Roser Pons

The Spectrum of Movement Disorders in Glut-1 Deficiency

To assess the spectrum of movement disorders, we reviewed video recordings and charts of 57 patients with Glut‐1 deficiency. Eighty‐nine percent of patients with Glut‐1 deficiency syndrome had a disturbance of gait. The most frequent gait abnormalities were ataxic‐spastic and ataxic. Action limb dystonia was observed in 86% of cases and mild chorea in 75%. Cerebellar action tremor was seen in 70% of patients, myoclonus in 16%, and dyspraxia in 21%. Nonepileptic paroxysmal events occurred in 28% of patients, and included episodes of ataxia, weakness, Parkinsonism and nonkinesogenic dyskinesias. The 40 patients (70%) who were on the ketogenic diet had less severe gait disturbances but more dystonia, chorea, tremor, myoclonus, dyspraxia, and paroxysmal events compared with the 17 patients on a conventional diet. Poor dietary compliance and low ketonuria appear to trigger the paroxysmal events in some patients. Gait disturbances and movement disorders are frequent in patients with Glut‐1 deficiency and are signs of chronic and intermittent pyramidal, cerebellar and extrapyramidal circuit dysfunction. These clinical symptoms reflect chronic nutrient deficiency during brain development and may be mitigated by chronic ketosis.

Deficient Muscle Carnitine Transport in Primary Carnitine Deficiency

Primary carnitine deficiency is associated with deficient blood and tissue carnitine concentrations. The clinical syndrome is dominated by heart and skeletal muscle symptoms, and the clinical response to oral carnitine supplementation is life-saving. Carnitine uptake has been shown to be defective in cultured skin fibroblasts and leukocytes obtained from patients with this condition. We report a new case of primary carnitine deficiency and offer direct evidence consistent with an impairment of carnitine uptake in differentiating muscle culture. The patient presented with severe and progressive cardiomyopathy and moderate proximal limb weakness. Plasma and muscle carnitine levels were very low, and the maximal rate of carnitine transport in cultured fibroblasts was deficient. An asymptomatic sister with intermediate levels of carnitine in plasma showed partially deficient carnitine uptake in fibroblasts, indicating heterozygosity. The patients condition improved dramatically with oral carnitine therapy. Further studies were performed in cultured muscle cells at different stages of maturation, which demonstrated deficient maximal rates of carnitine uptake. Our findings are consistent with the concept that primary carnitine deficiency is the result of a generalized defect involving carnitine transport across tissue membranes.

Leigh-type neuropathology in Pearson syndrome associated with impaired ATP production and a novel mtDNA deletion

Pearson syndrome is a systemic disorder of oxidative phosphorylation in infants, predominantly affecting the bone marrow and exocrine pancreas and associated with single deletions in mitochondrial DNA (mtDNA).CNS involvement may occur in patients who survive the infantile hematopoietic disorder. We describe a Pearson syndrome patient who developed neurologic manifestations associated with the pathologic features of Leigh syndrome. Biochemical studies in muscle and skin fibroblasts showed partial deficiencies of complexes I and IV of the respiratory chain. Adenosine triphosphate production in mitochondria isolated from skin fibroblasts was reduced to 25% of controls. We detected a novel 3.6 Kb mtDNA deletion in skin fibroblasts from the proband but not in his mothers white blood cells. Leigh syndrome seems to be the common neuropathologic expression of any disorder causing severe impairment of oxidative energy production in the CNS. NEUROLOGY 1996;47: 1320-1323

Clinical and molecular heterogeneity in very–long-chain acyl-coenzyme a dehydrogenase deficiency

Very-long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency is an increasingly recognized defect of mitochondrial fatty acid beta-oxidation manifesting with episodes of metabolic decompensation or isolated recurrent myoglobinuria. In this report the clinical, biochemical, and molecular studies in a series of five patients (four Italian and one Spanish) with this disorder are discussed. Biochemical studies included the determination of fibroblast substrate oxidation rates and enzyme activity and Western blot analysis of VLCAD protein. Molecular analysis was performed by sequencing the VLCAD gene from the genomic DNA. Clinical features were within the spectrum previously reported. Four patients presented in infancy or childhood with episodes of severe metabolic decompensation and dicarboxylic aciduria. Two exhibited cardiomyopathy. The fifth patient presented with isolated recurrent rhabdomyolysis, with no cardiomyopathy or dicarboxylic aciduria. In all patients a significant loss of VLCAD activity associated with a marked reduction of VLCAD protein levels occurred. Molecular analysis disclosed one novel missense mutation (Cys437Tyr) and four previously reported mutations, including two missense substitutions (Phe418Leu and Arg419Trp), a single amino acid deletion (Lys258del), and one splice site mutation (IVS8-C(-2)), which was present in all four Italian patients. All patients exhibited compound heterozygosity. The phenotypic variability and the high genotypic heterogeneity of this hereditary metabolic disorder is reported.

Levodopa‐induced dyskinesias in tyrosine hydroxylase deficiency

The objective of this study was to characterize levodopa (l‐dopa)–induced dyskinesias in patients with tyrosine hydroxylase deficiency. Clinical observation was carried out on 6 patients who were diagnosed with tyrosine hydroxylase deficiency and were treated with escalating doses of l‐dopa. All 6 patients showed l‐dopa‐induced dyskinesias of variable intensity early in the course of treatment and regardless of the age of initiation. l‐Dopa–induced dyskinesias were precipitated by increases in the dose of l‐dopa and also by febrile illnesses and stress. They caused dysfunction and distress in 2 patients. The dyskinesias were improved by decreasing the l‐dopa dose or by slowing its titration upward. Increasing the dose frequency was helpful in 2 patients, and introducing amantadine was helpful in another 2 patients. l‐Dopa–induced dyskinesias are a common phenomenon in tyrosine hydroxylase deficiency. The current observations show that l‐dopa–induced dyskinesias are frequent in a dopamine‐deficient state in the absence of nigrostriatal degeneration. Although l‐dopa–induced dyskinesias in tyrosine hydroxylase deficiency are phenomenologically similar to those that occur in Parkinsons disease, they are different in a number of other respects, suggesting intrinsic differences in the pathophysiologic basis of l‐dopa–induced dyskinesias in the 2 conditions.

Homovanillic acid in cerebrospinal fluid of 1388 children with neurological disorders.

To determine the prevalence of dopaminergic abnormalities in 1388 children with neurological disorders, and to analyse their clinical, neuroradiological, and electrophysiological characteristics.

Neonatal Blood Carnitine Concentrations: Normative Data by Electrospray Tandem Mass Spectometry

Despite a number of published reports, there is limited information about carnitine metabolism in the newborn. To establish normative data, we analyzed whole-blood carnitine concentrations in 24,644 newborns at age 1.85 ± 0.95 d and umbilical cord whole blood and plasma carnitine concentrations in 50 full-term newborns. Total carnitine (TC), free carnitine (FC), and acylcarnitine (AC) were measured by electrospray tandem mass spectrometry. AC/FC ratios were derived from these measurements. The entire cohort was stratified according to TC values into a middle TC group representing 90% of the population and lower and upper TC groups representing 5% of the population, respectively. Normative data were derived from the middle TC group of full-term infants (N = 19,595). TC was 72.42 ± 20.75 μM, FC was 44.94 ± 14.99 μM, AC was 27.48 ± 8.05 μM, and AC/FC ratio was 0.64 ± 0.19 (±SD). These values differed significantly from umbilical cord whole blood TC values of 31.27 ± 10.54 μM determined in 50 samples. No meaningful correlation was found between TC and gestational age or birth weight in any group. In controlled analyses, prematurity was not associated with TC levels, whereas low birth weight (<2500 g) and male sex were significantly associated with higher TC levels. The association of low birth weight with higher TC values may be related to decreased tissue carnitine uptake. The sex effect may be related to hormonal influences on carnitine metabolism. Our study provides normative data of carnitine values measured by the highly precise method of electrospray tandem mass spectrometry in a large cohort of newborns and provides the basis for future studies of carnitine metabolism in health and disease states during the neonatal period.

Consensus guideline for the diagnosis and treatment of aromatic l-amino acid decarboxylase (AADC) deficiency

Aromatic L-amino acid decarboxylase deficiency (AADCD) is a rare, autosomal recessive neurometabolic disorder that leads to a severe combined deficiency of serotonin, dopamine, norepinephrine and epinephrine. Onset is early in life, and key clinical symptoms are hypotonia, movement disorders (oculogyric crisis, dystonia, and hypokinesia), developmental delay, and autonomic symptoms.In this consensus guideline, representatives of the International Working Group on Neurotransmitter Related Disorders (iNTD) and patient representatives evaluated all available evidence for diagnosis and treatment of AADCD and made recommendations using SIGN and GRADE methodology. In the face of limited definitive evidence, we constructed practical recommendations on clinical diagnosis, laboratory diagnosis, imaging and electroencephalograpy, medical treatments and non-medical treatments. Furthermore, we identified topics for further research. We believe this guideline will improve the care for AADCD patients around the world whilst promoting general awareness of this rare disease.German abstractDer Aromatische L-Aminosäuren Decarboxylase Mangel (AADCD) ist eine seltene autosomal rezessive neurometabolische Störung, die zu einem schweren kombinierten Mangel an Serotonin, Dopamin, Norepinephrin und Epinephrin führt. Die Symptome setzen in einer frühen Phase des Lebens ein. Die klinischen Hauptsymptome sind muskuläre Hypotonie, Bewegungsstörungen (Okkulogyre Krisen, Dystonie und Hypokinesie), Entwicklungsverzögerung und autonome Symptome.In diesen Konsensus basierten Leitlinien haben Mitglieder der “International Working Group on Neurotransmitter Related Disorders (iNTD)” sowie Patientenvertreter die verfügbare Evidenz für die Diagnose und Behandlung von AADCD ausgewertet und evidenzbasierte Empfehlungen nach den Methoden von SIGN und GRADE formuliert. Stets im Bewusstsein der limitierten Evidenz haben wir praktische Empfehlungen für die klinische Diagnose, Labordiagnose, Bildgebung und EEG, medizinische und nicht medizinische Behandlung formuliert. Des Weiteren haben wir Themen identifiziert, die der weiteren Forschung bedürfen. Wir glauben, dass diese Leitlinie die Behandlung von Patienten mit AADCD verbessert und gleichzeitig das Bewusstsein für diese seltene Erkrankung geschärft wird.Spanish abstractLa deficiencia de la descarboxilasa de aminoácidos aromáticos (AADCD) es una enfermedad neurometabólica minoritaria de herencia autosómica recesiva que causa un defecto grave de dopamina, serotonina, epinefrina y norepinefrina. El inicio de la enfermedad es precoz, y sus síntomas principales incluyen hipotonía, trastornos del movimiento (crisis oculógiras, distonía e hipocinesia), retraso del desarrollo y signos disautonómicos.En esta guía de consenso han participado representantes del grupo de trabajo internacional sobre trastornos de la neurotransmisión (iNTD) y representantes de las asociaciones de pacientes, que han evaluado todas las evidencias existentes en relación al diagnóstico y tratamiento de la AADCD. Las recomnedaciones se han realizado siguiendo la metodología SIGN y GRADE. A pesar de los bajos niveles de evidencia existentes, se han podido establecer recomendaciones prácticas y que pueden ser muy útiles sobre el diagnóstico clínico y de laboratorio, las pruebas de neuroimagen y electroencefalográficas y sobre tratamientos tanto médicos como de soporte. Se han identificado además temas que pueden ser interesantes a desarrollar en el campo de la investigación de la AADCD.En conclusión, pensamos que esta guía aumentará la calidad en los cuidados de los pacientes con AADCD en todo el mundo, y que aumentará el conocimiento de esta rara enfermedad.

Paroxysmal non-kinesigenic dyskinesia due to a PNKD recurrent mutation: Report of two Southern European families

Paroxysmal non-kinesigenic dyskinesia (PNKD) is an autosomal dominant disorder characterized by attacks of dystonic or choreathetotic movements precipitated by stress, fatigue, coffee, alcohol or menstruation. In this report we present two families with PNKD of Southern European origin carrying a PNKD recurrent mutation. Incomplete penetrance and intrafamilial variability was detected in both families. Treatment with valproic acid and levetiracetam provided favorable response.

Tyrosine Hydroxylase Deficiency in Three Greek Patients with a Common Ancestral Mutation

We present the clinical, biochemical, and molecular findings of three Greek patients with tyrosine hydroxylase (TH) deficiency. All patients presented with a severe clinical phenotype characterized by prominent motor delay, infantile parkinsonism, oculogyric crises, and signs of autonomic dysfunction. Cerebrospinal fluid analysis disclosed reduced dopamine metabolites and normal pterins. Response to levodopa was favorable though not dramatic. All patients were homozygous for a previously reported mutation (p.L236P). SNP haplotype analysis was consistent with a common ancestral mutation, thus indicating a founder effect in Greek patients with TH deficiency.