Cytosolic Phosphoenolpyruvate Carboxykinase Deficiency: Cause of Hypoglycemia-Induced Seizure and Death.

Cytosolic phosphoenolpyruvate carboxykinase (PEPCK) deficiency (MIM 261680, EC 4.1.1.32, encoded by PCK1) is a rare disorder of gluconeogenesis presenting with recurrent hypoglycemia, hepatic dysfunction, and lactic acidosis. We report on a previously healthy 3-year-old boy who was initially admitted under the suspicion of a febrile seizure during an upper airway infection. Diagnostic workup revealed hypoglycemia as well as a cerebral edema and ruled out an infection. After a complicated course with difficult to treat symptomatic seizures, the child died on the 5th day of admission due to progressive cerebral edema. The metabolic screening showed elevated urinary lactate and Krebs cycle intermediates in line with a primary or secondary energy deficit. Due to the unclear and fatal course, trio exome sequencing was initiated postmortem ("molecular autopsy") and revealed the diagnosis of cytosolic PEPCK deficiency based on the compound heterozygosity of a known pathogenic (c.925G > A, p.(Gly309Arg)) and a previously unreported (c.724G > A, p.(Gly242Arg)) variant in PCK1 (NM_002591.3). Sanger sequencing ruled out the disease and carrier status in three older brothers. Molecular autopsy was performed due to the unclear and fatal course. The diagnosis of a cytosolic PEPCK deficiency not only helped the family to deal with the grief, but especially took away the fear that the siblings could be affected by an unknown disease in the same manner. In addition, this case increases the genetic and phenotypic spectrum of cytosolic PEPCK deficiency.

A novel pathogenic variant in MYO18B associating early-onset muscular hypotonia, and characteristic dysmorphic features, delineation of the phenotypic spectrum of MYO18B-related conditions.

Homozygous loss-of-function variants in MYO18B have been associated with congenital myopathy, facial dysmorphism and Klippel-Feil anomaly. So far, only four patients have been reported. Comprehensive description of new cases that help to highlight recurrent features and to further delineate the phenotypic spectrum are still missing. We present the fifth case of MYO18B-associated disease in a newborn male patient. Trio exome sequencing identified the previously unreported homozygous nonsense variant c.6433C>T, p.(Arg2145*) in MYO18B (NM_032608.5). While most phenotypic features of our patient align with previously reported cases, we describe the prenatal features for the first time. Taking the phenotypic description of our patient into account, we propose that the core phenotype comprises a severe congenital myopathy with feeding difficulties in infancy and characteristic dysmorphic features.

ATP synthase deficiency due to TMEM70 mutation leads to ultrastructural mitochondrial degeneration and is amenable to treatment.

TMEM70 is involved in the biogenesis of mitochondrial ATP synthase and mutations in the TMEM70 gene impair oxidative phosphorylation. Herein, we report on pathology and treatment of ATP synthase deficiency in four siblings. A consanguineous family of Roma (Gipsy) ethnic origin gave birth to 6 children of which 4 were affected presenting with dysmorphic features, failure to thrive, cardiomyopathy, metabolic crises, and 3-methylglutaconic aciduria as clinical symptoms. Genetic testing revealed a homozygous mutation (c.317-2A>G) in the TMEM70 gene. While light microscopy was unremarkable, ultrastructural investigation of muscle tissue revealed accumulation of swollen degenerated mitochondria with lipid crystalloid inclusions, cristae aggregation, and exocytosis of mitochondrial material. Biochemical analysis of mitochondrial complexes showed an almost complete ATP synthase deficiency. Despite harbouring the same mutation, the clinical outcome in the four siblings was different. Two children died within 60 h after birth; the other two had recurrent life-threatening metabolic crises but were successfully managed with supplementation of anaplerotic amino acids, lipids, and symptomatic treatment during metabolic crisis. In summary, TMEM70 mutations can cause distinct ultrastructural mitochondrial degeneration and almost complete deficiency of ATP synthase but are still amenable to treatment.

T-cell homeostasis in pediatric multiple sclerosis: old cells in young patients.

OBJECTIVE: To assess pediatric patients with multiple sclerosis (MS) for early signs of homeostatic and functional abnormalities in conventional (Tcon) and regulatory T cells (Treg). METHODS: We studied the composition of the peripheral T-cell compartment and Treg function in a cross-sectional study with 30 pediatric MS (pMS) patients by multicolor flow cytometry and proliferation assays. Data were compared to those obtained from adult patients (n = 26) and age-matched control donors (n = 67). RESULTS: Proportions of naive T cells were 10%-20% higher in children than in adults, reflecting the age-related decline. pMS patients, however, had clearly lower numbers of naive T cells, among them recent thymic emigrants (RTE), whereas percentages of memory T cells were increased. In the Treg compartment, reduced RTE numbers coincided with markedly dampened suppressive capacities of total Treg. These homeostatic changes in circulating T cells precisely paralleled the pattern seen in adult MS. As in adults, treatment with immunomodulatory drugs attenuated these alterations. CONCLUSION: The homeostatic changes detected in the T-cell compartment in pMS are similar to those in adult-onset disease. With ratios between naive and memory T-cell subsets matching those of 20- to 30-years-older controls, signs of early thymic involution are already found in pMS, suggesting that an intrinsic compromise in thymic-dependent T-cell neogenesis might contribute to MS pathogenesis.

Rasmussen encephalitis: incidence and course under randomized therapy with tacrolimus or intravenous immunoglobulins.

PURPOSE: Rasmussen encephalitis (RE) leads to progressive tissue and function loss of one brain hemisphere and often intractable epilepsy. This is the first randomized prospective treatment trial in RE. METHODS: Germany-wide, patients with suspected recent-onset RE were recruited and if eligible randomized to tacrolimus or intravenous immunoglobulins (IVIGs). A loss of motor function or hemispheric volume by ≥ 15% (in patients >12 years at disease onset: ≥ 8%) led to study exit. Untreated patients served as a historical control group. KEY FINDINGS: Over 6.3 years, 21 patients with recent-onset RE were identified. Sixteen were randomized to tacrolimus (n = 9) or IVIG (n = 7). Immunotreated patients had a longer "survival" than the historical controls. Neither treatment was more efficacious than the other. Two tacrolimus patients experienced serious adverse events. No immunotreated but several untreated patients developed intractable epilepsy. No patient with refractory epilepsy became treatment-responsive under immunotherapy. SIGNIFICANCE: The countrywide incidence rate of diagnosed RE is estimated as 2.4 cases/107 people ≤ age 18/year. Treatment with tacrolimus or IVIG may slow down tissue and function loss and prevent development of intractable epilepsy. However, immunotherapy may "arrest" patients in a dilemma state of pharmacoresistant epilepsy but too good function to be offered functional hemispherectomy. These compounds may therefore contribute to the therapeutic armamentarium for RE patients without difficult-to-treat epilepsies.

Febrile infection-related epilepsy syndrome without detectable autoantibodies and response to immunotherapy: a case series and discussion of epileptogenesis in FIRES.

Febrile infection-related epilepsy syndrome (FIRES) is a severe postinfectious epileptic encephalopathy in previously healthy children and has three phases: the initial phase with a simple febrile infection, a few days later the acute phase characterized by a peracute onset of highly recurrent seizures or refractory status epilepticus often with no more fever and generally without additional neurological features (the classical pure seizure phenotype), and last, the chronic phase with a drug-resistant epilepsy and neuropsychological impairments. FIRES seems to be sporadic and very rare: we estimated the annual incidence in children and adolescents by a prospective hospital-based German-wide surveillance as 1 in 1,000,000. Because of the preceding infection and lacking evidence of infectious encephalitis, an immune-mediated pathomechanism and, therefore, a response to immunotherapies may be involved. To test the hypothesis that antibodies against neuronal structures cause FIRES, we analyzed sera of 12 patients aged 2 to 12 years (median 6 years) and cerebral spinal fluids (CSFs) of 3 of these 12 patients with acute or chronic FIRES. We studied six patients (two including CSF) 1 to 14 weeks (median 3 weeks) and six patients 1 to 6 years (median 3.5 years) after seizure onset. All samples were analyzed for antibodies against glutamate receptors of type N-methyl-D-aspartate (NMDA) and type α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA), gamma-aminobutyric acid (GABA)B-receptors, voltage-gated potassium channel (VGKC)-associated proteins leucin-rich glioma inactivated 1 (LGI1) and contactin-associated protein like 2 (CASPR2), and glutamic acid decarboxylase (GAD) by a multiparametric recombinant immunofluorescence assay employing human embryonic kidney (HEK) cells transfected with cDNAs for the antigens. In addition, indirect immunohistochemistry using rat whole-brain sections was done in three patients. Finally, sera of 10 patients were tested for VGKC complex antibodies by radioimmunoprecipitation assay (RIA). None of the antibody tests were positive in any of the patients. Moreover, steroids, immunoglobulins, and plasmapheresis had no clear effect in the seven patients receiving immunotherapy. The failure of antibody-detection against the known neuronal antigens as well as the ineffectiveness of immunotherapy questions a role for autoantibodies in the epileptogenesis of classical FIRES. As we discuss, other underlying causes need to be considered including the possibility of a mitochondrial encephalopathy.

Neurodegeneration in ataxia telangiectasia: what is new? What is evident?

This article summarizes evident and recent findings on the characteristics of the neurological phenotype in ataxia telangiectasia (AT), reviews neuropathological and neuroradiological findings, and outlines therapeutic treatment options. In addition, this review offers an overview of current hypotheses on mechanisms of neurodegeneration in AT and discusses their relevance in clinical neurology. The obvious features of neurodegeneration in AT-cerebellar ataxia and dysarthia-are accompanied by a variety of further disabling disease symptoms. Review of the literature outlines a complex pattern of central nervous degeneration in AT that might have been underestimated so far. Neurodegeneration in AT is closely related to the absence or partial lack of the ataxia telangiectasia-mutated (ATM) kinase. ATM is a central player in maintaining cellular homeostasis. Systemic review of the literature reveals a subset of cellular targets hypothesized to count responsible for degeneration in ATM-deficient neurons. Further systematic cliniconeurological, pathoanatomical, and neuroradiological studies are required to understand the structural basis of this neurodegenerative disease. This better understanding has implications for the treatment of AT patients. Second, biochemical and molecular biological studies aimed at deciphering the pathomechanisms of this progressive disorder are necessary for the development of promising future therapies.

Encephalopathy and sinustachycardia in childhood--a possible differential diagnosis.

We report on a 7-year-old girl with generalized seizures, somnolence, fever, and respiratory distress. The increase of sinus tachycardia with good hydration, sufficient analgesia, and hyperthermia in our patient led to the determination of thyroid hormones, and therefore finally to the diagnosis of a thyrotoxic crisis in Graves' disease. Thyrotoxic crisis is a very rare but severe disease with an incidence of 0.1/100,000-3/100,000 among children. Important differential diagnoses of hyperthyroidism are Hashimoto thyroiditis, paraneoplastic thyroid-stimulating hormone production, thyroid autonomy, as well as central hyperthyroidism. Although symptoms disappear by thyrostatic therapy (thiamazole, carbimazole, dexamethasone), a euthyroid status could only be achieved by thyroidectomy. Thyrotoxic crisis should be considered a differential diagnosis in case of resistant unexplained sinus tachycardia, seizures, and encephalopathy. Immediate and adequate therapy contributes significantly to a reduction in the high morbidity and mortality rates. A combination of several treatment approaches for hyperthyroidism can lead to a successful outcome.

Rare brain biopsy findings in a first ADEM-like event of pediatric MS: histopathologic, neuroradiologic and clinical features.

Pediatric MS tends to present more often with an acute onset and a polysymptomatic form of the disease, possibly with encephalopathy and large tumefactive lesions similar to those observed in some cases of acute disseminated encephalomyelitis (ADEM), which makes it more difficult to differentiate between an explosive and severe onset of MS vs. ADEM. An ADEM-like first demyelinating event can be the first attack of pediatric MS, but international consensus definitions require two or more non-ADEM demyelinating events for diagnosis of MS. In our patient KIDMUS MRI criteria for MS (Mikaeloff et al. J Pediatr 144:246-252, 2004a; Mikaeloff et al. Brain 127:1942-1947, 2004b) were negative at first attack, but Barkhof criteria for lesion dissemination in space in adults (Barkhof et al. 120:2059-2069, 1997), Callen modified MS-criteria and Callen MS-ADEM criteria for children (Callen et al. Neurology 72:961-967, 2009a; Callen et al. Neurology 72:968-973, 2009b) were positive suggesting pediatric MS. As the clinical course was devastating with non-responsiveness upon high-dose immune modulatory therapy and due to the absence of an alternative diagnosis other than demyelinating disease brain biopsy was performed. Brain biopsy studies or autopsy case reports of fulminant pediatric MS patients are extremely rare. Histopathology revealed an inflammatory demyelinating CNS process with confluent demyelination, indicating the likelihood of a relapsing disease course compatible with an acute to subacute demyelinating inflammatory disease. This pattern was corresponding to the early active multiple sclerosis subtype I of Lucchinetti et al. (Ann Neurol 47(6):707-717, 2000).

Spectroscopy of untreated pilocytic astrocytomas: do children and adults share some metabolic features in addition to their morphologic similarities?

OBJECTIVE: Pilocytic astrocytomas may show heterogeneous histopathological and imaging features which are commonly attributed to malignant gliomas. Using magnetic resonance (MR) spectroscopy, we assessed if pilocytic astrocytomas show increased choline (tCho), classically related to proliferation and malignancy of gliomas. METHODS: Sixteen patients (five adults, age 20-55 years and 11 children, age 6 months-15 years) with histologically proven pilocytic astrocytomas were evaluated retrospectively. MR spectroscopy was performed prior to surgery or biopsy in all patients. Intensities of tCho and total creatine (tCr) signals were normalised to the respective signal intensity of contralateral brain tissue and statistically evaluated for group differences between adults and children. RESULTS: The tCho levels covered a wide range with a trend towards elevated values, especially in the adult group. tCho levels ranged from 0.78 to 2.92 in the paediatric group (mean 1.15) and from 1.15 to 3.03 in the adult group (mean 1.35). Diminished or normal tCr values were observed in all patients but one. CONCLUSIONS: The well-known positive correlation between increase of tCho and the grade of gliomas seems to be violated by WHO grade I pilocytic astrocytomas showing a wide range of tCho values with an even marked increase in some cases. No significant differences have been identified in the MR spectroscopy metabolite profiles between paediatric and adult pilocytic astrocytomas.

An overview of L-2-hydroxyglutarate dehydrogenase gene (L2HGDH) variants: a genotype-phenotype study.

L-2-Hydroxyglutaric aciduria (L2HGA) is a rare, neurometabolic disorder with an autosomal recessive mode of inheritance. Affected individuals only have neurological manifestations, including psychomotor retardation, cerebellar ataxia, and more variably macrocephaly, or epilepsy. The diagnosis of L2HGA can be made based on magnetic resonance imaging (MRI), biochemical analysis, and mutational analysis of L2HGDH. About 200 patients with elevated concentrations of 2-hydroxyglutarate (2HG) in the urine were referred for chiral determination of 2HG and L2HGDH mutational analysis. All patients with increased L2HG (n=106; 83 families) were included. Clinical information on 61 patients was obtained via questionnaires. In 82 families the mutations were detected by direct sequence analysis and/or multiplex ligation dependent probe amplification (MLPA), including one case where MLPA was essential to detect the second allele. In another case RT-PCR followed by deep intronic sequencing was needed to detect the mutation. Thirty-five novel mutations as well as 35 reported mutations and 14 nondisease-related variants are reviewed and included in a novel Leiden Open source Variation Database (LOVD) for L2HGDH variants (http://www.LOVD.nl/L2HGDH). Every user can access the database and submit variants/patients. Furthermore, we report on the phenotype, including neurological manifestations and urinary levels of L2HG, and we evaluate the phenotype-genotype relationship.

Extracerebellar MRI-lesions in ataxia telangiectasia go along with deficiency of the GH/IGF-1 axis, markedly reduced body weight, high ataxia scores and advanced age.

Ataxia telangiectasia (AT) is a rare autosomal recessive disorder characterized by progressive ataxia, neurodegeneration, immunodeficiency, and cancer predisposition. Pathoanatomical studies reported a degeneration of cerebellar Purkinje cells as the striking feature of the disease. Although recent studies suggested the involvement of extracerebellar structures such as the brainstem and basal ganglia, this has rarely been studied in human AT. Thus, we performed a detailed cliniconeuroradiological investigation of 11 AT patients, aged 8 to 26 years by collecting clinical neurological data, ataxia scores, growth status, body mass index (BMI), growth hormone (GH), and insulin-like-growth factor 1 (IGF-1) and correlated them to extracerebellar neuroimaging findings in human AT. Neuroimaging was done by cranial and spine magnetic resonance imaging (MRI) with T1- and T2-weighted spin-echo and fluid attenuated inversion recovery sequences. We compared clinical and neuroradiological findings of six patients with IGF-1 levels and BMI below the third percentile to five patients with normal IGF-1 serum levels and BMI above the third percentile. Three of the six first mentioned patients older than 20 years and two patients older than 12 years showed noticeable high Klockgether ataxia scores above 25 points. Three of these patients presented with marked hyperintense lesions in the cerebral white matter of T2-weighted MR images. Interestingly, all six patients suffered from marked spinal atrophy. Two of the patients presented with severe extra-pyramidal symptoms, but only one patient showed associated MRI abnormalities of the basal ganglia. MRI in patients with normal IGF-1 levels showed the expected cerebellar lesions in four patients, whereas spinal atrophy was found only in two patients. There was no affection of the cerebral white matter or basal ganglia in this group. We conclude that central cerebral white matter affection, spinal atrophy, and extrapyramidal symptoms are more often present in patients with pronounced deficiency of the GH/IGF-1 axis accompanied by markedly reduced body weight and high ataxia scores. This may point to a major role of IGF-1 and nutritional status in neuroprotective signaling.

Dystonia with secondary contractures: a psychogenic movement disorder mimicking its neurological counterpart.

We report the case of an 11-year-old girl presenting with a 1.5-year history of swan neck-like deformed joint contractures of both hands. A possible diagnosis was sought in a wide range of rheumatological, metabolic, and neurological disorders. After detailed diagnostic procedures to exclude an organic pathology, steps were taken to establish a psychogenic origin. She showed symptoms that were incongruent with an organic neurological disorder, for example, a paroxysmal fluctuating course, reaction to placebo, and complete remission with psychotherapy and physiotherapy. The psychosomatic evaluation revealed a highly emotional conflict. This bizarre case demonstrates that secondary contractures are by no means an exclusion criterion for a psychogenic dystonia.

N-carbamylglutamate enhances ammonia detoxification in a patient with decompensated methylmalonic aciduria.

In patients with methylmalonic aciduria (MMA), the accumulating metabolite propiony-CoA results in an inhibition of the urea circle via the decreased synthesis of N-acetylglutamate, an essential activator of carbamylphosphat synthetase (CPS). This results in one of the major clinical problems which is hyperammonaemia. In a patient with decompensated MMA, the CPS activator carbamylglutamate was tested for its ability to antagonize the propionyl-CoA-induced hyperammonaemia. Oral carbamylgutamate administration resulted in an impressive increase in ammonia detoxification compared to peritoneal dialysis. Safe, fast and easy to administer, carbamylglutamate improves the acute therapy of decompensated MMA by increasing ammonia detoxification and avoiding hyperammonaemia.

Cyst of the third ventricle as an unusual cause of acquired hydrocephalus.

Cysts of the third ventricle are rare congenital suprasellar malformations of arachnoidal, endodermal, or neuroepithelial origin. Depending on their size and location, they can cause space-occupying intracranial lesions and hydrocephalus occlusus by obstruction of the aqueduct or foramen of Monro. They can be missed on routine computer tomography and magnetic resonance imaging. A 2-year-old boy presented signs of intracranial pressure. Initial magnetic resonance imaging revealed a triventricular internal hydrocephalus with no visible etiologic lesion. An extended investigation with the constructive interference in steady state-technique showed a mobile cystic cerebrospinal fluid-intense lesion within the third ventricle, causing transient occlusion of the foramen of Monro. A suprasellar cyst of the third ventricle is an important differential diagnosis in apparently "idiopathic" internal hydrocephalus. In such cases, magnetic resonance imaging using the constructive interference in steady state-technique with a slice thickness of 1 mm is the method of choice for detecting intraventricular cysts. Neurosurgical fenestration and/or resection of the cyst by neuroendoscopy can resolve cerebrospinal fluid circulation disturbances and seems to be superior to a shunt.

Midline developmental anomalies in Down syndrome.

Infants with Down syndrome are known to have a high frequency of birth defects, particularly cardiac and gastrointestinal defects. Mental retardation of different degrees is common, but accompanying central nervous system malformations are rare. We report a boy born spontaneously in the 37th postconceptional week with multiple malformations: microcephaly, hypertelorism, blepharophimosis, medial cleft palate, micrognathia, omphalocele, and pathologic palmar and plantar creases. Cardial sonography revealed a ventricular septal defect and mild pulmonary stenosis. Cranial magnetic resonance imaging demonstrated a general but infratentorial stressed brain atrophy with widening of the inner and outer cerebrospinal fluid spaces and dysplasia of the corpus callosum. Chromosomal analysis showed a free trisomy 21. The boy had muscular hypotonia and developed severe motor and mental retardation, accompanied by microsomia and generalized epileptic seizures. At age 8 months, he died of sudden nocturnal respiratory and cardiac failure. The peculiarity of this case is the combination of Down syndrome with midline developmental defects (callosal dysplasia, medial cleft palate, omphalocele) accompanied by severe malformative encephalopathy. There are no previous reports of this combination, but there are genetic links between Down syndrome and midline defects concerning the Drosophila single-minded (sim) gene. The expression pattern of the human sim corresponding gene suggests that it might be involved in the pathogenesis of midline defects in Down syndrome.