Variants in NGLY1 lead to intellectual disability, myoclonus epilepsy, sensorimotor axonal polyneuropathy and mitochondrial dysfunction.

NGLY1 encodes the enzyme N-glycanase that is involved in the degradation of glycoproteins as part of the endoplasmatic reticulum-associated degradation pathway. Variants in this gene have been described to cause a multisystem disease characterized by neuromotor impairment, neuropathy, intellectual disability, and dysmorphic features. Here, we describe four patients with pathogenic variants in NGLY1. As the clinical features and laboratory results of the patients suggested a multisystem mitochondrial disease, a muscle biopsy had been performed. Biochemical analysis in muscle showed a strongly reduced ATP production rate in all patients, while individual OXPHOS enzyme activities varied from normal to reduced. No causative variants in any mitochondrial disease genes were found using mtDNA analysis and whole exome sequencing. In all four patients, variants in NGLY1 were identified, including two unreported variants (c.849T>G (p.(Cys283Trp)) and c.1067A>G (p.(Glu356Gly)). Western blot analysis of N-glycanase in muscle and fibroblasts showed a complete absence of N-glycanase. One patient showed a decreased basal and maximal oxygen consumption rates in fibroblasts. Mitochondrial morphofunction fibroblast analysis showed patient specific differences when compared to control cell lines. In conclusion, variants in NGLY1 affect mitochondrial energy metabolism which in turn might contribute to the clinical disease course.

Progressive myoclonus epilepsy and ceroidolipofuscinosis 14: The multifaceted phenotypic spectrum of KCTD7-related disorders.

BACKGROUND: Mutations in the KCTD7 gene have been associated with progressive myoclonus epilepsy and, in a single patient, with the so-called "Neuronal Ceroid Lipofuscinosis 14" (characterised by myoclonic seizures, cognitive regression, optic atrophy leading to visual loss, and progressive cortical and cerebellar atrophy). CLINICAL REPORTS: We describe two new patients carrying two novel pathogenic mutations in the KCTD7 gene. Patient 1 (NM_153033.4: c.[533C > T], NP_694578: p.[(Ala178Val)]) was a 17-year-old girl who presented with early-onset epilepsy resembling epilepsia partialis continua (responsive to intravenous corticosteroids and immunoglobulins), and later developed myoclonic seizures and atypical absences, photosensitivity to very low frequencies and progressive seizures-related neurocognitive and motor deterioration. Patient 2 (NM_153033.4: c.[172G>A], NP_694578: p.[(Gly58Arg)]) presented with early neurological regression, myoclonic seizures and lysosomal storage material which was consistent with a neuronal ceroid lipofuscinosis (NCL) at skin biopsy. Both patients had non epileptic myoclonus. CONCLUSIONS: The two reported patients carrying novel pathogenic variants in KCTD7 gene presented with a remarkable phenotypic heterogeneity including: a) progressive myoclonus epilepsy without NCL-type lysosomal storages; b) progressive myoclonus epilepsy with lysosomal storages resembling NCL pattern (NCL14); c) progressive myoclonus epilepsy with epilepsia partialis continua.

Ictal single photon emission computed tomographic study of myoclonic absence seizures.

BACKGROUND: Epilepsy with myoclonic absences (EMAs) is a rare epileptic disorder characterized by a predominant type of seizures, myoclonic absences (MAs). The pathophysiology of MAs in patients with EMAs remains unknown. Here, we report the first characterization of the ictal phase of MAs by single photon emission computed tomography (SPECT). METHODS: We evaluated 1 male (Patient 1) and 1 female (Patient 2) patient with EMAs, aged 8 and 4years at first SPECT investigation, respectively. We performed ictal and interictal 99 mTc-ethyl cysteinate dimer (ECD) SPECT. We then generated images of subtraction ictal SPECT co-registered to MRI (SISCOM) from the interictal and ictal data to evaluate topographic changes in cerebral blood flow (CBF) during MAs as compared to the interictal state. RESULTS: In Patient 1, the CBF increased in the perirolandic areas, thalamus, caudate nucleus, and precuneus, and decreased in the middle frontal gyrus and bilateral orbitofrontal regions. In Patient 2, CBF increased in the thalamus, putamen, and globus pallidus. In contrast to the CBF in Patient 1, CBF was decreased in the precuneus. CONCLUSIONS: Using SPECT, we showed that, in addition to the thalamus and basal ganglia, the perirolandic cortical motor area is involved in MAs. We hypothesize that in MAs the blood perfusion in the perirolandic cortical motor area might have changed under the influence of the cortico-thalamic network oscillation features. The CBF properties observed by means of our SPECT procedure may represent key features of the pathophysiological mechanisms underlying MAs.

Novel Compound Heterozygous Mutations Expand the Recognized Phenotypes of FARS2-Linked Disease.

Mutations in mitochondrial aminoacyl-tRNA synthetases are an increasingly recognized cause of human diseases, often arising in individuals with compound heterozygous mutations and presenting with system-specific phenotypes, frequently neurologic. FARS2 encodes mitochondrial phenylalanyl transfer ribonucleic acid (RNA) synthetase (mtPheRS), perturbations of which have been reported in 6 cases of an infantile, lethal disease with refractory epilepsy and progressive myoclonus. Here the authors report the case of juvenile onset refractory epilepsy and progressive myoclonus with compound heterozygous FARS2 mutations. The authors describe the clinical course over 6 years of care at their institution and diagnostic studies including electroencephalogram (EEG), brain magnetic resonance imaging (MRI), serum and cerebrospinal fluid analyses, skeletal muscle biopsy histology, and autopsy gross and histologic findings, which include features shared with Alpers-Huttenlocher syndrome, Leigh syndrome, and a previously published case of FARS2 mutation associated infantile onset disease. The authors also present structure-guided analysis of the relevant mutations based on published mitochondrial phenylalanyl transfer RNA synthetase and related protein crystal structures as well as biochemical analysis of the corresponding recombinant mutant proteins.

Identification of MRI1, encoding translation initiation factor eIF-2B subunit alpha/beta/delta-like protein, as a candidate locus for infantile epilepsy with severe cystic degeneration of the brain.

Several neurodegenerative disorders are known to predominantly affect the white matter of the brain including vanishing white matter disease (VWMD), an autosomal recessive disorder characterized by leukodystrophy of varying severity in addition to variable systemic involvement. We report a consanguineous Arab family with three affected children, all of whom presented with severe neonatal epilepsy and profound neurodegenerative disease characterized by marked leukodystrophy with white matter cavitation mimicking VWMD. We combined autozygome and exome analysis to identify a novel variant in the gene encoding a member of the eIF2B-related family of proteins (MRI1). This is a poorly understood family of proteins of unclear function. Our results represent the first link between a variant in a member of this family and a human disease, and suggest that it converges with the highly homologous eIF2B, known to be mutated in VWMD, on the molecular pathogenesis of neurodegeneration.

Frontal lobe epilepsy may present as myoclonic seizures.

We describe a patient with seizures arising from right anterior-inferior frontal lobe presenting as myoclonic epilepsy. A 19-year-old man had experienced frequent paroxysmal bilateral myoclonic jerks involving his upper arms, shoulders, neck, and upper trunk since the age of 10. His baseline EEG showed intermittent right frontal spikes, and his ictal EEG showed rhythmic sharp theta discharges in the same area. MRI revealed cortical dysplasia in the right inferior frontal gyrus, and ictal-interictal SPECT analysis by SPM showed increased signal abnormality in this region. Diffusion tensor imaging (DTI) showed defects in fasciculi in the same area. These findings suggest that frontal lobe epilepsy should be considered in some patients with myoclonic seizures.

Cerebral blood flow abnormality in patients with idiopathic generalized epilepsy.

PURPOSE: To investigate the regional cerebral blood flow (rCBF) changes in patients with idiopathic generalized epilepsy (IGE), we compared brain single photon emission computed tomography (SPECT) images of drug naïve IGE patients with those of age/sex matched healthy volunteers. METHODS: Brain interictal 99mTc-ethylcysteinate dimer SPECT was performed in 21 patients with IGE (M/F = 10/11, 21.3 +/- 2.7 years) and 21 normal controls. The seizure types were generalized tonic-clonic seizure in 14 patients and myoclonic seizures with rare generalized tonic-clonic seizures in seven. Differences of rCBF between an IGE group and a normal control group were examined by the statistical parametric mapping (SPM) of brain SPECT images using independent t test. RESULTS: The SPM analysis showed that the rCBF of the IGE patients was significantly reduced in the anterior and posterior cingulate gyri, bilateral anterior nuclei and right dorsolateral nucleus of the thalamus, right superior colliculus of the midbrain, and the cerebellum at the level of uncorrected p < 0.005. In the small volume correction analysis for the thalamus and brainstem, the rCBF was also significantly decreased in the same brain regions at the level of FDR corrected p < 0.05. No brain regions of the IGE patients had increased rCBF. CONCLUSION: Our study demonstrates that the interictal rCBF in drug naive IGE patients is reduced in the cingulate gyrus, thalamus, brainstem and cerebellum. This result suggests that dysfunctions in these brain regions are associated with IGE.

Focal abnormalities detected by 18FDG PET in epileptic encephalopathies.

A prospective study of 32 children with epileptic encephalopathies 12 years or younger revealed a high incidence of focal cortical metabolic defects on 18-fluorodeoxyglucose positron emission tomography (PET) not suspected from clinical, EEG, or magnetic resonance imaging findings. PET scans were normal in all five children with typical de novo Lennox-Gastaut syndrome but showed cortical metabolic abnormalities in three out of four with atypical de novo Lennox-Gastaut syndrome, five out of six with Lennox-Gastaut syndrome following infantile spasms, six out of eight with severe myoclonic epilepsy in infancy, one out of two with epilepsy with myoclonic-astatic seizures, and four out of six with an unclassified epileptic encephalopathy. This suggests that some children with epileptic encephalopathies previously thought to have primary generalised seizures or seizures due to multifocal pathology may have unifocal cortical origin for their seizures. Such an origin may be amenable to surgery.

A Croatian case of the Schinzel-Giedion syndrome.

The Schinzel-Giedion syndrome is an infrequently described malformation syndrome, mainly characterized by a profound mental deficiency, a typical face including a midface hypoplasia, urogenital abnormalities, and minor radiographic features. Death prior to two year of age is the rule. A boy with typical features of the syndrome is described. He died at the age of 21 months. This is the first case of this syndrome reported from Croatia. The recurrence in only one of the 20 families, does not firmly sustain an autosomal recessive pattern of inheritance, although this still remains possible.

Vertebral arch nonfusion and juvenile myoclonic epilepsy.

Neural tube defects (NTD) are known to occur at a higher rate in pregnancies of women with epilepsy. Antiepileptic drugs (AEDs), notably valproate (VPA) and carbamazepine (CBZ), have been identified as risk factors, but a familial aggregation of this condition also occurs in the absence of pharmacologic teratogens. Spina bifida occulta, defined as a nonsymptomatic nonfusion of vertebral arches, has been suggested to be genetically determined, with an increased prevalence in patients with primary generalized epilepsy, and that the presence of this trait in fetal development can be enhanced pharmacologically to produce NTD such as meningomyelocele. In this study, plain abdominal radiographs were obtained from 56 patients with juvenile myoclonic epilepsy (JME) and 56 age- and sex-matched controls. The radiographs were presented in a random order to an unbiased radiologist. No difference in prevalence of vertebral arch nonfusion (VAN) was noted between the two groups. Even if it has no increased frequency in patients with epilepsy, however, VAN is a common radiologic finding, and its relation to symptomatic neural tube defects should be clarified in future studies.

Single photon emission computed tomography with 99mTc hexamethyl propylene amine oxime (HMPAO) and focal motor seizures.

The proper localization of regions of interest (ROIs) in Single Photon Emission Computed Tomography (SPECT) is an essential task. The limited spatial resolution makes it difficult to define regions by their structure. The particular problems are: 1) the difficulty to find the appropriate slice and its orientation in space; 2) the individual variation of the brain in dimension and shape. Referring to the basic work of Talairach and Szikla (1967), research is conducted to overcome these methodical problems in interpreting cranial computed tomography by using a proportional localization system. We analyzed four cases with focal motor seizures of different aetiology (tumour, hemorrhagic infarction, intracerebral hematoma, multifocal leukencephalopathy) by 99mTc HMPAO SPECT. The accumulation of the radiopharmacon was measured in ROIs which were delineated with the aid of the above mentioned system. The regions were selected in accordance to the autoradiographic study of penicillin induced epileptic seizures in animal experiments. Dependent on the severity of the clinical manifestation we were able to document the involvement of the supposed primary focus and of several related zones. We suggest that this approach should prove some usefulness in the examination of the interdependency of different brain areas.

Computed tomography in patients with recurrent seizures.

Eighty patients had Computed Tomography (CT) performed for evaluation of epileptic seizures. Abnormal scans were found in 37 of the 80 patients (46.3%). Focal CT abnormalities were seen in 26 of the 80 patients (32.5%). Tumors were present in four and arteriovenous malformation (AVM) in three. Simple partial motor seizures were most strongly correlated with abnormal scans (five, 45.4%). Nineteen out of 21 patients with focal electro-encephalographic (EEG) abnormalities had focal CT abnormality compared to one out of 15 of those with generalised abnormality. 88.9% of patients with hemiplegia had abnormal scans. Whilst focal EEG abnormalities and abnormal neurologic signs pointed to a higher likelihood of CT abnormality, two subjects who were shown to have vascular malformations had normal EEG and neurologic exams. Routine CT scanning for evaluation of patients with recurrent seizures is advocated.

Infant-onset progressive myoclonus epilepsy.

We report the clinical, electroencephalographic, neurophysiologic, and neuroimaging findings in eight children with infant-onset progressive myoclonus epilepsy, all of whom had muscle biopsies performed as as part of the diagnostic evaluation. Each child had myoclonic seizures, generalized tonic-clonic seizures, and neurologic regression or marked developmental delay. Four children died before 3 years of age. Electroencephalograms in seven children showed an abnormally slow background with bilateral multifocal paroxysmal discharges but no burst suppression pattern or photoparoxysmal response. Muscle biopsy specimens were submitted for histopathology and respiratory-chain enzyme studies. Nonspecific abnormalities on light microscopy or electron microscopy were found in seven samples, including increased subsarcolemmal deposits of mitochondria or morphologic mitochondrial changes, but no ragged-red fibers were seen. Respiratory-chain enzyme studies were performed on five samples and in three children (all of whom had a history of elevated lactate in serum or cerebrospinal fluid), there were low levels of rotenone-sensitive reduced nicotinamide adenine dinucleotide (NADH) cytochrome c reductase characteristic of a defect in the complex I part of the respiratory-chain pathway. This study has shown that infant-onset progressive myoclonus epilepsy can be distinguished from other myoclonic epilepsy syndromes of infancy by clinical and electrographic features. Furthermore, respiratory-chain enzyme defects are a relatively common cause of infant-onset progressive myoclonus epilepsy. The absence of ragged-red fibers on muscle histopathology does not preclude a mitochondrial enzyme abnormality.