Adina Joseph

Molecular basis of lipoamide dehydrogenase deficiency in Ashkenazi Jews

We studied 13 patients with lipoamide dehydrogenase (LAD) deficiency, originating from seven Ashkenazi Jewish families. Their disease was characterized by recurrent attacks of vomiting, abdominal pain, and encephalopathy accompanied by elevated liver transaminases, prolonged prothrombin time, and occasionally associated with lactic and ketoacidemia or with myoglobinuria. Two patients who presented neonatally suffered from residual neurological damage with attention deficit hyperactive disorder, mild ataxia, motor incoordination, muscle hypotonia, and weakness. Nine patients who presented in early childhood or later suffered from exertional fatigue between decompensation episodes but were otherwise asymptomatic. Two patients died because of intractable metabolic acidosis and multi-organ failure. In all patients LAD activity was reduced to 8 to 21% of the control in muscle or lymphocytes. In four patients LAD protein in muscle was reduced to 20 to 60% of the control. Direct sequencing of the cDNA of the LAD gene showed that 12 of the 14 mutated alleles carried the G229C mutation and two carried an insertion mutation 105insA (Y35X). The patients who presented neonatally and had more severe sequelae were compound heterozygotes for the two mutations; patients who presented in early childhood or later were homozygous for the G229C mutation. Using an allele-specific oligonucleotide hybridization technique, nine heterozygotes for the G229C mutation were identified among 845 anonymous individuals of Ashkenazi Jewish origin disclosing a carrier rate of 1:94. Because of the significant morbidity associated with the disease, screening for the G229C mutation among Ashkenazi Jewish couples should be considered.

3-METHYLGLUTACONIC ACIDURIA IN THE IRAQI-JEWISH “OPTIC ATROPHY PLUS‘ (COSTEFF) SYNDROME

Eleven new patients of Iraqi‐Jewish origin with bilateral optic atrophy, neurological abnormalities (‘optic atrophy plus’ syndrome) and 3‐methylglutaconic aciduria (type III) are described. Clinical abnormalities in decreasing order of frequency were bilateral optic atrophy, extrapyramidal signs, spasticity, ataxia, dysarthria and cognitive deficit. An association with age was found only for spasticity. Spasticity, extrapyramidal signs and optic atrophy frequently led to major disability, in contrast to ataxia, dysarthria and cognitive deficit. The combined excretion of 3‐methylglutaconic and 3‐methylglutaric acid ranged between 9 and 187mmol/mol creatinine. The primary enzymatic defect possibly may reside in the mitochondrial respiratory chain.

Recurrent metabolic decompensation in profound carnitine palmitoyltransferase II deficiency

A 3-year-old boy had recurrent episodes of lethargy, encephalopathy, and hepatomegaly accompanied by hypoglycemia, elevated liver aminotransferase and creatine kinase values, and nonketotic dicarboxylic aciduria; the serum carnitine level was moderately reduced. Carnitine palmitoyltransferase II activity was decreased in lymphocytes and fibroblasts. Therapy with L-carnitine and a diet low in long-chain triglycerides did not prevent recurrent episodes.

Hallucinations during methylphenidate therapy

Methylphenidate (MPH) is the medication of choice for attention deficit hyperactivity disorder (ADHD), administered to millions of children with minimal side effects.1 The appearance of hallucinations at therapeutic doses of MPH has rarely been reported.1,2⇓ We describe three children with ADHD, who were treated with low doses of MPH and developed complex visual and haptic hallucinations. The causal role of MPH in the development of hallucinations was based on their appearance after ingestion of the drug, resolving after its withdrawal, and the absence of psychiatric comorbidity that could explain such phenomena. In one patient, the hallucinations reappeared after an inadvertent rechallenge. ### Case 1. A 7-year-old adopted boy with ADHD and oppositional defiant disorder was treated with MPH, 0.3 mg/kg (7.5 mg), once daily. After 1 year of treatment, he reported seeing and feeling snakes crawling on and around him starting 1 hour after drug ingestion. The teaching staff assumed an emotional …

Anaesthetic management of a patient with Leigh’s syndrome

PurposeLeigh’s syndrome, a progressive neurodegenerative disorder of infancy and childhood, is clinically charactenzed mainly by developmental delay, nervous system dysfunction and respiratory abnormalities such as aspiration, wheezing, breathing difficulties, gasping, hypoventilation and apnoea. Acute exacerbation and respiratory failure may follow surgery, general anaesthesia or intercurrent illnesses. Hyperlactataemia is variably present. Histopathological findings include necrosis, vascular proliferation, astrocytosis and demyelination of several brain areas. We present a 30-month-old patient with Leigh’s syndrome anaesthetized for extracorporeal shockwave lithotripsy, and describe the anaesthetic considerations.Clinical featuresLeigh’s syndrome was diagnosed at five months of age based on failure to thrive, lethargy, hypotonicity, choreo-athetosis and lactic acidaemia, with basal ganglia hypodense areas demonstrated by brain computerized tomographic scan. Muscle pyruvate dehydrogenase complex and NADH-coenzyme Q oxidoreductase activity were 25% and 13% of control. No preoperative respiratory symptoms or signs were present. Preoperative fasting lasted two hours and gastric aspiration was negative. Anaesthesia was induced with ketamine and midazolam im, and N2O in oxygen, and maintained with propofol and N2O. No volatile anaesthetics were used. Intravenous fluids given were 1/2 normal saline and glucose 5% administered. Besides laryngospasm dunng anaesthetic induction, relieved by sublingual succinylcholine injection, the perianaesthetic course was uneventful. The lungs were mechanically ventilated and lithotripsy was performed. No adverse sequelae have occurred, and the patient was discharged one day later.ConclusionPerioperative management of patients with Leigh’s syndrome requires cautious attention to the metabolic, neurological and respiratory aspects of the disease, and appropriate selection of anaesthetic drugs.RésuméObjectifLe syndrome de Leigh, une maladie infantile neuromusculaire progressive, est caracténsé par un retard du développement, un dysfonctionnement nerveux et par des anomalies respiratoires comme l’aspiration, le wheezing, les difficultés respiratoires, le halétement, l’hypoventilation et l’apnée. Une aggravation aiguë et une défaillance respiratoire peuvent survenir après la chirurgie, l’anesthésie générale ou une maladie concomitante. Le syndrome s’accompagne parfois d’hyperlactatémie. Lhistopathologie révèle de la nécrose, de la prolifération vasculaire, de l’astrocytose et de la démyélinisation de plusieurs régions du cerveau. Nous présentons le cas d’un enfant de 30 mois souffrant du syndrome de Leigh anesthésié pour une lithotripsie extracorporelle par ondes de choc amsi qu’un aperçu des considérations anesthésiques.Éléments cliniquesUn diagnostic de syndrome de Leigh a été porté a l’âge de trois mois devant l’absence de développement, la léthargie, l’hypotonicité, la choréo-athétose et l’acidémie lactique et la démonstration d’une démyélinisation des ganglions de la base par tomographie informatisée. Le complexe pyruvate-déshydrogénase et l’activité du coenzyme NADH Q oxydoréductase titraient à 25% et 30% du contrôle. En préopératoire, le patient ne présentait aucun signe symptômes respiratoires. Un jeûne préopératoire de deux heures a été imposé; l’aspiration gastrique s’est avérée négative. L’anesthésie a été induite avec de la kétamine et du midazolam im et du N2O en oxygène et maintenue avec propofol et N2O sans agent volatil. Le patient a reçu en liquide intraveineux une solution de NaCl 0,45% et de glucose 5%. À l’exception d’un laryngospasme traité à la succinylcholine sublinguale à l’induction, la période périanesthésique s’est déroulée sans incident. La lithotripsie a été réalisée sous ventilation mécanique. II n’a pas eu de séquelles et le patient a obtenu son congé le lendemain.ConclusionLa prise en charge périopératoire du syndrome de Leigh exige une attention particulière au profil métabolique, neurologique et respiratoire de la maladie ainsi qu’une sélection pertinente des agents anesthésiques.