Pascale E. Karam

Deep brain stimulation as a mode of treatment of early onset pantothenate kinase-associated neurodegeneration

We report a case of a young girl with early onset pantothenate kinase-kssociated neurodegeneration (PKAN) whose initial clinical manifestation was ataxia at the age of 2.5 years. Subsequently the patient presented to us with refractory severe dystonia resulting in essentially complete loss of motor control. She had a mutation in PANK2 gene consisting of an aminoacid change of Alanine to Valine in exon 5 (A382V). After Globus Pallidus deep brain stimulation (DBS) at the age of 11 years, the patient regained useful motor function and speech with a marked decrease in the severity of the dystonia. The patients condition gradually returned to her pre-DBS status when the device had to be removed 3 months later due to infection. Our case is the sixth case with classical PKAN that was treated by Globus Pallidus stimulation, the fifth one to have a favorable response to it and the only one in whom response was proven by the inadvertent removal of the DBS device due to infection. In addition, our case had a novel mutation and novel clinical features (onset with ataxia, occurrence of early seizure activity) on top of her other symptoms that were otherwise typical of early onset disease.

Diagnostic challenges of aminoacidopathies and organic acidemias in a developing country: A twelve-year experience

BACKGROUND Diagnosis of aminoacidopathies and organic acidemias constitutes a real challenge in a developing country with high consanguinity rate and no systematic newborn screening. We report a twelve-year experience with the identification of these disorders in Lebanon, based on their clinical and biochemical profiles. METHODS In this retrospective study, we reviewed clinical presentation and biochemical investigations of 294 patients. Traditional chromatographic methods were used for analyses. Findings were linked to the identified disorders. RESULTS Out of 2921 patients, presenting to our metabolic program with neurological, digestive, family history and/or other symptoms suggestive of aminoacidopathy or organic acidemia, 294 patients were included with confirmed amino or organic acid disorder. The overall analytical yield was 10%. Aminoacidopathies were three-fold higher than organic acidemias. Phenylketonuria and methylmalonic acidemia were the most frequent. The majority of patients (79%) were symptomatic (median age: 14months, range: 1day-44years), mainly with neurological manifestations (87%). Intellectual disability was mostly due to phenylketonuria (73%). Chronic liver failure was frequent in maple syrup urine disease (53%). Plasma amino and urine organic acid chromatography were diagnostic in 8.8% and 3.9% of analyzed cases, respectively. Change in chromatographic technique from reversed-phase to ion-exchange enhanced the detection of many aminoacidopathies. CONCLUSIONS In the absence of newborn screening, the majority of aminoacidopathy and organic acidemia cases are still diagnosed clinically. This study emphasizes the importance of clinical awareness and accurate biochemical analyses as key tools for diagnosis in countries like ours, and the necessity for a comprehensive national newborn screening program.

Novel mutation causing partial biotinidase deficiency in a syrian boy with infantile spasms and retardation

We report a case of partial biotinidase deficiency (plasma biotinidase levels: 1.30 nm/minute/mL) in a 7-month-old boy who presented with evidence of perinatal distress followed by developmental delay, hypotonia, seizures, and infantile spasms without alopecia or dermatitis. His neurologic symptoms improved markedly on biotin supplementation and antiepileptic drug therapy. DNA mutational analysis revealed that the patient was homozygous for a novel E64K mutation and his parents were heterozygous for the same mutation. Whereas preexisting perinatal distress probably contributed to the severity of the patients symptoms, the described mutation is novel and is possibly responsible for at least some of his clinical manifestations. (J Child Neurol 2006;21:978-981; DOI 10.2310/ 7010.2006.00200).

Biotin-Responsive Basal Ganglia Disease : Case Report and Review of the Literature

Biotin-responsive basal ganglia disease is a rare entity of which 10 cases have been reported in the literature. We report a case of biotin-responsive basal ganglia disease with similarities and differences compared to the previously reported cases by Ozand et al. Our case presented much earlier, was milder and responded better to lower doses of biotin, compared to the cases reported previously. Since our case showed differences with those in the literature, it might represent a new entity or a milder form of the same entity.

Experience with hyperphenylalaninemia in a developing country: unusual clinical manifestations and a novel gene mutation.

We report our experience in a cohort of patients with hyperphenylalaninemia in a tertiary care referral center in Lebanon. Forty-one sequential patients were studied: 34 classical phenylketonuria (PKU), 3 hyperphenylalaninemia (non-PKU), and 4 biopterin metabolism defects. The majority of cases were clinically diagnosed at variable ages with variable neurological outcomes. Only 29.3% were detected by neonatal screening. Two unusual cases were observed in the context of inadequate treatment in 1 and delayed therapy in the other: a newborn with PKU developed severe keratomalacia; and a 5-year-old girl with dihydropteridine reductase deficiency due to a novel mutation identified in the quinoid dihydropteridine reductase gene developed Lennox-Gastaut syndrome and white matter changes with periventricular cysts. Part of our experience parallels that in the West. However, the clinical manifestations observed in our patients emphasize the importance of a national newborn screening program with efficient management of diagnosed cases.

Two new familial severe infantile spasm syndromes in males

We describe two new familial severe infantile spasm syndromes (ISSs) unrelated to Aristaless-related homeobox (ARX) gene mutation. Family A contains two male siblings each with dysmorphism, profound psychomotor delay, gastroesophageal reflux, infantile spasms, hypsarrhythmia, prominent independent central apneas, and early death. Family B contains two male siblings with dysmorphism, profound psychomotor delay, ambiguous genitalia, macular hypoplasia, neurosensory hearing deficit, gastroesophageal reflux, infantile spasms, no hypsarrhythmia, apneas, and early death in one sibling. Etiologic workup and ARX gene sequencing were negative. This indicates that several familial ISSs exist but are not genetically characterized.

Pamidronate Rescue Therapy for Hypercalcemia in a Child With Williams Syndrome

A 15-month-old male infant diagnosed with Williams Syndrome (WS) was admitted with severe hypercalcemia and nephrocalcinosis. Intravenous hydration and furosemide failed to yield an appreciable and sustainable fall in serum calcium, while the injection of pamidronate achieved a significant decrease in serum calcium in a short period of time. This bisphosphonate could be considered as a second-line treatment for refractory hypercalcemia in WS.

Treatable Genetic Metabolic Epilepsies

Opinion statementIn the absence of a culprit epileptogenic lesion, pharmacoresistant seizures should prompt the physician to consider potentially treatable metabolic epilepsies, especially in the presence of developmental delays. Even though the anti-seizure treatment of the epilepsies remains symptomatic and usually tailored to an electroclinical phenotype rather than to an underlying etiology, a thorough metabolic workup might reveal a disease with an etiology-specific treatment. Early diagnosis is essential in the case of treatable metabolic epilepsies allowing timely intervention. Despite the advances in genetic testing, biochemical testing including cerebrospinal fluid studies are still needed to expedite the diagnostic workup and potential therapeutic trials. The diagnostician should have a high index of suspicion despite potential clinical digressions from seminal publications describing the initial cases, as these index patients may represent the most severe form of the condition rather than its most common presenting form. The often gratifying developmental outcome and seizure control with early treatment calls for a prompt diagnostic consideration of treatable metabolic diseases; even though relatively rare or potentially only seemingly so.