Efficacy and safety of cyclic pyranopterin monophosphate substitution in severe molybdenum cofactor deficiency type A: a prospective cohort study.

BACKGROUND: Molybdenum cofactor deficiency (MoCD) is characterised by early, rapidly progressive postnatal encephalopathy and intractable seizures, leading to severe disability and early death. Previous treatment attempts have been unsuccessful. After a pioneering single treatment we now report the outcome of the complete first cohort of patients receiving substitution treatment with cyclic pyranopterin monophosphate (cPMP), a biosynthetic precursor of the cofactor. METHODS: In this observational prospective cohort study, newborn babies with clinical and biochemical evidence of MoCD were admitted to a compassionate-use programme at the request of their treating physicians. Intravenous cPMP (80-320 µg/kg per day) was started in neonates diagnosed with MoCD (type A and type B) following a standardised protocol. We prospectively monitored safety and efficacy in all patients exposed to cPMP. FINDINGS: Between June 6, 2008, and Jan 9, 2013, intravenous cPMP was started in 16 neonates diagnosed with MoCD (11 type A and five type B) and continued in eight type A patients for up to 5 years. We observed no drug-related serious adverse events after more than 6000 doses. The disease biomarkers urinary S-sulphocysteine, xanthine, and urate returned to almost normal concentrations in all type A patients within 2 days, and remained normal for up to 5 years on continued cPMP substitution. Eight patients with type A disease rapidly improved under treatment and convulsions were either completely suppressed or substantially reduced. Three patients treated early remain seizure free and show near-normal long-term development. We detected no biochemical or clinical response in patients with type B disease. INTERPRETATION: cPMP substitution is the first effective therapy for patients with MoCD type A and has a favourable safety profile. Restoration of molybdenum cofactor-dependent enzyme activities results in a greatly improved neurodevelopmental outcome when started sufficiently early. The possibility of MoCD type A needs to be urgently explored in every encephalopathic neonate to avoid any delay in appropriate cPMP substitution, and to maximise treatment benefit. FUNDING: German Ministry of Education and Research; Orphatec/Colbourne Pharmaceuticals.

Pediatric Resuscitation: Do We Maintain Adequate Skills?

Adequate skills and knowledge is necessary in pediatric cardiopulmonary resuscitation. We conducted a study to evaluate the current status of resuscitation knowledge and skills among the pediatric medical and nursing staff at the Royal London Hospital, London.

Adenosine infusion for the management of persistent pulmonary hypertension of the newborn.

OBJECTIVE: To determine the effect of adenosine for the management of persistent pulmonary hypertension of the newborn. DESIGN: Prospective, observational case series report. SETTING: A single, tertiary referral neonatal intensive care unit. PATIENTS: Nine neonates with persistent pulmonary hypertension of the newborn requiring mechanical ventilation and inhaled nitric oxide at 20 parts per million. INTERVENTIONS: A continuous intravenous infusion of adenosine at 50 microg/kg/min. MEASUREMENTS AND MAIN RESULTS: Peripheral arterial oxygen saturation, arterial oxygen tension, invasive systemic arterial blood pressure, and pulmonary arterial pressure, estimated using echocardiography, were recorded. There was a significant improvement in arterial oxygenation tension in six of nine neonates who responded to adenosine: PaO2 increased from 66.8 (range, 47-70.5) torr (8.8 kPa) to 73.5 (range, 58.5-94.2) (p=.02) and pulmonary arterial pressure decreased significantly from 63 (range, 42.5-64.0) to 43.5 (range, 32.75-49) mm Hg (p=.002). The pulmonary to systemic mean artery pressure ratio fell from 1.27 (range, 0.88-1.5) to 0.81 (range, 0.64-0.84) (p=.002). Three neonates did not respond to adenosine infusion. CONCLUSIONS: The use of adenosine infusion in combination with inhaled nitric oxide may be a potentially valuable therapeutic option for the treatment of pulmonary hypertension of the newborn. Neonates with irreversible lung pathology may not respond to adenosine infusion.

Medullary sponge kidney.

Medullary sponge kidney is a benign asymptomatic developmental anomaly of the kidney mostly seen in adult females. Presentation in childhood is uncommon. Urinary tract infection, nephrolithiasis, hematuria and hypercalciuria are the common complications. We report a eleven-year-old female child who presented with recurrent urinary tract infection and nephrolithiasis and was found to have bilateral medullary sponge kidney.

Budd-Chiari syndrome due to antithrombin III deficiency.

Budd-Chiari syndrome is a disease complex with varied etiology and is one of the causes of post-hepatic portal hypertension. We report a 2 year-old boy who presented with Budd-Chiari syndrome due to congenital antithrombin III deficiency, who was managed with an expandable metal stent placed in the inferior vena cava and oral anticoagulation.

Tuberous sclerosis with hypothyroidism and precocious puberty.

Tuberous sclerosis complex has been associated though infrequently, with abnormalities in the endocrine tissues. Alterations in thyroid function, in patients with tuberous sclerosis have been reported rarely. We report a patient with tuberous sclerosis complex who presented with hypothyroidism and precocious puberty.

Acute disseminated encephalomyelitis.

The authors report 6 children with the diagnosis of acute disseminated encephalomyelitis. Diagnosis was based on clinical and radiological findings. The most common presenting symptoms were fever and disturbed consciousness, followed by cranial nerve abnormalities and pyramidal signs. Brain MRI showed hyperintense signals on T2-weighted images, most commonly in the subcortical and periventricular white matter, brainstem, basal ganglia and thalamus. The lesions were bilateral, asymmetrical and highly variable in size and number. A preceding infection was present in 3 of 6 children. Early high-dose corticosteroids were given to all the patients. All patients recovered clinically. Follow-up ranged from 10 months to 2 years. No relapses were observed during this period. Early high-dose steroid therapy seems to be an effective treatment in acute disseminated encephalomyelitis.

Achalasia--alacrima--ACTH insensitivity syndrome (Triple A syndrome).

Triple A syndrome is characterized by achalasia of the cardia, alacrima, adrenocorticotrophic hormone (ACTH) resistant adrenal insufficiency and progressive neurological abnormalities including autonomic nervous dysfunction. An 8-year-old girl presented to the pediatric intensive care unit with sudden loss of consciousness and was diagnosed subsequently to have this condition. The authors present this condition since it is easily treatable and can be fatal if undiagnosed.

Persistent hyperinsulinemic hypoglycemia of infancy--successful therapy with nifedipine.

Recent studies have demonstrated a role for calcium channel blocking agents in the treatment of persistent hyperinsulinemic hypoglycemia of infancy. We report a 30 day old infant with PHHI whom we successfully treated with oral nifedipine alone.

Staphylococcal scalded skin syndrome.

Staphylococcal Scalded Skin Syndrome (SSSS) is a disease primarily of young children, characterized by exfoliative dermatitis caused by exfoliative toxin producing Staphylococcus aureus. We had three cases of SSSS with varied dermatological manifestations-diffuse/scarlitiniform erythema, generalized exfoliation, sand paper skin texture, flaccid bullae, erosions, seborrheic dermatitis like scaling and cracking in skin creases which can be confused with other skin conditions. Hence, a high index of suspicion, early diagnosis and prompt treatment is imperative.

The congenital long QT syndrome.

OBJECTIVE: The long QT syndrome (LQTS) is a disorder of the electrical system of the heart, due to dysfunction of the ion channels and involving the repolarisation process. The inherited form occurs when there is a mutation in one of the genes which encode the making of a channel. Prolongation of the QT interval renders the patient vulnerable to an arrythmia called torsade de pointes, resulting in syncope and sudden death. METHODS: Three children with the congenital long QT syndrome presented to the pediatric department, one of them also having a 2:1 atrio-ventricular block. The parents and siblings of these children were screened for the long QT syndrome with an electrocardiogram. 2D echocardiography was done to rule out structural abnormalities and audiometry for deafness. RESULTS: Four family members were identified on screening to have LQTS. Propranolol was started on all children with LQTS. The child with heart block also received a pacemaker. LQTS must be considered in all patients presenting with syncope especially if associated with deafness and/or a family history of sudden deaths in infancy or childhood. CONCLUSION: The corrected QT interval must be determined in all children with heart block since the two conditions are often associated.

Exchange transfusion in children with severe falciparum malaria and heavy parasitaemia.

While exchange transfusion has been advocated as an adjunctive treatment in severe falciparum malaria complicated by heavy parasitaemia, its role in severe life-threatening disease refractory to standard life support measures is less well recognised. We describe four children with severe falciparum malaria, multi-system involvement and heavy parasitaemia in whom we undertook exchange transfusion because of their deteriorating clinical condition despite antimalarials and supportive therapy. All patients received quinine (one also received artesunate). All patients improved dramatically following the procedure, with subsequent complete clinical recovery.