Recommendations for diagnosing and managing individuals with glutaric aciduria type 1: Third revision.

Glutaric aciduria type 1 is a rare inherited neurometabolic disorder of lysine metabolism caused by pathogenic gene variations in GCDH (cytogenic location: 19p13.13), resulting in deficiency of mitochondrial glutaryl-CoA dehydrogenase (GCDH) and, consequently, accumulation of glutaric acid, 3-hydroxyglutaric acid, glutaconic acid and glutarylcarnitine detectable by gas chromatography/mass spectrometry (organic acids) and tandem mass spectrometry (acylcarnitines). Depending on residual GCDH activity, biochemical high and low excreting phenotypes have been defined. Most untreated individuals present with acute onset of striatal damage before age 3 (to 6) years, precipitated by infectious diseases, fever or surgery, resulting in irreversible, mostly dystonic movement disorder with limited life expectancy. In some patients, striatal damage develops insidiously. In recent years, the clinical phenotype has been extended by the finding of extrastriatal abnormalities and cognitive dysfunction, preferably in the high excreter group, as well as chronic kidney failure. Newborn screening is the prerequisite for pre-symptomatic start of metabolic treatment with low lysine diet, carnitine supplementation and intensified emergency treatment during catabolic episodes, which, in combination, have substantially improved neurologic outcome. In contrast, start of treatment after onset of symptoms cannot reverse existing motor dysfunction caused by striatal damage. Dietary treatment can be relaxed after the vulnerable period for striatal damage, that is, age 6 years. However, impact of dietary relaxation on long-term outcomes is still unclear. This third revision of evidence-based recommendations aims to re-evaluate previous recommendations (Boy et al., J Inherit Metab Dis, 2017;40(1):75-101; Kolker et al., J Inherit Metab Dis 2011;34(3):677-694; Kolker et al., J Inherit Metab Dis, 2007;30(1):5-22) and to implement new research findings on the evolving phenotypic diversity as well as the impact of non-interventional variables and treatment quality on clinical outcomes.

Proposed recommendations for diagnosing and managing individuals with glutaric aciduria type I: second revision.

Glutaric aciduria type I (GA-I; synonym, glutaric acidemia type I) is a rare inherited metabolic disease caused by deficiency of glutaryl-CoA dehydrogenase located in the catabolic pathways of L-lysine, L-hydroxylysine, and L-tryptophan. The enzymatic defect results in elevated concentrations of glutaric acid, 3-hydroxyglutaric acid, glutaconic acid, and glutaryl carnitine in body tissues, which can be reliably detected by gas chromatography/mass spectrometry (organic acids) and tandem mass spectrometry (acylcarnitines). Most untreated individuals with GA-I experience acute encephalopathic crises during the first 6 years of life that are triggered by infectious diseases, febrile reaction to vaccinations, and surgery. These crises result in striatal injury and consequent dystonic movement disorder; thus, significant mortality and morbidity results. In some patients, neurologic disease may also develop without clinically apparent crises at any age. Neonatal screening for GA-I us being used in a growing number of countries worldwide and is cost effective. Metabolic treatment, consisting of low lysine diet, carnitine supplementation, and intensified emergency treatment during catabolism, is effective treatment and improves neurologic outcome in those individuals diagnosed early; treatment after symptom onset, however, is less effective. Dietary treatment is relaxed after age 6 years and should be supervised by specialized metabolic centers. The major aim of this second revision of proposed recommendations is to re-evaluate the previous recommendations (Kölker et al. J Inherit Metab Dis 30:5-22, 2007b; J Inherit Metab Dis 34:677-694, 2011) and add new research findings, relevant clinical aspects, and the perspective of affected individuals.

Clinical awareness for health care professionals: Fatal encephalopathy complicating persistent vomiting in pregnancy.

Women with persistent vomiting during pregnancy need early referral to appropriate health facilities. Delayed referral and inappropriate management may lead to metabolic encephalopathy from a variety of causes, including electrolyte derangements or thiamine deficiency (Wernicke's encephalopathy) (WE). We present a case of persistent vomiting in pregnancy in which there was delayed referral, inappropriate treatment and failure to associate neurological signs such as terminal neck stiffness with WE, resulting in poor fetomaternal outcomes. In this report, we discuss the following lessons: (i) the need for early transfer of a patient with persistent vomiting and enigmatic clinical features to a higher healthcare facility; (ii) failure to associate neurological signs with complications of hyperemesis gravidarum/WE; (iii) lack of thiamine supplementation; and (iv) the advantages of magnetic resonance imaging over a computed tomography scan in the diagnosis of WE.

[Metabolic encephalopathy secondary to vitamin D intoxication]. / Encefalopatía metabólica secundaria a intoxicación por vitamina D.

The association between vitamin D deficiency and increased risk of, among others, cardiovascular and autoimmune diseases has lead in the last years to an enhanced interest in the usage of supplements to achieve the normalization of plasmatic values at 25(OH) D. Apparently this search for normalization is resulting in an higher incidence on vitamin D intoxication. We present the case of an 81 years old woman with metabolic encephalopathy and renal failure secondary to iatrogenic vitamin D intoxication. Calcium and vitamin D oral supplements were prescribed after an osteoporotic vertebral fracture. The patient improved clinically as well as analytically after receiving treatment with diuretics and hydration. We emphasize the importance of discarding hypercalcemia as a cause of metabolic encephalopathy; moreover we highly recommend keeping vitamin D intoxication in mind as an uncommon although always possible etiology of reversible hypercalcemia and renal failure.

La asociación entre la deficiencia de vitamina D y un mayor riesgo de diversas enfermedades, entre ellas cardiovasculares y autoinmunes, ha aumentado en los últimos años el uso de suplementos para la normalización de los valores plasmáticos de esta vitamina. Desde entonces se ha descrito un mayor número de casos de intoxicación iatrogénica por vitamina D. Presentamos una enferma de 81 años con encefalopatía metabólica e insuficiencia renal secundarias a una intoxicación por vitamina D. Los suplementos orales con calcio y vitamina D se le prescribieron después de sufrir una fractura vertebral osteoporótica. La enferma mejoró clínica y analíticamente tras hidratación y diuréticos. Es importante destacar la hipercalcemia como causa de encefalopatía metabólica y considerar la intoxicación por vitamina D como etiología poco frecuente pero posible de hipercalcemia e insuficiencia renal reversibles.

Pyridoxine and pyridoxalphosphate-dependent epilepsies.

To date we know of four inborn errors of autosomal recessive inheritance that lead to vitamin B6-dependent seizures. Among these, pyridoxine-dependent seizures due to antiquitin deficiency is by far the most common, although exact incidence data are lacking. In PNPO deficiency, samples have to be collected prior to treatment, while PDE, hyperprolinemia type II and congenital HPP can be diagnosed while on vitamin B6 supplementation. A vitamin B6 withdrawal for diagnostic purposes is nowadays only indicated in patients with a clear vitamin B6 response but normal biochemical work-up. In the presence of therapy-resistant neonatal seizures, early consideration of a vitamin B6 trial over 3 consecutive days is crucial in order to prevent irreversible brain damage. While PLP would be effective in all four disorders, pyridoxine fails to treat seizures in PNPO deficiency. As PLP is unlicensed within Europe and North America, pyridoxine is widely used as the first line drug, but if it is ineffective it should be followed by a trial with PLP, especially in neonates. As severe apnea has been described in responders, resuscitation equipment should be at hand during a first pyridoxine/PLP administration. Patients and parents have to be informed about the lifelong dependency and recurrence risks in forthcoming pregnancies.

[Wernicke's encephalopathy associated with pellagra encephalopathy: rare and unusual complication in an elderly woman hospitalized for aspiration pneumonia]. / Encéphalopathie de Gayet Wernicke associée à une encéphalopathie pellagrique : complication rare et inhabituelle chez une femme âgée hospitalisée pour pneumopathie d'inhalation.

INTRODUCTION: Wernicke's encephalopathy caused by thiamine deficiency is typically characterised by a mental-status change, oculomotor dysfunction and an ataxia. Pellagra is the clinical presentation of niacin deficiency comprising cutaneous, gastrointestinal and neuropsychiatric manifestations. OBSERVATION: We report a case of encephalopathy due to dual vitamin deficiency of both thiamine (vitamin B1) and niacin (vitamin PP) in an 80-year-old women, hospitalized for severe sepsis caused by aspiration pneumonia. Severe malnutrition and alcohol consumption pointed to a diagnosis of vitamin deficiency. The clinical presentation and magnetic resonance imaging (MRI) were compatible with Wernicke's encephalopathy that remained irreversible despite vitamin B1 supplementation. Niacin supplementation allowed for complete regression of the observed symptoms compatible with niacin deficiency. CONCLUSION: Malnourished and alcoholic patients showing signs of encephalopathy should receive supplemental multivitamins including niacin.

Suspected acquired hypocobalaminaemic encephalopathy in a cat: resolution of encephalopathic signs and MRI lesions subsequent to cobalamin supplementation.

UNLABELLED: PRESENTING SIGNS AND INITIAL INVESTIGATIONS: An 8-year-old female spayed British shorthair cat was presented with a history of waxing and waning neurological signs. Neuroanatomical localisation was consistent with a diffuse forebrain disease. Blood ammonia concentration was increased. Abdominal ultrasonography and a bile acid stimulation test were normal. Magnetic resonance imaging (MRI) revealed hyperintense, bilaterally symmetrical, diffuse lesions on T2-weighted sequences, predominantly, but not exclusively, affecting the grey matter. Serum cobalamin (vitamin B12) concentration was low. Hypocobalaminaemia resulting in a urea cycle abnormality was considered a likely cause of the hyperammonaemia. TREATMENT: Daily cobalamin injections resulted in a rapid clinical improvement. Eight weeks into treatment neurological examination was unremarkable and there was complete resolution of the MRI lesions. CLINICAL IMPORTANCE: This is the first reported case of acquired feline hypocobalaminaemia resulting in an encephalopathy. Additionally, this case is unique in describing reversible brain MRI abnormalities in a cobalamin-deficient companion animal.

Complementary dietary treatment using lysine-free, arginine-fortified amino acid supplements in glutaric aciduria type I - A decade of experience.

The cerebral formation and entrapment of neurotoxic dicarboxylic metabolites (glutaryl-CoA, glutaric and 3-hydroxyglutaric acid) are considered to be important pathomechanisms of striatal injury in glutaric aciduria type I (GA-I). The quantitatively most important precursor of these metabolites is lysine. Recommended therapeutic interventions aim to reduce lysine oxidation (low lysine diet, emergency treatment to minimize catabolism) and to enhance physiologic detoxification of glutaryl-CoA via formation of glutarylcarnitine (carnitine supplementation). It has been recently shown in Gcdh(-/-) mice that cerebral lysine influx and oxidation can be modulated by arginine which competes with lysine for transport at the blood-brain barrier and the inner mitochondrial membrane [Sauer et al., Brain 134 (2011) 157-170]. Furthermore, short-term outcome of 12 children receiving arginine-fortified diet showed very promising results [Strauss et al., Mol. Genet. Metab. 104 (2011) 93-106]. Since lysine-free, arginine-fortified amino acid supplements (AAS) are commercially available and used in Germany for more than a decade, we evaluated the effect of arginine supplementation in a cohort of 34 neonatally diagnosed GA-I patients (median age, 7.43 years; cumulative follow-up period, 221.6 patient years) who received metabolic treatment according to a published guideline [Kölker et al., J. Inherit. Metab. Dis. 30 (2007) 5-22]. Patients used one of two AAS product lines during the first year of life, resulting in differences in arginine consumption [group 1 (Milupa Metabolics): mean=111 mg arginine/kg; group 2 (Nutricia): mean=145 mg arginine/kg; p<0.001]. However, in both groups the daily arginine intake was increased (mean, 137 mg/kg body weight) and the dietary lysine-to-arginine ratio was decreased (mean, 0.7) compared to infants receiving human milk and other natural foods only. All other dietary parameters were in the same range. Despite significantly different arginine intake, the plasma lysine-to-arginine ratio did not differ in both groups. Frequency of dystonia was low (group 1: 12.5%; group 2: 8%) compared with patients not being treated according to the guideline, and gross motor development was similar in both groups. In conclusion, the development of complementary dietary strategies exploiting transport competition between lysine and arginine for treatment of GA-I seems promising. More work is required to understand neuroprotective mechanisms of arginine, to develop dietary recommendations for arginine and to evaluate the usefulness of plasma monitoring for lysine and arginine levels as predictors of cerebral lysine influx.

Acquired encephalopathy associated with carnitine deficiency after cefditoren pivoxil administration.

We describe a 47-year-old woman who presented with palinopsia and subacute altered mental change after cefditoren pivoxil administration. The patient showed characteristic clinical manifestations of hypocarnitinemia, which affected her state of consciousness and she had radiologic findings that revealed metabolic encephalopathy with cytotoxic edema in the right occipital area and intracranial hemorrhages in right occipital and left frontal areas. Follow-up imaging after oral carnitine supplementation demonstrated complete resolution of the bilateral frontal subcortical T2 high-intensity lesions. Carnitine deficiency due to cefditoren pivoxil treatment may present as metabolic encephalopathy in adults. This possibility should be considered with the differential diagnosis of encephalopathies, and carnitine levels should be checked in patients treated with cefditoren pivoxil.

Diagnosis, treatment and outcome of glutaric aciduria type I in Zhejiang Province, China.

BACKGROUND: Glutaric aciduria type I (GA I; MIM 231670) is a rare autosomal recessive disorder resulting from glutaryl-CoA dehydrogenase deficiency. This article reports our experience in the diagnosis, treatment and outcome of GA I patients in Zhejiang Province, China. MATERIAL/METHODS: A total of 129,415 newborns (accounting for approximately one-tenth of the annual births in Zhejiang Province) and 9640 high-risk infants were screened for inborn errors of metabolism in the Neonatal Screening Center of Zhejiang Province during a 3-year period. Tandem mass spectrometry and gas chromatography-mass spectrometry were used for diagnosis of the patients. Dietary modification, carnitine supplementation and aggressive treatment of intercurrent illnesses were adapted for GA I patients. RESULTS: Three infants were diagnosed with GA I by high-risk screening (detection rate: 1/3,213) and 2 were diagnosed by newborn screening (incidence: 1/64,708). Four patients (3 by high-risk screening and 1 by neonatal screening) undergoing MRI examination showed remarkable changes on T2-weighted image. Four patients accepted timely treatment, and in the patient diagnosed by neonatal screening, treatment was delayed until hypotonia appeared 3 months later. Neuropsychological assessment showed mental and motor retardation in 3 patients after treatment, including the patient diagnosed by neonatal screening. CONCLUSIONS: Individualized timely treatment and close monitoring of GA I patients needs to be optimized in China. Appropriate communication with parents may help to achieve successful management of GA I patients.

1H-magnetic resonance spectroscopy indicates damage to cerebral white matter in the subacute phase after CO poisoning.

OBJECTIVE: The authors examined whether (1)H-magnetic resonance spectroscopy (MRS) can identify damage to the centrum semiovale in the subacute phase after CO exposure. METHODS: Subjects comprised 29 adult patients who were treated with hyperbaric oxygenation within a range of 4-95 h (mean 18.7 h) after CO exposure. Subjects were classified into three groups according to clinical behaviours: Group A, patients with transit acute symptoms only; Group P, patients with persistent neurological symptoms; and Group D, patients with 'delayed neuropsychiatric sequelae' occurring after a lucid interval. MRS of bilateral centrum semiovale was performed 2 weeks after CO inhalation for all patients and 13 healthy volunteers. The mean ratios of choline-containing compounds/creatine ((mean)Cho/Cr) and N-acetylaspartate/Cr ((mean)NAA/Cr) for bilateral centrum semiovale were calculated and compared between the three CO groups and controls. Myelin basic protein (MBP) concentration in cerebrospinal fluid was examined at 2 weeks to evaluate the degree of demyelination in patients. RESULTS: MBP concentration was abnormal for almost all patients in Groups P and D, but was not abnormal for any Group A patients. The (mean)Cho/Cr ratios were significantly higher in Groups P and D than in Group A. No significant difference in (mean)NAA/Cr ratio was seen between the three pathological groups and controls. A significant correlation was identified between MBP and (mean)Cho/Cr ratio. CONCLUSIONS: These results suggest that the Cho/Cr ratio in the subacute phase after CO intoxication represents early demyelination in the centrum semiovale, and can predict chronic neurological symptoms.

Lead encephalopathy in an infant mimicking a neurometabolic disorder.

We report the case of a 7-month-old child who presented with regression of milestones, seizures, altered sensorium, and vomiting. An elder sibling had died of similar complaints. Lead encephalopathy was considered because of presence of microcytic hypochromic anemia and dense metaphyseal bands on wrist radiogram. Magnetic resonance imaging (MRI) of the brain revealed diffuse dysmyelination involving both periventricular and subcortical white matter. Such diffuse changes have not been described previously. The child's father was operating an illicit lead-acid battery manufacturing unit at home. The child was subjected to chelation therapy, which was accompanied by environmental exposure source modification. He showed significant improvement. Our case highlights the importance of taking a detailed occupational history and considering lead poisoning in the differential diagnosis of encephalopathy of unidentifiable cause.

Diagnosis, treatment, and long-term outcomes of late-onset (type III) multiple acyl-CoA dehydrogenase deficiency.

We report 4 children with late-onset (type III) multiple acyl-CoA dehydrogenase deficiency, also known as glutaric aciduria type II, which is an autosomal recessive disorder of fatty acid and amino acid metabolism. The underlying deficiency is in the electron transfer flavoprotein or electron flavoprotein dehydrogenase. Clinical presentations include fatal acute neonatal metabolic encephalopathies with/without organ system anomalies (types I and II) and late-onset acute metabolic crises, myopathy, or neurodevelopmental delays (type III). Two patients were identified in childhood following a metabolic crisis and/or neurodevelopmental delay, and 2 were identified by newborn metabolic screening. Our cases will illustrate the difficulty in making a biochemical diagnosis of late-onset (type III) multiple acyl-CoA dehydrogenase deficiency from plasma acylcarnitines and urine organic acids in both symptomatic and asymptomatic children. However, they emphasize the need for timely diagnosis to urgently implement prophylactic treatment for life-threatening metabolic crises with low protein/fat diets supplemented with riboflavin and carnitine.

Phosphorus and proton magnetic resonance spectroscopy demonstrates mitochondrial dysfunction in early and advanced Parkinson's disease.

Mitochondrial dysfunction hypothetically contributes to neuronal degeneration in patients with Parkinson's disease. While several in vitro data exist, the measurement of cerebral mitochondrial dysfunction in living patients with Parkinson's disease is challenging. Anatomical magnetic resonance imaging combined with phosphorus and proton magnetic resonance spectroscopic imaging provides information about the functional integrity of mitochondria in specific brain areas. We measured partial volume corrected concentrations of low-energy metabolites and high-energy phosphates with sufficient resolution to focus on pathology related target areas in Parkinson's disease. Combined phosphorus and proton magnetic resonance spectroscopic imaging in the mesostriatal region was performed in 16 early and 13 advanced patients with Parkinson's disease and compared to 19 age-matched controls at 3 Tesla. In the putamen and midbrain of both Parkinson's disease groups, we found a bilateral reduction of high-energy phosphates such as adenosine triphophosphate and phosphocreatine as final acceptors of energy from mitochondrial oxidative phosphorylation. In contrast, low-energy metabolites such as adenosine diphophosphate and inorganic phosphate were within normal ranges. These results provide strong in vivo evidence that mitochondrial dysfunction of mesostriatal neurons is a central and persistent phenomenon in the pathogenesis cascade of Parkinson's disease which occurs early in the course of the disease.

Defectos de creatina cerebral: ¿cómo poder diagnosticar estas enfermedades y cambiar su evolución? / Brain creatine defects: how can these uncommon diseases be diagnosed and their evolution changed?

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Intracortical inhibition of the motor cortex in Segawa disease (DYT5).

BACKGROUND: Segawa disease (autosomal dominant guanosine triphosphate cyclohydrolase I [GTP-I] deficiency, DYT5) is a hereditary dopa-responsive generalized dystonia. OBJECTIVE: To investigate the pathophysiologic mechanisms for dystonia in Segawa disease, we studied intracortical inhibition of the primary motor cortex in patients with Segawa disease. METHODS: We studied 9 patients with Segawa disease (8 genetically confirmed patients and 1 with abnormally low GTP-I activity) and 12 age-matched normal control subjects. We studied the active motor threshold (AMT) using single pulse transcranial magnetic stimulation (TMS) and the short-interval intracortical inhibition (SICI) of the motor cortex using the previously reported paired pulse TMS method. Responses were recorded from the first dorsal interosseous (FDI) and tibialis anterior (TA) muscles. RESULTS: The AMT was not significantly different between the patients and normal subjects. For both studied muscles, in Segawa disease, normal amount of SICI was evoked at interstimulus intervals (ISIs) of 1 to 4 msec even though they had dystonia in those muscles. CONCLUSION: Normal SICI of the motor cortex in Segawa disease stands in remarkable contrast to the previously reported reduction of SICI in focal dystonia. This suggests that the gamma-aminobutyric acid A system of the motor cortex is intact in Segawa disease. The pathophysiologic mechanisms for dystonia must be partly different between Segawa disease and focal dystonia.

Triphasic waves versus nonconvulsive status epilepticus: EEG distinction.

BACKGROUND: Triphasic waves (TWs) and generalized nonconvulsive status epilepticus (GNCSE) share morphological features that may create diagnostic ambiguity. OBJECTIVE: To describe electroencephalographic differences between TWs and GNCSE. METHODS: We retrospectively compared the electroencephalograms (EEGs) of two groups of patients presenting with decreased level of consciousness; those with TWs associated with metabolic encephalopathy and those with GNCSE. We studied the following: demographics, etiology and EEG morphological features. All EEGs were classified blindly (TWs or GNCSE) by two expert EEGers. Agreement between experts and concordance with clinical diagnosis were measured. RESULTS: We analysed 87 EEGs (71 patients) with TWs and 27 EEGs (13 patients) with GNCSE. Agreement between experts and concordance with clinical diagnosis were excellent. When compared to TWs, epileptiform discharges associated with GNCSE had a higher frequency (mean=2.4Hz vs 1.8Hz) (p<0.001), a shorter duration of phase one (p=0.001), extra-spikes components (69% vs 0%) (p<0.001) and less generalized background slowing (15.1% vs 91.1%) (p<0.001). Amplitude predominance of phase two was common with TWs (40.8% vs 0%) (p=0.01). Lag of phase two was absent in all cases of GNCSE but present in 40.8% of patients with TWs. Noxious or auditory stimulation frequently increased the TWs (51%) while it had no effect on the epileptiform pattern (p=0.008). CONCLUSIONS: Certain EEG morphological criteria and the response to stimulation are very helpful in distinguishing TWs from GNCSE.

Hyperammonaemic encephalopathy secondary to selective cobalamin deficiency in a juvenile Border collie.

An eight-month-old Border collie was presented with anorexia, cachexia, failure to thrive and stupor. Laboratory tests demonstrated a mild anaemia, neutropenia, proteinuria and hyperammonaemia. Serum bile acid concentrations were normal, but an ammonia tolerance test (ATT) was abnormal. The dog responded to symptomatic therapy for hepatoencephalopathy. When a low serum cobalamin (vitamin B12) concentration and methylmalonic aciduria were noted, the dog was given a supplement of parenteral cobalamin. Two weeks later, a repeat ATT was normal. Cobalamin supplementation was continued every two weeks, and all clinical signs, except for proteinuria, resolved despite withdrawing all therapy for hepatoencephalopathy. A presumptive diagnosis of hereditary selective cobalamin malabsorption was made, based on the young age, Border collie breed, low serum cobalamin concentration and methylmalonic aciduria. Although hereditary selective cobalamin malabsorption in Border collies, giant schnauzers, Australian shepherd dogs and beagles has previously been reported in North America, to the authors' knowledge this is the first report of the condition in the UK and the first to document an abnormal ATT in a cobalamin-deficient dog.

[Macrocephaly the first manifestation of glutaric aciduria type I: the importance of early diagnosis]. / Macrocefalia como forma de presentación de la aciduria glutárica tipo 1. Importancia de un diagnóstico precoz.

INTRODUCTION: The clinical manifestations of glutaric aciduria type I (GA-I) usually develop during the first two years of life as acute encephalopathic crisis leading to irreversible dystonic. Progressive macrocephaly can be an early clinical sign. We report a 9 month old patient with macrocephaly diagnosed of GA-I in the presyntomatic stage. This early diagnosis and treatment avoided the irreversible neurologic damage associated to this disease. CASE REPORT: A 9 month old male referred to the pediatrics neurology clinic because of macrocephaly with a head circumference of 51 cm (> 97th percentle). At birth this head circumference was 37.5 cm (97th percentile) and showed rapid growth during the first 4 months of life. In the physical exam there was mild hypotonia and no other neurologic alterations with normal psychomotor development. In the work up for macrocephaly urinary organic acids were determined showing a glutaric acid: 78,000 mmol/mol creatinine (normal values: 2-10); 3-hydroxyglutaric acid: 250 mmol/mol creatinine (normal values: 1-12). Cerebral magnetic resonance (MR) performed at 12 months of age showed frontotemporal atrophy with enlargement of subarachnoid spaces, a high signal in T2 in the pallidus nucleus and subdural hematomas. Genetic analysis showed a mutation S 305 L/Q 352 X in GCDH gene. L-carnitine and riboflavin supplementation and a diet with restriction of lysine and tryptophan was started. Intercurrent illnesses were treated with intravenous fluid, glucose and L-carnitine. At 3 years and 6 month of age, he had not shown any encephalopathic crisis, he had a normal psychomotor development and no dystonia. MR shows mild temporal lobe atrophy without basal ganglia alterations. CONCLUSIONS: In GA-I, macrocephaly is an early sign before other neurologic alterations. In patients with little or no neurological symptoms, early treatment may prevent the acute encephalopathic crisis and neurological deterioration, improving the prognosis and may also normalize the basal ganglia neuroradiological alterations. Urinary organic acid analysis should be performed in the work up of macrocephaly of unknown aetiology.

Macrocefalia como forma de presentación de la aciduria glutárica tipo 1. Importancia de un diagnóstico precoz / Macrocephaly in the first manifestation of glutaric aciduria type I: the importance of early diagnosis

Introducción. La aciduria glutárica tipo I (AG-I) habitualmente se presenta con un deterioro neurológico agudo en los primeros 2 años de vida con secuelas irreversibles. La macrocefalia progresiva puede ser una manifestación precoz de la enfermedad. Presentamos un caso diagnosticado en la fase presintomática, por estudio de macrocefalia, en el cual el tratamiento instaurado precozmente evitó las crisis encefalopáticas y el deterioro neurológico. Caso clínico. Varón de 9 meses de edad remitido por macrocefalia de 51 cm (> p97). El perímetro cefálico al nacimiento era de 37,5 cm (p97) y presentó un incremento acelerado durante los primeros 4 meses de vida. En la exploración física presentaba una discreta hipotonía axial sin otros hallazgos y desarrollo psicomotor normal. Exploraciones complementarias: ácidos orgánicos (o): glutárico: 78.000 mmolfmol creatinina (normal: 2-10); 3-hidroxiglutárico: 250 mmolfmol creatinina (normal: 1-12). Resonancia magnética (RM) cerebral a los 12 meses: atrofia frontotemporal con aumento del espacio subaracnoideo de predominio bitemporal, hiperintensidad en T2 en núcleos pálidos y hematomas subdurales bilaterales. Estudio genético: mutación S 305 L/Q 352 X. Se inició tratamiento con carnitina y riboflavina y dieta restringida en lisina y triptófano. Los procesos intercurrentes infecciosos o de intolerancia oral fueron tratados con aportes intravenosos de líquidos, glucosa y carnitina. Con 3 años y 6 meses no ha presentado crisis encefalopáticas y el desarrollo es normal sin distonías. La RM muestra atrofia de predominio temporal, sin alteraciones de núcleos de la base. Conclusiones. En la AG-I la macrocefalia con frecuencia precede al resto de las manifestaciones neurológicas. El tratamiento en la fase presintomática puede prevenir las crisis encefalopáticas, mejorar el pronóstico e incluso mantener al paciente asintomático. También las alteraciones neurorradiológicas de los núcleos de la base pueden desaparecer con el tratamiento precoz. Ante una macrocefalia de diagnóstico incierto debe realizarse un estudio de ácidos orgánicos en orina

Introduction. The clinical manifestations of glutaric aciduria type 1 (GA-I) usually develop during the first two years of life as acute encephalopathic crisis leading to irreversible dystonic. Progressive macrocephaly can be an early clinical signo We report a 9 month old patient with macrocephaly diagnosed of GA-I in the presyntomatic stage. This early diagnosis and treatment avoided the irreversible neurologic damage associated to this disease. Case report. A 9 month old male referred to the pediatrics neurology clinic because of macrocephaly with a head circumference of 51 cm (> 97th percentle). At birth this head circumference was 37.5 cm (97th percentile) and showed rapid growth during the first 4 months of life. In the physical exam there was ínild hypotonia and no other neurologic alterations with normal psychomotor development. In the work up for macrocephaly urinary organic acids were determined showing a glutaric acid: 78,000 mmolfmol creatinine (normal values: 2-10); 3-hydroxyglutaric acid: 250 mmolfmol creatinine (normal values: 1-12). Cerebral magnetic resonance (MR) performed at 12 months of age showed frontotemporal atrophy with enlargement of subarachnoid spaces, a high signal in T2 in the pallidus nucleus and subdural hematomas. Genetic analysis showed a mutation S 305 LfQ 352 X in GCDH gene. L-camitine and riboflavin supplementation and a diet with restriction of lysine and tryptophan was started. Intercurrent illnesses were treated with intravenous fluid, glucose and L-camitine. At 3 years and 6 month of age, he had not shown any encephalopathic crisis, he had a normal psychomotor development and no dystonia. MR shows mild temporal lobe atrophy without basal ganglia alterations. Conclusions. In GA-I, macrocephaly is an early sign before other neurologic alterations. In patients with little or no neurological symptoms, early treatment may prevent the acute encephalopathic crisis and neurological deterioration, improving the prognosis and may also normalize the basal ganglia neuroradiological alterations. Urinary organic acid analysis should be performed in the work up of macrocephaly of unknown aetiology