4-aminopyridine improves evoked potentials and ambulation in the taiep rat: A model of hypomyelination with atrophy of basal ganglia and cerebellum.

The taiep rat is a tubulin mutant with an early hypomyelination followed by progressive demyelination of the central nervous system due to a point mutation in the Tubb4a gene. It shows clinical, radiological, and pathological signs like those of the human leukodystrophy hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC). Taiep rats had tremor, ataxia, immobility episodes, epilepsy, and paralysis; the acronym of these signs given the name to this autosomal recessive trait. The aim of this study was to analyze the characteristics of somatosensory evoked potentials (SSEPs) and motor evoked potentials (MEPs) in adult taiep rats and in a patient suffering from H-ABC. Additionally, we evaluated the effects of 4-aminopyridine (4-AP) on sensory responses and locomotion and finally, we compared myelin loss in the spinal cord of adult taiep and wild type (WT) rats using immunostaining. Our results showed delayed SSEPs in the upper and the absence of them in the lower extremities in a human patient. In taiep rats SSEPs had a delayed second negative evoked responses and were more susceptible to delayed responses with iterative stimulation with respect to WT. MEPs were produced by bipolar stimulation of the primary motor cortex generating a direct wave in WT rats followed by several indirect waves, but taiep rats had fused MEPs. Importantly, taiep SSEPs improved after systemic administration of 4-AP, a potassium channel blocker, and this drug induced an increase in the horizontal displacement measured in a novelty-induced locomotor test. In taiep subjects have a significant decrease in the immunostaining of myelin in the anterior and ventral funiculi of the lumbar spinal cord with respect to WT rats. In conclusion, evoked potentials are useful to evaluate myelin alterations in a leukodystrophy, which improved after systemic administration of 4-AP. Our results have a translational value because our findings have implications in future medical trials for H-ABC patients or with other leukodystrophies.

Corrigendum: ALG1-CDG Caused by Non-Functional Alternative Splicing Involving a Novel Pathogenic Complex Allele.

[This corrects the article DOI: 10.3389/fgene.2021.744884.].

ALG1-CDG Caused by Non-functional Alternative Splicing Involving a Novel Pathogenic Complex Allele.

This study reports on a Mexican mestizo patient with a multi-systemic syndrome including neurological involvement and a type I serum transferrin profile. Clinical exome sequencing revealed complex alleles in ALG1, the encoding gene for the chitobiosyldiphosphodolichol beta-mannosyltransferase that participates in the formation of the dolichol-pyrophosphate-GlcNAc2Man5, a lipid-linked glycan intermediate during N-glycan synthesis. The identified complex alleles were NM_019109.5(ALG1): c.[208 + 16_208 + 19dup; 208 + 25G > T] and NM_019109.5(ALG1): c.[208 + 16_208 + 19dup; 1312C > T]. Although both alleles carried the benign variant c.208 + 16_208 + 19dup, one allele carried a known ALG1 pathogenic variant (c.1312C > T), while the other carried a new uncharacterized variant (c.208 + 25G > T) causing non-functional alternative splicing that, in conjunction with the benign variant, defines the pathogenic protein effect (p.N70S_S71ins9). The presence in the patient's serum of the pathognomonic N-linked mannose-deprived tetrasaccharide marker for ALG1-CDG (Neu5Acα2,6Galß1,4-GlcNAcß1,4GlcNAc) further supported this diagnosis. This is the first report of an ALG1-CDG patient from Latin America.

Longitudinal Evaluation of Cerebellar Signs of H-ABC Tubulinopathy in a Patient and in the taiep Model.

Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is a central neurodegenerative disease due to mutations in the tubulin beta-4A (TUBB4A) gene, characterized by motor development delay, abnormal movements, ataxia, spasticity, dysarthria, and cognitive deficits. Diagnosis is made by integrating clinical data and radiological signs. Differences in MRIs have been reported in patients that carry the same mutation; however, a quantitative study has not been performed so far. Our study aimed to provide a longitudinal analysis of the changes in the cerebellum (Cb), corpus callosum (CC), ventricular system, and striatum in a patient suffering from H-ABC and in the taiep rat. We correlated the MRI signs of the patient with the results of immunofluorescence, gait analysis, segmentation of cerebellum, CC, and ventricular system, performed in the taiep rat. We found that cerebellar and callosal changes, suggesting a potential hypomyelination, worsened with age, in concomitance with the emergence of ataxic gait. We also observed a progressive lateral ventriculomegaly in both patient and taiep, possibly secondary to the atrophy of the white matter. These white matter changes are progressive and can be involved in the clinical deterioration. Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) gives rise to a spectrum of clinical signs whose pathophysiology still needs to be understood.

Auditory impairment in H-ABC tubulinopathy.

Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is a neurodegenerative disease due to mutations in TUBB4A. Patients suffer from extrapyramidal movements, spasticity, ataxia, and cognitive deficits. Magnetic resonance imaging features are hypomyelination and atrophy of the striatum and cerebellum. A correlation between the mutations and their cellular, tissue and organic effects is largely missing. The effects of these mutations on sensory functions have not been described so far. We have previously reported a rat carrying a TUBB4A (A302T) mutation and sharing most of the clinical and radiological signs with H-ABC patients. Here, for the first time, we did a comparative study of the hearing function in an H-ABC patient and in this mutant model. By analyzing hearing function, we found that there are no significant differences in the auditory brainstem response (ABR) thresholds between mutant rats and WT controls. Nevertheless, ABRs show longer latencies in central waves (II-IV) that in some cases disappear when compared to WT. The patient also shows abnormal AEPs presenting only Waves I and II. Distortion product of otoacoustic emissions and immunohistochemistry in the rat show that the peripheral hearing function and morphology of the organ of Corti are normal. We conclude that the tubulin mutation severely impairs the central hearing pathway most probably by progressive central white matter degeneration. Hearing function might be affected in a significant fraction of patients with H-ABC; therefore, screening for auditory function should be done on patients with tubulinopathies to evaluate hearing support therapies.

[Application of BARS scale in children with ataxia in a child rehabilitation center in Chiapas, Mexico]. / Aplicación de la escala BARS en niños con ataxia en un centro de rehabilitación infantil en Chiapas.

BACKGROUND: Ataxias are an heterogeneous group of diseases with different etiologies. Scales are used to understand better its natural history and evaluate properly drug efficacy in clinical trials. SARA and ICARS scales have been the most studied and validated so far. BARS scale is based on a modified form of the ICARS scale and is valid, reliable and sufficiently fast for clinical purposes. METHODS: Cross-sectional, descriptive and correlational study. Kruskall-Wallis test was used. We administered BARS to children from 4 to 18 years of age, with ataxic syndrome, without cognitive impairment, in active status, from February, 2007 to September, 2014, at the CRIT (Centro de Rehabilitación Infantil Teletón) from Chiapas, Mexico. RESULTS: 14 children were included. The main BARS score was 17.9/30; 4H syndrome with the worst score was 27.6/30; ataxia telangiectasia 15.6/30; ataxic cerebral palsy 12/30; and others 16.1/30. Kruskall-Wallis test did not show a significant statistically difference when comparing the etiology with BARS score (p = 0.068). CONCLUSIONS: BARS items were an easy way to assess ataxic clinic in children; worse condition was found in neurodegenerative ataxias and better results in ataxic cerebral palsy.

INTRODUCCIÓN: las ataxias son enfermedades con diferentes etiologías. Las escalas son usadas para entender mejor la historia natural de la enfermedad y evaluar la eficacia de los tratamientos en ensayos clínicos. Las escalas SARA e ICARS han sido las mejor validadas hasta el momento. La escala BARS se basa en una modificación de ICARS y es valida, confiable y suficientemente rápida para propósitos clínicos. Métodos: estudio transversal, descriptivo y correlacional, en el que se empleó la prueba de Kruskall-Wallis. Se aplicó la escala BARS a niños de 4 a 18 años, con ataxia sin deterioro cognitivo, en estado activo, de febrero 2007 a septiembre 2014 en el CRIT de Chiapas, México. RESULTADOS: se incluyeron 14 niños. El promedio de BARS fue 17.9/30; el síndrome de 4H con el peor promedio fue de 27.6/30; la ataxia telangiectasia 15.6/30; la parálisis cerebral atáxica 12/30, y otras etiologías 16.1/30. La prueba KruskalWallis no mostró diferencia significativa cuando se comparó la etiología con BARS (p = 0.068). CONCLUSIONES: los ítems de la escala BARS son una manera rápida de evaluar clínica de ataxia en niños; los peores puntajes fueron encontrados en enfermedades neurodegenerativas y los mejores en parálisis cerebral atáxica.

[Wernicke's encephalopathy and Caine criteria. Report of six cases]. / Encefalopatía de Wernicke y criterios de Caine. Informe de seis casos.

BACKGROUND: Wernicke's encephalopathy is an acute and reversible neurologic disorder due to deficiency of thiamin. Chronic alcoholism was the main cause in the past; currently, there are many other situations which favour this condition: prolonged intravenous feeding, hyperemesis gravidarum, anorexia nervosa, regional enteritis, malabsorption syndrome, hemodialysis, peritoneal dialysis, and abdominal surgery. CLINICAL CASE: We report six patients, three male and three female, who had in common total parenteral nutrition over two months, secondary to abdominal surgery complications and restriction to enteral nutrition. Clinical manifestations were drowsiness, psychomotor hyperactivity, ophthalmoplegia with bilateral abduction impairment, horizontal nystagmus; three patients with ataxia and appendicular dysmetria. Magnetic resonance imaging showed abnormal T2 hyperintensity of the superior colliculus, periaqueductal gray matter, mammillary bodies and dorsomedial nucleus of the thalamus, as well as abnormal T1 hyperintensity in both lenticular nucleus from manganese deposits due to total parenteral nutrition. CONCLUSIONS: The classical triad is global confusional state, ocular abnormalities and ataxia. However, using the Caine criteria, the diagnosis could be faster in susceptible patients without previous alcoholism.

INTRODUCCIÓN: la encefalopatía de Wernicke es un desorden neurológico agudo y reversible debido a deficiencia de tiamina. En el pasado, se reconocía al alcoholismo crónico como una de las principales causas; actualmente se conocen otras condiciones que lo favorecen: nutrición parenteral prolongada, hiperémesis gravídica, anorexia nerviosa, enteritis regional, síndrome de malabsorción, hemodiálisis, diálisis peritoneal y cirugía abdominal extensa, entre otras. CASOS CLÍNICOS: se describen seis pacientes, tres hombres y tres mujeres que tuvieron en común nutrición parenteral total por más de dos meses debido a complicaciones quirúrgicas abdominales que impedían la vía oral. Las manifestaciones clínicas fueron somnolencia, agitación psicomotriz, oftalmoplejía con limitación para la abducción bilateral y nistagmo horizontal; tres pacientes presentaron ataxia y dismetría apendicular. Los hallazgos en la resonancia magnética fueron hiperintensidad en T2 en los colículos superiores, sustancia gris periacueductal, tubérculos mamilares y núcleos dorsomediales del tálamo; así como hiperintensidad en T1 en ambos núcleos lenticulares por depósito de manganeso debido a la nutrición parenteral total. CONCLUSIONES: la tríada característica está integrada por síndrome confusional, oftalmoplejía y ataxia. Con el empleo de los criterios de Caine, el diagnóstico puede ser más rápido y oportuno en los pacientes susceptibles sin antecedente de alcoholismo.