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The article discusses development associated with paediatric neurology in Australia and New Zealand. It is noted that very significant technical changes which have revolutionised the medical industry to characterise and treat neurological conditions in children, and which have affected all aspects of neurological investigation and management.

Aim: Mutations in the genes encoding the riboflavin transporters RFVT2 and RFVT3 have been identified in Brown-Vialetto-Van Laere syndrome, a neurodegenerative disorder characterized by hearing loss and pontobulbar palsy. Treatment with riboflavin has been shown to benefit individuals with the phenotype of RFVT2 deficiency. Understanding the characteristics of hearing loss in riboflavin transporter deficiency would enable early diagnosis and therapy.Method: We performed hearing assessments in seven children (from four families) with RFVT2 deficiency and reviewed results from previous assessments. Assessments were repeated after 12 months and 24 months of riboflavin therapy and after cochlear implantation in one individual.Results: Hearing loss in these individuals was due to auditory neuropathy spectrum disorder (ANSD). Hearing loss was identified between 3 years and 8 years of age and progressed rapidly. Hearing aids were not beneficial. Riboflavin therapy resulted in improvement of hearing thresholds during the first year of treatment in those with recent-onset hearing loss. Cochlear implantation resulted in a significant improvement in speech perception in one individual.Interpretation: Riboflavin transporter deficiency should be considered in all children presenting with an auditory neuropathy. Speech perception in children with ANSD due to RFVT2 deficiency may be significantly improved by cochlear implantation. [ABSTRACT FROM AUTHOR]

Background: Adenylyl cyclase 5 (ADCY5) mutations is associated with heterogenous syndromes: familial dyskinesia and facial myokymia; paroxysmal chorea and dystonia; autosomal-dominant chorea and dystonia; and benign hereditary chorea. We provide detailed clinical data on 7 patients from six new kindreds with mutations in the ADCY5 gene, in order to expand and define the phenotypic spectrum of ADCY5 mutations.Methods: In 5 of the 7 patients, followed over a period of 9 to 32 years, ADCY5 was sequenced by Sanger sequencing. The other 2 unrelated patients participated in studies for undiagnosed pediatric hyperkinetic movement disorders and underwent whole-exome sequencing.Results: Five patients had the previously reported p.R418W ADCY5 mutation; we also identified two novel mutations at p.R418G and p.R418Q. All patients presented with motor milestone delay, infantile-onset action-induced generalized choreoathetosis, dystonia, or myoclonus, with episodic exacerbations during drowsiness being a characteristic feature. Axial hypotonia, impaired upward saccades, and intellectual disability were variable features. The p.R418G and p.R418Q mutation patients had a milder phenotype. Six of seven patients had mild functional gain with clonazepam or clobazam. One patient had bilateral globus pallidal DBS at the age of 33 with marked reduction in dyskinesia, which resulted in mild functional improvement.Conclusion: We further delineate the clinical features of ADCY5 gene mutations and illustrate its wide phenotypic expression. We describe mild improvement after treatment with clonazepam, clobazam, and bilateral pallidal DBS. ADCY5-associated dyskinesia may be under-recognized, and its diagnosis has important prognostic, genetic, and therapeutic implications. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Aim: The alpha-1 isoform of the calcium channel gene is expressed abundantly in neuronal tissue, especially within the cerebellum. Mutations in this gene may manifest with hemiplegic migraine, spinocerebellar ataxia type 6 (SCA6) and episodic ataxia type 2 (EA2) in adults. There are reports of children with CACAN1A mutations presenting with paroxysmal tonic upgaze, abnormal saccades and congenital nystagmus as well as severe forms of hemiplegic migraine. The aim of this study was to review the clinical presentation and subsequent course of all children with a CACNA1A mutation who presented to a tertiary children's hospital.Method: We reviewed retrospectively nine children with a proven CACNA1A mutation who presented to the Children's Hospital at Westmead between 2005-2015. The initial and subsequent clinical presentation, radiological features and molecular genetic profile of each child was reviewed.Results: Nine children presented to out institute over a 10 year period; six were female and three male. The median age of presentation was 1.2 years. Eye movement disorders were the presenting feature in eight children. Three of these children later presented with severe hemiplegic migraine episodes often requiring ICU care. Affected children also had developmental delay and developed classical hemiplegic migraine, episodic ataxia and seizures. Calcium channel blockers were used with some efficacy in preventing severe HM episodes.Interpretation: Eye movement disorders are an early manifestation of CACNA1A mutations in children. Improved recognition of the CACNA1A phenotype in childhood is important for early diagnosis, counselling and appropriate emergency management. There is some early evidence that calcium channel blockers may be an effective prophylactic agent for the severe hemiplegic migraine episodes. [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine whether transplantation of umbilical cord blood from unrelated donors before the development of symptoms could halt the progression of early juvenile onset cases of MLD in whom the disease was diagnosed based on the family history. Three asymptomatic children (aged 2 years 4 months, 2 years 8 months and 5 years 5 months, two of whom were sisters) underwent unrelated umbilical cord blood transplantation (UCBT) and two untreated symptomatic siblings were included in the study. In 14-year and 6-year follow-ups after transplantation, clinical examination, ARSA enzyme levels, neurophysiological, neuroimaging, and psychological status were assessed. All three transplanted patients remain well, and the parameters evaluated remain stable. Of the treated patients, the two sisters had ongoing evidence of demyelinating sensorimotor neuropathy on nerve conduction tests, and with a early sensorimotor neuropathy in the older sister , and the other patient has mild intellectual impairment. One of the two un-transplanted controls, 15 years after MLD diagnosis, has relentlessly progressed to full dependency with epilepsy, severe mental retardation, dystonic movements, dysphagia and recurrent respiratory problems. Six years after diagnosis, the other control has a slowly progressive course with spastic dystonic quadriplegia, epilepsy, dysphagia, continual drooling and incontinence. Our data show that, in comparison with their untreated siblings, UCBT significantly slowed the progression of the disease in the treated patients. We conclude that UCBT benefits children with pre-symptomatic early juvenile onset MLD by favourably altering the natural history of the disease. [ABSTRACT FROM AUTHOR]

Epilepsy-aphasia syndromes (EAS) are a group of rare, severe epileptic encephalopathies of unknown etiology with a characteristic electroencephalogram (EEG) pattern and developmental regression particularly affecting language. Rare pathogenic deletions that include GRIN2A have been implicated in neurodevelopmental disorders. We sought to delineate the pathogenic role of GRIN2A in 519 probands with epileptic encephalopathies with diverse epilepsy syndromes. We identified four probands with GRIN2A variants that segregated with the disorder in their families. Notably, all four families presented with EAS, accounting for 9% of epilepsy-aphasia cases. We did not detect pathogenic variants in GRIN2A in other epileptic encephalopathies (n = 475) nor in probands with benign childhood epilepsy with centrotemporal spikes (n = 81). We report the first monogenic cause, to our knowledge, for EAS. GRIN2A mutations are restricted to this group of cases, which has important ramifications for diagnostic testing and treatment and provides new insights into the pathogenesis of this debilitating group of conditions. [ABSTRACT FROM AUTHOR]

Objective: Charcot-Marie-Tooth disease (CMT) is a common heritable peripheral neuropathy. There is no treatment for any form of CMT, although clinical trials are increasingly occurring. Patients usually develop symptoms during the first 2 decades of life, but there are no established outcome measures of disease severity or response to treatment. We identified a set of items that represent a range of impairment levels and conducted a series of validation studies to build a patient-centered multi-item rating scale of disability for children with CMT. Methods: As part of the Inherited Neuropathies Consortium, patients aged 3 to 20 years with a variety of CMT types were recruited from the USA, United Kingdom, Italy, and Australia. Initial development stages involved definition of the construct, item pool generation, peer review, and pilot testing. Based on data from 172 patients, a series of validation studies were conducted, including item and factor analysis, reliability testing, Rasch modeling, and sensitivity analysis. Results: Seven areas for measurement were identified (strength, dexterity, sensation, gait, balance, power, endurance), and a psychometrically robust 11-item scale was constructed (CMT Pediatric Scale [CMTPedS]). Rasch analysis supported the viability of the CMTPedS as a unidimensional measure of disability in children with CMT. It showed good overall model fit, no evidence of misfitting items, and no person misfit, and it was well targeted for children with CMT. Interpretation: The CMTPedS is a well-tolerated outcome measure that can be completed in 25 minutes. It is a reliable, valid, and sensitive global measure of disability for children with CMT from the age of 3 years. ANN NEUROL 2012; [ABSTRACT FROM AUTHOR]

Mitochondrial diseases in children are often associated with a peripheral neuropathy but the presence of the neuropathy is under-recognized because of the overwhelming involvement of the central nervous system (CNS). These mitochondrial neuropathies are heterogeneous in their clinical, neurophysiological, and histopathological characteristics. In this article, we provide a comprehensive review of childhood mitochondrial neuropathy. Early recognition of neuropathy may help with the identification of the mitochondrial syndrome. While it is not definite that the characteristics of the neuropathy would help in directing genetic testing without the requirement for invasive skin, muscle or liver biopsies, there appears to be some evidence for this hypothesis in Leigh syndrome, in which nuclear SURF1 mutations cause a demyelinating neuropathy and mitochondrial DNA MTATP6 mutations cause an axonal neuropathy. POLG1 mutations, especially when associated with late-onset phenotypes, appear to cause a predominantly sensory neuropathy with prominent ataxia. The identification of the peripheral neuropathy also helps to target genetic testing in the mitochondrial optic neuropathies. Although often subclinical, the peripheral neuropathy may occasionally be symptomatic and cause significant disability. Where it is symptomatic, recognition of the neuropathy will help the early institution of rehabilitative therapy. We therefore suggest that nerve conduction studies should be a part of the early evaluation of children with suspected mitochondrial disease. [ABSTRACT FROM AUTHOR]

Pes cavus in Charcot-Marie-Tooth disease type 1A (CMT1A) is thought to be due to muscle imbalance of the lower leg. Botulinum toxin type A (BoNT-A) can modify foot deformity in other conditions of muscle imbalance. We tested the safety and effectiveness of BoNT-A on pes cavus progression in pediatric CMT1A. A 24-month, randomized, single-blind trial of BoNT-A was undertaken in 10 affected children (20 legs), aged 3-14 years. The treated leg received intramuscular BoNT-A injections at 6-month intervals in the tibialis posterior and peroneus longus. The control leg received no injections. Primary outcome was radiographic alignment at 24 months. Secondary outcomes were foot posture, ankle flexibility, and strength, assessed every 6 months. Radiographically, BoNT-A produced a small non-significant reduction in cavus progression. There was no effect of BoNT-A on secondary outcomes. There were no serious adverse events. At 24 months, the intramuscular BoNT-A injections proved safe and well-tolerated but did not affect the progression of pes cavus in CMT1A. Muscle Nerve, 2010 [ABSTRACT FROM AUTHOR]

Cognitive screening tools designed for children can also be used with adolescents. However, early studies suggest that scores can approach a maximum at about age 10 or 11 years. The inital hypothesis was this apparent ''ceiling effect'' is due to limits in the materials, where items can be insufficiently challenging for some adolescents. The alternative hypothesis is that general cognitive screening has a true limit by early adolescence. Participants (N = 85) were 10 to 15-year-old girls and boys, with a database (N = 1249) of 4 to 12-year-old children. The School-Years Screening Test for the Evaluation of Mental Status (SYSTEMS) cognitive screening was extended by more difficult items. Results show that scores increase rapidly for young children and tend toward a maximum in early adolescence. This characteristic asymptotic curve explained a substantial proportion of the variance. We can conclude that, although specific functions continue to develop, there is an upper limit in early adolescence for such general cognitive functioning. The findings support cognitive screening across a broad age range and suggest worthwhile research and clinical applications. [ABSTRACT FROM AUTHOR]

The authors studied the health-related quality of life of children aged 5 to 18 years with Charcot-Marie-Tooth disease of varying types and severity and compared it with the general pediatric population. To capture and compare the quality-of-life data across a broad range of ages, the Child Health Questionnaire was completed by parents of 127 children with Charcot-Marie-Tooth disease. Affected children exhibited lower physical, psychological, and social well-being than the general pediatric population, with subsequent worsening of many domains with age. The type of Charcot-Marie-Tooth disease influenced some physical and behavioral quality-of-life domains, while gender, body size, and ethnicity did not. Parent characteristics had generally little impact on the reporting of their child's quality of life, although parents with Charcot-Marie-Tooth disease reported higher bodily pain in their children than those without. Overall, quality of life is negatively affected by the presence and severity of Charcot-Marie-Tooth disease in childhood. [ABSTRACT FROM AUTHOR]

Background: Mutations in the gene encoding mitofusin 2 (MFN2) cause Charcot-Marie-Tooth disease type 2 (CMT2), with heterogeneity concerning severity and associated clinical features. Objective: To describe MFN2 mutations and associated phenotypes in patients with hereditary motor and sensory neuropathy (HMSN). Design: Direct sequencing of the MFN2 gene and clinical investigations of patients with MFN2 mutations. Setting: Molecular genetics laboratory of a university hospital and the Limoges National Referral Center for Rare Peripheral Neuropathies. Patients: One hundred fifty index patients with HMSN and a median motor nerve conduction velocity of 25 m/s or greater and without mutations in the genes encoding connexin 32 and myelin protein zero. Main Outcome Measures: Results of genetic analyses and phenotypic observations. Results: Twenty different missense mutations were identified in 20 index patients. Mutation frequency was 19 of 107 (17.8%) in patients with CMT2 and 1 of 43 (2.3%) in patients with a median motor nerve conduction velocity less than 38 m/s. Four patients had proven de novo mutations, 8 families had autosomal dominant inheritance, and 3 had autosomal recessive inheritance. The remaining 5 patients were sporadic cases with heterozygous mutations. Phenotypes varied from mild forms to early-onset severe forms. Additional features were encountered in 8 patients (32%). Six patients underwent sural nerve biopsy: electronic microscopy showed prominent mitochondrial abnormalities on longitudinal sections. Conclusions: MFN2 mutations are a frequent cause of CMT2, with variable severity and either dominant or recessive inheritance. MFN2 gene testing must be a first-line analysis in axonal HMSN irrespective of the mode of inheritance or the severity of the peripheral neuropathy. [ABSTRACT FROM AUTHOR]

We studied the timing and progression of foot and ankle changes in 81 children with genetically confirmed Charcot-Marie-Tooth disease type 1A (CMT1A) and determined their impact on motor function and walking ability. Foot deformity, weakness, pain, cramps, and instability were a common feature of CMT1A. Foot structure evolved toward pes cavus from early childhood to adolescence, although a subgroup with normal and planus feet remained. Foot strength increased with age, although compared to age-equivalent norms it declined from 4 years. Factors associated with evolving foot deformity included muscle weakness/imbalance, restricted ankle flexibility, and joint hypermobility. Regression modeling identified dorsiflexion weakness, global foot weakness, and difficulty toe-walking as independent predictors of motor dysfunction, while pes cavus and difficulty heel-walking were predictors of poor walking ability. Foot problems are present from the earliest stages of the disease and can have a negative impact on function. Early foot and ankle intervention may prevent long-term disability and morbidity in CMT1A. Muscle Nerve 39: 158-166, 2009 [ABSTRACT FROM AUTHOR]

Although Charcot-Marie-Tooth disease type 1A (CMT1A) initially manifests in the first decade, there are no large studies describing its neurophysiologic features in childhood. We report neurophysiologic findings in 80 children aged 2–16 years with CMT1A who underwent median motor and sensory nerve conduction studies. Neurophysiologic abnormalities were present in all children. Median motor nerve conduction velocity was invariably less than 33 m/s (mean 18.7 m/s, range 9.0–32.9 m/s), with conduction velocities significantly slower in children aged 7–16 years compared with children aged 6 years and below. All children had prolonged distal motor latencies (mean 7.3 ms, range 4.0–12.3 ms). The compound muscle action potential (CMAP) amplitude was reduced from an early age (mean 7.1 mV, range 2.1–13.5 mV), and its normal increase with age was attenuated. Median sensory responses were present in only seven children, all aged less than 9 years and with slowed sensory conduction. Neurophysiologic abnormalities are present in all children with CMT1A from the age of 2 years. Motor conduction slowing progresses through the first 6 years of life and thereafter remains stable. CMAP amplitude is reduced from an early age, and the normal physiologic increase with age is attenuated. Median sensory responses may be recorded in younger children, and their presence does not exclude the diagnosis of CMT1A. [ABSTRACT FROM AUTHOR]

Preschool-age children with neuromuscular disorders are often excluded from clinical trials due to the lack of reliable and objective strength measures. We evaluated the reliability of measuring foot and ankle muscle strength in 60 healthy children age 2-4 years. The strength of foot inversion and eversion, ankle plantarflexion, and dorsiflexion was measured using a hand-held dynamometer. Intrarater and interrater reliability of two assessors was determined for each muscle group using intraclass correlation coefficients (ICCs), 95% confidence intervals (CIs), and standard error of measurement (SEM). For all muscle groups intrarater (ICC2,2 = 0.85-0.94, 95% CI = 0.75-0.96, SEM = 1.5-4.7 N) and interrater (ICC2,1 = 0.88-0.96, 95% CI = 0.81-0.98, SEM = 1.2-4.6 N) reliability was high for all children. As expected, reliability was generally highest in 3- and 4-year-old children and lowest in 2-year-old children. Hand-held dynamometry can reliably measure foot and ankle strength in very young children and may help aid in diagnosis and in characterizing disease progression in disorders affecting the foot and ankle. Muscle Nerve, 2008 [ABSTRACT FROM AUTHOR]

The hereditary motor and sensory neuropathies (HMSNs, Charcot-Marie-Tooth neuropathies) are the most common degenerative disorders of the peripheral nervous system. In recent years a dramatic expansion has occurred in our understanding of the molecular basis and cell biology of the recessively inherited demyelinating and axonal neuropathies, with delineation of a number of new neuropathies. Mutations in some genes cause a wide variety of clinical, neurophysiologic, and pathologic phenotypes, rendering diagnosis difficult. The X-linked forms of HMSN represent at least 10%-15% of all HMSNs and have an expanded disease spectrum including demyelinating, intermediate, and axonal neuropathies, transient central nervous system (CNS) dysfunction, mental retardation, and hearing loss. This review presents an overview of the recessive and X-linked forms of HMSN observed in childhood, with particular reference to disease phenotype and neurophysiologic and pathologic abnormalities suggestive of specific diagnoses. These findings can be used by the clinician to formulate a differential diagnosis and guide targeted genetic testing. Muscle Nerve, 2007 [ABSTRACT FROM AUTHOR]

Peroxiredoxins (PRDXs) belong to a family of peroxidases that are highly expressed in mammalian tissues. Comparatively, little is known about their expression in the nervous system. In this study, we examined in human sural nerve, the expression of PRDX5, the most recently defined peroxiredoxin family member. Immunohistochemical staining of paraffin sections showed that PRDX5 expression was mainly localised to the axon and, to a lesser extent, to the Schwann cells. Immunogold labelling electron microscopy further revealed that PRDX5 is widely distributed in multiple cellular compartments, most importantly in mitochondria but also in axoplasm, Schwann cell cytosol, nucleus, and myelin. A progressive decline in PRDX5 expression with advancing age was identified in human nerves at different ages. The wide distribution of PRDX5 in cellular and sub-cellular structures indicates that it may play important roles in a wide range of tissue components in normal peripheral nerves. [ABSTRACT FROM AUTHOR]

SYSTEMS is a screening tool of general cognitive functioning for school-aged children that entails cognitive manipulation and information skills. Our aim was to extend the test for 4- and 5-year-old children at preschool to estimate theoretical starting points in typical cognitive profiles, which are critical in the early years. Participants (N = 1164, girls/boys, 50%) were 4 to 11 years old (mean 7.9, SD 2.2) at preschools and schools in diverse socioeconomic areas of Sydney, Australia. Children's responses created the normative database, and the parameters were derived from curve estimation and regression procedures. The results suggest that cognitive screening is reliable and valid for younger and older children and show a nonlinear relation of children's test scores with age, which is characteristic of rapid change for younger children. The characteristic curve with the best fit to the data had a theoretical starting point before school age, at around 3 years of age. The findings are discussed in light of alternative models and the clinical and educational applications. (J Child Neurol 2004; 19:313-317). [ABSTRACT FROM AUTHOR]

This study addresses the test reliability of a screening test and stability of children's cognitive functioning. Children aged 5 to 8 years in western Sydney were assessed on three occasions. The first assessment provided a baseline, with the second assessment at 2-, 4-, or 12-week intervals. The final assessment was 4 weeks later. Indicators of reliability and stability suggested that a distinction can be made between test reliability and the phenomenon (cognitive functioning) stability. Cognitive functioning was assessed using the School-Years Screening Test for the Evaluation of Mental Status (SYSTEMS). The findings have implications for indicators of reliability and stability of cognitive assessments in developmental research and clinical practice. (J Child Neurol 2003;18:5-11). [ABSTRACT FROM AUTHOR]

Evaluates the use of brief assessments for children with low intellectual functioning. Assessment of the SYSTEMS cognitive screening test; Analysis of the Aspects of Self Knowledge-KIDS inventory of children's self-concepts; Results of the cognitive screening tests.

Initial reports of patients with laminin α2 chain (merosin) deficiency had a relatively homogeneous phenotype, with classical congenital muscular dystrophy (CMD) characterised by severe muscle weakness, inability to achieve independent ambulation, markedly raised creatine kinase, and characteristic white matter hypodensity on cerebral magnetic resonance imaging. We report a series of five patients with laminin α2 deficiency, only one of whom has this severe classical CMD phenotype, and review published reports to characterise the expanded phenotype of laminin α2 deficiency, as illustrated by this case series. While classical congenital muscular dystrophy with white matter abnormality is the commonest phenotype associated with laminin α2 deficiency, 12% of reported cases have later onset, slowly progressive weakness more accurately designated limb-girdle muscular dystrophy. In addition, the following clinical features are reported with increased frequency: mental retardation (∼6%), seizures (∼8%), subclinical cardiac involvement (3-35%), and neuronal migration defects (4%). At least 25% of patients achieve independent ambulation. Notably, three patients with laminin a2 deficiency were asymptomatic, 10 patients had normal MRI (four with LAMA2 mutations reported), and between 10-20% of cases had maximum recorded creatine kinase of less than 1000 U/1. LAMA2 mutations have been identified in 25% of cases. Sixty eight percent of these have the classical congenital muscular dystrophy, but this figure is likely to be affected by ascertainment bias. We conclude that all dystrophic muscle biopsies, regardless of clinical phenotype, should be studied with antibodies to laminin α2. In addition, the use of multiple antibodies to different regions of laminin α2 may increase the diagnostic yield and provide some correlation with severity of clinical phenotype. [ABSTRACT FROM AUTHOR]

In order to find the optimal dosage schedule of phenobarbitone for neonatal convulsions, four groups of patients were studied. Twelve infants (group 1) received a mean phenobarbitone dose of 9.5 mg/kg a day given intramuscularly for 3 days followed by 5.8 mg/kg a day given intramuscularly and then orally. Six infants (group 2) received a mean intravenous loading dose of 9.5 mg/kg followed by 6.8 mg/kg a day given intramuscularly or orally. Nine infants (group 3) received a mean loading dose of 14.9 mg/kg intravenously followed by a maintenance dose of 5.9 mg/kg a day. Thirteen patients (group 4) received a mean intramuscular loading dose of 15.2 mg/kg followed by 5.9 mg/kg a day. Blood samples were taken regularly and phenobarbitone levels were determined by gas liquid chromatography. A mean intravenous or intramuscular loading dose of 15 mg/kg of phenobarbitone safely achieved therapeutic levels within 2 hours of injection and high therapeutic levels were maintained with a dose of 6 mg/kg a day. [ABSTRACT FROM AUTHOR]

Mitofusin 2, a large transmembrane GTPase located in the outer mitochondrial membrane, promotes membrane fusion and is involved in the maintenance of the morphology of axonal mitochondria. Mutations of the gene encoding mitofusin 2 ( MFN2) have recently been identified as the cause of approximately one-third of dominantly inherited cases of the axonal degenerative forms of Charcot–Marie–Tooth disease (CMT type 2A) and of rarer variants. The latter include a severe, early-onset axonal neuropathy, which may occur in autosomal dominant or recessive forms, as well as some instances associated with pyramidal tract involvement (CMT type 5), with optic atrophy (CMT type 6), and, occasionally, with alterations of cerebral white matter. All individuals with a dominantly or recessively inherited or otherwise unexplained, chronic progressive axonal degenerative polyneuropathy should be tested for mutations of MFN2. [ABSTRACT FROM AUTHOR]

Classic spinal muscular atrophy (SMA) is caused by mutations in the telomeric copy of SMN1. Its product is involved in various cellular processes, including cytoplasmic assembly of spliceosomal small nuclear ribonucleoproteins, pre-mRNA processing and activation of transcription. Spinal muscular atrophy with respiratory distress (SMARD) is clinically and genetically distinct from SMA. Here we demonstrate that SMARD type 1 (SMARD1) results from mutations in the gene encoding immunoglobulin pbinding protein 2 (IGHMBP2; on chromosome 11q13.2-q13.4). In six SMARD1 families, we detected three recessive missense mutations (exons 5, 11 and 12), two nonsense mutations (exons 2 and 5), one frameshift deletion (exon 5) and one splice donor-site mutation (intron 13). Mutations in mouse Ighmbp2 (ref. 14) have been shown to be responsible for spinal muscular atrophy in the neuromuscular degeneration (nmd) mouse, whose phenotype resembles the SMARD1 phenotype. Like the SMN1 product, IGHMBP2 colocalizes with the RNA-processing machinery in both the cytoplasm and the nucleus. Our results show that IGHMBP2 is the second gene found to be defective in spinal muscular atrophy, and indicate that IGHMBP2 and SMN share common functions important for motor neuron maintenance and integrity in mammals. [ABSTRACT FROM AUTHOR]