Benign nocturnal alternating hemiplegia of childhood: A clinical and nomenclatural reappraisal.

OBJECTIVE: To describe the clinical spectrum of benign nocturnal alternating hemiplegia of childhood (BNAHC) including long-term follow-up data of previously published cases and to propose an underlying genetic cause of this disorder. METHODS: We studied the medical data of two novel patients, reviewed the literature on BNAHC, and gathered information of the most recent follow-up of published cases regarding the course of episodes, further development, attempted drugs, ancillary investigations, and sequelae. RESULTS: All patients, i.e. two novel cases and twelve patients identified in the literature (13 boys, 1 girl, age at onset four months to three years), experienced episodes of hemiplegia during nocturnal or daytime sleep heralded by inconsolable crying. Possible triggers included stress and sleep deprivation. Eleven of fourteen patients had a family history of migraine or 'intermittent headache' and two sets of siblings are reported. In one case, exome sequencing revealed a heterozygous 16p11.2 deletion involving 33 genes, including the PRRT2 gene. EEG showed ictal and/or interictal contralateral slowing in four patients. Treatment efficacy was generally disappointing. A complete disappearance of attacks appeared in nearly all cases at most recent follow-up. In a remarkably high number of cases (10/14, 71%), hyperactive behaviour was reported during follow-up. CONCLUSION: We underscore the phenotypic homogeneity including the self-limiting course of BNAHC episodes and suggest the condition be renamed 'benign childhood hemiplegia during sleep' (BCHS). We propose a role for the PRRT2 gene and the resulting neuronal hyperexcitability as one of its possible underpinning mechanisms and discuss the clinical similarities of BCHS with the recognized PRRT2-related disorders.

Trastornos del movimiento / Movement disorders

Gracias a la aplicación de modernas técnicas como la siguiente secuenciación (next-generation sequencing) en el estudio de encefalopatías aparentemente no heredadas ha sido posible descubrir mutaciones patógenas de novo en genes insospechados y definir los fenotipos de estas mutaciones. Es interesante que, en la mayoría de los casos, sus cuadros clínicos muestran un espectro en el que se solapan encefalopatía epiléptica, trastorno del neurodesarrollo y movimientos anormales de tipo hipercinético. Su fisiopatología se localiza en la sinapsis (sinaptopatías). En este artículo se hace una breve síntesis de estos trastornos y se añade una sencilla nota, en honor al Dr. Natalio Fejerman (1934-2018), sobre la base del denominado "trastorno polimorfo benigno del lactante"

Thanks to the application of modern techniques such as next-generation sequencing in the study of apparently non-inherited encephalopathies it has become possible to describe de novo pathogenic mutations in unsuspected genes and to define the phenotypes of these mutations. Interestingly, in most cases, their clinical signs and symptoms show a spectrum in which epileptic encephalopathy, neurodevelopmental disorder and hyperkinetic abnormal movement disorders overlap. Their pathophysiology is located in synapses (synaptopathies). This article offers a brief summary of these disorders and also includes a simple note, in honour of Dr Natalio Fejerman (1934-2018), on the so-called 'benign polymorphic disorder of infancy'

Transient benign paroxysmal movement disorders in infancy.

This review summarizes the current empirical and clinical literature on benign paroxysmal movement disorders in infancy most relevant to practitioners. Paroxysmal benign movement disorders are a heterogeneous group of movement disorders characterized by their favourable outcome. We pay special attention to the recognition and management of these abnormal motor conditions strongly suggestive of epileptic disorders. They include: neonatal jitteriness; benign neonatal sleep myoclonus; benign paroxysmal tonic upgaze; paroxysmal tonic downgaze, benign paroxysmal torticollis and benign polymorphous movement disorder of infancy.

Environmental circumstances influencing tic expression in children.

AIM: To assess the clinical features and severity of tics and environmental factors influencing tic expression in a cohort of children with tic disorders. METHODS: We performed a cross-sectional study in a cohort of children and adolescents (N = 92) with tic disorders referred to the outpatient clinic of a tertiary-level paediatric centre in Barcelona. The severity of tics was evaluated using the Yale Global Tic Severity Scale (YGTSS). A questionnaire including a list of environmental factors and common daily activities that might influence tic occurrence was completed for patients greater than 5 years old. RESULTS: Children were classified as having Tourette syndrome (TS) (52 patients), chronic motor or phonic tics (22 patients) and tics of less than 12 months' duration (18 patients). Tics worsened with stressful situations, activities related to school, playing video games and watching TV. A significant proportion of children reported a reduction in tics while they were concentrating on artistic or creative activities or when playing sports and participating in outdoor activities. The YGTSS scores were higher for TS patients (P < .001) and correlated positively with the time of evolution of tics (r = .273, P = .026). Poor school performance was associated with TS (p = .043) and higher scores on the YGTSS (P = .018), as well as attention deficit/hyperactivity disorder (P = .007). CONCLUSIONS: Several activities of daily living were identified as modifying tic severity in children and may be important clues for tic management. In a subgroup of children with TS, tics were associated with significant morbidity and poor academic performance. Our results emphasise the importance of developing specific school programmes and tailored recommendations in patients with TS.

Paroxysmal movement disorders and episodic ataxias.

This chapter summarizes clinical symptoms of some paroxysmal dyskinesias (PDs) of infancy and childhood, as well as episodic ataxias. PDs refer to a complex group of disorders whose main feature is the occurrence of sudden, intermittent attacks of abnormal postures and involuntary movements. PDs can sometimes be symptomatic (secondary PDs), but usually an underlying cerebral lesion is not present (primary PDs). Some of the primary PDs are transient, such as benign paroxysmal torticollis of infancy. Chronic PDs are subdivided into nonkinesigenic (Mount and Reback type), kinesigenic (Kertesz type), and exercise-induced (Lance type) but cases that overlap with these types are on record. They are autosomal dominant inherited conditions. The myofibrillogenesis regulator-1 gene is responsible for nonkinesigenic PDs. To date, the genetic basis of kinesigenic PDs remains unknown. Several clinical entities associated epilepsy with PDs, such as infantile convulsions and choreoathetosis (ICCA). Exercise-induced PD type can be produced by mutations in the SLC2A1 gene that encodes Glut1 (glucose transporter type1). Episodic ataxias are inherited disorders of intermittent ataxia. The attacks are brief and triggered by abrupt exercise and emotional stimulus. Between attacks, palpebral and hand muscle myokymia is often seen in episodic ataxia type 1 (EA1). In episodic ataxia type 2 (EA2) interictal nystagmus is usually present. Some of these latter patients develop progressive ataxia with vermian atrophy. This disorder is associated with mutations in the human Ca channel alfa 1 subunit CACN1A4 gene.

Reversible generalized dystonia and encephalopathy from thiamine transporter 2 deficiency.

BACKGROUND: Thiamine transporter-2 deficiency, a condition resulting from mutations in the SLC19A3 gene, has been described in patients with subacute dystonia and striatal necrosis. The condition responds extremely well to treatment with biotin and has thus been named biotin-responsive basal ganglia disease. Recently, this deficiency has also been related to Wernicke's-like encephalopathy and atypical infantile spasms, showing heterogeneous responses to biotin and/or thiamine. METHODS: Two Spanish siblings with a biotin-responsive basal ganglia disease phenotype and mutations in SLC19A3 presented with acute episodes of generalized dystonia, rigidity, and symmetrical lesions involving the striatum, midline nuclei of the thalami, and the cortex of cerebral hemispheres as shown by magnetic resonance imaging. RESULTS: The clinical features resolved rapidly after thiamine administration. CONCLUSIONS: Despite the rarity of thiamine transporter-2 deficiency, it should be suspected in patients with acute dystonia and basal ganglia injury, as thiamine can halt disease evolution and prevent further episodes. © 2012 Movement Disorder Society.

TITF-1 gene mutation in a case of sporadic non-progressive chorea. Response to levodopa treatment.

Benign hereditary chorea (BHC) is a rare autosomal dominant disorder characterized by non-progressive chorea of early onset, without other underlying progressive neurologic dysfunction. Hypothyroidism and pulmonary problems may also be associated. Recently, mutations in the thyroid transcription factor 1 gene (TITF-1), linked to chromosome 14q, have been related to this disorder. We describe the clinical phenotype and response to levodopa treatment in a 6 year-old girl affected with sporadic non-progressive chorea, and a de novo TITF-1 gene mutation, in order to increase understanding of this rare and misdiagnosed disorder.

Update on pediatric dystonias: etiology, epidemiology, and management.

Dystonia is a movement disorder characterized by sustained muscle contractions producing twisting, repetitive, and patterned movements or abnormal postures. Dystonia is among the most commonly observed movement disorders in clinical practice both in adults and children. It is classified on the basis of etiology, age at onset of symptoms, and distribution of affected body regions. ETIOLOGY: The etiology of pediatric dystonia is quite heterogeneous. There are many different genetic syndromes and several causes of symptomatic syndromes. Dystonia can be secondary to virtually any pathological process that affects the motor system, and particularly the basal ganglia. CLASSIFICATION: The etiological classification distinguishes primary dystonia with no identifiable exogenous cause or evidence of neurodegeneration and secondary syndromes. TREATMENT: Treatment for most forms of dystonia is symptomatic and includes drugs (systemic or focal treatments, such as botulinum toxin) and surgical procedures. There are several medications including anticholinergic, dopamine-blocking and depleting agents, baclofen, and benzodiazepines. In patients with dopamine synthesis defects L-dopa treatment may be very useful. Botulinum toxin treatment may be helpful in controlling the most disabling symptoms of segmental or focal dystonia. Long-term electrical stimulation of the globus pallidum internum appears to be especially successful in children suffering from generalized dystonia.

Childhood chorea with cerebral hypotrophy: a treatable GLUT1 energy failure syndrome.

OBJECTIVE: To expand the spectrum of glucose transporter type 1 deficiency syndromes with a novel clinical and radiological phenotype not associated with microcephaly. DESIGN: Case report. SETTING: Two academic medical centers. Patient A 7-year-old patient followed up for 4 years. RESULTS: The patient exhibited a predominant syndrome of chorea and mental retardation associated with a combination of paroxysmal ataxia, dysarthria, dystonia and aggravated intellectual disability induced by fasting or exertion. She harbored a sporadic, heterozygous amino acid insertion in the GLUT1 transporter (insY292) that, in all likelihood, impaired blood-brain glucose flux. Her brain configuration appeared hypotrophic via magnetic resonance imaging, particularly over the occipital lobes. A ketogenic diet resulted in brain growth that accompanied a favorable symptomatic outcome. CONCLUSIONS: To date, glucose transporter type 1 deficiency syndrome includes several epileptic and movement disorder phenotypes caused by the clinical expressivity of the prominent cortical, basal ganglia, and cerebellar abnormalities found in the disease, but hypomorphic or novel variants are probably yet to be discovered.

[Cerebral creatine deficiency: first Spanish patients harbouring mutations in GAMT gene]. / Deficiencia cerebral de creatina: primeros pacientes españoles con mutaciones en el gen GAMT.

BACKGROUND AND OBJECTIVE: Brain creatine (Cr) deficiencies are a group of inborn errors of metabolism that are characterized by an absence or severe reduction of brain Cr. Clinically, these patients can display psychomotor/mental retardation and language disorders, commonly associated with epilepsy or movement disorders. Three metabolic defects are known: two affect synthesis - guanidinoacetate metiltransferase (GAMT) and glycine amidinotransferase (AGAT) deficiencies- and one affect the Cr transporter (CRTR). We present the first three Spanish patients with GAMT deficiency, and we compare their clinical phenotype and treatment response with other published cases. PATIENTS AND METHOD: The three patients presented mental retardation, epilepsy and autistic behaviour. Patient 1 also had severe chorea. Diagnosis was done by biochemical and genetic procedures (guanidinoacetate quantification, determination of GAMT activity and mutation analysis in the GAMT gene). RESULTS: An increase of guanidinoacetate was detected in urine and plasma. Brain magnetic resonance spectroscopy revealed low Cr levels. Enzymatic studies revealed a decreased GAMT activity in fibroblasts. Molecular analysis detected pathogenic mutations in the GAMT gene. After the deficiency was confirmed, the patients started treatment with Cr. In addition, patient 2 and 3 received an arginine-restricted diet and ornithine supplements. All them showed a partial improvement. CONCLUSIONS: Patients with GAMT deficiency have an unspecific but relatively constant clinical presentation. Brain Cr deficiency should be considered in patients with mental retardation of unknown aetiology, specially in those with movement disorders or epilepsy. Early diagnosis is important in cases with known treatment such as GAMT deficiency.

Deficiencia cerebral de creatina: primeros pacientes españoles con mutaciones en el gen GAMT / Cerebral creatine deficiency: First Spanish patients harbouring mutations in GAMT gene

Fundamento y objetivo: Los síndromes de deficiencia cerebral de creatina (Cr) constituyen un grupo de enfermedades neurometabólicas caracterizadas por deficiencia o ausencia de Cr en el cerebro. Cursan con retraso del desarrollo/mental y trastornos del lenguaje, y puede asociarse a epilepsia o a trastornos del movimiento. Se conocen 3 defectos: 2 de la síntesis —deficiencia de guanidinoacetato metiltransferasa (GAMT) y argininaglicina amidinotransferasa (AGAT)— y uno del transporte (CRTR). En este trabajo presentamos los 3 primeros pacientes españoles con deficiencia de GAMT y comparamos su fenotipo clínico y respuesta al tratamiento con otros casos publicados. Pacientes y método: Los pacientes presentan retraso mental, epilepsia y conducta autista. La paciente 1 asocia corea grave. Pacientes y método: El diagnóstico se realizó mediante estudios bioquímicos para cuantificar metabolitos específicos y actividad enzimática y genéticos del gen GAMT. Resultados: En orina y plasma se detectó aumento de guanidinoacetato. La resonancia magnética con espectroscopia reveló reducción marcada de Cr cerebral. Los estudios enzimáticos mostraron disminución de la actividad GAMT en fibroblastos y el estudio molecular reveló mutaciones en el gen GAMT. Tras el diagnóstico, se inició tratamiento con suplemento de Cr, y se asoció en los pacientes 2 y 3 una dieta restringida en arginina y suplemento de ornitina, con mejoría parcial. Conclusiones: Los pacientes con deficiencia de GAMT presentan un fenotipo inespecífico pero relativamente constante. Deben buscarse los síndromes de deficiencia cerebral de Cr en pacientes con retraso mental/psicomotor de etiología desconocida, especialmente si se acompañan de trastornos del movimiento y epilepsia. Es importante el diagnóstico precoz en casos tratables como la deficiencia de GAMT (AU)

Background and objetive: Brain creatine (Cr) deficiencies are a group of inborn errors of metabolism that are characterized by an absence or severe reduction of brain Cr. Clinically, these patients can display psychomotor/mental retardation and language disorders, commonly associated with epilepsy or movement disorders. Three metabolic defects are known: two affect synthesis – guanidinoacetate metiltransferase (GAMT) and glycine amidinotransferase (AGAT) deficiencies– and one affect the Cr transporter (CRTR). We present the first three Spanish patients with GAMT deficiency, and we compare their clinical phenotype and treatment response with other published cases. Patients and method: The three patients presented mental retardation, epilepsy and autistic behaviour. Patient 1 also had severe chorea. Diagnosis was done by biochemical and genetic procedures (guanidinoacetate quantification, determination of GAMT activity and mutation analysis in the GAMT gene).Results: An increase of guanidinoacetate was detected in urine and plasma. Brain magnetic resonance spectroscopy revealed low Cr levels. Enzymatic studies revealed a decreased GAMT activity in fibroblasts. Molecular analysis detected pathogenic mutations in the GAMT gene. Results: After the deficiency was confirmed, the patients started treatment with Cr. In addition, patient 2 and 3 received an arginine-restricted diet and ornithine supplements. All them showed a partial improvement. Conclusions: Patients with GAMT deficiency have an unspecific but relatively constant clinical presentation. Brain Cr deficiency should be considered in patients with mental retardation of unknown aetiology, specially in those with movement disorders or epilepsy. Early diagnosis is important in cases with known treatment such as GAMT deficiency (AU)

Movement disorders in children: recent advances in management.

In recent years there has been a growing interest towards pediatric movement disorders (PMD). The data derived from the synthesis of clinical observation, neuroimaging, biochemical and, molecular genetics studies have allowed for the identification of a significant number of pediatric diseases featuring movement disorders. The purpose of this review is to outline an approach to the advances in management of dystonia, neurotransmitter disorders, tics, and paroxysmal dyskinetic syndromes starting in children younger than 18 yr of age.

Syndrome of fixed dystonia in adolescents--short term outcome in 4 cases.

We describe the clinical features, investigations and outcome of 4 adolescents aged 13, 16, 17 and 19 years, with fixed dystonia. The diagnosis was made within 6 months of the onset of symptoms. One patient had an identifiable traumatic precipitant. All the affected extremities had pain, sudomotor and vascular changes which were consistent with complex regional pain syndrome. The extremities affected by dystonia were the foot and the hand. The dystonia spread to affect other extremities in one patient. One patient had hemifacial spasm. Examination of the central and peripheral nervous system and allied investigations failed to reveal an organic cause. Common genetic causes for dystonia were excluded. The response to physical treatments for the affected extremities, such as Botulinum Toxin and surgery was poor. In all our cases there were significant psychological and psychiatric factors. Three patients fully met the criteria for psychogenic dystonia and responded well to psychological intervention. Fixed dystonia in adolescents is an uncommon disorder of unknown aetiology, usually presenting in girls, which can be very disabling and difficult to treat. The affected parts of the body are usually painful and show vascular changes. The condition is allied to CRPS. Treatment with multidisciplinary approach including psychological measures and physiotherapy is more likely to be successful and may prevent unnecessary physical measures.

A homozygous tyrosine hydroxylase gene promoter mutation in a patient with dopa-responsive encephalopathy: clinical, biochemical and genetic analysis.

We report a recessive mutation in the tyrosine hydroxylase gene (TH) promoter (c.1-71C>T), present at homozygosity in a patient with dopa-responsive encephalopathy. The change lies in a cAMP response element (CRE) and alters a binding site for the CREM transcription factor. Previous studies support that the CRE in the TH gene is essential for its transcription, suggesting that mutations within this consensus motif may cause an impairment of catecholamine biosynthesis and lead to a pathogenic phenotype.

[Usefulness of analysis of cerebrospinal fluid for the diagnosis of neurotransmitters and pterin defects and glucose and folate transport deficiencies across blood brain barrier]. / Utilidad del análisis del líquido cefalorraquídeo para el estudio de las deficiencias del metabolismo de neurotransmisores y pterinas y del transporte de glucosa y folato a través de la barrera hematoencefálica.

BACKGROUND AND OBJECTIVE: In the last few years, it has been described inborn errors of neurotransmitter and pterin metabolism and defects in folate and glucose transport across blood brain barrier. All these defects are classified as rare diseases and needs cerebrospinal fluid (CSF) sample analysis for diagnosis. Our aim was to evaluate the results of the application of a CSF analysis protocol in a pediatric population from Spain and Portugal presenting with neurological disorders of unknown origin. PATIENTS AND METHOD: We studied CSF samples from and 283 patients with neurological disorders of unknown origin and 127 controls. Neurotransmitters were analysed by HPLC with electrochemical detection, and pterins and 5-methyltetrahydrofolate were determined by HPLC with fluorescence detection. RESULTS: We diagnosed 3 patients with tyrosine hidroxylase deficiency, 2 with dopa responsive dystonia, 14 with GTP-ciclohydrolase deficiency, 2 with glucose transport deficiency and 43 with cerebral folate deficiency. CONCLUSIONS: This study allowed us to diagnose new patients, and more importantly, the establishment in all of them of a pharmacological or nutritional treatment. The most frequent defect found was CSF 5-methyltetrahydrofolate deficiency, which was present in different groups of patients.

Utilidad del análisis del líquido cefalorraquídeo para el estudio de las deficiencias del metabolismo de neurotransmisores y pterinas y del transporte de glucosa y folato a través de la barrera hematoencefálica / Usefulness of analysis of cerebrospinal fluid for the diagnosis of neurotransmitters and pterin defects and glucose and folate transport deficiencies across blood brain barrier

Fundamento y objetivo: En la última década se ha descrito diferentes errores congénitos del metabolismo de los neurotransmisores (NT), en especial de las vías dopaminérgica y serotoninérgica y de las pterinas. También se ha descrito defectos primarios en el transporte de glucosa y 5-metiltetrahidrofolato (5-MTHF) a través de la barrera hematoencefálica, todos ellos enfermedades raras para cuyo diagnóstico es necesario el estudio en líquido cefalorraquídeo (LCR). Nuestro objetivo ha sido evaluar los resultados de la aplicación de un protocolo de análisis de LCR en España y Portugal durante 3 años en pacientes pediátricos con trastornos neurológicos de origen desconocido. Pacientes y método: Se estudió a 127 individuos control y 283 pacientes con trastornos neurológicos de origen desconocido. El análisis de NT se realizó mediante HPLC con detección electroquímica y el análisis de pterinas y 5-MTHF, mediante HPLC con detección de fluorescencia. Resultados: Se ha diagnosticado 3 deficiencias de tirosina hidroxilasa en una misma familia, 2 casos de distonía sensible a L-dopa, 2 familias con defiencia de guanosinatrifosfato-ciclohidrolasa dominante (14 casos), 2 deficiencias del transportador de glucosa y 43 deficiencias de folato en LCR. Conclusiones: Este estudio ha permitido el diagnóstico de nuevos pacientes y, lo que es más importante, el establecimiento en todos ellos de un tratamiento farmacológico o nutricional. Las deficiencias de 5-MTHF han sido las más frecuentes y se las ha detectado en diferentes grupos de pacientes

Background and objective: In the last few years, it has been described inborn errors of neurotransmitter and pterin metabolism and defects in folate and glucose transport across blood brain barrier. All these defects are classified as rare diseases and needs cerebrospinal fluid (CSF) sample analysis for diagnosis. Our aim was to evaluate the results of the application of a CSF analysis protocol in a pediatric population from Spain and Portugal presenting with neurological disorders of unknown origin. Patients and method: We studied CSF samples from and 283 patients with neurological disorders of unknown origin and 127 controls. Neurotransmitters were analysed by HPLC with electrochemical detection, and pterins and 5-methyltetrahydrofolate were determined by HPLC with fluorescence detection. Results: We diagnosed 3 patients with tyrosine hidroxylase deficiency, 2 with dopa responsive dystonia, 14 with GTP-ciclohydrolase deficiency, 2 with glucose transport deficiency and 43 with cerebral folate deficiency. Conclusions: This study allowed us to diagnose new patients, and more importantly, the establishment in all of them of a pharmacological or nutritional treatment. The most frequent defect found was CSF 5-methyltetrahydrofolate deficiency, which was present in different groups of patients

Determination of 5-methyltetrahydrofolate in cerebrospinal fluid of paediatric patients: reference values for a paediatric population.

BACKGROUND: Cerebral folate deficiency (CFD) has been described as a neurological syndrome associated with low 5-methyltetrahydrofolate (5-MTHF) values in cerebrospinal fluid (CSF) with normal folate concentrations in plasma. Our aim was to analyse CSF 5-MTHF concentrations in a paediatric control population and in patients with various neurological disorders. METHODS: We studied plasma and CSF samples from 63 paediatric controls (age range: 2 days to 18 years, average: 3.8 years) and from 165 patients (age range: 1 day to 22 years, average: 5.0 years) with severe epileptic encephalopathies of unknown origin, movement disorders, Rett syndrome and mitochondrial diseases. CSF 5-methyltetrahydrofolate was analysed by reverse phase HPLC with fluorescence detection (excitation: 295 nm and emission: 355 nm). RESULT: A negative correlation between 5-MTHF values and age of controls was observed (r=-0.468; p<0.0001) and reference values were therefore stratified into 3 age groups. Regarding patients, 122 out of 165 showed normal CSF 5-MTHF values while 43 showed decreased values ranging from profound to mild deficiencies. Increased CSF total protein values were associated with the presence of low 5-MTHF concentrations (chi(2)=7.796; p=0.005). CONCLUSIONS: The application of this method has been useful for the establishment of reference values and for diagnosis of CFD in paediatric patients. Furthermore, increased CSF total protein concentrations should be considered as a marker of a possible CFD.

Characterization of tremor in phenylketonuric patients.

Tremor of unknown origin is detected in 10-30% of early-treated and in more than 30% late-treated phenylketonuric patients. With the aim of characterizing tremor in phenylketonuria, we carried out a systematic study in 54 patients aged 6 to 37 years. Tremor examination was done by applying the WHIGET Tremor Rating Scale and by accelerometer recording (BYOPAC System MP100WSW). Age at diet onset, IQ test results, concomitant plasma phenylalanine levels and index of dietary control were also studied. Tremor was not observed at rest in any case, but was apparent in 22 patients (40.7%) when carrying out a kinetic task. In 15 patients tremor was also evident during maintenance of a postural task at a frequency ranging between 7.5 and 12.7 Hz. Frequency of tremor was not significantly modified by loading the arms or by increasing muscle contraction. Patients with tremor had a later age at onset of phenylalanine restricted diet (p < 0.001). Other treatment-related variables did not differ between patients with and without tremor. Our results of the neurophysiological examination suggest that tremor in phenylketonuric patients is dependent on a dysfunction of central nervous system networks and may be an index of cerebral damage.

Association between male gender and pediatric essential tremor.

Approximately 5% of new essential tremor (ET) cases arise during childhood. The goal of the current report was to examine the possible association between male gender and pediatric ET, using data from 95 pediatric ET cases seen at three medical centers (two in the United States and one in Spain). The odds of ET in our sample of cases were threefold higher in boys compared to girls. Whether this association between male gender and pediatric ET represents a selection bias or a true gender-mediated biological difference in disease expression is not known, although some data support the latter possibility.

HPLC with electrochemical and fluorescence detection procedures for the diagnosis of inborn errors of biogenic amines and pterins.

The analysis of biogenic amines (BA) and pterins in cerebrospinal fluid (CSF) is essential for the early diagnosis of neurotransmission defects in the paediatric age. Our aim was to standardize previously reported HPLC procedures for the analysis of BA and pterins in CSF and to establish reference values for a paediatric population. Samples from 127 subjects (age range 11 days to 16 years; average 3.8) were analyzed by HPLC with electrochemical and fluorescence detection. Both BA (homovanilic and 5-hydroxyindoleacetic acid) and pterins (neopterin and biopterin) concentrations in CSF showed a negative correlation with age. This finding led us to stratify reference values into six groups according to age. In conclusion, analysis of BA and pterins in CSF by HPLC procedures is a useful set of tools for the diagnosis of inborn errors of metabolism of these compounds. The establishment of reference intervals may be difficult, since there is a strong correlation between BA concentrations and the age of controls and, as a result, a large number of CSF samples from control populations would be necessary for this purpose.