Jyotindra Narayan Goswami

Siblings with L2 Hydroxy Glutaric Aciduria

Two male siblings aged 9 and 16 y born to nonconsanguineous Punjabi parents, presented with complaints of infantile-onset developmental delay and progressively increasing limb tremulousness. On examination, both children had moderate intellectual impairment and macrocephaly (Head circumferences: 58 cm and 57.5 cm respectively) along with action-exacerbated limb tremulousness (upper >lower). Their neuroimaging revealed signature features of L2 Hydroxy glutaric aciduria (Figs. 1 and 2). Urinary Gas Chromatography Mass Spectroscopy (GC-MS) of both children displayed grossly elevated 2 Hydroxy glutaric acid levels. Targeted gene sequencing performed in the younger

Unusual Neuroimaging Finding in Infantile Tay-Sach’s Disease

To the Editor: Tay-Sach’s disease is a lysosomal storage disorder characterized by signature neuroimaging pattern of bilaterally symmetrical thalamic hypointensities and late symmetrical white matter involvement [1]. We report an infant with Tay-Sach’s disease with atypical neuroimaging findings to sensitize readers about the same. The case portrays the role of clinical suspicion in justifying early enzymatic investigations for diagnosing this entity in the face of atypical neuroimaging. A 2-y-old boy, born to third degree consanguineous parents, presented with regression of milestones following a trivial diarrheal episode at 7mo. Simultaneously he started having multiple daily episodes of brief focal seizures and excessive startle. On examination, his weight was 10 kg (0 to −2 SD); head circumference: 46 cm (Between 0 to -1SD) and length: 84 cm (0 to +2SD). He was apathetic and did not have neck control and mother recognition or fixing/following. Fundoscopy revealed bilateral cherry red spots. The child had spastic quadriparesis, exaggerated deep tendon reflexes and extensor plantars. Examination of his abdomen, respiratory and cardiovascular sytems were unremarkable. The MRI brain showed asymmetric basal ganglionic (left > right) lesions with left caudate/left putaminal hyperintensities, hyperintense external capsule/ claustrum, deep periventricular and cerebellar white matter and midbrain hyperintensity (Fig. 1). The leucocyte and plasma hexosaminidaseA levels using 4MU β-D-N acetyl glucosaminide-6-sulfate were 1.43 nmol/h/mg (normal: 74-284 nmol/h/mg) and 0.21 nmol/h/ml (normal: 20-96.5 nmol/h/mg) respectively, confirming the diagnosis of Tay-Sach’s disease. The child was given supportive care and parents were counseled regarding prenatal diagnosis. The child succumbed to illness 6 mo after the diagnosis and a repeat neuroimaging could not be performed. Prominent involvement of bilateral external capsule/ claustrum and midbrain hyperintensity along with asymmetric basal ganglionic lesion, as seen in the index case is rarely reported in Tay-Sach’s disease [2, 3]. Though underlying pathogenetic mechanism is unclear, extensive accumulation of GM2 gangliosides could have possibly led to this multifocal pattern of involvement. Hayase et al. reported a case of Tay-Sach’s disease with frequent focal seizures and early symmetrical involvement progressing to an asymmetrical one, which was hypothesized to arise from asymmetrical hemispheric excitotoxicity similar to the pathogenesis of hemiconvulsion-hemiplegia-epilepsy syndrome [2]. Our patient too had focal seizures and was imaged late into his illness. This can possibly explain the atypical neuroimaging in our child. * Pratibha Singhi doctorpratibhasinghi@gmail.com

Spinal Muscular Atrophy with Preserved Deep Tendon Reflexes

To the Editor: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder in which there is areflexia [1]. We report an atypical case of a child with SMA and preserved deep tendon reflexes. A 6-y-old boy presented with progressively increasing walking difficulty from five years of age. At presentation, he could not walk briskly, climb upstairs or get up from sitting position unaided. He did not have slippage of slippers, upper limb weakness, tingling/numbness, tremor, ataxia, bladder/bowel symptoms. His anthropometry, vital parameters, skull/spine, higher-mental functions, speech, cranial nerves and tone were normal. He had bilaterally reduced power of hip-flexion and extension (Grade III/V). Power across other joints was normal. He had brisk ankle jerks, ill-sustained clonus and paraspinal fasciculations. Other deep tendon jerks were normally elicitable. Plantars were flexor. There were no tongue-fasciculations or acral-tremors. Examination of sensory, cerebellar, autonomic functions and other systems was unremarkable. His creatine phosphokinase, thyroid function test, spinal MRI and nerve conduction study were normal. Electromyography revealed fasciculations and fibrillations in vastus lateralis and first dorsal interosseus. Hence, gene mutation analysis for Survival Motor Neuron 1 (SMN 1) was obtainedwhich revealed exon-7 deletion from both copies of SMN 1 gene establishing diagnosis of SMA. Child was started on physiotherapy. Follow-up after six months revealed generalized areflexia with static functional status. Muscular weakness, areflexia and fasciculations are hallmarks of SMA [2]. Brisk tendon reflexes posed major diagnostic dilemma in index child. Hence, muscle/ spinal cord pathology were initially excluded. Literature search did not reveal any instance of SMA with preserved reflexes. We hypothesize that the child presented when partial anterior horn cell function was present. Later, he developed areflexia with progressive anterior horn cell degeneration. Our case attempts to sensitize pediatricians about the rare possibility of preserved reflexes in SMA early in its temporal course. Clinical follow-up, electrophysiology and genetic testing help in this scenario.

Myasthenia Gravis in HIV Positive Girl

To the Editor: Myasthenia gravis (MG) is an autoimmune disorder of neuromuscular transmission [1]. MG in association with HIV infection is rare [2–4]. We discuss a 5-y-old girl with perinatally acquired HIV infection developing MG, and highlight challenges faced in her management. A 5-y-old girl presented with history of bilateral fluctuating ptosis from five months. Consultation was sought after she developed dysarthria, dysphagia, and bulbar weakness for the past 2 wk. Other than myasthenia she was asymptomatic and was not on combination antiretroviral therapy (cART). On examination she had bilateral ptosis, external ophthalmoplegia, bulbar and proximal muscle weakness. In view of her oculo-bulbar symptoms, the differentials considered were, myasthenia gravis, or a space occupying or inflammatory lesion of the brain stem. The repetitive nerve stimulation test (RNST) at 3 Hz frequency at left abductor digiti minimi showed a decrimental response of 31% (Fig. 1, normal <10%). She had prompt reversal of ptosis and improvement in speech after intramuscular neostigmine challenge test establishing the diagnosis of MG; however, serum anti-acetylcholine receptor (AChR) antibodies were negative. Her CD4+ T cell counts were 1289/μL and CD3+ T cell counts were 2010/μL. She was treated with oral pyridostigmine and prednisolone (2 mg/kg/d) and her symptoms subsided. After 6 wk, on tapering prednisolone she had recurrence of symptoms hence she required hiking dosage. She was initiated on cART (zidovudine, lamivudine, and nevirapine) because of decline in CD4+ T cell counts (516/μL) after initiation of steroid therapy. She remained well during follow-up; gradually she was weaned from steroids and pyridostigmine. At the last follow-up, 2 y after the diagnosis of MG, she remained in clinical remission; with normal CD4+ T cell counts on cART. The initiation, choice of drug, dosage and monitoring of therapeutic immune suppression in a HIV-positive child with MG is challenging. MG associated with HIV infection is very rare and even rarer in pediatric age [2–5].We came across <20 adult patients with MG in association with HIV [2–4]. Myasthenia gravis (MG) is an autoimmune disorder of neuromuscular transmission. In MG the immune system is activated against skeletal muscle AChR or the muscle specific tyrosine kinase receptor (MuSK) located at the postsynaptic membrane. Anti-AChR antibodies bind to the neuromuscular junction, activate complement and accelerate AChR destruction, causing failure of neuromuscular transmission and the resulting myasthenic symptoms. A disturbed T-cell homeostasis in HIV leads to immune dysregulation and predisposes to autoimmune conditions. Though the exact pathogenesis remains unclear, auto reactive AChR-specific CD4+ T cells may play an important role. Through interactions with B cells these CD4 + T cells lead to formation of anti-AChR antibodies. Patients with HIV with MG have been reported to have anti-AChR or anti-MuSK antibodies [2]. Existing literature suggest that myasthenic symptoms in patients with HIV tend to improve with progressive immunosupression with decline in the immune status, with a reduction in CD4+ T cell count, T-cells responses to alloantigens, and anti-AChR antibody titers [4]. However, in the index child a progressive decline in CD4+ T cell counts accompanied a clinical relapse of MG. We achieved further remission by increasing the steroid dose * Pratibha Singhi doctorpratibhasinghi@gmail.com

Angelman Syndrome Due to UBE3A Gene Mutation

A 12-y-old boy presented with developmental delay, autism, epilepsy, limb tremors and behavioral problems which posed a diagnostic challenge. Though his clinical profile and electroencephalogram were suggestive of Angelman syndrome, initial genetic tests were unyielding. Exome sequencing revealed a previously unreported mutation of Ubiquitin Protein Ligase E3A (UBE3A) gene, confirming the diagnosis of Angelman syndrome. The case is aimed to sensitize pediatricians about Angelman syndrome and to highlight the role of sequential investigations in establishing the diagnosis.

Dolichoectasia of the anterior cerebral arteries: a rare cause of headache in a young child

Dear Editor: Dolichoectasia of intracranial arteries is a vascular anomaly, which is characterized by dilated, fusiform elongation of vessels. Dolichoectasia of the anterior cerebral artery (ACA) is rarely reported in pediatric population. Here, we report a case of dolichoectasia of bilateral ACA in an 8-year-old child and in our best knowledge; this is the youngest case with isolated ectasia of bilateral ACA in the literature. An 8-year-old boy presented with history of recurrent headache since the last 3 months. He reported one to two episodes of headache per week. It was sudden, maximum at onset, throbbing in nature, bifrontal in location, and mild tomoderate in severity and lasted for 5 to 30 min and occurs mostly in morning hours. It was nonprogressive in nature, had no relation with sleep, not associated with restricted activity, aggravated by sudden standing up, and subsided usually by its own but sometimes analgesic medicines were required. There was no history of giddiness, cranial nerve involvement, focal deficit, seizures, nausea, vomiting, fever, visual impairment, photophobia, phonophobia, tinnitus, ear discharge, palpitation, trauma, and recurrent upper respiratory symptoms. On examination, he had a faint continuous bruit over bilateral orbital region. Rest of the examination was within normal limits. Based on the history and clinical examination, a possibility of an intracranial vascular malformation was suspected. Magnetic resonance imaging (MRI) of brain was done which showed bunch of serpiginous flow voids in the anterior interhemispheric fissure (Fig. 1a). The magnetic resonance angiography (MRA) (Fig. 1b, c) of intracranial vessels showed hypertrophied bilateral anterior cerebral arteries (ACA). The digital subtraction angiography (DSA) also showed hypertrophied bilateral ACA (A2 segment) (Fig. 2a– f), and it was consisted with dolichoectasia of the anterior cerebral arteries. Parents were counseled about the nature of the condition, and symptomatic treatment in form of analgesics was given to the child. Dolichoectasia of intracranial arteries is characterized by dilated, tortuous, elongation of the arteries at the base of the brain. In the general population, incidence of this condition ranges from 0.06 to 5.8% [1]. Although the middle and anterior cerebral arteries can be involved but dolichoectasia is most frequently encountered in vertebrobasilar arterial system [2]. The clinical manifestation of this condition depends upon the affected arteries and associated direct compression of the intracranial structures or vascular infarcts. ACA dolichoectasia usually presents with visual field defects, seizures, psychiatric manifestations, headache, and rarely with subarachnoid hemorrhage. Middle cerebral artery involvement may present with stroke, focal deficit, and headache. Headache, seizures, stroke, ataxia, hydrocephalus, and lower cranial nerve palsies are the usual manifestation of vertebrobasilar involvement [2]. Dolichoectasia is usually found in adult population and it is rarely present in children. Doran et al. [3] reported isolated dolichoectasia of the bilateral anterior cerebral arteries in a 14year-old adolescent girl who presented with complex partial seizures. The etiology of this condition may be acquired or congenital. The acquired cases are usually found in adults with atherosclerosis, diabetes mellitus, hypertension, coronary artery disease, and dyslipidemia. In children, it is usually congenital or rarely associated with other conditions like human immune deficiency virus, Marfan syndrome, polycystic disease of kidney, and some syndromic association [4]. Previous reports described associated calcification and anomalies of * Naveen Sankhyan drnsankhyan@yahoo.co.in

Drug reaction with eosinophilia and systemic symptoms in a child on multiple antiepileptics

Goswami JN, Vaidya PC, Saini AG, De D, Radotra BD, Singhi PD. Drug reaction with eosinophilia and systemic symptoms in a child on multiple antiepileptics. Turk J Pediatr 2017; 59: 197-199. Drug reaction with eosinophilia and systemic symptoms (DRESS) is an adverse drug-reaction that may mimic systemic illnesses and have a fulminant presentation. We describe an 8-year-old girl with epilepsy and exposure to multiple anti-epileptics who presented with fever, extensive maculopapular rash, cervical lymphadenopathy, hepatomegaly, progressive anemia and transaminitis. Infections, autoimmune disorders and hematological or reticuloendothelial malignancies were excluded. Based on the proposed diagnostic criteria, a diagnosis of DRESS was concluded. Her skin biopsy showed atypical findings consistent with erythema multiforme. Suspected anti-epileptic drugs were discontinued. She was administered pulse methyl-prednisolone therapy and broad-spectrum antibiotics along with adequate supportive management. Unfortunately, the child succumbed to nosocomial sepsis. Our case highlights the importance of early suspicion for diagnosis of pediatric DRESS, avoidance of polytherapy and institution of early immunomodulation to improve the outcomes in children in this condition.

An Indian family with tyrosine hydroxylase deficiency

BackgroundTyrosine Hydroxylase deficiency is a rare neurotransmitter disorder.Case CharacteristicsAn Indian family with the disorder.ObservationPhenotypic variation, elevated serum prolactin, genetic confirmation, and partial treatment-responsiveness.MessagesTyrosine Hydroxylase deficiency is a treatable inborn error of metabolism and serum prolactin assists in diagnosis.

Probable Moyamoya Syndrome in Association with Hemophilia A in an Infant

To the Editor: A 6-mo-old boy developed acute-onset fever, drowsiness, right focal seizures followed by right hemiparesis. On examination, he had ecchymotic patches at puncture sites, mild pallor, normal sensorium, right hemiparesis, bilateral brisk muscle stretch reflexes and extensor plantar response. Rest of the neurological and systemic examination was non-contributory. An underlying bleeding diathesis was considered. Coagulogram showed isolated prolonged aPTT (58 s) and normal prothrombin time, prothrombin index, international normalized ratio, fibrinogen and negative D-dimer in blood. Hemoglobin was 89 g/L and platelet count was 440,000 cells/μL. Factor VIII assay showed 1 % activity (normal 60-160 %). Magnetic resonance imaging (MRI) of brain showed left-sided ischemic infarct and moya-moya vessels (Fig. 1). Peripheral blood film examination, fasting blood sugar, serum electrolytes, renal and liver functions, calcium, lipid profile, ammonia and arterial lactate, hemoglobin electrophoresis, complement levels and titers of anti-nuclear antibodies, echocardiography and doppler ultrasonography of neck vessels was normal. Protein C, antithrombin III, factor V Leiden mutation and anticardiolipin antibodies were normal. He received fresh frozen plasma and cryoprecipitate for 5 d and was referred for neurosurgical revascularization. At last follow-up at 18 mo of age, the child has no hemiparesis, is gaining milestones with no recurrence of seizures or fresh deficits and revascularization procedure is awaited. Common mechanisms of ischemic strokes in hemophilia are thromboses associated with cryoprecipitate infusion, factor VIII concentrate and factor V Leiden mutation [1, 2]. Moyamoya syndrome, as the cause of ischemic stroke in hemophilia, has been anecdotally described before in a 10-y-old boy with hemophilia A [3]. A recent genetic predisposition to moyamoya syndrome and ischemic strokes in severe hemophilia A (SHAM syndrome) has been proposed due to large Xq28 deletions encompassing F8 (causing hemophilia) and BRCC3 (causing moyamoya) genes [4, 5]. However, the additional features of this syndrome (facial dysmorph i sm , endoc r i nopa thy, sho r t s t a t u r e , hypergonadotrophic hypogonadism, premature greying hair, hypertension and osteopenia) were not yet seen in the index patient. Genetic testing is not currently available at our center. Beneficial role of revascularization * Pratibha Singhi doctorpratibhasinghi@gmail.com