Next-Generation Sequencing in Unexplained Intellectual Disability.

OBJECTIVES: To determine the diagnostic yield of next generation sequencing (NGS) in patients with moderate/severe/profound intellectual disability (ID) unexplained by conventional tests and to assess the impact of definitive diagnosis on the clinical management and genetic counselling of these families. METHODS: This was a ambi-directional study conducted at Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi. The study comprised 227 patients (prospective cohort - 126, retrospective cohort - 101) in whom NGS based tests were performed. RESULTS: The mean age of study cohort was 4.5 ± 4.4 y (2.5 mo to 37.3 y). The male: female ratio was 1.6:1. The overall diagnostic yield of NGS was 53.3% (121/227) with causative variants identified in 84 known ID genes. Autosomal recessive intellectual disability (ARID) (23.3%, 53/227) was the most common followed by autosomal dominant intellectual disability (ADID) (20.7%, 47/227) and X-linked intellectual disability (XLID) (9.2%, 21/227). The diagnostic yield was notably higher for ID plus associated condition group (55.6% vs. 20%) (p = 0.0075, Fisher's exact test) compared to isolated ID group. The impact of diagnosis on active or long-term management was observed in 17/121 (14%) and on reproductive outcomes in 26/121 (21.4%) families. CONCLUSIONS: There is paucity of data on molecular genetic spectrum of ID from India. The current study identifies extensive genetic heterogeneity and the impact of NGS in patients with ID unexplained by standard genetic tests. The study identified ARID as the most common cause of ID with additional implications for reproductive outcomes. It reiterates the importance of phenotype in genetic testing.

Benign Intracranial Hypertension -Is it Really Benign Always?

BACKGROUND: In children, benign or idiopathic intracranial hypertension (IIH) is uncommon. The presenting symptoms are usually variable, which attribute to delay in diagnosis. Frequently encountered symptoms include; headache, vomiting, visual impairment, neck pain and diplopia. IIH in pre-pubertal children has distinct characteristics from the adult form. Delayed diagnosis in children usually attributes to the inability in picking subtle visual changes, which can subsequently leads to permanent visual damage. OBJECTIVE: We report cases of two adolescent girls having IIH who presented with papilloedema, could be managed with lumboperitoneal shunting which resulted in favorable outcomes in terms of improved visual acuity and relief of symptoms. CASE: We report two cases of IIH, presented with headache and severe visual loss, which showed non responsiveness to medical management and improved with a lumboperitoneal shunt procedure. CONCLUSION: In IIH cases, enhanced awareness, prompt diagnosis and treatment are important, to avoid the risk of permanent visual damage. Urgent surgical intervention is essential in patients who do not respond to medical treatment.

Severe combined immunodeficiency caused by a new homozygous RAG1 mutation with progressive encephalopathy.

We describe an unusual case of severe combined immunodeficiency (SCID) with neutropenia and central nervous system (CNS) manifestations in which a novel RAG1 mutation was identified. A 15-month-old boy presented with failure to thrive, neutropenia and recurrent infections. He was diagnosed with T-B-NK+ SCID. He subsequently developed right partial seizures with ipsilateral hemiparesis and became comatose. Magnetic resonance imaging (MRI) of the brain revealed an inflammatory lesion in the left thalamus which later progressed to diffuse meningo-encephalitis on serial imaging. No CNS infection was documented. Genetic work-up in the child revealed a novel homozygous deleterious mutation in the RAG1 gene (c:2881T>C; p:I794T), for which both parents were heterozygous. He underwent a haploidentical bone marrow transplant without conditioning and died on day +35 with no improvement in his neurological status. The features of neutropenia and progressive encephalopathy could be linked to the novel genetic defect but more data is required to establish this conclusively.

Acute disseminated encephalomyelitis: case report and brief review.

Acute disseminated encephalomyelitis (ADEM) is a rare disease of central nervous system with myriads of presentation. It is a diagnosis of exclusion and relies on neuroimaging which may be normal at the onset. It is a diagnostic challenge at its first attack. Here we present a case of ADEM which initially presented with atypical feature and normal neuroimaging but later turned out to be a case of ADEM. Early diagnosis and treatment holds the key for favorable outcome.

Stroke in children.

Stroke is a thrombohemorrhagic disorder of the central nervous system, with a fairly good outcome in pediatric age group except for the infancy period. In children ischemic type is more common than hemorrhagic type. Though it is difficult to distinguish between thrombotic and embolic phenomenon but it is largely due to cardiovascular lesions, at times it may be the first symptom to appear. The signs and symptoms also appear to be vague in children, hence difficult to pinpoint the etiology. The treatment of stroke is largely for stabilization of the patient, but it is very important to know the cause to prevent future strokes. Use of heparin in ischemic stroke is very promising and thrombolytic therapy is under trial.

Migraine: a common cause of headache.

Acute headaches in a child evoke anxiety in parents, of a possible catastrophic underlying intracranial pathology. Headaches constitute up to 2 to 6% of all emergency room visit. The prevalence of migraine is increasing. The majority of children have migraine without aura, and about one fifth have migraine with aura. Complicated migraine presents with dramatic neurologic signs and remains a diagnosis of exclusion. Children with migraine require reassurance, modification of life style and food habits, combined with judicious use of simple abortive medications and antiemetics. Prophylaxis in migraine is recommended for frequent or severe attacks and in complicated migraine.

Paramedian diencephalic syndrome. Report of 3 cases.

We report three patients who lapsed into coma and subsequently manifested hypersomnolence, amnesia and vertical gaze paresis. Computed tomography revealed bilateral paramedian thalamic infarcts. This clinical symptomatology comprises the paramedian diencephalic syndrome.

Hemiplegic migraine.

Eight patients with hemiplegic migraine are described. Majority were in their second decade and suffered two or more episodes of dense hemiplegia outlasting the headache. Complete recovery was the rule.

Cerebellar and thalamic infarctions in basilar artery migraine.

We report a 25 year old male who suffered thalamic and multiple cerebellar infarctions during infrequent attacks of basilar artery migraine. Migraine-related infarcts at these sites are uncommon.

Juvenile diabetes manifesting as epilepsia partialis continua.

Epilepsia partialis continua was the chief initial complaint in a young diabetic who was found to have hyperosmolar non ketotic hyperglycaemia. Such a presentation in a juvenile diabetic is rare. Literature relevant to this interesting neurologic disturbance has been briefly reviewed.

"Top of the basilar" syndrome: a clinical and CT analysis.

Fifteen patients presenting with visual, oculomotor and behavioural disturbances were diagnosed to be suffering from "top of the basilar" syndrome. Computed tomography confirmed the distribution of infarctions in the vascular territory of the rostral basilar artery. The clinical profile comprised cortical blindness and visual field defects, vertical gaze paresis, memory and behavioural disturbances and in one patient, the paramedian diencephalic syndrome.