LPIN1 - étude génétique d'une nouvelle cause de rhabdomyolyse héréditaire et analyses physiopathologiques à partir de myoblastes de patients

Les rhabdomyolyses correspondent à la destruction de fibres musculaires striées squelettiques et mettent en jeu le pronostic vital. La principale cause génétique est liée à un défaut d oxydation des acides gras ; néanmoins, plus de la moitié des cas n ont pas de cause identifiée. En 2008, des mutations du gène LPIN1 ont été rapportées comme une nouvelle étiologie de rhabdomyolyse de transmission autosomique récessive. La protéine lipin1 a une double fonction : un rôle de PAP1 intervenant dans la synthèse du triacylglycérol et des phospholipides membranaires ; un rôle de co-activateur transcriptionnel en association avec les PPARs et PGC1a pour réguler de nombreux gènes impliqués dans le métabolisme, dont certains de l OAG. Lipin1 a deux homologues, lipin2 et lipin3, qui possèdent une activité PAP1 et un site de fixation à des récepteurs nucléaires tels que les PPARs. Nous avons montré que les mutations de LPIN1 rendent compte de plus de 50% des cas de rhabdomyolyse sévère de la petite enfance, une fois écarté le diagnostic de déficit de l OAG. Une délétion intragénique en phase a été fréquemment identifiée chez les Caucasiens. Nous avons montré qu il s agissait d un probable effet fondateur et que cette délétion est délétère. En effet, à l inverse de la forme normale de lipin1, la forme délétée est incapable de complémenter la levure pah1, déficiente pour l homologue de LPIN1. Nous avons ensuite étudié, dans une série de 171 patients, l implication de LPIN1 dans des pathologies musculaires moins sévères, ainsi que le rôle des deux homologues LPIN2 et LPIN3. Les mutations de LPIN1 sont impliquées dans les rhabdomyolyses sévères et précoces uniquement et les accès de rhabdomyolyse ont toujours un facteur déclenchant, le principal étant les infections aiguës fébriles. Aucune altération majeure de LPIN2 et de LPIN3 n a été identifiée, même dans des phénotypes modérés. Enfin, nous avons cultivé des myoblastes et des myotubes de patients avec mutations de LPIN1 afin d étudier les mécanismes de rhabdomyolyse. Les myoblastes déficients en lipin1 ont une activité PAP1 très diminuée et une accumulation de gouttelettes lipidiques. Le niveau d expression des gènes cibles des facteurs de transcription co-activés par lipin1 (PPAR , PPARa, PGC1a, ACADVL, CPT1B and CPT2) sont inchangés par rapport aux contrôles, alors que le niveau de lipin2 est augmenté. L analyse transcriptomique sur cultures de myotubes a identifié chez les patients 19 gènes sous-exprimés et 51 sur-exprimés, notamment ACACB, qui code pour Accb, enzyme clé de la balance synthèse d acides gras/OAG. L invalidation d ACACB par siRNA dans des myoblastes déficients en lipin1 diminue le nombre de gouttelettes lipidiques, confirmant le lien entre la sur-expression d ACACB et l accumulation d acides gras libres chez les patients. Cependant, le taux de malonyl-CoA, produit d Accb, et l activité CPT1 (étape limitatrice de l OAG, inhibée par le malonyl-CoA), sont comparables entre myoblastes de patients et de contrôles. Néanmoins, le traitement des cultures par l association de tumor necrosis factor alpha et d interleukine-1 b, choisis pour simuler les conditions pro-inflammatoires des infections aiguës, entraîne une augmentation encore plus poussée du taux de malonyl-CoA, une diminution de l activité CPT1 et une augmentation de l accumulation de gouttelettes lipidiques chez les patients. Au total, nos données placent LPIN1 comme une cause importante de rhabdomyolyse héréditaire. Le déficit en lipin1 entraine une perturbation du métabolisme lipidique, via une sur-expression d ACACB, qui est exacerbée en conditions pro-inflammatoires. Nos résultats suggèrent que les conséquences du déficit en lipin1 sont compensées par des mécanismes d'adaptation suffisants en condition normale, mais insuffisants pour la demande métabolique induite par des stress environnementaux comme l'infection, conduisant aux rhabdomyolyses.Rhabdomyolyses correspond to the destruction of skeletal muscular fibers and are possibly life-threatening. The main genetic cause is linked to defects of fatty acid oxidation (FAO) ; nevertheless, half of the cases have no identified aetiology. In 2008, mutations of LPIN1 gene have been reported as a new cause of autosomal recessive rhabdomyolysis. Lipin1 protein has a double function : 1) a role of phosphatidate phosphatase 1 (PAP1) involved in synthesis of triacylglycerol and membrane phospholipids ; 2) a role of transcriptional co-activator which regulates, in association with the PPARs (peroxysome-proliferator activated receptor) and PGC1a (PPARg-coactivator1a), numerous genes involved in the metabolism including some genes encoding FAO enzymes. Lipin1 has got two homologues, lipin2 and lipin3, which have a PAP1 activity and a binding site for nuclear receptors, such as the PPARs. We have shown that LPIN1 mutations account for more than 50% of the cases of severe rhabdomyolysis of early infancy, when FAO defects have been excluded. An intragenic in frame deletion has been frequently identified in Caucasians. We have shown that it probably comes from a founding effect and that this deletion is deleterious. Unlike normal lipin1, deleted lipin1 protein is unable to complement the pah1 yeast which is defective for the yeast LPIN1 homolog. In a series of 171 patients, we have further studied the involvement LPIN1 in less severe muscular diseases, as well as the role of the two homologues LPIN2 and LPIN3. LPIN1 mutations are involved only in severe and early rhabdomyolyses and the bouts of rhabdomyolysis always have a triggerring factor, mainly acute febrile infections. No major alteration of LPIN2 and LPIN3 has been identified, even in milder phenotypes. Eventually, we have cultivated myoblasts and myotubes of patients with LPIN1 mutations in order to study the mechanisms of the rhabdomyolysis. Lipin1-deficient myoblasts have a drastically decreased PAP1 activity and an accumulation of lipid droplets. The expression level of target genes of the transcription factors co-activated by lipin1 (PPAR , PPARa, PGC1a, acyl-Coenzyme A very long chain dehydrogenase (ACADVL), carnitine palmitoyl-transferase 1B and 2 (CPT1B and CPT2)) are similar to controls, whereas the level of lipin2 is increased. Transcriptomic analysis of myotube cultures have identified in patients 19 under-expressed genes and 51 over-expressed ones, notably ACACB, which encodes Accb (acetyl-CoA carboxylase b), key enzyme of the balance between fatty acid synthesis and FAO. ACACB invalidation by siRNA in lipin1-deficient myoblasts decreases the number of lipid droplets, comforting the link between ACACB over-expression and free fatty acid accumulation in patients. However, the level of malonyl-CoA, product of Accb, and CPT1 activity (limitative step of FAO, inhibited by malonyl-CoA), are similar between myoblasts of patients and controls. But treatment of the cultures with an association of tumor necrosis factor a and interleukin-1 b (TNFa + IL-1b), chosen for mimicking pro-inflammatory conditions of acute infections, leads to a further increase of the level of malonyl-CoA, a decrease of CPT1 activity and an increase of lipid droplets accumulation in patients. In total, our data show that LPIN1 is an important cause of inherited rhabdomyolysis. Lipin1 deficiency leads to a disturbance of the lipidic metabolism, via ACACB over-expression, which is exacerbated in pro-inflammatory conditions. Our results suggest that the consequences of lipin1 deficiency are counterbalanced by adaptative mechanisms which are sufficient at basal state, but insufficient for the metabolic request induced by environmental stresses, such as infections, leading to the rhabdomyolyses. Next step is the study of adipose tissue and the establishment of the inflammatory signature of the patients, in order to determine if this new disease is an auto-inflammatory pathology.PARIS5-Bibliotheque electronique (751069902) / SudocSudocFranceF

Nouveautés radiologiques dans le dépistage et le diagnostic des erreurs innées du métabolisme

Les maladies héréditaires du métabolisme ont acquis une place de plus en plus importante dans la pathologie pédiatrique. Leur nombre ne cesse d’augmenter au fur et à mesure de la progression des connaissances en biologie cellulaire et des progrès techniques d’investigation. Nous traiterons ici de trois maladies métaboliques que l’imagerie fonctionnelle et la spectroscopie IRM ont permis d’identifier. Il s’agit des déficits en créatine traitables par l’administration de créatine et les défauts du métabolisme des polyols qui ouvrent le champ sur de nouveaux déficits enzymatiques responsables de présentations cliniques très variées. Nous aborderons également les hyperinsulinismes du jeune enfant dont le diagnostic et la prise en charge ont été récemment transformées par l’utilisation de la [18F]-fluoro-L-DOPA en tomographie par émission de positons.New metabolic diseases are regularly identified by a genetic or biochemical approach. Indeed, the metabolic diseases result from an enzymatic block with accumulation of a metabolite upstream to the block and deficit of a metabolite downstream. The characterization of these abnormal metabolites by MRI spectroscopy permitted to identify the deficient enzyme in two new groups of diseases, creatine deficiencies and polyol anomalies. Creatine deficiency is implicated in unspecific mental retardation. A low peak of creatine at MRI spectroscopy is evocating of creatine deficiency which is treatable by creatine administration. Deficiency of synthesis of polyols, metabolites on the pentose pathway, represent new described metabolic diseases with variable symptoms including a neurological distress, liver disease, splenomegaly, cutis laxa and renal insufficiency. The deficit of ribose-5-phosphate isomerase, one of the enzymes whose diagnosis is evoked in front of the accumulation of ribitol, arabitol and xylitol leads to a leucodystrophy in adults. This new deficit was highlighted by the identification of an abnormal peak in cerebral MRI-spectroscopy corresponding to the abnormal accumulation of polyols in brain. Congenital hyperinsulinism (HI) is characterized by profound hypoglycaemia related to inappropriate insulin secretion. Focal and diffuse forms of hyperinsulinism share a similar clinical presentation but their treatment is dramatically different. Until recently, preoperative differential diagnosis was based on pancreatic venous sampling, an invasive and technically demanding technique. Positron emission tomography (PET) after injection of [18F]Fluoro-L-DOPA has been evaluated for the preoperative differentiation between focal and diffuse HI, by imaging uptake of radiotracer and the conversion of [18F]Fluoro-L-DOPA into dopamine by DOPA decarboxylase. PET with [18F]Fluoro-L-DOPA has been validated as a reliable test to differentiate diffuse and focal HI and is now a major differential diagnosis tool in infantile hyperinsulinemic hypoglycaemia

Congenital hyperinsulinism: current trends in diagnosis and therapy

Congenital hyperinsulinism (HI) is an inappropriate insulin secretion by the pancreatic β-cells secondary to various genetic disorders. The incidence is estimated at 1/50, 000 live births, but it may be as high as 1/2, 500 in countries with substantial consanguinity. Recurrent episodes of hyperinsulinemic hypoglycemia may expose to high risk of brain damage. Hypoglycemias are diagnosed because of seizures, a faint, or any other neurological symptom, in the neonatal period or later, usually within the first two years of life. After the neonatal period, the patient can present the typical clinical features of a hypoglycemia: pallor, sweat and tachycardia. HI is a heterogeneous disorder with two main clinically indistinguishable histopathological lesions: diffuse and focal. Atypical lesions are under characterization. Recessive ABCC8 mutations (encoding SUR1, subunit of a potassium channel) and, more rarely, recessive KCNJ11 (encoding Kir6.2, subunit of the same potassium channel) mutations, are responsible for most severe diazoxide-unresponsive HI. Focal HI, also diazoxide-unresponsive, is due to the combination of a paternally-inherited ABCC8 or KCNJ11 mutation and a paternal isodisomy of the 11p15 region, which is specific to the islets cells within the focal lesion. Genetics and 18F-fluoro-L-DOPA positron emission tomography (PET) help to diagnose diffuse or focal forms of HI. Hypoglycemias must be rapidly and intensively treated to prevent severe and irreversible brain damage. This includes a glucose load and/or a glucagon injection, at the time of hypoglycemia, to correct it. Then a treatment to prevent the recurrence of hypoglycemia must be set, which may include frequent and glucose-enriched feeding, diazoxide and octreotide. When medical and dietary therapies are ineffective, or when a focal HI is suspected, surgical treatment is required. Focal HI may be definitively cured when the partial pancreatectomy removes the whole lesion. By contrast, the long-term outcome of diffuse HI after subtotal pancreatectomy is characterized by a high risk of diabetes, but the time of its onset is hardly predictable

Long-term neurological outcome of a cohort of 80 patients with classical organic acidurias.

International audienceBACKGROUND: Classical organic acidurias including methylmalonic aciduria (MMA), propionic aciduria (PA) and isovaleric aciduria (IVA) are severe inborn errors of the catabolism of branched-chain amino acids and odd-numbered chain fatty acids, presenting with severe complications. METHODS: This study investigated the long-term outcome of 80 patients with classical organic aciduria (38 with MMA, 24 with PA and 18 with IVA) by integrating clinical, radiological, biochemical and genetic data. RESULTS: Patients were followed-up for a mean of 14 years [age 3.3-46.3 years]. PA included a greater number of patients with abnormal neurological examination (37% in PA, 24% in MMA and 0% in IVA), lower psychometric scores (abnormal evaluation at age 3 years in 61% of patients with PA versus 26% in MMA and 18% in IVA) and more frequent basal ganglia lesions (56% of patients versus 36% in MMA and 17% in IVA). All patients with IVA presented a normal neurological examination and only 1/3 presented cognitive troubles. Prognosis for MMA was intermediate. Biochemical metabolite analysis excluding acute decompensations revealed significant progressive increases of glycine, alanine and glutamine particularly in PA and possibly in MMA but no correlation with neurological outcome. A significant increase of plasma methylmalonic acid was found in MMA patients with intellectual deficiency (mean level of 199 mumol/L versus 70 mumol/L, p < 0.05), with an estimated significant probability of severe outcome for average levels between birth and age 6 years above 167 mumol/L. Urinary 3-hydroxypropionate (3-HP) levels were significantly higher in PA patients with intellectual deficiency (mean level of 68.9 mumol/mmol of creatinine versus 34.6 mumol/mmol of creatinine, p < 0.01), with an estimated significant probability of severe outcome for average levels between birth and age 6 years above 55 mumol/mmol. As for molecular analysis, prognosis of MMA patients with mutations involving the MMAA gene was better compared to patients with mutations involving the MUT gene. CONCLUSION: Propionic aciduria had the most severe neurological prognosis. Our radiological and biochemical data are consistent with a mitochondrial toxicity mechanism. Follow-up plasma MMA and urinary 3-HP levels may have prognostic significance calling for greater efforts to optimize long-term management in these patients

Острый рабдомиолиз

Rhabdomyolysis results from the rapid breakdown of skeletal muscle fibers, which leads to leakage of potentially toxic cellular contents into the systemic circulation. Acquired causes by direct injury to the sarcolemma are the most frequent. The inherited causes are: metabolic with failure of energy production, including mitochondrial fatty acid ß-oxidation defects, LPIN1 mutations, inborn errors of glycogenolysis and glycolysis, more rarely mitochondrial respiratory chain deficiency, purine defects and peroxysomalα-Methylacyl-CoA-racemase defect (AMACR); dystrophinopathies and myopathies; calcic causes with RYR1 mutations; inflammatory with myositis. Irrespective of the cause of rhabdomyolysis, the pathophysiologic events follow a common pathway, the ATP depletion leading to an increased intracellular calcium concentration and necrosis. Most episodes of rhabdomyolysis are triggered by an environmental stress, mostly fever. This condition is associated with two events, elevated temperature and high circulating levels of pro-inflammatory mediators such as cytokines and chemokines. We describe here an example of rhabdomyolysis related to high temperature, aldolase deficiency, in 3 siblings with episodic rhabdomyolysis without hemolytic anemia. Myoglobinuria was always triggered by febrile illnesses. We show that the underlying mechanism involves an exacerbation of aldolase A deficiency at high temperatures that affected myoblasts but not erythrocytes. Thermolability was enhanced in patient myoblasts compared to control. The aldolase A deficiency was rescued by arginine supplementation in vitro. Lipid droplets accumulated in patient myoblasts relative to control and this was increased by cytokines. Lipotoxicity may participate to myolysis. Our results expand the clinical spectrum of aldolase A deficiency to isolated temperature-dependent rhabdomyolysis, and suggest that thermolability may be tissue specific. We also propose a treatment for this severe disease. Some other diseases involved in rhabdomyolysis may implicate pro-inflammatory cytokines and may be proinflammatory diseases.Острый рабдомиолиз – драматичное внезапное разрушение мышечных волокон скелетных мышц. К генетическим этиологическим факторам относят: метаболические расстройства, сопровождаемые дефицитом окисления жирных кислот, дефицитом липина-1, аномалии гликогенолиза и гликолиза, реже – дефицит митохондриальной дыхательной цепи, дефицит пурина и пероксизмальный дефицит α-метил-ацил-КоА-рацемазы (α-methyl-acyl-CoA-acemase, AMACR); структурные патологии в рамках дистрофинопатий и миопатий; аномалии кальциевого обмена с мутациями в гене RYR1; воспалительные реакции, ассоциированные с миозитом. Независимо от причины, дефицит аденозинтрифосфата в миоците приводит к повышению содержания внутриклеточного кальция и некрозу мышечных волокон. Провоцирующим фактором рабдомиолиза могут быть экзогенные факторы, среди которых травматизация мышц является самой частой причиной рабдомиолиза метаболического генеза. В случае лихорадки следует учитывать 2 фактора: повышение температуры тела и существование провоспалительных цитокинов. В статье описан случай рабдомиолиза у 3 детей от близкородственного брака, спровоцированный гипертермией и вызванный дефицитом альдолазы А, не сопровождаемой гемолитической анемией. В рассматриваемом случае миоглобинурия была всегда вызвана фебрильной температурой. В свою очередь, фермент альдолаза-А обладает тканеспецифичной термолабильностью: при тестируемых температурах он обнаружен в миобластах, но не в эритроцитах, что объясняет специфическую симптоматику у описываемых пациентов. Существуют предположения, что в клеточной липотоксичности участвуют так называемые жировые капли. В ходе исследований in vitro дефицит альдолазы А был возмещен добавлением аргинина. Другие типы рабдомиолиза метаболического генеза, вероятно, являются провоспалительными заболеваниями.перевод: Мария Олеговна Ковальчу

LPIN1 gene mutations: a major cause of severe rhabdomyolysis in early childhood.

International audienceAutosomal recessive LPIN1 mutations have been recently described as a novel cause of rhabdomyolysis in a few families. The purpose of the study was to evaluate the prevalence of LPIN1 mutations in patients exhibiting severe episodes of rhabdomyolysis in infancy. After exclusion of primary fatty acid oxidation disorders, LPIN1 coding sequence was determined in genomic DNA and cDNA. Among the 29 patients studied, 17 (59%) carried recessive nonsense or frameshift mutations, or a large scale intragenic deletion. In these 17 patients, episodes of rhabdomyolysis occurred at a mean age of 21 months. Secondary defect of mitochondrial fatty oxidation or respiratory chain was found in skeletal muscle of two patients. The intragenic deletion, c.2295-866_2410-30del, was identified in 8/17 patients (47%), all Caucasians, and occurred on the background of a common haplotype, suggesting a founder effect. This deleted human LPIN1 form was unable to complement ∆pah1 yeast for growth on glycerol, in contrast to normal LPIN1. Since more than 50% of our series harboured LPIN1 mutations, LPIN1 should be regarded as a major cause of severe myoglobinuria in early childhood. The high frequency of the intragenic LPIN1 deletion should provide a valuable criterion for fast diagnosis, prior to muscle biopsy

Should patients with Phosphomannomutase 2-CDG (PMM2-CDG) be screened for adrenal insufficiency?

PMM2-CDG is the most common congenital disorder of glycosylation (CDG) accounting for almost 65% of known CDG cases affecting N-glycosylation. Abnormalities in N-glycosylation could have a negative impact on many endocrine axes. There is very little known on the effect of impaired N-glycosylation on the hypothalamic-pituitary-adrenal axis function and whether CDG patients are at risk of secondary adrenal insufficiency and decreased adrenal cortisol production. Cortisol and ACTH concentrations were simultaneously measured between 7:44 am to 1 pm in forty-three subjects (20 female, median age 12.8 years, range 0.1 to 48.6 years) participating in an ongoing international, multi-center Natural History study for PMM2-CDG (ClinicalTrials.gov Identifier: NCT03173300). Of the 43 subjects, 11 (25.6%) had cortisol below 5 μg/dl and low to normal ACTH levels, suggestive of secondary adrenal insufficiency. Two of the 11 subjects have confirmed central adrenal insufficiency and are on hydrocortisone replacement and/or stress dosing during illness; 3 had normal and 1 had subnormal cortisol response to ACTH low-dose stimulation test but has not yet been started on therapy; the remaining 5 have upcoming stimulation testing planned. Our findings suggest that patients with PMM2-CDG may be at risk for adrenal insufficiency. Monitoring of morning cortisol and ACTH levels should be part of the standard care in patients with PMM2-CDG.Glycomine, Inc. was the sponsor of this study, and was involved in the study design and in the and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. Several authors of this publication are members of the European Reference Network for Rare Hereditary Metabolic Disorders (MetabERN) - Project ID No 739543.info:eu-repo/semantics/publishedVersio

Genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy (ALDH7A1 deficiency)

Pyridoxine-dependent epilepsy was recently shown to be due to mutations in the ALDH7A1 gene, which encodes antiquitin, an enzyme that catalyses the nicotinamide adenine dinucleotide-dependent dehydrogenation of L-{alpha}-aminoadipic semialdehyde/L-{Delta}1-piperideine 6-carboxylate. However, whilst this is a highly treatable disorder, there is general uncertainty about when to consider this diagnosis and how to test for it. This study aimed to evaluate the use of measurement of urine L-{alpha}-aminoadipic semialdehyde/creatinine ratio and mutation analysis of ALDH7A1 (antiquitin) in investigation of patients with suspected or clinically proven pyridoxine-dependent epilepsy and to characterize further the phenotypic spectrum of antiquitin deficiency. Urinary L-{alpha}-aminoadipic semialdehyde concentration was determined by liquid chromatography tandem mass spectrometry. When this was above the normal range, DNA sequencing of the ALDH7A1 gene was performed. Clinicians were asked to complete questionnaires on clinical, biochemical, magnetic resonance imaging and electroencephalography features of patients. The clinical spectrum of antiquitin deficiency extended from ventriculomegaly detected on foetal ultrasound, through abnormal foetal movements and a multisystem neonatal disorder, to the onset of seizures and autistic features after the first year of life. Our relatively large series suggested that clinical diagnosis of pyridoxine dependent epilepsy can be challenging because: (i) there may be some response to antiepileptic drugs; (ii) in infants with multisystem pathology, the response to pyridoxine may not be instant and obvious; and (iii) structural brain abnormalities may co-exist and be considered sufficient cause of epilepsy, whereas the fits may be a consequence of antiquitin deficiency and are then responsive to pyridoxine. These findings support the use of biochemical and DNA tests for antiquitin deficiency and a clinical trial of pyridoxine in infants and children with epilepsy across a broad range of clinical scenarios

Genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy (ALDH7A1 deficiency)

Pyridoxine-dependent epilepsy was recently shown to be due to mutations in the ALDH7A1 gene, which encodes antiquitin, an enzyme that catalyses the nicotinamide adenine dinucleotide-dependent dehydrogenation of l-α-aminoadipic semialdehyde/l-Δ1-piperideine 6-carboxylate. However, whilst this is a highly treatable disorder, there is general uncertainty about when to consider this diagnosis and how to test for it. This study aimed to evaluate the use of measurement of urine l-α-aminoadipic semialdehyde/creatinine ratio and mutation analysis of ALDH7A1 (antiquitin) in investigation of patients with suspected or clinically proven pyridoxine-dependent epilepsy and to characterize further the phenotypic spectrum of antiquitin deficiency. Urinary l-α-aminoadipic semialdehyde concentration was determined by liquid chromatography tandem mass spectrometry. When this was above the normal range, DNA sequencing of the ALDH7A1 gene was performed. Clinicians were asked to complete questionnaires on clinical, biochemical, magnetic resonance imaging and electroencephalography features of patients. The clinical spectrum of antiquitin deficiency extended from ventriculomegaly detected on foetal ultrasound, through abnormal foetal movements and a multisystem neonatal disorder, to the onset of seizures and autistic features after the first year of life. Our relatively large series suggested that clinical diagnosis of pyridoxine dependent epilepsy can be challenging because: (i) there may be some response to antiepileptic drugs; (ii) in infants with multisystem pathology, the response to pyridoxine may not be instant and obvious; and (iii) structural brain abnormalities may co-exist and be considered sufficient cause of epilepsy, whereas the fits may be a consequence of antiquitin deficiency and are then responsive to pyridoxine. These findings support the use of biochemical and DNA tests for antiquitin deficiency and a clinical trial of pyridoxine in infants and children with epilepsy across a broad range of clinical scenario

Tyrosine hydroxylase deficiency: a treatable disorder of brain catecholamine biosynthesis

Tyrosine hydroxylase deficiency is an autosomal recessive disorder resulting from cerebral catecholamine deficiency. Tyrosine hydroxylase deficiency has been reported in fewer than 40 patients worldwide. To recapitulate all available evidence on clinical phenotypes and rational diagnostic and therapeutic approaches for this devastating, but treatable, neurometabolic disorder, we studied 36 patients with tyrosine hydroxylase deficiency and reviewed the literature. Based on the presenting neurological features, tyrosine hydroxylase deficiency can be divided in two phenotypes: an infantile onset, progressive, hypokinetic-rigid syndrome with dystonia (type A), and a complex encephalopathy with neonatal onset (type B). Decreased cerebrospinal fluid concentrations of homovanillic acid and 3-methoxy-4-hydroxyphenylethylene glycol, with normal 5-hydroxyindoleacetic acid cerebrospinal fluid concentrations, are the biochemical hallmark of tyrosine hydroxylase deficiency. The homovanillic acid concentrations and homovanillic acid/5-hydroxyindoleacetic acid ratio in cerebrospinal fluid correlate with the severity of the phenotype. Tyrosine hydroxylase deficiency is almost exclusively caused by missense mutations in the TH gene and its promoter region, suggesting that mutations with more deleterious effects on the protein are incompatible with life. Genotype-phenotype correlations do not exist for the common c.698G>A and c.707T>C mutations. Carriership of at least one promotor mutation, however, apparently predicts type A tyrosine hydroxylase deficiency. Most patients with tyrosine hydroxylase deficiency can be successfully treated with l-dop