L-2-hydroxyglutaric aciduria and brain tumors in children with mutations in the L2HGDH gene: neuroimaging findings

L-2-Hydroxyglutaric aciduria (L-2-HGA, MIM 236792) is a rare autosomal recessive neurodegenerative disorder characterized by psychomotor delay, cerebellar and extrapyramidal signs and subcortical leukoencephalopathy with basal ganglia and dentate nuclei involvement. Mutations in the gene L2HGDH ( C14ORF160/DURANIN/) have been identified as causative for L-2-HGA. A feature disproportionally associated with L-2-HGA is the development of malignant brain tumors. In our cohort of 40 patients with L-2-HGA, two developed medulloblastoma and glioblastoma multiforme during the course of the disease. Two missense mutations in two patients were identified in the L2HGDH gene in exon 3 (c.292C-->T) and in exon 7 (c.887T-->A). Both mutations were present in the homozygous state. Serial MR imaging findings as well as MR spectroscopy imaging is reported in a patient who developed glioblastoma multiforme.     

Interleukin-1beta, interleukin-1 receptor antagonist levels in patients with subacute sclerosing panencephalitis and the effects of different treatment protocols.

Subacute sclerosing panencephalitis is a rare progressive inflammatory disease of the central nervous system caused by a persistent aberrant measles virus infection. Cytokines are polypeptides that regulate immune responses and inflammatory reactions. Interleukin-1beta has been implicated as a central mediator of tissue damage and destruction in a number of central nervous system diseases. Interleukin-1 receptor antagonist could function as an important anti-inflammatory cytokine. We studied interleukin-1beta and interleukin-1 receptor antagonist levels in the cerebrospinal fluids of patients with subacute sclerosing panencephalitis and evaluated the effects of different treatment protocols on these cytokines. Interleukin-1beta and interleukin-1 receptor antagonist levels were measured in 15 patients who had a recent diagnosis of subacute sclerosing panencephalitis (group 1), 6 patients who had been treated with isoprinosine (group 2), 5 patients with intraventricular interferon-alpha (group 3), and 6 patients with interferon-beta (group 4). The results were compared within the groups and also with the results of 10 patients with other neurologic disease (group 5).The interleukin-1beta concentrations in cerebrospinal fluid and sera were all below the detection limits (3.9 pg/mL). Interleukin-1 receptor antagonist levels were not statistically different, except for the group treated with intraventricular interferon-alpha. Interleukin-1 receptor antagonist levels were 170 +/- 52, 175 +/- 58, 1605 +/- 518, 77.5 +/- 24, and 108 +/- 18 pg/mL in groups 1 to 5, respectively. Interleukin-1 receptor antagonist levels and cerebrospinal fluid serum ratios were significantly increased during interferon-alpha treatment. In conclusion, interleukin-1 and interleukin-1 receptor antagonist levels were not elevated in the patients with subacute sclerosing panencephalitis. The only treatment protocol that affects interleukin-1 receptor antagonist levels in cerebrospinal fluid was intraventricular interferon-alpha. Further studies on higher numbers of patients may better document the immunologic status of patients with subacute sclerosing panencephalitis and the effects of different treatment modes.     

Tissue inflammatory response in subacute sclerosing panencephalitis (SSPE).

The pattern of inflammatory infiltration was studied in the frontal brain biopsies of 28 cases with subacute sclerosing panencephalitis (SSPE) by immunohistochemistry. Lymphocytic infiltration and gliosis were common pathologic findings. CD4+ T lymphocytes were often observed in perivascular areas and CD8+ lymphocytes in the parenchyma. B lymphocytes were located in large perivascular cuffs associated with longer and slower disease. Major histocompatibility complex antigens, interferon-gamma, and tumor necrosis factor-alpha (TNF-alpha) were expressed in endothelial and glial cells. The inflammatory lesions in subacute sclerosing panencephalitis consist of various cell subtypes and cytokines localized in particular areas of the brain tissue and show certain associations with clinical course.     

Cardiac autonomic function evaluation in pediatric and adult patients with congenital myasthenic syndromes

Cardiac autonomic dysfunction has been examined in myasthenia gravis but not in congenital myasthenic syndromes (CMS). We aimed to evaluate cardiac autonomic functions in genetically defined CMS. Patients diagnosed with and under treatment for CMS were reviewed for 24-hour cardiac rhythm monitoring. Heart rate variability (HRV) measures were defined as: SDNN, mean of the standard deviations for all R-R intervals; SDNNi, standard deviation of all R-R intervals in successive five-minute epochs; RMSSD, square root of the mean of squared differences between successive R-R intervals. Ten patients with mutations in the epsilon subunit of the acetylcholine receptor (AChRε) and five patients with mutations in the collagen-like tail of asymmetric acetylcholinesterase (ColQ) were included. Median age at evaluation was 17 (2.5–46) years. In the AChRε group, RMSSD values; and in the ColQ group, SDNN, SDNNi and RMSSD values were significantly lower than those of healthy subjects. This first extensive report examining HRV in CMS showed alterations in patients with ColQ mutations and, to a lesser extent, in the group with AChRε mutations. This might indicate an increased risk of cardiac arrhythmias. We suggest cardiological follow-up in CMS, and consideration of any potential cardiovascular effects of therapeutic agents used in management.     

Bilateral temporal cysts in a case of subacute sclerosing panencephalitis.

Magnetic resonance imaging in subacute sclerosing panencephalitis (SSPE) usually demonstrates changes in white matter signal intensity, cerebral atrophy, or, in early disease, normal findings. We observed bilateral cystic temporal lobe lesions in a patient with early stage SSPE. Other degenerative conditions associated with such lesions were ruled out based on a normal head circumference, the absence of white matter changes, and normal cerebrospinal fluid lactate level. This observation suggests the inclusion of SSPE in the differential diagnosis of cystic white matter lesions.     

Atypical clinical course in juvenile metachromatic leukodystrophy involving novel arylsulfatase A gene mutations

A male and female with juvenile metachromatic leukodystrophy (MLD) with unusual manifestations are presented, each involving a novel arylsulfatase A gene mutation. One patient demonstrated acute intermittent encephalopathic episodes for 1 year after having received the diagnosis of MLD at the age of 6 years. The other patient presented at the age of 5 years with acute hemiparesis, which was diagnosed as acute disseminated encephalomyelitis and resolved in 3 weeks. After 2 years of remission he started to show progressive neurological deterioration. The episodic manifestations in both patients were associated with acute, resolving cerebral lesions on magnetic resonance imaging accompanying or preceding the classical demyelinating lesions of MLD. The diagnosis of MLD was based on arylsulfatase A enzyme activity levels and genetic analysis, and after the exclusion of neurological conditions such as encephalitis, vasculopathy, or mitochondrial disorders. The pathogenesis of this previously undescribed finding in MLD is unknown but might be related to a susceptibility of myelin to acute damage.     

Bilateral brachial plexopathy complicating Henoch-Schönlein purpura

An 11-year-old boy presented with convulsion, fever, rash, abdominal pain, swelling on the eyelids, elbow and wrists, oliguria and hematuria. Based on the abnormal findings the patient was diagnosed with Henoch-Schönlein purpura. On the 3rd day of admission, neurological examination showed ataxic gait, loss of deep tendon reflexes, and decreased (4/5) of muscle strength on all extremities. Additionally, bilateral loss of touch, pain and temperature sensation in a glove, from the elbows to distal region (on C5-T1 level) was diagnosed. Cerebrospinal fluid examination and cranial magnetic resonance imaging (MRI) were normal. The patient was discharged with oral prednisolone on the 7th day of admission. One week after discharging from the hospital, he was re-admitted with vertigo and seizures. He was in coma. MRI of cranial, cervical and cervical plexus were normal. Electromyography showed severe bilateral brachial plexopathy. Prednisolone and intravenous immunglobulin (IVIG) therapy were given without significant improvement. He was discharged from the hospital on the 17th day of admission. On the second month of follow-up, a second cure of IVIG was given because of no clinical improvement. Now, he is on the 4th month of follow-up, unfortunately, no improvement was noted on his muscle strength and sensorial abnormalities on the upper extremities.     

Association between low serum ferritin and restless legs syndrome in patients with attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder (ADHD) is a neurobehavioral disorder characterized by pervasive inattention and/or hyperactivity-impulsivity. It has been suggested that ADHD symptoms are associated with restless legs syndrome (RLS), which is a neurological condition that is defined by an irresistible urge to move the legs. Increasing evidence suggests iron deficiency may underlie common pathophysiological mechanisms in subjects with ADHD and with RLS. To further define the relationship between iron deficiency and RLS in children and adolescents with ADHD, we evaluated 87 ADHD subjects: 79 boys and 8 girls with age 9.3 +/- 2.5 years (6-16 years). Various psychopathologies and the severity of the ADHD symptoms and serum ferritin levels were assessed. Diagnosis of RLS was made according to the International RLS Group criteria. The patients were evaluated for the iron deficiency (ferritin < 12 ng/ml). RLS was found in 29 (33.3%) of the 87 ADHD subjects. Parent- and teacher-rated behavioral and emotional problems and the severity of ADHD symptoms were not significantly different between ADHD subjects with RLS and those without RLS (n = 58). The rate of iron deficiency was significantly higher in ADHD subjects with RLS (n = 6, 20.7%) when compared with ADHD subjects without RLS (n = 1, 1.7%, p = 0.005). Our results showed that depleted iron stores might increase the risk of having RLS in ADHD subjects. Iron deficiency, which is associated with both ADHD and RLS, seems to be an important modifying factor in the relationship between these two conditions.     

Viral studies in the cerebrospinal fluid in subacute sclerosing panencephalitis

OBJECTIVES: The pathogenesis of subacute sclerosing panencephalitis (SSPE), and particularly, the cause of measles virus (MV) reactivation following a latent period after primary measles infection is unknown. The hypothesis of other viruses contributing to the pathogenesis of SSPE by affecting the in vivo state of MV was investigated. METHODS: We examined the cerebrospinal fluid of SSPE patients (n=43) for DNA or RNA and antibodies against HSV type 1 and 2, EBV, CMV, VZV, Hepatitis B, Hepatitis C, JC virus, human herpesvirus (HHV)-6, HHV-7, HHV-8, HTLV-1, and HTLV-2. We compared the findings with those of patients with other neurological disorders (n=39). RESULTS: CMV DNA and HSV type 1 IgG were found more frequently in SSPE patients. Other positive results were at similar incidence in SSPE and control groups. The clinical features of SSPE cases with and without positive viral tests did not differ from each other. CONCLUSION: These data do not support a specific role for these agents in SSPE, but imply that the passage of some viruses to the CNS and local antibody synthesis may be facilitated by inflammation. The persistence or reactivation of MV in SSPE may be related to other factors pertaining to the host or environment.     

Impaired heart rate variability as a marker of cardiovascular autonomic dysfunction in multiple sclerosis

Multiple sclerosis (MS) can cause alterations in autonomic cardiovascular functions. We aimed to investigate the correlation of disease activity and disability with heart rate variability (HRV) of cardiovascular autonomic dysfunction (CAD) demonstrated by 24-h Holter monitorization. Thirty-four patients with clinically active relapsing-remitting MS, age 33.8 +/- 7.6 years, were studied. Twenty healthy volunteers served as controls. The time domain long-term HRV parameters were recorded by a digicorder recorder calculated by ambulatory electrocardiograms. Variabilities in time domain were lower in the MS patients: SDNN (standard deviation of all R-R intervals, p = 0,019), SDANN (standard deviation of the averages of R-R intervals in all 5-minute segments of the entire recordings, p = 0,040), RMSSD (the square root of the mean of the sum of the squares of differences between adjacent R-R intervals, p = 0,026), HRVM (mean of the SDNN in all the 5-minute intervals, p = 0,029), HRVSD (standard deviation of the SDNN in all the 5-minute, p = 0,043). These results suggest that MS causes CAD manifesting as long-term HRV abnormalities. This illness seems to cause a dysfunction in parasympathetic cardiovascular tone. Depressed HRV parameters are independent from the clinicalfindings, but the illness progression partially seems to provoke a decrease in such parameters.