Objective: 3‐Methylglutaconic aciduria, dystonia–deafness, hepatopathy, encephalopathy, Leigh‐like syndrome (MEGDHEL) syndrome is caused by biallelic variants in SERAC1.Methods: This multicenter study addressed the course of disease for each organ system. Metabolic, neuroradiological, and genetic findings are reported.Results: Sixty‐seven individuals (39 previously unreported) from 59 families were included (age range = 5 days–33.4 years, median age = 9 years). A total of 41 different SERAC1 variants were identified, including 20 that have not been reported before. With the exception of 2 families with a milder phenotype, all affected individuals showed a strikingly homogeneous phenotype and time course. Severe, reversible neonatal liver dysfunction and hypoglycemia were seen in >40% of all cases. Starting at a median age of 6 months, muscular hypotonia (91%) was seen, followed by progressive spasticity (82%, median onset = 15 months) and dystonia (82%, 18 months). The majority of affected individuals never learned to walk (68%). Seventy‐nine percent suffered hearing loss, 58% never learned to speak, and nearly all had significant intellectual disability (88%). Magnetic resonance imaging features were accordingly homogenous, with bilateral basal ganglia involvement (98%); the characteristic “putaminal eye” was seen in 53%. The urinary marker 3‐methylglutaconic aciduria was present in virtually all patients (98%). Supportive treatment focused on spasticity and drooling, and was effective in the individuals treated; hearing aids or cochlear implants did not improve communication skills.Interpretation: MEGDHEL syndrome is a progressive deafness–dystonia syndrome with frequent and reversible neonatal liver involvement and a strikingly homogenous course of disease. Ann Neurol 2017;82:1004–1015

Recently, CLPB deficiency has been shown to cause a genetic syndrome with cataracts, neutropenia, and 3‐methylglutaconic aciduria. Surprisingly, the neurological presentation ranges from completely unaffected to patients with virtual absence of development. Muscular hypo‐ and hypertonia, movement disorder and progressive brain atrophy are frequently reported. We present the foetal, peri‐ and neonatal features of 31 patients, of which five are previously unreported, using a newly developed clinical severity scoring system rating the clinical, metabolic, imaging and other findings weighted by the age of onset. Our data are illustrated by foetal and neonatal videos. The patients were classified as having a mild (n = 4), moderate (n = 13) or severe (n = 14) disease phenotype. The most striking feature of the severe subtype was the neonatal absence of voluntary movements in combination with ventilator dependency and hyperexcitability. The foetal and neonatal presentation mirrored the course of disease with respect to survival (current median age 17.5 years in the mild group, median age of death 35 days in the severe group), severity and age of onset of all findings evaluated. CLPB deficiency should be considered in neonates with absence of voluntary movements, respiratory insufficiency and swallowing problems, especially if associated with 3‐methylglutaconic aciduria, neutropenia and cataracts. Being an important differential diagnosis of hyperekplexia (exaggerated startle responses), we advise performing urinary organic acid analysis, blood cell counts and ophthalmological examination in these patients. The neonatal presentation of CLPB deficiency predicts the course of disease in later life, which is extremely important for counselling.

The prevalence of isolated hearing loss (HL) associated with the m.3243A>G mutation is unknown. The aim of this study was to assess the frequency and heteroplasmy level of the m.3243A>G mutation in a large group of Polish patients with postlingual bilateral sensorineural HL of unidentified cause. A molecular search was undertaken in the archival blood DNA of 1482 unrelated patients with isolated HL that had begun at ages between 5 and 40 years. Maternal relatives of the probands were subsequently investigated and all carriers underwent audiological tests. The m.3243A>G mutation was found in 16 of 1482 probands (an incidence of 1.08%) and 18 family members. Of these 34 individuals, hearing impairment was detected in 29 patients and the mean onset of HL was at 26 years. Some 42% of the identified m.3243A>G carriers did not develop multisystem symptomatology over the following 10 years. Mean heteroplasmy level of m.3243A>G was lowest in blood at a level of 14% and highest in urine at 58%. These values were independent of the manifested clinical severity of the disease. A single m.3243A>G carrier can usually be found among each 100 individuals who have postlingual hearing loss of unknown cause. Urine samples are best for detecting the m.3243A>G mutation and diagnosing mitochondrially inherited hearing loss.

Pompe disease is a progressive metabolic myopathy. Disease progression is characterized, among other features, by progressive dysfunction of the voice apparatus. The aim of this study was to employ electroglottographic, acoustic and nasalance measurement methods on patients with late-onset Pompe disease in order to provide detailed information on the effect of the disease on voice quality. Voice quality is the key factor for estimating the effectiveness of ERT in late-onset Pompe disease. The study compared clinical phoniatric examination with electroglottographic, acoustic and nasalance measurement methods. The consistency of the aforementioned analyses was assessed. The study examined 19 patients with late-onset Pompe disease (including 9 with the juvenile form of the disease). Of these, a total of 17 patients underwent otolaryngological examination with detailed phoniatric evaluation of their articulatory organs. Electroglottographic recordings and nasalance measurements (using the nasalance Separator Handle) were obtained from all patients. MATLAB (COVAREP toolkit) was used to analyse voice recording data. Dysphonia observed in patients with late-onset Pompe disease is mainly caused by dysfunction of vocal fold closure and weakness of vocal muscle. However, substantial speech nasality is caused by insufficient closure of the soft palate. Electroglottographic signal analysis, acoustic and nasalance testing methods indicated that more significant changes in the function of the voice apparatus presented in the juvenile form than in the adult form of late-onset Pompe disease. It was found that speech nasality and electroglottographic tests are more repeatable, comparable and versatile than phoniatric examination, allowing for earlier detection of voice pathology in late-onset Pompe disease. These sensitive and non-invasive acoustic and electroglottographic methods allow for the tracking of changes in voice as patients undergo treatment or as the disease progresses.