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Objective To describe fetal, clinical, radiological, morphological features of TUBB3 related syndrome. Methods We report two families each of two generations harboring a novel and a previously described heterozygous TUBB3 pathogenic variants. We compared these patients with other published TUBB3-related cases. We describe the pathological features of dysgyria in the two aborted fetuses. Results The mother and son from family 1 had a history of mild developmental delay in motor and language skills and demonstrated mild cerebellar signs and mirror movements. Neuroimaging findings included: hypoplastic corpus callosum (CC), asymmetric ventriculomegaly and cerebellar vermis hypoplasia in all patients and frontal dysgyria in three. Autopsy of the fetal brain showed an unusual shape and orientation of the frontal sulci and gyri with normal cortical layering and no abnormal cell types. The mother of family 2 had congenital strabismus, mild muscle weakness on the right and a past history of developmental delay. Fetal brain MRI showed abnormal cerebral sulcation, hemispheric asymmetry, asymmetric ventriculomegaly, dysmorphic short CC and frontal cortical interdigitation. Autopsy demonstrated fronto-parietal predominant dysgyria, bilateral ventriculomegaly, hippocampal and CC hypoplasia, abnormal Sylvian fissure. Lamination and neuron morphology in the areas of dysgyria were normal. Conclusions TUBB3 related cortical malformations can be mild, consistent with dysgyria rather than typical pachygyria or polymicrogyria. The autopsy findings in fetal TUBB3 related dysgyria are abnormal orientation of sulci and gyri, but normal neuron morphology and layering. We suggest that TUBB3 – associated brain malformations can be suspected in-utero which in turn can aid in prognostic counselling and interpretation of genetic testing.

Adenylosuccinate lyase deficiency is a rare autosomal recessive disorder of purine metabolism. The disorder manifests with developmental delay, postnatal microcephaly, hypotonia, involuntary movements, epileptic seizures, ataxia and autistic features. Paroxysmal non-epileptic motor events are not a typical presentation of the disease. We describe an 8-year-old boy who presented with an infantile onset of prolonged episodes of multifocal sustained myoclonic tremor lasting from minutes to days on a background of global developmental delay and gait ataxia. Ictal EEG during these episodes was normal. Ictal surface EMG of the involved upper limb showed a muscular activation pattern consistent with cortical myoclonus. Brain MRI showed mild cerebral atrophy. Whole exome sequencing revealed a novel homozygous variant in the ADSL gene: c.1027G > A; p. Glu343Lys, inherited from each heterozygous parent. There was a marked elevation of urine succinyladenosine, confirming the diagnosis of adenylosuccinate lyase deficiency. In conclusion, myoclonic tremor status expands the spectrum of movement disorders seen in adenylosuccinate lyase deficiency.

Objective Early onset epileptic encephalopathies (EOEEs) are a group of devastating diseases, manifesting in the first year of life with frequent seizures and/or prominent interictal epileptiform discharges on the electroencephalogram (EEG), developmental delay/regression and usually a poor prognosis. There are numerous causes for EOEEs making the diagnostic workup time consuming and costly. We describe the diagnostic workup in two siblings with EOEE, profound global developmental delay (GDD) and post natal microcephaly. Neuro-imaging disclosed non-specific progressive cerebral atrophy. Methods Whole-exome sequencing analysis. Results Two causative mutations in the gene encoding for mitochondrial arginyl-transfer RNA synthetase, RARS2, were found. This gene is presently related to ponto-cerebellar hypoplasia (PCH) type 6. Reviewing our cases and 16 others published, a common phenotype emerges of EOEE with onset in the immediate post natal or early infantile period (range 1 day-4 months). Many children had more than one seizure type; the most frequent types were myoclonic (50%) followed by clonic (31.5%). The seizures were described as multifocal/alternating sides in 37.5%. Initial EEG demonstrated slowing of the background in 62.5% and epileptiform discharges in 50%. EEG was reported as initially normal in 19%, but almost all the following recordings showed deterioration. Few patients demonstrated initial response to an anti-epileptic drug but eventually all but one had intractable epilepsy. All patients displayed profound GDD – none attained any significant milestones. Most patients had normal occipito-frontal circumference at birth, but almost all developed progressive microcephaly, up to –6 standard deviations. The most common radiological finding was progressive cerebral (100%) and cerebellar (93%) atrophy and NOT progressive PCH (present in 67%). The condition proved to be fatal in 50%. Conclusion We suggest that RARS2 gene mutations can cause a metabolic neurodegenerative disease manifesting primarily as EOEE with post natal microcephaly, without the distinctive radiological feature of PCH.

Pontocerebellar hypoplasia (PCH) encompasses a group of neurodegenerative disorders. There are ten known subtypes with common characteristics of pontine and cerebellar hypoplasia or atrophy, neocortical atrophy, and microcephaly. PCH is associated with anterior horn cell degeneration in PCH1a and PCH1b due to mutations in the VRK1 and EXOSC3 genes. Late onset PCH1 has been described in single case reports. The molecular etiology remains mostly unknown. We describe two siblings from a consanguineous Moslem Arabic family with a unique combination of progressive cerebellar atrophy and a SMA-like anterior horn cell degeneration due to a homozygous mutation in the PLA2G6 gene (NM_003560.2). The PLA2G6 gene encodes phospholipase A2 beta, which is involved in the remodeling of membrane phospholipids, signal transduction and calcium signaling, cell proliferation and apoptosis. Mutations in PLA2G6 are known to cause Neurodegeneration with brain iron accumulation 2 (NBIA2): Our patients have some similarities with NBIA2; both are characterized by rapidly progressive psychomotor regression and cerebellar atrophy. However, NBIA2 is not known to exhibit anterior horn cell degeneration. Our patients' phenotype is more consistent with late onset PCH1; thus, indicating that the spectrum of clinical and radiological presentations of PLA2G6 mutations should be extended and that this gene should be included in the molecular evaluation of patients with late onset PCH1.

Background ARSACS (autosomal–recessive spastic ataxia of Charlevoix-Saguenay) is a neurodegenerative disorder caused by SACS gene mutations and characterized by a triad of symptoms: early-onset cerebellar ataxia, spasticity and peripheral neuropathy. A characteristic retinal nerve fiber hypertrophy has been reported in several individuals with ARSACS. Methods We describe a patient with a unique clinical presentation of ataxia, nystagmus, dysarthria, hearing impairment, and retinal degeneration. Whole-exome-sequencing was performed as well as morphological studies in the patient's fibroblasts. Results A compound heterozygosity for a novel D3269N and N2380K mutations in the SACS gene was found. The parents are carriers. Morphological studies revealed a dramatic decrease in the number of cell mitochondria as well as a difference in mitochondrial network morphology. Conclusions Retinal degeneration has never been reported in ARSACS. Since sacsin is involved in the mitochondrial fusion-fission process, we speculate that defected fission process may be responsible for an impaired mitochondrial function and retinal degeneration. Our patient has a unique clinical presentation of SACS mutations inconsistent with the classic ARSACS triad but also different from the “atypical” presentations described in the literature. Further studies are necessary to clarify the factors that modify the SACS related phenotype.

Objective Paroxysmal tonic upward gaze was initially described as a benign phenomenon with negative investigations and eventual complete resolution of symptoms. Later publications demonstrated that a similar clinical picture may arise from structural brain lesions, channelopathies, neurotransmitter disorders, and epileptic seizures. CACNA1A related disorders manifest as a wide spectrum of paroxysmal neurological disorders: episodic ataxia 2, hemiplegic migraine, benign paroxysmal torticollis of infancy, and paroxysmal vertigo. Paroxysmal tonic upward gaze as a phenomenon in patients with mutations in the CACNA1A gene has only been reported once. Methods We describe three patients with multiple episodes of paroxysmal tonic upward gaze that appeared during the first months of life. In addition the patients demonstrated motor and language delay and cerebellar ataxia. A sequence analysis of the CACNA1A gene in one patient and whole exome sequencing in the other patients were performed. Results Sequence analysis of the CACNA1A gene in one patient and whole exome sequencing in the two other patients revealed 3 different de-novo mutations in the CACNA1A gene. Conclusion CACNA1A mutations should be evaluated in infants and young children with paroxysmal tonic upgaze especially if associated with developmental delay, cerebellar signs, and other types of paroxysmal event.

Ohtahara syndrome is a devastating early infantile epileptic encephalopathy caused by mutations in different genes. We describe a patient with Ohtahara syndrome who presented on the first day of life with refractory tonic seizures and a suppression-burst pattern on EEG. The patient developed severe microcephaly, and never achieved any developmental milestones. He died at the age of 5 years. A de novo missense mutation (c. 4007C>A, p.S1336Y) in SCN2A was found. Interestingly, the father has another son with Ohtahara syndrome from a different mother. The half brother carries the same SCN2A mutation, strongly suggesting paternal gonadal mosaicism of the mutation. The broad clinical spectrum of SCN2A mutations now includes Ohtahara syndrome. This is the first report of familial Ohtahara syndrome due to a germline mosaic SCN2A mutation. Somatic mosaicism, including germline, has been described in several epileptic encephalopathies such as Dravet syndrome, KCNQ2 neonatal epileptic encephalopathy, SCN8A epileptic encephalopathy and STXBP1 related Ohtahara syndrome. Mosaicism should be considered as one of the important inheritance patterns when counseling parents with a child with these devastating diseases.

Introduction There are many similarities, both clinical and radiological, between mitochondrial leukoencephalopathies and Alexander disease, an astrogliopathy. Clinically, both can manifest with a myriad of symptoms and signs, arising from the neonatal period to adulthood. Radiologically, both can demonstrate white matter changes, signal abnormalities of basal ganglia or thalami, brainstem abnormalities and contrast enhancement of white matter structures. Magnetic resonance spectroscopy may reveal elevation of lactate in the abnormal white matter in Alexander disease making the distinction even more challenging. Patient and Methods We present a child who was considered to have an infantile onset mitochondrial disorder due to a combination of neurological symptoms and signs (developmental regression, failure to thrive, episodic deterioration, abnormal eye movements, pyramidal and cerebellar signs), urinary excretion of 3-methyl-glutaconic acid and imaging findings (extensive white matter changes and cerebellar atrophy) with a normal head circumference. Whole exome sequence analysis was performed. Results The child was found to harbor the R416W mutation, one of the most prevalent mutations in the glial fibrillary acidic protein (GFAP) gene that causes Alexander disease. Conclusions Alexander disease should be considered in the differential diagnosis of infantile leukoencephalopathy, even when no macrocephaly is present. Next generation sequencing is a useful aid in unraveling the molecular etiology of leukoencephalopathies.

The hereditary spastic paraplegias (HSP) are a heterogeneous group of genetic neurodegenerative disorders in which the main feature is progressive spasticity of the lower limbs due to pyramidal tract dysfunction. Clinically HSP are divided into two forms: a pure form that presents with progressive lower limb spasticity and weakness, sensory signs and bladder dysfunction, and a complicated form, associated with more extensive neurological and extra neurological signs as well as pathological findings on brain imaging. The clinical variability observed in HSP is supported by the large underlying genetic heterogeneity. Hereditary spastic paraplegia with thin corpus callosum (HSP-TCC) is a frequent subtype of complicated HSP clinically characterized by a slowly progressive spastic paraparesis with cognitive impairment and thin corpus callosum (TCC). SPG11, the most frequent gene associated with HSP-TCC, encodes spatacsin, a protein of unknown function. We describe two siblings from an Arabic consanguineous family with slowly progressive spastic paraparesis, mental retardation, seizures, thin corpus callosum and periventricular white matter abnormalities. Homozygosity mapping identified a novel single candidate region of 7.3 Mb on chromosome 1p13.2-1p12. The finding of a new locus for AR-HSP-TCC further demonstrates the extensive genetic heterogeneity of this condition.

We describe two siblings with childhood onset, slowly progressive generalized dystonia and cerebellar signs. Brain neuroimaging revealed white matter abnormalities compatible with a neuronal degenerative disorder. An extensive evaluation for mitochondrial, metabolic, autoimmune or other known neurodegenerative disorders did not reveal the etiology of the disease. During a three-year follow-up other neurological signs appeared, but progression was very slow. We believe that our patients have a new type of a leukoencephalopathy with slowly progressive dystonia and cerebellar signs.

Despite major recent advances in our understanding of developmental cerebellar disorders, classification and delineation of these disorders remains difficult. The term pontocerebellar hypoplasia is used when there is a structural defect, originating in utero of both pons and cerebellar hemispheres. The term olivopontocerebellar atrophy is used when the disorder starts later in life and the process is a primary degeneration of cerebellar neurons. Pontocerebellar hypoplasia type 1 is associated with spinal anterior horn cell degeneration, congenital contractures, microcephaly, polyhydramnion and respiratory insufficiency leading to early death. However, anterior horn cell degeneration has also been described in cases with later onset pontocerebellar atrophy and recently the spectrum has even been further extended to include the association of anterior horn cell degeneration and cerebellar atrophy without pontine involvement. We describe two siblings from a consanguineous Moslem Arabic family who presented with progressive degeneration of both the cerebellum and the anterior horn cells. The patients presented after 1 year of age with a slow neurodegenerative course that included both cognitive and motor functions. There is considerable phenotypic variability; the sister shows a much milder course. Both children are still alive at 6 and 9 years. The sister could still crawl and speak two word sentences at the age of 3 years while the brother was bedridden and only uttered guttural sounds at the same age. Our cases further extend the phenotype of the cerebellar syndromes with anterior horn cell involvement to include a childhood onset and protracted course and further prove that this neurodegenerative disorder may start in utero or later in life.

Objective To describe an 8 year old girl, with a new autosomal recessive syndrome presenting with severe dystonia and on MRI a unique pattern of infolded polymicrogyria. Methods An 8 year old girl is the product of consanguineous Arab-Moslem parents. Prenatal ultrasound demonstrated bilateral clubfeet. She achieved walking at the age of 5.5 years but has no speech. On examination she demonstrates:generalized dystonia, hypotonia with muscle wasting, clubfeet, and a a pseudobulbar syndrome with no expressive speech but good comprehension. Results MRI shows a unique pattern of bilateral infolded extensive perisylvian polymicrogyria. The findings are more prominent on the right side and do not resemble the classical patterns of polymicrogyria. Conclusion To date there is no description of this unique pattern of imaging of perisylvian polymicrogyria. The inheritance of classical bilateral perislvian polymicrogyria is mostly autosomal dominant and this syndrome is assumed to be autosomal recessive due to parental consanguinity. The severe movement disorder in our case has not been mentioned in other perisylvian syndromes.

Objective To describe 3 patients representing the wide phenotypic spectrum of TUBB4A-related disorders. Methods The setting: Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Israel. The subjects: Patient 1: An 8 year old girl with a classic clinical and radiologic picture of hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC). She presented with delayed motor development and gait instability by the end of her first year of life, followed by slowly progressive motor deterioration and extrapyramidal signs. She has mild intellectual disability and severe dysarthria. Her half-brother suffered from a similar disease and died in the second decade. Patient 2: A 3 year old girl with hypomyelination but without atrophy of the basal ganglia or cerebellum. Presented with congenital nystagmus, generalized dystonia, postnatal microcephaly and global developmental delay. Patient 3: A 9.5 year old boy with gait instability from the second year of life, followed by slowly progressive spastic paraparesis, segmental dystonia, mild intellectual disability, severe behavioral problems and regional hypomyelination with progressive cerebellar atrophy. Sequence analysis of the TUBB4A gene in the first patient's DNA and whole exome sequencing in the other 2 patients were performed. Results The first patient and her half-brother were found to carry the common D249N mutation known in H-ABC. Their mother is negative for the mutation, suggesting germline mosaicism. A novel de-novo mutation, V179L was found in the second patient and a de-novo E410K mutation was found in the third patient. Conclusions Mutations in the TUBB4A gene have been described in association with two main clinical phenotypes: childhood-onset hypomyelination with atrophy of the basal ganglia and cerebellum, and late-onset dystonia. Our cases demonstrate that the spectrum of TUBB4A-related disorders also includes: familial cases due to germline mosaicism, lack of cerebellar atrophy on neuroimaging, regional hypomyelination and a clinical phenotype consistent with complicated spastic paraparesis.

Objective To describe an atypical presentation of the Adenylosuccinate lyase (ADSL) deficiency syndrome. Methods A three year-old boy presented to our clinic because of intractable epilepsy. At the age of 10 months he had a single episode of status epilepticus. At the age of 16 months recurrent episodes of rapid semi-rhythmic jerking movements occurred, involving mostly the upper limbs and spreading homolaterally or contralaterally to other body parts. These attacks started without any apparent trigger, lasted up to a few hours, constantly disappeared during sleep and returned a few minutes after awakening. There was no change of consciousness or behavior. Some of the paroxysms were accompanied by dystonic limb or neck posturing. Ictal Electroencephalogram (EEG) did not show epileptic activity. Ictal surface Electromyography (EMG) demonstrated irregular bursts lasting less than 50 msec. with a frequency of 14 Hz. Results Whole exome sequencing revealed homozygous mutations in the ADSL gene. The diagnosis was confirmed by highly elevated urine succinyladenosine. Treatment with ketogenic diet significantly improved these paroxysmal attacks. Conclusion ADSL deficiency is a defect of purine metabolism. The disorder can present with a wide spectrum of symptoms. Epilepsy, usually intractable is the most constant feature. Our patient has a unique phenotype: only one unprovoked seizure and a paroxysmal movement disorder which is the most predominant feature.

Objective Paroxysmal tonic upward gaze was initially described as a benign phenomenon with negative investigations and eventual complete resolution of symptoms. Later publications demonstrated that a similar clinical picture may arise from structural brain lesions, channelopathies, neurotransmitter disorders, and epileptic seizures. CACNA1A related disorders manifest as a wide spectrum of paroxysmal neurological disorders: episodic ataxia 2, hemiplegic migraine, benign paroxysmal torticollis of infancy, and paroxysmal vertigo. Paroxysmal tonic upward gaze as a phenomenon in patients with mutations in the CACNA1A gene has only been reported once. Methods We describe three patients with multiple episodes of paroxysmal tonic upward gaze that appeared during the first months of life. In addition the patients demonstrated motor and language delay and cerebellar ataxia. A sequence analysis of the CACNA1A gene in one patient and whole exome sequencing in the other patients were performed. Results Sequence analysis of the CACNA1A gene in one patient and whole exome sequencing in the two other patients revealed 3 different de-novo mutations in the CACNA1A gene. Conclusion CACNA1A mutations should be evaluated in infants and young children with paroxysmal tonic upgaze especially if associated with developmental delay, cerebellar signs, and other types of paroxysmal events.