A Novel GEMIN4 Variant in a Consanguineous Family Leads to Neurodevelopmental Impairment with Severe Microcephaly, Spastic Quadriplegia, Epilepsy, and Cataracts

Pathogenic variants in GEMIN4 contribute to a hereditary disorder characterized by neurodevelopmental features, microcephaly, cataracts, and renal abnormalities (known as NEDMCR). To date, only two homoallelic variations have been linked to the disease. Moreover, clinical features associated with the variants have not been fully elucidated yet. Here, we identified a novel variant in GEMIN4 (NM_015721:exon2:c.440A>G:p.His147Arg) in two siblings from a consanguineous Saudi family by using whole exome sequencing followed by Sanger sequence verification. We comprehensively investigated the patients’ clinical features, including brain imaging and electroencephalogram findings, and compared their phenotypic characteristics with those of previously reported cases. In silico prediction and structural modeling support that the p.His147Arg variant is pathogenic.

MANAGEMENT OF SPASTIC QUADRIPLEGIA (SARVANGGHAT) WITH VATKULANTAK RASA & SHASHTIKA SHALI PINDA SWEDA - A CASE STUDY

Background- Spastic Quadriplegia also known as spastic tetraplegia is a subset of Spastic cerebral palsy that af- fects all four limbs (both arms and legs). Spastic quadriplegia usually displays equal involvement of both upper and lower extremities with severe involvement of legs, arms and floppiness of neck. Spastic quadriplegia is gen- erally caused by brain damage either before birth, during or shortly after. In Ayurveda quadriplegia can be corre- lated with Sarvangghat which is a vatavyadhi. It is a nanatmaja vatavyadhi according to charaka. As the disease was caused by vata-kapha dosha. The treatment is mainly aimed at mitigating vata kapha dosha which helps to clear the blocked micro-channels involved in the pathology. Aim and objective- To study the effect of Vatkulan- taka rasa and Shashtika shali pinda sweda in the management of Spastic quadriplegia (Sarvangghat). Material and methods-The present case study is upon 16 years old (male patient) diagnosed case of spastic quadriplegia with complaints of difficulty in walking with stiffness for 6 years at the kayachikitsa IPD of Pt. khushilal Sharma govt. ayurvedic hospital Bhopal. He was treated with shashtika shali pind sweda & Vatkulantaka rasa. The dura- tion of the study is 21 days. The assessment was done on the basis of symptomatic relief after treatment. Observation- The Ayurvedic therapy and oral medication yielded complete symptomatic relief from pain, stiffness and improve quality of life. Conclusion- On the basis of the result obtained, it can be concluded that Shashtika shali pinda sweda and Vatku- lantaka rasa can be used as an effective treatment in the management of Spastic quadriplegia (Sarvangghat). Keywords: Sarvangghat, Spastic quadriplegia, Shashtika shali pinda sweda, Vatkulantaka rasa.

Liver, Renal, and Cardiovascular Failure After Unintentional Overdose of Tizanidine in a 2-Year-Old Child

Tizanidine is a central alpha-2 adrenergic receptor agonist indicated for the treatment of spasticity in adults; however, its use in the pediatric population is considered off-label. In adults, the dose is gradually titrated until the desired reduction in muscle tone is achieved. Hypotension is a frequent adverse effect, but impaired liver function is not characteristic of alpha-2 adrenergic agonist overdose. We report a 2-year-old male affected with spastic quadriplegia (treated with clonazepam and tizanidine) and dysphagia (he was fed by nasogastric tube). Two days before admission caregivers ran out of clonazepam so they increased the tizanidine dose from 0.15 mg/kg/day to 1.6 mg/kg/day. Simultaneously his nasogastric tube fell out; therefore, he was unable to maintain proper oral nutrition and hydration. He presented to the emergency department hemodynamically unstable, with impaired consciousness and signs of severe dehydration. Blood tests revealed hepatic dysfunction without cholestasis and renal dysfunction. He was transferred to the pediatric intensive care unit. Treatment was mainly supportive, apart from tizanidine discontinuation. Metabolic and infectious diseases were ruled out so he was finally diagnosed as having liver, renal, and cardiovascular failure after tizanidine overdose, worsened by dehydration. His clinical status improved, and after 3 weeks he was discharged from the hospital, receiving clonidine instead of tizanidine to treat spasticity. Tizanidine overdose can result in serious complications that can be worsened because of patient comorbidities.

Sleep disorders and associated factors in children with cerebral palsy

Background Sleep disorders are a condition affecting quality and quantity of sleep. Children with cerebral palsy (CP) have higher risk of sleep disorders than those with no chronic disease. Objective To determine the prevalence and factors associated with sleep disorders in children with CP. Methods We conducted an analytic, observational study with cross-sectional design in children aged 4-10 years with CP. Subjects were recruited consecutively; children with chronic diseases (cardiovascular, malignancy, chronic obstructive pulmonary disease, and diabetes mellitus) were excluded from the study. Primary data including sociodemographics, intensity of physiotherapy outside Sardjito General Hospital (SGH), sleep hygiene, and sleep disorders were collected from the Children’s Sleep Habit Questionnaire (CSHQ). Secondary data were acquired from medical records, such as type of CP, severity of motor function impairment, presence of epilepsy, intensity of physiotherapy performed at SGH, as well as anti-epileptic, anti-spastic, and sleep-affecting medicines. Results We found sleep disorders in 64 of 75 (85%) subjects, mostly bedtime resistance (66%). Spastic quadriplegia (OR=3.63; 95%CI 1.82 to15.94) and presence of epilepsy (OR=7.82; 95%CI 1.53 to 39.84) were significantly associated with sleep disorders in children with CP aged 4-10 years. Conclusion Sleep disorders are common in children with CP, with the majority experiencing bedtime resistance. Sleep disorders are more prevalent in subjects with spastic quadriplegia and epilepsy.

Congenital cytomegalovirus infection presenting as cerebral palsy

A 9 month old boy presented with history of delayed attainment of milestones. He was born to a primigravida mother, with an uneventful perinatal period, but had a low birth weight (2.1 kg) for gestational age. There was no history of seizures, abnormal movements, loss of previously gained milestones or prior sibling deaths. On examination, he had severe microcephaly, failure to thrive and hepatosplenomegaly. Neurological examination revealed severe axial hypotonia and spastic quadriplegia with brisk deep tendon reflexes and intermittent scissoring of lower limbs. Fundus examination and hearing evaluation were normal. His current developmental age was 4 months and developmental quotient was 30.

Ocular defect in children with cerebral palsy and its correlation with the types of cerebral palsy

Background: Cerebral palsy (CP) describes a group of permanent disorder of the development of movement and posture, causing activity limitation, that are attributed to non-progressive disturbance that occurred in the developing fetal or infant brain. The motor disorders of cerebral palsy are often accompanied by disturbances of sensation, perception, cognition, communication and behavior, by epilepsy, and secondary musculoskeletal problem. However, no known study has been found on this aspect. Objective of this study was to evaluate the ocular defect in children with cerebral palsy and to correlate with the types of CP.Methods: Study was done in the Paediatric Neurology unit of BSMMU from January 2012 to July 2012. One hundred thirty children with cerebral palsy were studied. The patients were randomly selected who full filled the inclusion criteria and ophthalmological examination was done.Results: Sixty four (64%) of CP patients had pathological finding and 36% percent had normal finding. Most of the abnormalities were squint (strabismus) (40%) and refractive error (36.9%). Most of the ocular defects were found in spastic cerebral palsy, mainly in spastic quadriplegia (34.6%) and spastic diplegia (29.2%).Conclusions: Ocular defect like squint and refractive error common associations of cerebral palsy. Spastic quadriplegic and diplegic children had more ocular defects.

Neuroradiologic Features Associated With Severe Restriction of Functional Mobility in Children With Cerebral Palsy in North India

Background: Few studies have focused on magnetic resonance imaging (MRI) brain findings associated with functional mobility in cerebral palsy. Objective: To determine association between MRI findings and Gross Motor Functional Classification System (GMFCS) levels in cerebral palsy. Methods: Prospective-observational study conducted in Pediatric Neurology Clinic at a public teaching hospital, Northern India. First 3 new cases of cerebral palsy were enrolled on particular neuro-clinic day per week for 1 year. Functional mobility was classified according to GMFCS. Association between MRI findings, cerebral palsy type, and GMFCS levels were evaluated using χ2 test. Results: A total of 138 cases (mean age 2.71 [SD = 1.91] years; male [64.5%]) were enrolled. Reported types of cerebral palsy were as follows: spastic quadriplegia (47.8%), spastic diplegia (28.35%), spastic hemiplegia (11.6%), extrapyramidal (6.5%), and ataxic/hypotonic (5.8%). GMFCS were classified into level 1 (13%), level 2 (7.2%), level 3 (4.3%), level 4 (10.9%), and level 5 (64.5%). Spastic quadriplegia and extrapyramidal cerebral palsy were significantly associated with higher (severe) levels (IV and V), whereas spastic diplegia and hemiplegia were significantly associated with lower (mild) levels (I-III) of GMFCS. MRI features of periventricular white matter injury, deep gray matter injury, basal ganglia and thalamic changes, and superficial gray matter injury were significantly associated with severe levels of GMFCS (V and IV). MRI was normal in 8 children (5 = mild category, 3 = severe category). Conclusion: Severe cerebral palsy is most often associated with spastic quadriplegia, extrapyramidal cerebral palsy, superficial gray matter lesions, deep gray matter lesions, and periventricular white matter injury. This information is useful for anticipating and addressing the needs of children with cerebral palsy and for prognostication.

Biallelic Variants in the COLGALT1 Gene Causes Severe Congenital Porencephaly

ObjectiveWe describe a third patient with brain small vessel disease 3 (BSVD3), being the first with a homozygous essential splice site variant in the COLGALT1 gene, with a more severe phenotype than the 2 children reported earlier.MethodsAnalysis of whole exome sequencing (WES) data of the child and parents was performed. We validated the missplicing of the homozygous variant using reverse transcription PCR and Sanger sequencing of the mRNA in a lymphocyte culture.ResultsThe patient presented antenatally with porencephaly on ultrasound and MRI. Postnatally, he showed a severe developmental delay, refractory epilepsy, spastic quadriplegia, and a progressive hydrocephalus. WES revealed a homozygous canonical splice site variant NM_024656.3:c.625-2A>C. PCR and Sanger sequencing of the mRNA demonstrated that 2 cryptic splice sites are activated, causing a frameshift in the major transcript and in-frame deletion in a minor transcript.ConclusionsWe report a third patient with biallelic pathogenic variants in COLGALT1, confirming the role of this gene in autosomal recessive BSVD3.

Two Italian Patients with ELOVL4-Related Neuro-Ichthyosis: Expanding the Genotypic and Phenotypic Spectrum and Ultrastructural Characterization

Elongation of Very Long Chain Fatty Acid-4 (ELOVL4) is a fatty acid elongase responsible for very long-chain fatty acid biosynthesis in the brain, retina, and skin. Heterozygous mutations in ELOVL4 gene cause Stargardt-like macular dystrophy and spinocerebellar ataxia type-34, while different homozygous mutations have been associated with ichthyosis, spastic quadriplegia, and mental retardation syndrome in three kindred. We report the first two Italian children affected with neuro-ichthyosis due to the previously undescribed ELOVL4 homozygous frameshift variant c.435dupT (p.Ile146TyrfsTer29), and compound heterozygous variants c.208C>T (p.Arg70Ter) and c.487T>C (p.Cys163Arg), respectively. Both patients were born with collodion membrane followed by development of diffuse mild hyperkeratosis and scaling, localized erythema, and palmoplantar keratoderma. One infant displayed mild facial dysmorphism. They suffered from failure to thrive, and severe gastro-esophageal reflux with pulmonary aspiration. The patients presented axial hypotonia, hypertonia of limbs, and absent head control with poor eye contact from infancy. Visual evoked potentials showed markedly increased latency and poor morphological definition, indicative of alteration of the retro-retinal visual pathways in both patients. Ultrastructural skin examination revealed abnormalities of lamellar bodies with altered release in the epidermal granular and horny layer intracellular spaces. Our findings contribute to expanding the phenotypic and genotypic features of ELOVL4-related neuro-ichthyosis.