apathy impeding her active daily activities, and she was suspected to have developed depression. Neurologic assessment revealed a parkinsonian syndrome that was less severe than that of the first patient. The EEG showed mild disturbance of background activity, and 99mTc-HmPAO SPECT demonstrated impaired regional cerebral blood flow over the basal ganglia. A parkinsonian extrapyramidal syndrome complicating SLE should therefore be taken into account in any patient with SLE presenting with marked behavioral alterations, rigidity, or akinetic mutism.