Susan Byrne

EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy

Vici syndrome is a progressive neurodevelopmental multisystem disorder caused by mutations in the autophagy gene EPG5. Byrne et al. characterise the phenotype of 50 affected children, revealing callosal agenesis, cataracts, hypopigmentation, cardiomyopathy, immune dysfunction, developmental delay and microcephaly. Downregulation of epg5 in Drosophila results in autophagic abnormalities and progressive neurodegeneration.

Fetal acetylcholine receptor inactivation syndrome: A myopathy due to maternal antibodies

Background: Transient neonatal myasthenia gravis (TNMG) affects a proportion of infants born to mothers with myasthenia gravis (MG). Symptoms usually resolve completely within the first few months of life, but persistent myopathic features have been reported in a few isolated cases. Methods: Here we report 8 patients from 4 families born to mothers with clinically manifest MG or mothers who were asymptomatic but had elevated acetylcholine receptor (AChR) antibody levels. Results: Clinical features in affected infants ranged from a mild predominantly facial and bulbar myopathy to arthrogryposis multiplex congenita. Additional clinical findings included hearing impairment, pyloric stenosis, and mild CNS involvement. In all cases, antibodies against the AChR were markedly elevated, although not always specific for the fetal AChR γ subunit. There was a correlation between maternal symptoms; the timing, intensity, and frequency of maternal treatment; and neonatal outcome. Conclusions: These findings suggest that persistent myopathic features following TNMG may be more common than currently recognized. Fetal AChR inactivation syndrome should be considered in the differential diagnosis of infants presenting with unexplained myopathic features, in particular marked dysarthria and velopharyngeal incompetence. Correct diagnosis requires a high degree of suspicion if the mother is asymptomatic but is crucial considering the high recurrence risk for future pregnancies and the potentially treatable nature of this condition. Infants with a history of TNMG should be followed up for subtle myopathic signs and associated complications.

Vici syndrome: a review

Vici syndrome [OMIM242840] is a severe, recessively inherited congenital disorder characterized by the principal features of callosal agenesis, cataracts, oculocutaneous hypopigmentation, cardiomyopathy, and a combined immunodeficiency. Profound developmental delay, progressive failure to thrive and acquired microcephaly are almost universal, suggesting an evolving (neuro) degenerative component. In most patients there is additional variable multisystem involvement that may affect virtually any organ system, including lungs, thyroid, liver and kidneys. A skeletal myopathy is consistently associated, and characterized by marked fibre type disproportion, increase in internal nuclei, numerous vacuoles, abnormal mitochondria and glycogen storage. Life expectancy is markedly reduced.Vici syndrome is due to recessive mutations in EPG5 on chromosome 18q12.3, encoding ectopic P granules protein 5 (EPG5), a key autophagy regulator in higher organisms. Autophagy is a fundamental cellular degradative pathway conserved throughout evolution with important roles in the removal of defective proteins and organelles, defence against infections and adaptation to changing metabolic demands. Almost 40 EPG mutations have been identified to date, most of them truncating and private to individual families.The differential diagnosis of Vici syndrome includes a number of syndromes with overlapping clinical features, neurological and metabolic disorders with shared CNS abnormalities (in particular callosal agenesis), and primary neuromuscular disorders with a similar muscle biopsy appearance. Vici syndrome is also the most typical example of a novel group of inherited neurometabolic conditions, congenital disorders of autophagy.Management is currently largely supportive and symptomatic but better understanding of the underlying autophagy defect will hopefully inform the development of targeted therapies in future.

An RYR1 mutation associated with malignant hyperthermia is also associated with bleeding abnormalities.

Gain-of-function RYR1 mutations cause increased Ca2+ sparks in vascular smooth muscle cells and prolong bleeding. Sparking greater blood loss When given certain general anesthetics, individuals with the inherited disorder malignant hyperthermia experience a dangerous increase in body temperature and severe muscle contractions. These life-threatening reactions are caused by excessively high Ca2+ concentrations in skeletal muscle cells resulting from hyperactivity of ryanodine receptor type 1 (RyR1). Lopez et al. investigated the effect of a malignant hyperthermia–associated RYR1 mutation in vascular smooth muscle cells, where local spikes in Ca2+ concentrations (called “Ca2+ sparks”) lead to vasodilation. Some patients with malignant hyperthermia bled for longer than their normal relatives, a phenotype that could result from excessive vasodilation. Consistent with this explanation, mice engineered with a RYR1 mutation found in some patients also bled for longer than their normal counterparts, and Ca2+ sparks were more frequent in vascular smooth muscle cells from mice with the RYR1 mutation. Because RyR1 is also found in other types of smooth muscle tissues, RYR1 mutations could have a wider range of effects than previously suspected. RYR1 mutations could also underlie mild bleeding abnormalities that are common but do not have a clear genetic basis. Malignant hyperthermia is a potentially fatal hypermetabolic disorder triggered by halogenated anesthetics and the myorelaxant succinylcholine in genetically predisposed individuals. About 50% of susceptible individuals carry dominant, gain-of-function mutations in RYR1 [which encodes ryanodine receptor type 1 (RyR1)], though they have normal muscle function and no overt clinical symptoms. RyR1 is predominantly found in skeletal muscle but also at lower amounts in immune and smooth muscle cells, suggesting that RYR1 mutations may have a wider range of effects than previously suspected. Mild bleeding abnormalities have been described in patients with malignant hyperthermia carrying gain-of-function RYR1 mutations. We sought to determine the frequency and molecular basis for this symptom. We found that some patients with specific RYR1 mutations had abnormally high bleeding scores, whereas their healthy relatives did not. Knock-in mice with the malignant hyperthermia susceptibility RYR1 mutation Y522S (MHS RYR1Y522S) had longer bleeding times than their wild-type littermates. Primary vascular smooth muscle cells from RYR1Y522S knock-in mice exhibited a higher frequency of subplasmalemmal Ca2+ sparks, leading to a more negative resting membrane potential. The bleeding defect of RYR1Y522S mice and of one patient was reversed by treatment with the RYR1 antagonist dantrolene, and Ca2+ sparks in primary vascular smooth muscle cells from the MHS RYR1Y522S mice were blocked by ryanodine or dantrolene. Thus, RYR1 mutations may lead to prolonged bleeding by altering vascular smooth muscle cell function. The reversibility of the bleeding phenotype emphasizes the potential therapeutic value of dantrolene in the treatment of such bleeding disorders.

SIL1-related Marinesco-Sjoegren syndrome (MSS) with associated motor neuronopathy and bradykinetic movement disorder

Marinesco-Sjoegren syndrome (MSS) is a recessively inherited multisystem disorder caused by mutations in SIL1 and characterized by cerebellar atrophy with ataxia, cataracts, a skeletal muscle myopathy, and variable degrees of developmental delay. Pathogenic mechanisms implicated to date include mitochondrial, nuclear envelope and lysosomal-autophagic pathway abnormalities. Here we present a 5-year-old girl with SIL1-related MSS and additional unusual features of an associated motor neuronopathy and a bradykinetic movement disorder preceding the onset of ataxia. These findings suggest that an associated motor neuronopathy may be part of the phenotypical spectrum of SIL1-related MSS and should be actively investigated in genetically confirmed cases. The additional observation of a bradykinetic movement disorder suggests an intriguing continuum between neurodevelopmental and neurodegenerative multisystem disorders intricately linked in the same cellular pathways.

Goldberg-Shprintzen megacolon syndrome with associated sensory motor axonal neuropathy

Goldberg–Shprintzen megacolon syndrome (GOSHS) (OMIM 609460) is characterized by a combination of learning difficulties, characteristic dysmorphic features and Hirschsprungs disease. Variable clinical features include iris coloboma, congenital heart defects and central nervous system abnormalities, in particular polymicrogyria. GOSHS has been attributed to recessive mutations in KIAA1279, encoding kinesin family member (KIF)‐binding protein (KBP) with a crucial role in neuronal microtubule dynamics. Here we report on a 7‐year‐old girl with GOSHS as a result of a homozygous deletion of exons 5 and 6 of the KIAA1279 gene. She had been referred with the suspicion of an underlying neuromuscular disorder before the genetic diagnosis was established, prompted by the findings of motor developmental delay, hypotonia, ptosis and absent reflexes. Neurophysiological studies revealed unequivocal evidence of a peripheral axonal sensory motor neuropathy. We hypothesize that an axonal sensory motor neuropathy may be part of the phenotypical spectrum of KIAA1279‐related GOSHS, probably reflecting the effects of reduced KBP protein expression on peripheral neuronal function.

Trigeminal autonomic cephalalgias in children and adolescents

The trigeminal autonomic cephalalgias (TACs) are a group of primary headache disorders characterized by unilateral head pain that occurs in association with prominent ipsilateral cranial autonomic features. The TACs include cluster headache (CH), paroxysmal hemicrania (PH), hemicrania continua (HC), and short-lasting unilateral neuralgiform headache attacks (SUNCT and SUNA) [1]. The TACs are relatively rare in the adult population and are considered to be even rarer in the pediatric population, hence poorly recognized. A detailed history and normal MRI is enough to make the diagnosis in most cases, with photographs or video of autonomic features clinching the diagnosis in the remaining cases. Given their rarity in the pediatric population and the lack of awareness of the condition among pediatricians and general practitioners, a delay of several years before the diagnosis is made is the rule. Furthermore, unlike migraine, which is often diagnosed by parents before seeking help from a healthcare professional, these headaches rarely have a familial component and so will often not have been seen before by parents. Given the age, many of the established treatments in adults with TACs are not suitable in the pediatric population, making the management challenging. The estimated prevalence of CH in the pediatric population (age 3–18 years) ranges from 0.03 to 0.1%. The traditional gender separation seen in adult CH seems to be less obvious in pediatric CH, at least until puberty. Onset in childhood is very rare, and about 5 to 10% of cases in the general CH population start in adolescence (mean age 11–14 years). Genetic factors appear to be involved in the same proportion as in the adult population, as a positive family history for CH has been found in approximately 10%. Interestingly, a particularly high exposure to secondhand smoke during childhood has been reported as a possible risk factor for developing CH [2]. The clinical presentation of pediatric CH is thought to be similar to that of adult onset. Minor differences in the children compared to the adult CH population include less frequent and shorter cluster periods and less numerous attacks during a given bout. Circannual and circadian periodicities are maintained in pediatric CH. Cranial autonomic features are less prominent in the adult population. Interestingly, the associating restlessness behavior during a CH episode is less frequently reported in the pediatric population. Moreover, at times, the behavior associated to the head pain can be more difficult to characterize compared to that in the adult population, leading to misdiagnosing children with CH as having psychogenic headaches, parasomnias, or pseudoseizures. The ratio between episodic and chronic CH in the pediatric population seems to be similar to that in the adult one. Symptoms normally occurring during migraine episodes, such as nausea, vomiting, photophobia, and phonophobia, have been reported in pediatric CH patients. These features alongside the known shorter duration of the headache episodes in pediatric migraine patients make migraine a challenging primary headache disorder to differentiate from CH in this group of people. In view of their rarity and potential life-threatening nature, secondary causes of CH, namely infectious, vascular and neoplastic intracranial lesions need to be ruled out with brain neuroimaging in pediatric patients [2]. Management of pediatric CH is not well substantiated by appropriate studies and is derived almost exclusively from experience in adult patients. Abortive treatments that could be used in pediatric CH population include inhalation of 100% oxygen, at 7–12 L/min for 15–30 min via a nonrebreathing facial mask. Given its good tolerability profile, oxygenis considered the abortive agent of choice for pediatric CH. While experience with the use of subcutaneous sumatriptan in the pediatric population is limited, sumatriptan nasal spray has been shown to be well tolerated in children between 12 and 17 years old at the dose of 20 mg. * Giorgio Lambru giorgiolambru@gmail.com

Autopsy findings in EPG5-related Vici syndrome with antenatal onset

Vici syndrome is one of the most extensive inherited human multisystem disorders and due to recessive mutations in EPG5 encoding a key autophagy regulator with a crucial role in autophagosome–lysosome fusion. The condition presents usually early in life, with features of severe global developmental delay, profound failure to thrive, (acquired) microcephaly, callosal agenesis, cataracts, cardiomyopathy, hypopigmentation, and combined immunodeficiency. Clinical course is variable but usually progressive and associated with high mortality. Here, we present a fetus, offspring of consanguineous parents, in whom callosal agenesis and other developmental brain abnormalities were detected on fetal ultrasound scan (US) and subsequent MRI scan in the second trimester. Postmortem examination performed after medically indicated termination of pregnancy confirmed CNS abnormalities and provided additional evidence for skin hypopigmentation, nascent cataracts, and hypertrophic cardiomyopathy. Genetic testing prompted by a suggestive combination of features revealed a homozygous EPG5 mutation (c.5870‐1G>A) predicted to cause aberrant splicing of the EPG5 transcript. Our findings expand the phenotypical spectrum of EPG5‐related Vici syndrome and suggest that this severe condition may already present in utero. While callosal agenesis is not an uncommon finding in fetal medicine, additional presence of hypopigmentation, cataracts and cardiomyopathy is rare and should prompt EPG5 testing.

Reply: Aberrant splicing induced by the most common EPG5 mutation in an individual with Vici syndrome

Sir, We read with interest the recent letter by Kane and colleagues (2016) reporting on ‘Aberrant splicing induced by the most common EPG5 mutation in an individual with Vici Syndrome’. Vici syndrome (OMIM 242840), originally described by Dionisi-Vici and colleagues in 1988 (Vici et al. , 1988), is one of the most extensive inherited human multisystem disorders identified to date, characterized by global developmental delay, failure to thrive, postnatally acquired microcephaly, callosal agenesis, cataracts, often fatal cardiomyopathy, combined immunodeficiency and generalized hypopigmentation (Cullup et al. , 2013; Byrne et al. , 2016 a , b ). Although the clinical phenotype is largely homogeneous, some features (in particular cardiac and immunological involvement) show considerable variability regarding onset and severity, with important effects on overall morbidity and life expectancy. EPG5 encodes a key component of the autophagy pathway in multicellular organisms (Tian et al. , 2010), ectopic P-granules autophagy protein 5 (EPG5), with a crucial role in autophagosome-lysosome fusion (Cullup et al. , 2013) and possibly other intracellular fusion events. Direct proof of the detrimental effects of EPG5 deficiency on the neuronal level has been recently provided in a Drosophila model (Byrne …