Development of a functional outcome measure for riboflavin transporter deficiency.

BACKGROUND AND AIMS: Riboflavin transporter deficiency (RTD) is a progressive inherited neuropathy of childhood onset, characterised clinically by pontobulbar palsy, sensory ataxia, sensorineural deafness, muscle weakness, optic atrophy and respiratory failure. A robust and responsive functional outcome measure is essential for future clinical trials of disease-modifying therapies including genetic therapies. The Charcot-Marie-Tooth disease Pediatric Scale (CMTPedS) is a well-validated outcome measure for CMT and related neuropathies, and might have utility for measuring disease progression in individuals with RTD. However, the CMTPedS requires modifications to account for phenotypic differences between children with CMT and RTD. The aim of this study was to develop a functional outcome measure based on the CMTPedS for specific use in individuals with RTD. METHODS: The CMTPedS data collected over the last 10 years in individuals with RTD attending the Peripheral Neuropathy Management Clinic at the Children's Hospital at Westmead (Sydney, Australia) were reviewed to evaluate each item within the CMTPedS. A literature review of articles published until September 2021 for functional outcome measures generated an item pool for pilot testing. The results of this pilot testing, alongside analysis of existing CMTPedS item scores in the RTD cohort, informed the modification of the CMTPedS. RESULTS: CMTPedS data were reviewed for eight individuals over the past 10 years. Two items were identified as requiring modification or removal and additional items of proximal strength and function needed to be considered. Six studies were identified in the literature review, and five items were selected for pilot testing. 'Shoulder internal rotation' and the '30-s sit to stand test' were added as proximal measures of strength and function. The composite balance item comprising nine tasks in the CMTPedS showed a ceiling effect and was replaced with the single 'Feet apart on a line eyes open' balance item. 'Pinprick sensation' was removed due to a floor effect. INTERPRETATION: This study provides preliminary evidence that the Riboflavin Transporter Deficiency Pediatric Scale (RTDPedS) is a functional outcome measure covering strength, upper and lower limb function, balance and mobility for individuals with RTD to assess disease severity and progression in clinical trials and cohort studies.

The audiovestibular profile of Brown-Vialetto-Van Laere syndrome.

BACKGROUND: Brown-Vialetto-Van Laere syndrome, a rare disorder associated with motor, sensory and cranial nerve neuropathy, is caused by mutations in riboflavin transporter genes SLC52A2 and SLC52A3. Hearing loss is a characteristic feature of Brown-Vialetto-Van Laere syndrome and has been shown in recent studies to be characterised by auditory neuropathy spectrum disorder. METHOD: This study reports the detailed audiovestibular profiles of four cases of Brown-Vialetto-Van Laere syndrome with SLC52A2 and SLC52A3 mutations. All of these patients had auditory neuropathy spectrum disorder. RESULTS: There was significant heterogeneity in vestibular function and in the benefit gained from cochlear implantation. The audiological response to riboflavin therapy was also variable, in contrast to generalised improvement in motor function. CONCLUSION: We suggest that comprehensive testing of vestibular function should be conducted in Brown-Vialetto-Van Laere syndrome, in addition to serial behavioural audiometry as part of the systematic examination of the effects of riboflavin.

Clinical Profile and Predictors of Mechanical Ventilation in Guillain-Barre Syndrome in North Indian Children.

OBJECTIVE: To describe the clinical-laboratory profile of pediatric Guillain-Barre syndrome and delineate features associated with need of mechanical ventilation. METHODS: In a prospective observational study at tertiary care hospital, clinical-laboratory assessment and nerve conduction studies were documented in consecutive children hospitalized with Guillain-Barre syndrome according to Brighton criteria. Clinical-laboratory features were compared between ventilated and nonventilated patients using univariate and multivariate analysis. RESULTS: Forty-six children (27 boys) with a mean age of 69.1±35.2 months were enrolled. History of preceding infection was present in 47.8%, bulbar palsy in 43.5%, feeble voice in 41.3%, sensory involvement in 13%, and autonomic involvement in 39.5%. Tetraparesis was noted in 87% of cases. Hughes disability scale >3 was noted in 44 children at admission and 39 (84.7%) at discharge. The most common electrophysiological type was acute motor axonal neuropathy (46.5%) followed by acute motor sensory axonal neuropathy (39.5%), acute inflammatory demyelinating polyneuropathy (7%), and inexcitable nerves (7%). Nine (19.7%) children were ventilated, 3 (6.5%) died or were lost, and 43 were discharged. Factors associated with need of mechanical ventilation on univariate analysis were older age, hypertension, bulbar palsy, feeble voice, lower Medical Research Council (MRC) sum, raised total leucocyte count, and history of preceding infection. Logistic regression revealed older age, history of predisposing illness, lower MRC sum at presentation, and bulbar palsy as independent predictors of mechanical ventilation. CONCLUSIONS: The most common electrophysiological subtype in northern Indian children is acute motor axonal neuropathy. Older age, preceding infection, low MRC sum, and bulbar palsy are predictors of mechanical ventilation in pediatric Guillain-Barre syndrome.

Automated Acoustic Analysis of Oral Diadochokinesis to Assess Bulbar Motor Involvement in Amyotrophic Lateral Sclerosis.

Purpose The purpose of this article was to validate a novel acoustic analysis of oral diadochokinesis (DDK) in assessing bulbar motor involvement in amyotrophic lateral sclerosis (ALS). Method An automated acoustic DDK analysis was developed, which filtered out the voice features and extracted the envelope of the acoustic waveform reflecting the temporal pattern of syllable repetitions during an oral DDK task (i.e., repetitions of /tɑ/ at the maximum rate on 1 breath). Cycle-to-cycle temporal variability (cTV) of envelope fluctuations and syllable repetition rate (sylRate) were derived from the envelope and validated against 2 kinematic measures, which are tongue movement jitter (movJitter) and alternating tongue movement rate (AMR) during the DDK task, in 16 individuals with bulbar ALS and 18 healthy controls. After the validation, cTV, sylRate, movJitter, and AMR, along with an established clinical speech measure, that is, speaking rate (SR), were compared in their ability to (a) differentiate individuals with ALS from healthy controls and (b) detect early-stage bulbar declines in ALS. Results cTV and sylRate were significantly correlated with movJitter and AMR, respectively, across individuals with ALS and healthy controls, confirming the validity of the acoustic DDK analysis in extracting the temporal DDK pattern. Among all the acoustic and kinematic DDK measures, cTV showed the highest diagnostic accuracy (i.e., 0.87) with 80% sensitivity and 94% specificity in differentiating individuals with ALS from healthy controls, which outperformed the SR measure. Moreover, cTV showed a large increase during the early disease stage, which preceded the decline of SR. Conclusions This study provided preliminary validation of a novel automated acoustic DDK analysis in extracting a useful measure, namely, cTV, for early detection of bulbar ALS. This analysis overcame a major barrier in the existing acoustic DDK analysis, which is continuous voicing between syllables that interferes with syllable structures. This approach has potential clinical applications as a novel bulbar assessment.

Differences in nerve excitability properties between isolated bulbar palsy and bulbar-dominant amyotrophic lateral sclerosis.

Objectives: Isolated bulbar palsy (IBP) is a rare variant that can show a benign course, while progressive bulbar palsy (PBP) has been regarded as a bulbar-dominant type of classical amyotrophic lateral sclerosis (cALS). This study aimed to identify differences in the excitability properties between them.Methods: We consecutively collected data on 22 ALS patients: 13 with cALS, 5 with PBP, and 4 with IBP. An automated nerve excitability test (NET) was applied to measure the strength-duration time constant, threshold electrotonus (TE), current-threshold relationship, and recovery cycle. The axonal excitability properties were compared between the ALS groups and 25 controls.Results: Compared to controls, the cALS group showed a greater change in the depolarizing phase of TE of 90-100 ms after depolarizing current [TEd(90-100)] (53.3±1.3 [mean±SEM] for cALS and 49.0±0.7 for control, P<0.01) and lower S2 accommodation (19.6±0.8 and 22.6±0.7, respectively; P=0.01). There was a nonsignificant tendency for a high TEd(90-100) pattern to be less prominent in the IBP group than in the PBP group (51.5±4.22 and 48.8±1.5, respectively). In addition, all of the parameters of nerve excitability other than S2 accommodation in the PBP and IBP groups did not differ significantly from those in the controls.Conclusions: The excitability properties of IBP and PBP differ from those of cALS. The pattern of NET in PBP was more similar to that in cALS than that in IBP. These findings suggest that IBP is a different entity from bulbar-dominant ALS and PBP.

The Clinical Journey of Patients with Riboflavin Transporter Deficiency Type 2.

PURPOSE: To identify symptoms and health care interactions with patients with riboflavin transporter deficiency (RTD) type 2 prior to diagnosis. METHODS: Parents of children with riboflavin transporter deficiency type 2 (n = 10) were interviewed to collect data on the patient's clinical journey. RESULTS: The average diagnostic delay was 27.6 months. Neurologists were the most commonly visited clinician (90%). Common symptoms during the first year of the patient's clinical journey included abnormal gait and/or ataxia (70%), nystagmus (50%), and upper body muscle weakness (40%). Prior to diagnosis, optic atrophy, sleep apnea, breath-holding spells, and dysphagia were commonly observed. Hearing loss was only reported in 40% of subjects prior to diagnosis. Riboflavin responsive megaloblastic anemia is reported for the first time. Mitochondrial disease was the most common suspected diagnosis (30%). CONCLUSION: Despite clinical variability, common early symptoms of riboflavin transporter deficiency type 2 exist that can better allow clinicians to more rapidly identify riboflavin transporter deficiency type 2.

Relationship between oral transit time and functional performance in motor neuron disease.

Oral phase swallowing impairment in motor neuron disease (MND) is caused by tongue weakness, fasciculation and atrophy, which may compromise oral transit time and total feeding time. OBJECTIVE To describe and correlate total oral transit time (TOTT) with functional performance in MND using different food consistencies. METHODS The study was conducted on 20 patients with MND, regardless of type or duration of the disease, of whom nine were excluded due to issues on the videofluoroscopic swallowing images. The remaining 11 patients (nine men and two women) ranged from 31 to 87 years of age (mean: 57 years) with scores on the Penetration Aspiration Scale ranging from ≤ 2 to ≤ 4. The Amyotrophic Lateral Sclerosis Functional Rating Scale - revised questionnaire was applied to classify individuals according to global, bulbar and bulbar/respiratory parameters. Videofluoroscopy of swallowing using 5ml of different consistencies was performed and a quantitative temporal analysis of the TOTT was carried out with the aid of specific software. RESULTS There was a wide variation in the TOTT within the same food consistency among MND patients. There was a correlation between the TOTT and overall functional performance for the thickened liquid consistency (r = -0.691) and between the TOTT and bulbar performance for the pureed consistency (r = -0.859). CONCLUSION Total oral transit time in MND varies within the same food consistency and the longer the TOTT, regardless of food consistency, the lower the functional performance in MND.

Secondary hypokalemic paralysis with bulbar weakness and reversible electrophysiologic abnormalities: A case report and systematic review.

Hypokalemic periodic paralysis secondary to distal renal tubular acidosis presenting with prominent bulbar symptoms is extremely rare. The exact pathophysiology by which hypokalemia causes weakness is yet to be elucidated though muscle and nerve membrane hyperpolarization have been hypothesized. The pathophysiology of bulbar involvement in this condition is even more unclear. We report a case presenting as acute flaccid quadriplegia with prominent bulbar symptoms that reversed once potassium levels returned to normal. Serial nerve conduction studies were performed at various potassium levels revealing electrophysiologic abnormalities that corrected with potassium repletion. A systematic review of the literature was also conducted focusing on bulbar symptoms and electrophysiologic findings in hypokalemic periodic paralysis. Nerve conduction abnormalities in this condition are seldom documented, but reports have shown reduced amplitudes of compound motor action potentials and abnormal F-waves during acute attacks of hypokalemic paralysis.

Relationship between oral transit time and functional performance in motor neuron disease / Relação entre tempo de trânsito oral e desempenho funcional na doença do neurônio motor

ABSTRACT Oral phase swallowing impairment in motor neuron disease (MND) is caused by tongue weakness, fasciculation and atrophy, which may compromise oral transit time and total feeding time. Objective: To describe and correlate total oral transit time (TOTT) with functional performance in MND using different food consistencies. Methods: The study was conducted on 20 patients with MND, regardless of type or duration of the disease, of whom nine were excluded due to issues on the videofluoroscopic swallowing images. The remaining 11 patients (nine men and two women) ranged from 31 to 87 years of age (mean: 57 years) with scores on the Penetration Aspiration Scale ranging from ≤ 2 to ≤ 4. The Amyotrophic Lateral Sclerosis Functional Rating Scale - revised questionnaire was applied to classify individuals according to global, bulbar and bulbar/respiratory parameters. Videofluoroscopy of swallowing using 5ml of different consistencies was performed and a quantitative temporal analysis of the TOTT was carried out with the aid of specific software. Results: There was a wide variation in the TOTT within the same food consistency among MND patients. There was a correlation between the TOTT and overall functional performance for the thickened liquid consistency (r = −0.691) and between the TOTT and bulbar performance for the pureed consistency (r = −0.859). Conclusion: Total oral transit time in MND varies within the same food consistency and the longer the TOTT, regardless of food consistency, the lower the functional performance in MND.

RESUMO O comprometimento na fase oral da deglutição na doença do neurônio motor (DNM) é ocasionado por fraqueza, fasciculação e atrofia de língua, podendo comprometer o tempo de trânsito oral (TTO) e o tempo total de alimentação. Objetivo: Descrever e relacionar o tempo de trânsito oral total (TTOT) com o desempenho funcional na DNM em distintas consistências de alimento. Métodos: Participaram 20 indivíduos com DNM, independente do tipo ou tempo de doença. Foram incluídos 11 indivíduos, nove homens e duas mulheres, faixa etária de 31 a 87 anos (média de idade de 57 anos) e com Penetration Aspiration Scale (Rosenbek et al., 1996) de ≤ 2 a ≤ 4. Foram excluídos nove indivíduos por questões técnicas relacionadas às imagens videofluoroscópicas de deglutição. Aplicado o questionário Amyotrophic Lateral Sclerosis Functional Rating Scale - revised para classificação dos indivíduos de acordo com parâmetros Global, Bulbar e Bulbar/Respiratório. Realizada videofluoroscopia da deglutição com diferentes consistências de alimento no volume de cinco ml e análise quantitativa do TTOT por meio de software específico. Resultados: Houve ampla variação no TTOT dentro da mesma consistência de alimento na DNM. Houve correlação entre o TTOT e o desempenho funcional global na consistência líquida espessada (r = −0,691) e para o TTOT e o desempenho bulbar na pastosa (r = −0,859). Conclusão: O tempo de trânsito oral total na DNM varia dentro da mesma consistência de alimento e quanto mais longo o TTOT, independente da consistência do alimento, menor foi o desempenho funcional na DNM.

The First Case of Riboflavin Transporter Deficiency in sub-Saharan Africa.

This report describes the first case of a child with genetically confirmed Brown-Vialetto-van Laere syndrome in sub-Saharan Africa. This is an extremely rare clinical condition that presents with an auditory neuropathy, bulbar palsy, stridor, muscle weakness, and respiratory compromise that manifests with diaphragmatic and vocal cord paralysis. It is an autosomal recessive condition for which the genetic mutation has only recently been linked to a riboflavin transporter deficiency. We describe an 11-month-old affected male infant. He has required long-term respiratory support and a gastrostomy tube to support feeding. With high-dose riboflavin supplementation, he had limited recovery of motor function. His respiratory chain enzyme studies were abnormal suggestive of mitochondrial (mt) dysfunction. In the setting of limited resources, recognition of this striking clinical phenotype is important to highlight, specifically regarding the genetic implications of the condition and the potentially remedial response to vitamin supplementation.

Genetic, Radiologic, and Clinical Variability in Brown-Vialetto-van Laere Syndrome.

Brown-Vialetto-van Laere syndrome is characterized by a progressive sensorimotor neuropathy, optic atrophy, hearing loss, bulbar dysfunction, and respiratory insufficiency. Mutations in SLC52A2 and SLC52A3, encoding riboflavin transporters RFVT2 and RFVT3, respectively, are the genetic basis of this disorder, often referred to as riboflavin transporter deficiency types 2 and 3, respectively. We present cases of both types of riboflavin transporter deficiency, highlighting the distinguishing clinical features of a rapidly progressive motor or sensorimotor axonal neuropathy, optic atrophy, sensorineural hearing loss, and bulbar dysfunction. One child presented with isolated central apnea and hypoventilation, not previously described in genetically confirmed Brown-Vialetto-van Laere, later complicated by diaphragmatic paralysis secondary to phrenic nerve palsy. Magnetic resonance imaging showed T2 hyperintensity in the dorsal spinal cord in 2 children, as well as previously unreported cervical nerve root enlargement and cauda equina ventral nerve root enhancement in 1 child. Novel homozygous mutations were identified in each gene-a NM_024531.4(SLC52A2):c.505C > T, NP_078807.1(SLC52A2):p.(Arg169Cys) variant in SLC52A2 and NM_033409.3(SLC52A3):c.1316G > A, NP_212134.3(SLC52A3):p.(Gly439Asp) variant in SLC52A3. Both treated children showed improvement on high-dose riboflavin supplementation, highlighting the importance of early recognition of this treatable clinical entity.

Fazio-Londe syndrome in siblings from India with different phenotypes.

BACKGROUND: Fazio-Londe syndrome also called progressive bulbar palsy of childhood is a very rare motor neuron disease of pediatric age group characterized by progressive paralysis of lower cranial nerves. OBJECTIVE: To describe Fazio-Londe syndrome in sibling with different phenotype. METHODS: A 6 years old female child presented with inability to close eyes, difficulty in swallowing, respiratory muscle weakness and voice change since 5 yr of age. Examination showed lower motor neuron facial nerve palsy, absent gag reflex, tongue atrophy, fasciculation, limb wasting and exaggerated deep tendon reflexes. An 11 year old boy, elder sibling of the above child presented with similar complaints at 10 years of age, other than later onset and lack of respiratory problem. Genetic testing in both cases confirmed the diagnosis of Fazio-Londe Syndrome. CONCLUSION: In any child who presents with progressive bulbar palsy with lower motor neuron facial palsy a diagnosis of Fazio-Londe Syndrome should be considered and family members should also be screened.

Insertion of intra-oral electrodes for cranial nerve monitoring using a Crowe-Davis retractor.

Acoustic neuroma resection is an example of a neurosurgical procedure where the brainstem and multiple cranial nerves are at risk for injury. Electrode placement for monitoring of the glossopharyngeal and hypoglossal nerves during acoustic neuroma resection can be challenging. The purpose of this report is to illustrate the use of a device for intra-oral electrode placement for intraoperative monitoring of the glossopharyngeal and hypoglossal nerves. A 60-year-old male presented for acoustic neuroma resection. Under general anesthesia, a Crowe-Davis retractor was used to open the mouth, providing access to the posterior pharynx. For glossopharyngeal monitoring, two bent subdermal needle electrodes were inserted just lateral to the uvula. Two additional electrodes were inserted on the lateral tongue to monitor the hypoglossal nerve. Cranial nerves monitoring was conducted utilizing both free running and triggered electromyography of the trigeminal and facial nerves in addition to the lower cranial nerves. The tumor was resected successfully. Monitoring of the cranial nerves (including the glossopharyngeal and hypoglossal nerves) revealed no concerning responses. The Crowe-Davis retractor and the technique described allowed insertion of electrodes for neural monitoring, contributing to neural preservation.

Amyotrophic lateral sclerosis progression: Iran-ALS clinical registry, a multicentre study.

This study was designed to evaluate ALS progression among different subgroups of Iranian patients. Three hundred and fifty-eight patients from centres around the country were registered and their progression rate was evaluated using several scores including Manual Muscle Test scoring (MMT) and the revised ALS Functional Rating Scale (ALSFRS-R). Progression rate was analysed separately in subgroups regarding gender, onset site, stage of disease and riluzole consumption. A significant difference in MMT deterioration rate (p = 0.01) was noted between those who used riluzole and those who did not. No significant difference was observed in progression rates between male/female and bulbar-onset/limb-onset groups using riluzole. In conclusion, riluzole has a significant effect on muscle force deterioration rate but not functional scale. Progression rate was not influenced by site of onset or gender.

Clinical features of amyotrophic lateral sclerosis in south-west China.

Our objective was to profile clinical features of amyotrophic lateral sclerosis (ALS); we performed a large sample, cross-sectional study based on a hospital registry of ALS in south-west China. Patients were coded in our tertiary referral centre from May 2006 to September 2014. Demographic data and disease-related parameters were collected. A total of 1131 patients were included. Mean age of onset was 54.3 ± 11.6 years and the highest proportion of onset age (30.6%) was between 51 and 60 years. Male:female ratio was 1.45:1. Nearly 30% of the patients were young onset, and 20.3% of the patients were bulbar onset; only 35% received riluzole treatment. The young-onset patients had a higher educational level with a higher proportion performing manual labour and living in rural areas, and a lower proportion with bulbar onset than those who were older at onset. The bulbar-onset patients were older at age of onset, with a lower proportion of males than spinal-onset patients. In conclusion, Chinese ALS patients may be younger at age of onset than Caucasian patients. Environmental and geographical factors are related to the occurrence of ALS. The large treatment gap indicated a pressing need for medical and financial support for Chinese ALS patients.