Onset In Early Childhood Research Articles

Russian Family with X-linked Alport Syndrome and Cardiovascular Abnormalities

Background: Alport syndrome (AS) is an inherited disease. Clinical findings usually include hematuria, proteinuria and arterial hypertension. Hearing loss and ocular abnormalities are common symptoms. In the last years there are some clinical observations of arterial disease (aortic aneurysm, aortic dissection) in males with AS. Methods: coding exons and splice sites of the abovementioned genes were sequenced in on Ion Torrent platform. Detailed clinical examination was obtained. Ophthalmologic and otologic evaluations, pure tone audiometry, electrocardiography, ECHO-cardiography, 24-hour blood pressure monitoring and retroperitoneal ultrasonography were performed. Results: a novel dominant missense mutation c.G3098A, p.1033 G>D in the collagen type IV alpha-5 gene (COL4A5) was revealed in five family members. New aspects of phenotype evaluated: cardiovascular abnormalities (asymptomatic aortic enlargement, left ventricular dilatation, aortic insufficiency); early childhood onset of systemic hypertension; absents of ocular abnormalities. Microhematuria, proteinuria (in progress up to 2,0 g/l) and early childhood onset of systemic hypertension are discussed as a result of heterozygous COL4A5 mutations in affected females. Conclusions: molecular genetics help to understand variable clinical phenotypes of AS patients. New findings about cardiovascular abnormalities should stimulate doctors to make cardiology examination in all affected subjects.

Pathophysiology of motor dysfunction in a childhood motor neuron disease caused by mutations in the riboflavin transporter

ObjectiveBrown–Vialetto–Van Laere (BVVL) syndrome is a progressive motor and sensory neuronopathy secondary to mutations in SLC52A2 encoding the riboflavin transporter type 2 (RFVT2). The phenotype is characterized by early childhood onset hearing loss and sensory ataxia followed by progressive upper limb weakness, optic atrophy, bulbar weakness and respiratory failure. To gain further insight into disease pathophysiology and response to riboflavin supplementation, the present study investigated whether axonal ion channel or membrane abnormalities were a feature of BVVL. MethodsAxonal excitability studies and clinical assessments were prospectively undertaken on six patients with BVVL secondary to riboflavin transporter deficiency type 2 (age range 10–21years) at baseline and after 12months of riboflavin (1000mg daily) therapy. ResultsAt baseline, depolarizing and hyperpolarizing threshold electrotonus was ‘fanned out’ and superexcitability was increased, while the resting current–threshold gradient and refractoriness were significantly reduced in BVVL patients when compared to controls. Mathematical modeling suggested that functional alterations of myelin underlay these findings with an increase in myelin permeability. Riboflavin therapy resulted in partial normalization of the axonal excitability findings, paralleled by maintenance of muscle strength. ConclusionsThe present study established that abnormalities in myelin permeability at the paranode was a feature of BVVL and were partially normalized with riboflavin therapy. SignificanceThis study reveals a novel pathophysiological process for motor nerve dysfunction in BVVL. It also indicates that nerve excitability studies may be further developed in larger cohorts as a potential biomarker to identify treatment response for BVVL patients.

A novel frameshift mutation in KCNQ4 in a family with autosomal recessive non-syndromic hearing loss

Mutation of KCNQ4 has been reported to cause autosomal dominant non-syndromic hearing loss (DFNA2A) that usually presents as progressive hearing loss starting from mild to moderate hearing loss during childhood. Here, we identified a novel KCNQ4 mutation, c.1044_1051del8, in a family with autosomal recessive non-syndromic hearing loss. The proband was homozygous for the mutation and was born to consanguineous parents; she showed severe hearing loss that was either congenital or of early childhood onset. The proband had a sister who was heterozygous for the mutation but showed normal hearing. The mutation caused a frameshift that eliminated most of the cytoplasmic C-terminus, including the A-domain, which has an important role for protein tetramerization, and the B-segment, which is a binding site for calmodulin (CaM) that regulates channel function via Ca ions. The fact that the heterozygote had normal hearing indicates that sufficient tetramerization and CaM binding sites were present to preserve a normal phenotype even when only half the proteins contained an A-domain and B-segment. On the other hand, the severe hearing loss in the homozygote suggests that complete loss of the A-domain and B-segment in the protein caused loss of function due to the failure of tetramer formation and CaM binding. This family suggests that some KCNQ4 mutations can cause autosomal recessive hearing loss with more severe phenotype in addition to autosomal dominant hearing loss with milder phenotype. This genotype–phenotype correlation is analogous to that in KCNQ1 which causes autosomal dominant hereditary long QT syndrome 1 with milder phenotype and the autosomal recessive Jervell and Lange-Nielsen syndrome 1 with more severe phenotype due to deletion of the cytoplasmic C-terminus of the potassium channel.

PP12.12 – 3038: Phenotyping children with neurodevelopmental conditions (NDCs), major Insomnia and familial Willis Ekbom disease/restless legs syndrome (WED/RLS)

Objective Diagnosing early-onset childhood WED/RLS can be challenging, as young children or children with NDCs might not be able to communicate their symptoms. Additional supportive criteria like positive family history or structured observations during a suggested clinical immobilization test (SCIT) are considered helpful. We investigated phenotypic characteristics of familial WED in children with NDCs and major chronic insomnia. Methods 31/346 children-mother pairs fulfilled the inclusion criteria of having mothers with clinical evidence of WED. All received a sleep/wake behaviour assessment, including a SCIT. Their presentations were captured prospectively in reports that utilized the concept of therapeutic emplotment, using narrative schema to analyze bedtime problems, nighttime awakenings, challenging daytime behaviours, and routines; these reports were shared with clients for quality control purposes; the database was developed retrospectively. Results 28/31 children-mother pairs were analyzed further: The mean age of the children was 8.5 years. All children were diagnosed or investigated for NDCs and 87% of patients showed at least one psychiatric comorbidity. All presented with major insomnia most probably due to familial WED, but only 45% could express experienced sensations and fulfilled the criteria of definitive WED/RLS with the help of the SCIT; 74% of them presented with probable PLM in sleep and 42% with PLM in wakefulness; 97% showed tactile sensitivities with a shifted pain threshold (60%), defined as less reactivity to pain; 55% experienced parasomnias, and 71% had signs of sleep disordered breathing. Conclusion In children with NDCs and major insomnia, typical WED symptoms may be overlaid with neurologic, behavioural and psychiatric disturbances; in addition many patients are not able to communicate symptoms. Including family history and developing a structured assessment concept started outlining the phenotypic spectrum of WED and will help to understand the dimension of WED in children with NDCs further.

Successful treatment with two siblings affected classic Bartter syndrome

Classic Bartter syndrome is a salt-wasting tubulopathy caused by mutations in the CLCNKB (chloride channel Kb) gene. Classic Bartter syndrome is characterized by early childhood onset. Herein, we report two Vietnamese siblings affected classic Bartter syndrome.

Atopic dermatitis from adolescence to adulthood in the TOACS cohort: prevalence, persistence and comorbidities.

While much is known about childhood atopic dermatitis, little is known about persistence of atopic dermatitis into adult life. We report, to our knowledge for the first time, the clinical course of atopic dermatitis in an unselected cohort of adolescents followed into adulthood. The course of atopic dermatitis from adolescence to adulthood was studied prospectively in a cohort of unselected 8th-grade schoolchildren established in 1995 and followed up in 2010 with questionnaire and clinical examination. The lifetime prevalence of atopic dermatitis was high (34.1%), and a considerable number of adults still suffered from atopic dermatitis evaluated both by questionnaire (17.1%) and clinical examination (10.0%). Persistent atopic dermatitis was found in 50% of those diagnosed in school age, and persistent atopic dermatitis was significantly associated with early onset, childhood allergic rhinitis and hand eczema. A close association was also found with allergic contact dermatitis and increased specific IgE to Malassezia furfur, but not with filaggrin gene defect. Persistence of atopic dermatitis in adulthood is common and affects quality of life. Persistent atopic dermatitis is particularly prevalent in those with early onset, allergic rhinitis and hand eczema in childhood. It is important to recognizing atopic dermatitis as a common and disabling disease not only in children but also in adults.

Autosomal ring chromosomes in human genetic disorders.

Ring chromosomes arise following breakage and rejoining in both chromosome arms. They are heterogeneous with variable size and genetic content and can originate from any chromosome. Phenotypes associated with ring chromosomes are highly variable as apart from any deletion caused by ring formation, imbalances from ring instability can also occur. Of interest is ring chromosome 20 which has a significant association with epilepsy with seizure onset in early childhood. Severe growth deficiency without major malformations is a common finding in the ring chromosome carrier. This phenotype associated with ring behaviour and mitotic instability and independent of the chromosome involved has been termed the "ring syndrome". Precise genotype-phenotype correlations for ring chromosomes may not be possible as influencing factors vary depending on the extent of deletion in ring formation, ring instability and the level of mosaicism. Although ring chromosomes usually arise as de novo events, familial transmission of rings from carrier to offspring has been described and prenatal diagnosis for any pregnancies should always be considered.

Treatment options for lactic acidosis and metabolic crisis in children with mitochondrial disease.

The mitochondrial pyruvate oxidation route is a tightly regulated process, which is essential for aerobic cellular energy production. Disruption of this pathway may lead to severe neurometabolic disorders with onset in early childhood. A frequent finding in these patients is acute and chronic lactic acidemia, which is caused by increased conversion of pyruvate via the enzyme lactate dehydrogenase. Under stable clinical conditions, this process may remain well compensated and does not require specific therapy. However, especially in situations with altered energy demands, such as febrile infections or longer periods of fasting, children with mitochondrial disorders have a high risk of metabolic decompensation with exacerbation of hyperlactatemia and severe metabolic acidosis. Unfortunately, no controlled studies regarding therapy of this critical condition are available and clinical outcome is often unfavorable. Therefore, the aim of this review was to formulate expert-based suggestions for treatment of these patients, including dietary recommendations, buffering strategies and specific drug therapy. However, it is important to keep in mind that a specific therapy for the underlying metabolic cause in children with mitochondrial diseases is usually not available and symptomatic therapy especially of severe lactic acidosis has its ethical limitations.

Tools for teen moms to reduce infant obesity: a randomized clinical trial.

BackgroundUnhealthy infant feeding practices, such as a combination of formula feeding and early introduction of solids may lead to rapid or excessive weight gain in early infancy. Adolescent mothers’ feeding behaviors are most directly related to infant weight gain in the first year of life. Compared to adult mothers, adolescent mothers are less knowledgeable, less responsive, more controlling, and less skilled in infant feeding, which interferes with infants’ healthy growth. The Tools for Teen Moms trial aims to compare the effect of a social media intervention for low-income adolescent, first-time mothers of infants 2 months of age or younger, versus standard care on infant weight, maternal responsiveness, and feeding style and practices. The intervention is conducted during the infant’s first four months of life to promote healthy transition to solids during their first year. Tools for Teen Moms is an intervention delivered via a social media platform that actively engages and coaches low-income adolescent mothers in infant-centered feeding to reduce rapid/excessive infant weight gain in the first six months of life.Methods/DesignWe describe our study protocol for a randomized control trial with an anticipated sample of 100 low-income African- American and Caucasian adolescent, first–time mothers of infants. Participants are recruited through Maternal-Infant Health Programs in four counties in Michigan, USA. Participants are randomly assigned to the intervention or the control group. The intervention provides infant feeding information to mothers via a web-based application, and includes daily behavioral challenges, text message reminders, discussion forums, and website information as a comprehensive social media strategy over 6 weeks. Participants continue to receive usual care during the intervention. Main maternal outcomes include: (a) maternal responsiveness, (b) feeding style, and (c) feeding practices. The primary infant outcome is infant weight. Data collection occurs at baseline, and when the baby is 3 and 6 months old.DiscussionExpected outcomes will address the effectiveness of the social media intervention in helping teen mothers develop healthy infant feeding practices that contribute to reducing the risk of early onset childhood obesity.Trial registrationClinical Trials.Gov NCT02244424, June 24, 2014

Novel TSC1 Gene Mutation in a Familial Case of Tuberous Sclerosis Complex: A Case Report

Introduction: Tuberous sclerosis complex (TSC) is a genetic disorder that can arise from sporadic or inherited mutations in TSC1 or TSC2 genes. It is characterized by tumors in multiple organs that result in broad clinical manifestations, usually affecting the central nervous system. Diagnosis is based upon clinical criteria that require careful clinical examination along with imaging and the availability of genetic testing to assess gene mutations linked to this disorder. We present a familial case of tuberous sclerosis complex with multiple subtle clinical manifestations and novel TSC1 mutation that were diagnosed in adulthood. This report adds to the growing literature on TSC1 gene by correlating specific nucleotide substitutions with possible secondary clinical manifestations. Case presentation: A 21 year-old Hispanic female presented with history of epilepsy onset in early childhood. Upon clinical examination and imaging testing, she was found to have lesions on her scalp, eyes and brain. Her mother is 51 years old with long-standing history of epilepsy with multiple lesions on skin, eyes, and similar findings in brain imaging to daughter. No additional family history was obtained suggestive of tuberous sclerosis complex. Conclusion: Milder forms of tuberous sclerosis complex can remain undiagnosed until adolescence and adulthood, which may lead to treatment delay and complications due to the lack of regular follow-up care. In this case report, both individuals’ presenting symptom was epilepsy and later other clinical findings were linked to the disorder. Additionally, a novel DNA sequence variant was detected, which expands our knowledge of known TSC1 gene mutations. Although these genetic test results cannot be used alone to make a definite diagnosis, they suggest an association to TSC given the clinical manifestations and family history.

Ataxia with vitamin e deficiency in norway.

ObjectiveAtaxia with vitamin E deficiency (AVED) is a rare autosomal recessive neurological disorder which usually starts in childhood. The clinical presentation is very similar to Friedreich ataxia, most patients have progressive truncal and extremity ataxia, areflexia, positive Babinski sign, dysarthria and sensory neuropathy.MethodsWe made an inquiry to our colleagues in Norway, we included information from a prevalence study published southern Norway and added data from our own known case.ResultsA newly published prevalence study of hereditary ataxias (total of 171 subjects) found only one subject with AVED in Southeast Norway. We describe two more patients, one from the Central part and one from the Northern part of Norway. All 3 cases had age of onset in early childhood (age of 4–5 years) and all experienced gait ataxia and dysarthria. The genetic testing confirmed that they had pathogenic mutations in the α-tocopherol transfer protein gene (TTPA). All were carriers of the non-sense c.400C > T mutation, one was homozygous for that mutation and the others were compound heterozygous, either with c.358G > A or c.513_514insTT. The homozygous carrier was by far the most severely affected case.ConclusionsWe estimate the occurrence of AVED in Norway to be at least 0.6 per million inhabitants. We emphasize that all patients who develop ataxia in childhood should be routinely tested for AVED to make an early diagnosis for initiating treatment with high dose vitamin E to avoid severe neurological deficits.

Audio-Vestibular Signs and Symptoms in Chiari Malformation Type I. Case Series and Literature Review

IntroductionChiari malformation is an alteration of the base of the skull with herniation through the foramen magnum of the brain stem and cerebellum. Although the most common presentation is occipital headache, the association of audio-vestibular symptoms is not rare. The aim of our study was to describe audio-vestibular signs and symptoms in Chiari malformation type I (CM-I). Materials and methodsWe performed a retrospective observational study of patients referred to our unit during the last 5 years. We also carried out a literature review of audio-vestibular signs and symptoms in this disease. ResultsThere were 9 patients (2 males and 7 females), with an average age of 42.8 years. Five patients presented a Ménière-like syndrome; 2 cases, a recurrent vertigo with peripheral features; 1 patient showed a sudden hearing loss; and 1 case suffered a sensorineural hearing loss with early childhood onset. The most common audio-vestibular symptom indicated in the literature in patients with CM-I is unsteadiness (49%), followed by dizziness (18%), nystagmus (15%) and hearing loss (15%). Nystagmus is frequently horizontal (74%) or down-beating (18%). Other audio-vestibular signs and symptoms are tinnitus (11%), aural fullness (10%) and hyperacusis (1%). Occipital headache that increases with Valsalva manoeuvres and hand paresthesias are very suggestive symptoms. ConclusionsThe appearance of audio-vestibular manifestations in CM-I makes it common to refer these patients to neurotologists. Unsteadiness, vertiginous syndromes and sensorineural hearing loss are frequent. Nystagmus, especially horizontal and down-beating, is not rare. It is important for neurotologists to familiarise themselves with CM-I symptoms to be able to consider it in differential diagnosis.

Novel GUCY2D Gene Mutations in Japanese Male Twins with Leber Congenital Amaurosis.

Purpose. Leber congenital amaurosis (LCA), a genetically and clinically heterogeneous disease, is the earliest onset retinitis pigmentosa (RP) and is the most severe of hereditary retinal dystrophies. This study was conducted to investigate genetic and clinical features of LCA in a set of Japanese male twins with LCA. Methods. To identify causative mutations, 74 genes known to cause RP or LCA were examined by targeted-next generation sequencing (NGS). Targeted-NGS was performed using a custom designed Agilent HaloPlex target enrichment kit with Illumina Miseq sequencer. Identified potential pathogenic mutations were confirmed using Sanger sequencing. Clinical analyses were based on ophthalmic examination, fundus photography, and electroretinography (ERG). Results. Compound heterozygous GUCY2D mutations of novel splicing mutation c.2113+2_2113+3insT and novel missense mutation p.L905P were detected in both twins. Their father and mother were heterozygous for c.2113+2_2113+3insT and p.L905P, respectively. The twins had phenotypic features similar to those previously reported in patients with GUCY2D mutations. This included early childhood onset of visual loss, nystagmus, unrecordable ERG, photophobia, and hyperopia. Conclusions. To the best of our knowledge, this is the first report of genetic and clinical features of Japanese LCA twins with GUCY2D mutation, which were detected using targeted-NGS.

Giant axonal disease: Report of eight cases.

Giant axonal neuropathy (GAN) is an autosomal recessive inherited progressive motor and sensory neuropathy with typical onset in early childhood. The disease is caused by GAN gene mutations on chromosome 16q24.1. To determine clinical and genetic results in Turkish patients with GAN. Eight children with GAN were retrospectively analyzed. Five (62.5%) were girls and 3 (37.5%) were boys with the mean age on admission 10.13±3.8 years (range: 5-15 years). Parental consanguinity was found in all the families. The patients had the classical clinical phenotype characterized by a severe axonal neuropathy with kinky hair. Two patients had contractures of extremities, and not walking. One patient was walking with aid. The other patients were walking without aid. Mutation analysis was performed in two patients and IVS9 (+1G>T) (homozygous) mutation was detected. The classical clinical findings allowed considering the GAN diagnosis, but, in atypical cases and milder phenotypes, the presence of giant axons in nerve biopsy was helpful to specify molecular analysis.

45. Clinical and electrophysiological non-SPG4 spectrum of HSP

SPG clinical spectrum of “pure” and “complicated” HSP is wide, including visual pathways and retina involvement, motor neuron and extrapyramidal syndromes. Two females (sporadic cases) and one male patient have been studied. (1) Disease onset in early childhood: mild mental retardation with learning disability, skeletal deformity and speech impairment have been related to complicated delivery with cyanosis and hypoxia with need to ICU support. The occurrence of progressive spastic paraparesis addressed to diagnostic evaluation by MRI and neurophysiological investigation. Abnormalities of MEPs, mild polyneuropathy support the hypothesis of AR-HSP. DNA sample analysis confirmed mutations in SPG11 gene. Gait was still possible. (2) Disease onset in early childhood: progressive muscle weakness and distal atrophy; at 24 years old age, she was wheelchair-bound. Neurophysiological assessment pointed out a peripheral motor neuron damage and abnormalities of MEPs; delayed visual evoked potentials with a normal elecroretinogram (both to luminance and contrast variations) was suggestive for the occurrence of optic neuropathy without retina involvement. Direct sequencing of SPG11 identified 2 heterozygous mutations. (3) Disease onset in adulthood: progressive paraparesis and pain in the lower limbs with pyramidal signs. There was a family history of paraparesis. Spine MRI was normal. Neurophysiological assessment showed normal peripheral motor conduction, normal VEPs and delayed MEPs. Direct sequencing of SPG 7 identified heterozygous mutation missense and splicing. Diverse clinical features have been reported with SPG mutations, including diversity in presentation and clinical course: comprehensive electrophysiological testing disclosed a more widespread affection of nervous system and could reflect different underlying pathomechanisms of HSP.

A mitochondrial tRNAMet mutation causing developmental delay, exercise intolerance and limb girdle phenotype with onset in early childhood

A 10-year-old girl presented with exercise intolerance, learning difficulty, and muscle weakness in a limb girdle distribution. She had delayed achievement of motor milestones and difficulties with social interaction at pre-school age. Muscle biopsy showed no myopathic or dystrophic features, but 90% COX negative fibres and ragged blue fibres. Respiratory chain enzyme analysis in muscle showed a combined deficiency and mitochondrial DNA sequencing revealed the presence of an m.4450G>A mutation in the MT-TM gene encoding the tRNA for methionine. The mutation was only detected in mtDNA extracted from muscle and skin fibroblast, and could not be found in other tissues or in the mother. This is the second patient reported in the literature with a mitochondrial myopathy due to a mt-tRNAMet mutation. The first patient, a 30-year-old woman, presented with exercise intolerance, limb girdle muscle weakness, lactic acidosis, learning difficulty, and growth retardation in early childhood. Thus, the two patients exhibit strikingly overlapping phenotypes.

Dejerine-Sottas syndrome with early onset in childhood

Dejerine-Sottas syndrome (DSS) is a progressive hypertrophic interstitial neuropathy of childhood characterized by defects in the myelin structure, with motor nerve conduction velocities below 10 m/sec. The phenotype is genetically heterogeneous with autosomal dominant and autosomal recessive inheritance but “de novo” mutations are also described. Nerve pathology is highly variable. The clinical course is severe, leading to sensory loss, distal followed by proximal weakness, foot deformities, scoliosis and contractures, cranial nerve deficits and occasionally spinal cord compression. In this case study we evaluated a case of DSS at a ten year old boy and we outlined the importance of the electrophysiological investigations together with magnetic resonance neurography in diagnosing the Dejerine-Sottas syndrome.

SGCE and myoclonus dystonia: motor characteristics, diagnostic criteria and clinical predictors of genotype.

Myoclonus dystonia syndrome (MDS) is a young-onset movement disorder. A proportion of cases are due to mutations in the maternally imprinted SGCE gene. We assembled the largest cohort of MDS patients to date, and determined the frequency and type of SGCE mutations. The aim was to establish the motor phenotype in mutation carriers and utility of current diagnostic criteria. Eighty-nine probands with clinical features compatible with MDS were recruited from the UK and Ireland. Patients were phenotypically classified as "definite", "probable" or "possible" MDS according to previous guidelines. SGCE was analyzed using direct sequencing and copy number variant analysis. In those where no mutation was found, DYT1 (GAG deletion), GCH1, THAP1 and NKX2.1 genes were also sequenced. Nineteen (21.3%) probands had an SGCE mutation. Three patterns of motor symptoms emerged: (1) early childhood onset upper body myoclonus and dystonia, (2) early childhood onset lower limb dystonia, progressing later to more pronounced myoclonus and upper body involvement, and (3) later childhood onset upper body myoclonus and dystonia with evident cervical involvement. Five probands had large contiguous gene deletions ranging from 0.7 to 2.3 Mb in size with distinctive clinical features, including short stature, joint laxity and microcephaly. Our data confirms that SGCE mutations are most commonly identified in MDS patients with (1) age at onset ≤10 years and (2) predominant upper body involvement of a pure myoclonus-dystonia. Cases with whole SGCE gene deletions had additional clinical characteristics, which are not always predicted by deletion size or gene involvement.

Manifestaciones audiovestibulares en la malformación de Chiari tipo i. Serie de casos y revisión bibliográfica

IntroductionChiari malformation is an alteration of the base of the skull with herniation through the foramen magnum of the brain stem and cerebellum. Although the most common presentation is occipital headache, the association of audio-vestibular symptoms is not rare. The aim of our study was to describe audio-vestibular signs and symptoms in Chiari malformation type i (CM-I). Materials and methodsWe performed a retrospective observational study of patients referred to our unit during the last 5 years. We also carried out a literature review of audio-vestibular signs and symptoms in this disease. ResultsThere were 9 patients (2 males and 7 females), with an average age of 42.8 years. Five patients presented a Ménière-like syndrome; 2 cases, a recurrent vertigo with peripheral features; one patient showed a sudden hearing loss; and one case suffered a sensorineural hearing loss with early childhood onset. The most common audio-vestibular symptom indicated in the literature in patients with CM-I is unsteadiness (49%), followed by dizziness (18%), nystagmus (15%) and hearing loss (15%). Nystagmus is frequently horizontal (74%) or down-beating (18%). Other audio-vestibular signs and symptoms are tinnitus (11%), aural fullness (10%) and hyperacusis (1%). Occipital headache that increases with Valsalva manoeuvres and hand paresthesias are very suggestive symptoms. ConclusionsThe appearance of audio-vestibular manifestations in CM-I makes it common to refer these patients to neurotologists. Unsteadiness, vertiginous syndromes and sensorineural hearing loss are frequent. Nystagmus, especially horizontal and down-beating, is not rare. It is important for neurotologists to familiarise themselves with CM-I symptoms to be able to consider it in differential diagnosis.

A.P.6 : Autosomal recessive myofibrillar myopathy caused by ACTA1 mutations

Myofibrillar myopathies (MFMs) are a heterogeneous group of muscle diseases frequently associated with cardiac abnormalities and characteristic muscle histopathology. Most cases show autosomal dominant inheritance and adult onset of symptoms. Muscle biopsy findings include Z-line abnormalities, accumulation of myofibrillar degradation products and cytoplasmic aggregations of proteins. To date, the genetic cause of MFMs remains unclear in approximately 50% of cases. Here we describe a brother and a sister presenting with a myopathy with early childhood onset. The brother developed slowly progressive proximal muscle weakness and wasting affecting the lower and upper limbs, scapular winging and cervical spine rigidity. At the age of 33 years he remains ambulatory, with no signs of cardiac or respiratory impairment. His older sister showed a more severe phenotype and died due to acute heart failure possibly secondary to pulmonary infection at the age of 34 years. CK levels were increased in both subjects (270–1680 IU/L). At the ages of 23 years the brother was diagnosed with MFM based on a muscle biopsy showing retention of granular cytoplasmic labelling for desmin and myotilin and presence of rimmed vacuoles. Electron microscopy revealed large areas of Z-line material, dense osmiophilic granular areas and areas of filamentous material, reminiscent of that seen in desmin myopathies. Exome and Sanger sequencing identified a homozygous mutation (Ile250Thr) in the ACTA1 gene in both siblings. There was not reported consanguinity within the family however the parents are originally from the Kurdish Sanjabi tribe in the Kermanshah province in Iran. Our finding enlarged the clinical and genetic heterogeneity of MFMs, describing a new autosomal recessive form characterised by childhood onset, slowly progressive limb girdle muscle weakness, possible cardiac involvement and typical myofibrillar muscle pathology.