Brain and Development

Editorial Board

2012-02-01

Challenges of supplementary treatment for neurodegenerative diseases

Masafumi Matsuo — 2011-11-10

In this issue of Brain & Development, Koga et al. reported an interesting article entitled “Beneficial effect of pyruvate therapy on Leigh syndrome due to a novel mutation in PDH E1α gene . They reported clinical benefits of pyruvate supplementation to Leigh syndrome (LS) caused by pyruvate dehydrogenase complex (PDHC) deficiency caused by a mutation in the pyruvate dehydrogenase E1α (PDHA1) gene, although it is a single case report. LS is an early-onset progressive neurodegenerative disorder showing heterogeneous clinical presentations. PDHC, consisting of three enzymes including PDHA, is a nuclear-encoded mitochondrial matrix multienzyme complex. PDHC deficiency causes LS and mutations in the PDHA1 gene show the X-linked LS. As PDHC catalyzes enzymatic conversion of pyruvate to acetyl CoA, the deficiency leads to inadequate removal of pyruvate and lactate resulting in lactic acidemia and insufficient energy production. There is no established treatment for the PDHC deficiency.

Beneficial effect of pyruvate therapy on Leigh syndrome due to a novel mutation in PDH E1α gene

2011-04-01

Abstract: Leigh syndrome (LS) is a progressive untreatable degenerating mitochondrial disorder caused by either mitochondrial or nuclear DNA mutations. A patient was a second child of unconsanguineous parents. On the third day of birth, he was transferred to neonatal intensive care units because of severe lactic acidosis. Since he was showing continuous lactic acidosis, the oral supplementation of dichloroacetate (DCA) was introduced on 31st day of birth at initial dose of 50mg/kg, followed by maintenance dose of 25mg/kg/every 12h. The patient was diagnosed with LS due to a point mutation of an A–C at nucleotide 599 in exon 6 in the pyruvate dehydrogenase E1α gene, resulting in the substitution of aspartate for threonine at position 200 (N200T). Although the concentrations of lactate and pyruvate in blood were slightly decreased, his clinical conditions were deteriorating progressively. In order to overcome the mitochondrial or cytosolic energy crisis indicated by lactic acidosis as well as clinical symptoms, we terminated the DCA and administered 0.5g/kg/day TID of sodium pyruvate orally. We analyzed the therapeutic effects of DCA or sodium pyruvate in the patient, and found that pyruvate therapy significantly decreased lactate, pyruvate and alanine levels, showed no adverse effects such as severe neuropathy seen in DCA, and had better clinical response on development and epilepsy. Though the efficacy of pyruvate on LS will be evaluated by randomized double-blind placebo-controlled study design in future, pyruvate therapy is a possible candidate for therapeutic choice for currently incurable mitochondrial disorders such as LS.

Diagnostic accuracy of blood and CSF lactate in identifying children with mitochondrial diseases affecting the central nervous system

2011-08-29

Abstract: Objective: To determine the diagnostic accuracy of blood and cerebrospinal fluid (CSF) lactate and pyruvate concentrations in identifying children with mitochondrial diseases (MD) affecting the central nervous system (CNS). Methods: We studied lactate and pyruvate concentrations in paired samples of blood and CSF collected concurrently from 17 patients with MD (Leigh encephalomyelopathy 10, MELAS 5, Pearson disease 1, PDH deficiency 1) and those from control patients (n=49). Results: Although blood and CSF variables (lactate, pyruvate concentrations and lactate/pyruvate ratio) were significantly higher in the mitochondrial group than in the control group, there was considerable overlap of individual values between these two groups. The maximum value of the area under the receiver operating characteristic curve (AUC) was observed for the CSF lactate concentration (0.994, optimal cut-off value 19.9mg/dl, sensitivity 0.941 and specificity 1.00), followed by the CSF pyruvate level (0.983). There was an inverse relationship between blood lactate and lactate CSF/blood ratio. For blood lactate concentrations between 20 and 40mg/dl, a significant difference was also noted in the lactate CSF/blood ratio between the two groups (AUC 1.0, optimal cut-off value 0.91, sensitivity 1.0 and specificity 1.0). Conclusions: Our study suggests that that CSF lactate level>19.9mg/dl is the most reliable variable for identifying patients with MD affecting the CNS. When blood lactate concentrations are marginally elevated (20–40mg/dl), lactate CSF/blood ratio>0.91 may also provide diagnostic information.

Close monitoring of initial enzyme replacement therapy in a patient with childhood-onset Pompe disease

2011-06-15

Abstract: Pompe disease is classified into infantile and late-onset (childhood and adult) forms based on onset age and degree of organ involvement. While benefits of enzyme replacement therapy (ERT) for the infantile form have been confirmed, efficacy for late-onset forms reportedly varies. We report close monitoring of initial ERT, focusing especially on the first year, in a 12-year-old boy with childhood-onset Pompe disease. At age 10, he started ERT at 20mg/kg every other week. Respiratory and motor functions were evaluated at each infusion, and by skeletal muscle computed tomography (CT) and cardiac echography every 4months. He gained the ability to climb stairs without a rail and % vital capacity improved just 1.5months after starting ERT. Grip power, manual muscle testing (MMT) and the timed and 6-min walking distance tests (6MWT) improved promptly, paralleling improvements in clinical symptoms. However, this steady improvement stopped around 8months, with deterioration to the initial level by about 24months. Antibody against recombinant human alpha-glucosidase was very low at 15months; therefore, the lack of treatment response did not completely correspond to antibody production. On the other hand, cardiac wall thickening worsened after 4months, then improved to better than baseline after 8months, and this improvement was well maintained. Among our set parameters, the timed test results corresponded better to his changing clinical course than did grip power, MMT or 6-min walking test results.

High-density CT of muscle and liver may allow early diagnosis of childhood-onset Pompe disease

2011-06-27

Abstract: Pompe disease is classified into infantile-, childhood- and adult-onset forms based on onset age and the degree of organ involvement. Differing from the infantile-onset form which is characterized by marked organ involvement, the childhood-onset form usually presents with muscle weakness and elevation of serum creatine kinase (CK), mimicking those of progressive muscular dystrophy. We report our successful early diagnosis and initiation of enzyme replacement therapy (ERT) in a young girl with childhood-onset Pompe disease before the development of skeletal muscle symptoms. She was referred to our hospital at the age of 2years 4months because of hyperCKemia detected incidentally. She was active and lacked developmental delay and muscle weakness; however, hepatomegaly was noted. The combination of high-density changes in the liver and skeletal muscle on computed tomography (CT) images was suggestive of glycogen storage disorder, especially childhood-onset Pompe disease. Low alpha-glucosidase (GAA) activity on dried blood spots facilitated the diagnostic process, and genetic analysis of GAA allowed a definitive diagnosis, without performing muscle biopsy. We promptly started ERT at the age of 2years 6months. After 1year, she still had not developed any skeletal muscle symptoms, and serum CK level was almost normal. Since the efficacy of ERT is thought to depend on the extent of muscle damage at its commencement, we expect that ERT may have prevented the manifestation of skeletal muscle involvement in this patient.

A boy with a severe phenotype of succinic semialdehyde dehydrogenase deficiency

2011-05-25

Abstract: Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessive disorder affecting γ-aminobutyric acid degradation. We describe here a boy with a severe phenotype of SSADH deficiency. He was referred because of a developmental delay at 4 months of age. At the age of 8 months, severe seizures developed. The diagnosis of SSADH deficiency was confirmed by an increase in 4-hydroxybutyric acid and heteroallelic mutation in the ALDH5A1 gene. His seizures were successfully treated with high-dose phenobarbital, and the electroencephalogram (EEG) abnormalities were ameliorated. However, the patient showed a degenerative clinical course with severe neurological deficits. A magnetic resonance imaging (MRI) scan revealed abnormal high intensities in the putamina and caudate nuclei on T2-weighted images, followed by marked atrophic changes. The clinical manifestation of our patient indicates the wide variety of SSADH deficiency phenotypes.

Methylmalonic acidemia and hyperglycemia: An unusual association

2011-07-29

Abstract: Introduction: Hyperglycemia is an exceptional manifestation of methylmalonic acidemia (MMA). We describe a patient with MMA in whom we observed a hyperglycemia which improved under treatment of the metabolic crisis. Case report: A 14month-old boy presented with an acute generalized dystonia and lethargy preceded by fever, vomiting and lethargy at the age of 13months. Biological investigations showed a hyperglycemia, a lactic acidosis and a hyperammonemia. Urinary organic acid analysis showed accumulation of methylmalonic acid, tiglylglycine and methylcitrate leading to the diagnosis of MMA. The patient underwent symptomatic treatment with rapid improvement of general condition, consciousness and gradual normalization of biological parameters especially glycemia after 6days without using insulinotherapy. Discussion: MMA is an autosomal recessive disorder caused by a deficiency of methylmalonyl-CoA mutase resulting in methylmalonic acid accumulation. Biochemically, the disorder is typically characterized by: metabolic acidosis, ketonemia or ketonuria, hyperammonemia, leukopenia, thrombocytopenia and anemia. Hypoglycemia is a frequent manifestation of MMA. Our patient presented a hyperglycemia, which is unusual in MMA, since we found only three patients reported with this association. Pathophysiology remains unknown. In reported cases, hyperglycemia was treated by insulin therapy and reducing glucose intravenous infusion, with fatal outcome. In our patient glycemia spontaneously normalized after treatment of the metabolic crisis. Conclusion: Hyperglycemia is an exceptional manifestation of MMA and could be a seriousness marker.

Liver-specific mitochondrial respiratory chain complex I deficiency in fatal influenza encephalopathy

2011-03-28

Abstract: We report on a 4-year-old boy who died from influenza encephalopathy. The clinical course and microscopic findings of the autopsied liver were compatible with Reye’s syndrome. We examined the mitochondrial respiratory chain function by blue native polyacrylamide gel electrophoresis (BN-PAGE), western blotting, and respiratory chain enzyme activity assays. The activity of liver respiratory chain complex (CO) I was markedly decreased (7.2% of the respective control activity); whereas, the other respiratory chain complex activities were substantially normal (CO II, 57.9%; CO III, 122.3%; CO IV, 161.0%). The activities of CO I–IV in fibroblasts were normal (CO I, 82.0%; CO II, 83.1%; CO III, 72.9%; CO IV, 97.3%). The patient was diagnosed with liver-specific complex I deficiency. This inborn disorder may have contributed to the fatal outcome. We propose that relying only on fibroblast respiratory chain complex activities may lead to the misdiagnosis of liver-specific complex I deficiency.

Histopathology of cortex and white matter in pediatric epileptic spasms: Comparison with those of partial seizures

2011-04-15

Abstract: Epileptic spasms in older children have increasingly been recognized as a distinct seizure type and subset of these patients are considered for surgical resection. This study compares histopathology and magnetic resonance imaging (MRI), especially focusing the difference between the cortical grey matter and the subcortical white matter to understand the extensive epileptic brain in patients with epileptic spasms. We examined 22 patients consisting of 11 patients with epileptic spasms and 11 with partial seizures. Scalp video electroencephalography (EEG) showed interictal generalized epileptiform discharges (9 patients with epileptic spasms vs. 1 with partial seizures) and ictal generalized epileptiform discharges (10 vs. 3). We found MRI abnormalities in a single lobe (6 vs. 7) and multiple lobes (2 vs. 1). Surgical resections were performed across multiple lobes (9 vs. 2), comparing within a single lobe (2 vs. 9), (p<0.001). Histopathology showed abnormal cortical organizations as FCD (2 vs. 5) and microdysgenesis (4 vs. 4), normal (4 vs. 1). Two patients with epileptic spasms showed hyaline proteoplasmic astrocytopathy. There were heterotopic neurons (10 vs. 10), cluster of oligodendroglia (8 vs. 7), balloon cells (2 vs. 5) and blurred myelination (1 vs. 4), in the white matter. Seizure-free outcomes were seen in seven patients with epileptic spasms (64%) and four with partial seizures (36%). The multilobar epileptogenic zones existed in patients with epileptic spasms, compared with the focal epileptogenic zone in patients with partial seizures. There was no difference of MRI and histopathology findings in cortex and subcortical white matter between two groups.

Oxidative stress in patients with clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS)

2011-05-16

Abstract: We examined oxidative stress markers, tau protein and cytokines in the cerebrospinal fluid (CSF) in six patients with clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS). In the CSF, 8-hydroxy-2′-deoxyguanosine (8-OHdG) and hexanoyl-lysine adduct levels increased over the cutoff index in four and one out of six MERS patients, respectively. The CSF IL-6 and IL-10 levels were increased in three out of six patients, two of which had extended lesion of the cerebral white matter. The CSF value of tau protein, marker of the axonal damage, was not increased, and neuron specific enolase (NSE) in the CSF was not increased. The increased 8-OHdG levels in the CSF, DNA oxidative stress marker, in four MERS patients, suggesting involvement of oxidative stress in MERS. MERS is occasionally accompanied with hyponatremia, although our patients lacked hyponatremia. It is possible that the disequilibrium of systemic metabolism including electrolytes may lead to facilitation of oxidative stress and reversible white matter lesion in MERS. The increase of cytokine production seems to be involved in the distribution of lesions in MERS.

Motor skills, haptic perception and social abilities in children with mild speech disorders

Iti Müürsepp, Herje Aibast, Helena Gapeyeva, Mati Pääsuke — 2011-03-07

Abstract: Aim: The aim of the study was to evaluate motor skills, haptic object recognition and social interaction in 5-year-old children with mild specific expressive language impairment (expressive-SLI) and articulation disorder (AD) in comparison of age- and gender matched healthy children. Methods: Twenty nine children (23 boys and 6 girls) with expressive-SLI, 27 children (20 boys and 7 girls) with AD and 30 children (23 boys and 7 girls) with typically developing language as controls participated in our study. The children were examined for manual dexterity, ball skills, static and dynamic balance by M-ABC test, haptic object recognition and for social interaction by questionnaire completed by teachers. Results: Children with mild expressive-SLI demonstrated significantly poorer results in all subtests of motor skills (p<0.05), in haptic object recognition and social interaction (p<0.01) compared to controls. There were no statistically significant differences (p>0.05) in measured parameters between children with AD and controls. Children with expressive-SLI performed considerably poorer compared to AD group in balance subtest (p<0.05), and in overall M-ABC test (p<0.01). Conclusions: In children with mild expressive-SLI the functional motor performance, haptic perception and social interaction are considerably more affected than in children with AD. Although motor difficulties in speech production are prevalent in AD, it is localised and does not involve children’s general motor skills, haptic perception or social interaction.

Etiological analysis of presumed perinatal stroke

Canan Kocaman, Yuksel Yilmaz — 2011-05-12

Abstract: This study aimed to investigate the maternal, pre- and perinatal, and prothrombotic factors with congenital hemiparesis due to presumed perinatal stroke (PPS). Prothrombotic risk factors including protein C and S, antithrombin III, lipoprotein (a), homocystein, factor VIII levels; anticardiolipin antibodies and lupus anticoagulant; methylenetetrahydrofolate reductase mutations, factor V Leiden, prothrombin G20210A mutations were investigated. Arterial ischemic stroke was detected in 60% and periventricular venous infarction in 40%. At least one prothrombotic risk factor was present in 69%, two in 17%, and three or more in 8.5% of cases. The most common combination was methylenetetrahydrofolate reductase C677T and factor V Leiden heterozygosity. The etiology and pathogenesis of PPS is still unclear. According to this study, most of the patients with PPS might have one or more prothrombotic risk factors and certain prenatal risk factors including intrauterine growth retardation, twin gestation and preeclampsia might be related to PPS.

Concurrence of multiple types of eyelid synkinesia in a patient with congenital anomalies

2011-03-24

Abstract: We report the case of a 5-year-old boy with multiple congenital anomalies, including ptosis, polydactyly, ventricular septal defect, epilepsy, and intellectual deficits. The patient presented with synkinetic eyelid movements accompanying jaw and ocular movements, including Marcus–Gunn phenomenon (eyelid elevation at mouth opening) in the right eye, inverse Marcus–Gunn phenomenon (aggravation of ptosis at mouth opening) in the left eye, and unilateral eyelid elevation on each side during ipsilateral abduction. This suggests that the different types of synkinesia may represent a common etiology of aberrant innervations and/or reflex phenomena of the cranial nerves caused by a specific genetic defect.

Macrocephaly-capillary malformation syndrome: Description of a case and review of clinical diagnostic criteria

2011-02-28

Abstract: Macrocephaly-capillary malformation (M-CM) is characterized by prenatal overgrowth, variable somatic and cerebral asymmetry, primary megalencephaly, characteristic facial features, an abnormal neurocognitive profile and cutaneous vascular malformations. It was previously known under the name macrocephaly-cutis marmorata telangiectatica congenital (M-CMTC). However a recent review of the previously reported cases has suggested that the vascular anomalies are not true CMTC but rather capillary malformations. The diagnosis is primary clinical and different criteria have been proposed for this purpose. However, M-CM is frequently associated with structural brain abnormalities that should be properly investigated and monitored because of their possible progressive development. We report the neuroradiological and morphological features observed in a girl with M-CM and we compared them with proposed diagnostic criteria found in the literature.

Klinefelter’s syndrome complicated with West syndrome in a 4-month-old boy

2011-04-07

Abstract: We, for the first time, report a boy with West syndrome associated with Klinefelter’s syndrome. He developed episodes of repetitive tonic spasms at the age of 4months. He had developmental delays and hypsarrhythmia on interictal electroencephalography recording. His karyotype turned out to be 47, XXY, while we failed to observe anomalies in his appearance. Adrenocorticotropic hormone therapy with antiepileptic drugs resulted in cessation of tonic spasms, and his developmental quotient was improved by the age of 1year. Further studies are needed to determine the causal association between West syndrome and Klinefelter’s syndrome.

Schinzel–Giedion syndrome: A further cause of early myoclonic encephalopathy and vacuolating myelinopathy

2011-04-20

Abstract: Here, we report a male child with Schinzel–Giedion syndrome associated with intramyelinic edema detected on brain magnetic resonance imaging (MRI) and persistent suppression-burst pattern on electroencephalography (EEG) with erratic myoclonus of the extremities and face. Similar to nonketotic hyperglycinemia, Schinzel–Giedion syndrome may be recognized as another causative genetic disease of early myoclonic encephalopathy and vacuolating myelinopathy.

Clinicogenetical features of a Japanese patient with giant axonal neuropathy

2011-02-28

Abstract: Giant axonal neuropathy (GAN) is a rare autosomal recessive disorder that affects both the peripheral nerves and central nervous system. Since the discovery in 2000 of the gigaxonin gene on chromosome 16q24.1 to be causative, more than 40 GAN mutations have been reported from different racial backgrounds. We report the clinicogenetic findings of a 24-year-old Japanese man with GAN. He had consanguineous parents and showed the phenotype of classical severe GAN. We found a novel homozygous nonsense mutation (p.R162X) in the GAN gene. This is the first genetically-determined Japanese case of GAN, with a follow-up period of more than 15years. In addition, this mutation is novel. We also reviewed previous reports of GAN to see whether there is any genotype–phenotype correlation.

Past, present and future of hypothermic neuroprotection for neonatal encephalopathy in Japan: Time to say good-by to the old remedies

Osuke Iwata, Toshiki Takenouchi — 2011-09-19

In October 2010, International Liaison Committee on Resuscitation (ILCOR) released its revised statement on neonatal resuscitation recommending therapeutic hypothermia (TH) in the tertiary care setting as a standard of care in term or near-term infants with moderate to severe neonatal encephalopathy. It states TH should be conducted under clearly defined protocols and treatment should be consistent with those used in the randomized clinical trials . However, in Japan, TH has been applied to various types of brain injury with originally-developed protocols. In order to promote standard cooling protocols for neonatal encephalopathy, here we review the history of TH for the treatment of neonatal encephalopathy in Japan.

Therapeutic hypothermia for neonatal encephalopathy: JSPNM & MHLW Japan Working Group Practice Guidelines: Consensus Statement from the Working Group on Therapeutic Hypothermia for Neonatal Encephalopathy, Ministry of Health, Labor and Welfare (MHLW), Japan, and Japan Society for Perinatal and Neonatal Medicine (JSPNM)

Toshiki Takenouchi, Osuke Iwata, Makoto Nabetani, Masanori Tamura — 2011-09-19

Abstract: Neonatal encephalopathy (NE) secondary to intrapartum asphyxia remains a major cause of post-natal death and permanent neurological deficits worldwide. Supportive therapy has been the mainstay of the treatment until recent series of large clinical trials demonstrating benefit of therapeutic hypothermia (TH) in this high risk population. Now the International Liaison Committee on Resuscitation (ILCOR) recommends TH as a standard of care with the protocols used in the large clinical trials as tentative standard protocols.Our goal is to develop a nationwide consensus practice guideline not only consistent with the international standard protocols but also practical and compatible with the current medical system in Japan.In summary, TH should be offered to newborn infants born ⩾36weeks gestational age and birth weight ⩾1800g exhibiting clinical signs of moderate to severe NE as well as evidence of hypoxia–ischemia, i.e. 10min Apgar score ⩽5, a need for resuscitation at 10min, blood pH<7.00, or base deficit ⩾16mmol/L. TH should be conducted in the NICUs capable of multidisciplinary care and under the standard protocols, i.e. utilization of cooling device, target (rectal or esophageal) temperatures at 33.5±0.5 and 34.5±0.5°C for whole body and selective head cooling respectively, duration of TH for 72h, gradual rewarming not exceeding the rate of 0.5°C/h. Long term follow-up with multidisciplinary approach including standardized psychological assessment is warranted.

Announcements and reports

2012-02-01

Brain and Development

Editorial Board

Challenges of supplementary treatment for neurodegenerative diseases

Beneficial effect of pyruvate therapy on Leigh syndrome due to a novel mutation in PDH E1α gene

Diagnostic accuracy of blood and CSF lactate in identifying children with mitochondrial diseases affecting the central nervous system

Close monitoring of initial enzyme replacement therapy in a patient with childhood-onset Pompe disease

High-density CT of muscle and liver may allow early diagnosis of childhood-onset Pompe disease

A boy with a severe phenotype of succinic semialdehyde dehydrogenase deficiency

Methylmalonic acidemia and hyperglycemia: An unusual association

Liver-specific mitochondrial respiratory chain complex I deficiency in fatal influenza encephalopathy

Histopathology of cortex and white matter in pediatric epileptic spasms: Comparison with those of partial seizures

Oxidative stress in patients with clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS)

Motor skills, haptic perception and social abilities in children with mild speech disorders

Etiological analysis of presumed perinatal stroke

Concurrence of multiple types of eyelid synkinesia in a patient with congenital anomalies

Macrocephaly-capillary malformation syndrome: Description of a case and review of clinical diagnostic criteria

Klinefelter’s syndrome complicated with West syndrome in a 4-month-old boy

Schinzel–Giedion syndrome: A further cause of early myoclonic encephalopathy and vacuolating myelinopathy

Clinicogenetical features of a Japanese patient with giant axonal neuropathy

Past, present and future of hypothermic neuroprotection for neonatal encephalopathy in Japan: Time to say good-by to the old remedies

Announcements and reports

Contents