Manish Prasad

Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2

Childhood onset motor neuron diseases or neuronopathies are a clinically heterogeneous group of disorders. A particularly severe subgroup first described in 1894, and subsequently called Brown-Vialetto-Van Laere syndrome, is characterized by progressive pontobulbar palsy, sensorineural hearing loss and respiratory insufficiency. There has been no treatment for this progressive neurodegenerative disorder, which leads to respiratory failure and usually death during childhood. We recently reported the identification of SLC52A2, encoding riboflavin transporter RFVT2, as a new causative gene for Brown-Vialetto-Van Laere syndrome. We used both exome and Sanger sequencing to identify SLC52A2 mutations in patients presenting with cranial neuropathies and sensorimotor neuropathy with or without respiratory insufficiency. We undertook clinical, neurophysiological and biochemical characterization of patients with mutations in SLC52A2, functionally analysed the most prevalent mutations and initiated a regimen of high-dose oral riboflavin. We identified 18 patients from 13 families with compound heterozygous or homozygous mutations in SLC52A2. Affected individuals share a core phenotype of rapidly progressive axonal sensorimotor neuropathy (manifesting with sensory ataxia, severe weakness of the upper limbs and axial muscles with distinctly preserved strength of the lower limbs), hearing loss, optic atrophy and respiratory insufficiency. We demonstrate that SLC52A2 mutations cause reduced riboflavin uptake and reduced riboflavin transporter protein expression, and we report the response to high-dose oral riboflavin therapy in patients with SLC52A2 mutations, including significant and sustained clinical and biochemical improvements in two patients and preliminary clinical response data in 13 patients with associated biochemical improvements in 10 patients. The clinical and biochemical responses of this SLC52A2-specific cohort suggest that riboflavin supplementation can ameliorate the progression of this neurodegenerative condition, particularly when initiated soon after the onset of symptoms.

Acute motor neuropathy with pure distal involvement – A case report of multifocal motor neuropathy

Multifocal motor neuropathy is an acquired pure motor neuropathy seen principally in adults and usually responds to treatment with intravenous immunoglobulin. We report a 12 year old boy with marked distal weakness in both upper and lower limbs with no proximal involvement. These clinical features appear to be distinct from more common inflammatory childhood neuropathies and are in keeping with a diagnosis of Multifocal Motor Neuropathy. Confirming the diagnosis, serial nerve conduction studies showed a pattern of pure motor conduction block with normal sensory potentials. To our knowledge this is only the second case report of this condition occurring in childhood.

Glutaric Aciduria Type II Presenting as Myopathy and Rhabdomyolysis in a Teenager

Late-onset glutaric aciduria type II has been described recently as a rare but treatable cause of proximal myopathy in teenagers and adults. It is an autosomal recessive disease affecting fatty acid, amino acid, and choline metabolism. This is usually a result of 2 defective flavoproteins: either electron transfer flavoprotein (ETF) or electron transfer flavoprotein–ubiquinone oxidoreductase (ETF:QO). We present a 14-year-old boy with a background of autistic spectrum disorder who presented with severe muscle weakness and significant rhabdomyolysis. Before the onset of muscle weakness, he was very active but was completely bedridden at presentation. Diagnosis was established quickly by urine organic acid and plasma acylcarnitine analysis. He has shown significant improvement after starting oral riboflavin supplementation and is now fully mobile. This case highlights that late-onset glutaric aciduria type II is an important differential diagnosis to consider in teenagers presenting with proximal myopathy and rhabdomyolysis and it may not be associated with hypoglycemia.

A Startling Case of Neonatal Hyperekplexia Responsive to Levetiracetam: A New Alternative in Management?

The authors report a case of hyperekplexia presenting in the neonatal period resistant to clonazepam that responded subsequently to levetiracetam. Hyperekplexia is often misdiagnosed as epilepsy and can be difficult to manage with a particular concern over neonatal apnea and an increased risk of sudden infant death syndrome. The mainstay of therapy to date has been with clonazepam. The authors describe the salient features of their case, clinical diagnosis, and issues pertaining to management. The authors believe this is the first reported case of the use of levetiracetam for effectively treating hyperekplexia within the neonatal and infant period.

Neonatal seizure: what is the cause?

A 7 day old girl presented with a one day history of decreased feeding, lethargy, and shaking of her extremities. She was born at term by normal vaginal delivery. She did not have a fever and there were no maternal risk factors for sepsis. She was hypotonic and minimally responsive on examination, with no signs of focal neurology. Urea, electrolytes, calcium, and glucose values were normal. She was started empirically on intravenous antibiotics and aciclovir after full septic screen. She was ventilated and given an infusion of midazolam because her generalised clonic seizures with apnoea failed to respond to intravenous phenobarbital. Her seizures finally responded and she was extubated after 24 hours; she was maintained on regular phenobarbital with good effect. Urgent neuroimaging (figs 1⇓ and 2⇓) was arranged because of her acute presentation with seizures and a history of deep vein thrombosis and pulmonary embolism in her mother and maternal uncle. Fig 1 Sagittal T1 weighted magnetic resonance image of the brain Fig 2 Axial T1 weighted magnetic resonance image of the brain ### 1 What are the causes of seizures in a neonate? #### Short answer Common causes of neonatal seizures include hypoxic ischaemic encephalopathy, intracranial haemorrhage, intracranial infections, congenital cerebral malformations, metabolic disorders, and focal ischaemic stroke. #### Long answer Seizures are more common in the neonatal period than in any other time of life, with 80% occurring in the first week of life. This is because the immature …

Atypical presentation of Chiari I malformation with monoplegia and acquired torticollis

There are several well-known causes for pediatric torticollis. However detailed review of the literature revealed only rarely association of torticollis with syringomyelia. We present a 4-year-old girl known to have torticollis since 18 months of age who presented acutely with right upper limb mono-paresis. Investigations revealed a Chiari type I malformation with extensive syringomyelia involving the whole of spinal cord extending from C1 to the conus. She responded very well to urgent posterior fossa decompression. Syringomyelia involving the entire spinal cord is very rare in children and presentation with monoplegia, to the best of our knowledge, has not been described before. We recommend that torticollis should always be taken seriously and a thorough clinical assessment supplemented by neuroimaging should be considered.

A child with hemicrania continua phenotype responsive to botulinum toxin type-A

Our aim is to describe the difficulties in the diagnosis and treatment of a child with continuous unilateral headache. We present the case of a 12-year-old child who had a two year history of continuous dull pain behind the right ear with frequent episodes of severe sharp pain as well as ipsilateral color change on the cheek. We assess the role of international classification of headache disorders in establishing the diagnosis and we assess the treatment options. The international classification of headache disorders criteria for the diagnosis of hemicrania continua are, based on experience with adults and may not be adequate in children. The child had a very poor quality of life due to his illness and failed to respond to indomethacin among many other medications. However, he responded well to treatment with botulinum toxin type-A on two occasions. Childhood hemicrania continua may have a different phenotype than that in adults. Botulinum toxin type-A may be an option for treatment in some patients.

Recurrent encephalopathy? No I'm a sleeping beauty!

To describe the clinical presentation of ‘Kleine-Levin (sleeping beauty) syndrome’ in a child, who presented with recurrent episodes consistent with encephalopathy, associated with excessive sleepiness, cognitive and behavioural disturbance and hyper sexuality. 14 years old boy presented acutely with excessive tiredness, sleeping excessively, abnormal behaviour and hypersexuality following a viral throat infection. On examination he was sleepy but easily arousable. His GCS (15/15) and rest of the neurological examination including fundoscopy and other systemic examination was completely unremarkable. All his initial investigations including electrolytes, LFTs, CSF, virology screen and MRI brain scan were normal. Detailed autoimmune screening was also negative. EEG showed non-specific diffuse slowing consistent with encephalopathy. His excessive sleepiness gradually improved together with his altered behaviour in about two weeks after presentation. Hyper sexuality became more overt during this phase. All these symptoms completely disappeared three weeks after his presentation and he attended school as before. He was readmitted six weeks later with exactly similar presentation and again only positive result being diffuse non-specific slowing of EEG. His recovery was also similar and he was completely back to his normal self in three weeks time. His recurrent symptoms were consistent with ‘Kleine-Levin syndrome (KLS)’ or ‘sleeping beauty syndrome’. KLS is a rare disorder which mainly affects adolescent males. Common symptoms include hypersomnia (100%), cognitive changes (96%), eating disturbances (80%), hypersexuality, compulsions, and depressed mood. The syndrome usually lasts for 8 years, with on an average seven episode of 10 days each recurring every 3.5 months. It is most frequently precipitated by infections and somnolence decreases using stimulants in nearly 40% of cases.

The Calm before the Storm: Late Onset Glycine Encephalopathy Masquerading as Gastro-oesophageal Reflux

Glycine encephalopathy also known as ‘Nonketotic Hyperglycinemia (NKH)’ is an autosomal recessive disorder caused by a defect in the glycine cleavage enzyme complex (GCS). The classic neonatal form typically presents with generalised hypotonia, lethargy, seizures, apnoeas and usually death by one year of age. In this report, we describe an unusual presentation of an infantile onset glycine encephalopathy presenting at 8 weeks of age with symptoms suggestive of gastro-oesophageal reflux (GOR) episodes. A normal neonatal developmental course in the first few months of life is the exception in this phenotype and has been rarely described in the literature. To the best of our knowledge this is the first case of glycine encephalopathy reported with initial symptoms suggestive of GOR.

Pediatric sciatic neuropathy presenting as painful leg: A case report and review of literature

Introduction: Mononeuropathies, in general, are very uncommon in childhood. Sciatic neuropathy (SN) is probably underappreciated in childhood and likely to represent nearly one quarter of childhood mononeuropathies. Materials and Methods: We present a 7-year-old girl who presented with painful right lower limb and abnormal gait. Detailed investigation revealed transient eosinophilia, abnormal neurophysiology, and magnetic resonance imaging (MRI) suggestive of isolated sciatic neuropathy. Results: She has responded very well to physiotherapy and has made a complete motor recovery, although she is left with an area of abnormal sensation affecting the lateral border of her right leg and the dorsum of her foot. Discussion: Differential diagnoses for pediatric SN have been discussed including compressive neuropathies in children and various hyper-eosinophilia syndromes. Compressive neuropathies in childhood are very rare and compression of the sciatic nerve is the second most common group after peroneal nerve lesion.