Epilepsy due to PNPO mutations: genotype, environment and treatment affect presentation and outcome.

The first described patients with pyridox(am)ine 5'-phosphate oxidase deficiency all had neonatal onset seizures that did not respond to treatment with pyridoxine but responded to treatment with pyridoxal 5'-phosphate. Our data suggest, however, that the clinical spectrum of pyridox(am)ine 5'-phosphate oxidase deficiency is much broader than has been reported in the literature. Sequencing of the PNPO gene was undertaken for a cohort of 82 individuals who had shown a reduction in frequency and severity of seizures in response to pyridoxine or pyridoxal 5'-phosphate. Novel sequence changes were studied using a new cell-free expression system and a mass spectrometry-based assay for pyridoxamine phosphate oxidase. Three groups of patients with PNPO mutations that had reduced enzyme activity were identified: (i) patients with neonatal onset seizures responding to pyridoxal 5'-phosphate (n = 6); (ii) a patient with infantile spasms (onset 5 months) responsive to pyridoxal 5'-phosphate (n = 1); and (iii) patients with seizures starting under 3 months of age responding to pyridoxine (n = 8). Data suggest that certain genotypes (R225H/C and D33V) are more likely to result in seizures that to respond to treatment with pyridoxine. Other mutations seem to be associated with infertility, miscarriage and prematurity. However, the situation is clearly complex with the same combination of mutations being seen in patients who responded and did not respond to pyridoxine. It is possible that pyridoxine responsiveness in PNPO deficiency is affected by prematurity and age at the time of the therapeutic trial. Other additional factors that are likely to influence treatment response and outcome include riboflavin status and how well the foetus has been supplied with vitamin B6 by the mother. For some patients there was a worsening of symptoms on changing from pyridoxine to pyridoxal 5'-phosphate. Many of the mutations in PNPO affected residues involved in binding flavin mononucleotide or pyridoxal 5'-phosphate and many of them showed residual enzyme activity. One sequence change (R116Q), predicted to affect flavin mononucleotide binding and binding of the two PNPO dimers, and with high residual activity was found in Groups (ii) and (iii). This sequence change has been reported in the 1000 Genomes project suggesting it could be a polymorphism but alternatively it could be a common mutation, perhaps responsible for the susceptibility locus for genetic generalized epilepsy on 17q21.32 (close to rs72823592). We believe the reduction in PNPO activity and B6-responsive epilepsy in the patients reported here indicates that it contributes to the pathogenesis of epilepsy.

Health-related quality-of-life and behavioural outcome in survivors of childhood meningitis.

OBJECTIVE: To describe behavioural and health-related quality-of-life (HRQoL) outcomes in survivors of childhood meningitis and identify variables predictive of psychosocial outcome. METHODS: Psychosocial outcomes were measured via parent and teacher report using the Strengths and Difficulties Questionnaire (SDQ) and the Paediatric Quality of Life Inventory (PedsQL Core & Fatigue versions). Participants were 346[corrected] consecutive survivors admitted to a regional children's hospital (1991-2007). One hundred and twelve of 346 (32%) [corrected] returned postal questionnaires and file review confirmed diagnosis in 100 cases. RESULTS: At a mean of 8 years post-illness 32% of parents and 19% of teachers reported clinically significant behavioural difficulties on the SDQ; along with significantly lowered HRQoL on PedsQL measures. Later sequelae such as learning disability and hearing/visual impairment, along with socioeconomic status, independently predicted behavioural and HRQoL outcome on regression analysis. Acute disease complications were associated with later occurrence of epilepsy, learning disability and visual impairment, but not directly with psychosocial outcomes at time of follow-up. CONCLUSIONS: Survivors with these sequelae should be screened for emotional and behavioural difficulties during key developmental transitions such as school entry. These findings strongly support recent UK clinical guidelines (NICE and SIGN) proposing that parents be made aware of possible psychological complications on discharge.

Brain involvement in muscular dystrophies with defective dystroglycan glycosylation.

OBJECTIVE: To assess the range and severity of brain involvement, as assessed by magnetic resonance imaging, in 27 patients with mutations in POMT1 (4), POMT2 (9), POMGnT1 (7), Fukutin (4), or LARGE (3), responsible for muscular dystrophies with abnormal glycosylation of dystroglycan (dystroglycanopathies). METHODS: Blinded review of magnetic resonance imaging brain scans from 27 patients with mutations in 1 of these 5 genes. RESULTS: Brain magnetic resonance images were normal in 3 of 27 patients; in another 5, only nonspecific abnormalities (ventricular dilatation, periventricular white matter abnormalities, or both) were seen. The remaining 19 patients had a spectrum of structural defects, ranging from complete lissencephaly in patients with Walker-Warburg syndrome to isolated cerebellar involvement. Cerebellar cysts and/or dysplasia and hypoplasia were the predominant features in four patients. Polymicrogyria (11/27) was more severe in the frontoparietal regions in 6, and had an occipitofrontal gradient in 2. Pontine clefts, with an unusual appearance to the corticospinal tracts, were seen in five patients with a muscle-eye-brain-like phenotype, three patients with POMGnT1, one with LARGE, and one with POMT2 mutations. Prominent cerebellar cysts were always seen with POMGnT1 mutations, but rarely seen in POMT1 and POMT2. Brainstem and pontine abnormalities were common in patients with POMT2, POMGnT1, and LARGE mutations. INTERPRETATION: Our results expand the spectrum of brain involvement associated with mutations in LARGE, POMGnT1, POMT1, and POMT2. Pontine clefts were visible in some dystroglycanopathy patients. Infratentorial structures were often affected in isolation, highlighting their susceptibility to involvement in these conditions.

Extreme phenotypic diversity and nonpenetrance in families with the LMNA gene mutation R644C.

Mutations in the LMNA gene result in diverse phenotypes including Emery Dreifuss muscular dystrophy, limb girdle muscular dystrophy, dilated cardiomyopathy with conduction system disease, Dunnigan type familial partial lipodystrophy, mandibulo acral dysplasia, Hutchinson Gilford progeria syndrome, restrictive dermopathy and autosomal recessive Charcot Marie Tooth type 2. The c.1930C > T (R644C) missense mutation has previously been reported in eight unrelated patients with variable features including left ventricular hypertrophy, limb girdle muscle weakness, dilated cardiomyopathy and atypical progeria. Here we report on the details of nine additional patients in eight families with this mutation. Patients 1 and 2 presented with lipodystrophy and insulin resistance, Patient 1 having in addition focal segmental glomerulosclerosis. Patient 3 presented with motor neuropathy, Patient 4 with arthrogryposis and dilated cardiomyopathy with left ventricular non-compaction, Patient 5 with severe scoliosis and contractures, Patient 6 with limb girdle weakness and Patient 7 with hepatic steatosis and insulin resistance. Patients 8 and 9 are brothers with proximal weakness and contractures. Nonpenetrance was observed frequently in first degree relatives. This report provides further evidence of the extreme phenotypic diversity and low penetrance associated with the R644C mutation. Possible explanations for these observations are discussed.

Accuracy of Screening Tools for Pap Smears in General Practice.

BACKGROUND: Data extraction tools (DETs) are increasingly being used for research and audit of general practice, despite their limitations.Objective This study explores the accuracy of Pap smear rates obtained with a DET compared to that of the Pap smear rate obtained with a manual file audit. METHOD: A widely available DET was used to establish the rate of Pap smears in a large multi-general practice (multi-GP) in regional New South Wales followed by a manual audit of patient files. The main outcome measure was identification of possible discrepancies between the rates established. RESULTS: The DET used significantly underestimated the level of cervical screening compared to the manual audit. In some instances, the patient file contained phone/specialist record of Pap smear conducted elsewhere, which accounted for the failure of the DET to detect some smears. Those patients who had Pap smears whose pathology codes differed between time intervals, i.e. from different pathology providers or from within the same provider but using a different code, were less likely to have had their most recent Pap smear detected by the DET (p < 0.001). CONCLUSION: Data obtained from DETs should be used with caution as they may not accurately reflect the rate of Pap smears from electronic medical records.How this fits in DETs are increasingly being used for research and audit of general practice. This study explores the accuracy of Pap smear rates obtained with a DET compared to that of the Pap smear rate obtained with a manual file audit The DET tested significantly underestimated the level of cervical screening compared to manual screening. Data obtained from DETs should be used with caution as they may not accurately reflect the rate of Pap smears from electronic medical records.

The movement disorders of Coffin-Lowry syndrome.

Coffin-Lowry syndrome (CLS) is an X-linked semi-dominant condition with learning difficulties and dysmorphism caused by mutations in the gene RSK2. Originally, epilepsy was reported as a feature. We and others have since described predominantly sound-startle induced drop attacks that have been labelled 'cataplexy', abnormal startle response and hyperekplexia. We sought to clarify why there should be controversy over the type of paroxysmal events. Review of the literature and our patients confirmed that each centre had studied only a small numbers of individuals (mean = 2). The type of movement disorder varied both with age and between individuals. One individual might have more than one movement disorder. One of our adult patients had several types of movement disorder and epilepsy that merged seamlessly: there was true cataplexy triggered by telling a joke, something close to cataplexy ('cataplexy') triggered by sound-startle, a predominantly hypertonic reaction varying from hyperekplexia to a more prolonged tonic reaction resembling startle epilepsy, and true unprovoked epileptic seizures. In the large database of the Coffin-Lowry Syndrome Foundation family support group, 34 of 170 (20%) individuals with CLS and known age had 'drop attacks' and an additional 9 (5%) of these had additional epileptic seizures. The onset of such events was usually after age 5 years, prevalence peaking at 15-20 years (27%). Many became wheelchair bound as a result. This unique combination of more than one non-epileptic movement disorder and epilepsy deserves further semiological and genetic study both for the patients with CLS and for the wider implications.

Variables predictoras del empoderamiento familiar en prácticas de atención temprana centradas en la familia / Predictor variables of family empowerment in family-centred early intervention

OBJETIVO: Determinar algunas de las variables predictoras de empoderamiento familiar en los servicios de atención temprana que implementan prácticas centradas en la familia. MÉTODO: Se plantea en una muestra de 431 familias que reciben servicios de atención temprana en España, un análisis de regresión lineal múltiple, para definir la relación entre las siguientes variables: tipo de prácticas en atención temprana, nivel de apoyos, estatus socioeconómico y diagnóstico de su hijo/a, como predictoras de empoderamiento familiar. RESULTADOS: Los resultados evidencian diferencias significativas entre el empoderamiento de las familias y los apoyos con los que cuentan, también se observan niveles de empoderamiento diferentes en relación al diagnóstico del hijo o la hija con trastornos del neurodesarrollo. CONCLUSIONES: A partir de los resultados, se sugiere reflexionar sobre las prácticas de atención temprana de profesionales en general y logopedas en particular, para potenciar el impacto sobre el empoderamiento de las familias, mejorando la fidelidad en la implementación de prácticas centradas en la familia, y favoreciendo la movilización de recursos y apoyos por parte de la familia, en ese mismo proceso de intervención

OBJECTIVE: To determine some of the predictive variables of family empowerment in early intervention services that implement family-centred practices. METHOD: A multiple linear regression analysis is proposed in a sample of 431 families receiving early care services in Spain, to define the relationship between the following variables: type of early intervention practices, supports, socioeconomic status and diagnosis of their child as predictors of family empowerment. RESULTS: The results show significant differences between the empowerment of the families and the supports they have, and different levels of empowerment are observed in relation to the diagnosis of the son or daughter with neurodevelopmental disorders. CONCLUSIONS: Based on the results, we suggest reflecting on professionals early intervention practices and those of speech therapists in particular, to enhance the impact on empowering families, improving fidelity in the implementation of family-centred practices, and favouring the mobilisation of resources and supports by the family, in that same intervention process

Growing up with spinal muscular atrophy with respiratory distress (SMARD1).

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an inherited neuromuscular condition resulting from recessive mutations in the immunoglobulin mu-binding protein (IGHMBP2) gene. Affected individuals characteristically present in infancy with progressive distal weakness and respiratory distress secondary to diaphragmatic weakness. Considerable clinical heterogeneity has been described both in its presentation and phenotype in childhood; however little data pertaining to phenotype in adulthood have been reported to date. This report describes a 21 year old woman with genetically confirmed SMARD1 who has stable muscle weakness, normal cognitive abilities and is able to lead a socially integrated lifestyle, using mechanical ventilation only overnight. This report adds new evidence for clinical variability throughout the course of SMARD1.

Cranial magnetic resonance imaging mistakenly suggests prenatal ischaemia in PEHO-like syndrome.

We describe two sisters with a PEHO-like syndrome. The first-born had early epileptic spasms with hypsarrhythmia, visual inattention with optic atrophy, progressive microcephaly and absence of development. Cranial magnetic resonance imaging revealed periventricular white matter changes. Cerebellar hypoplasia, characteristic of true PEHO syndrome, was absent. The MRI changes were interpreted as periventricular leucomalacia due to prenatal ischaemia, and a low recurrence risk was suggested. Subsequently, the younger sister was born similarly affected. The PEHO syndrome (progressive encephalopathy, hypsarrhythmia and optic atrophy) is a rare, autosomal recessive, encephalopathy of infancy. Diagnosis is clinical but cerebellar hypoplasia on neuroimaging is regarded as an additional necessary criterion. A heterogeneous group of PEHO-like patients, who lack cerebellar hypoplasia but have varying supratentorial abnormalities, have been reported. This is the second report of siblings with a PEHO-like syndrome, and supports the existence of a distinct, autosomal recessive condition in which neuroimaging abnormalities may be misinterpreted.

Congenital myopathies with secondary neuromuscular transmission defects; a case report and review of the literature.

Congenital myopathies are a clinically and genetically heterogeneous group of disorders characterized by early onset hypotonia, weakness and characteristic, but not pathognomonic, structural abnormalities in muscle fibres. The clinical features overlap with muscular dystrophies, myofibrillar myopathies, neurogenic conditions and congenital myasthenic syndromes. We describe a case of cap myopathy with myasthenic features due to a mutation in the TPM2 gene that responded to anticholinesterase therapy. We also review other published cases of congenital myopathies with neuromuscular transmission abnormalities. This report expands the spectrum of congenital myopathies with secondary neuromuscular transmission defects. The recognition of these cases is important since these conditions can benefit from treatment with drugs enhancing neuromuscular transmission.

A combination of Botulinum Toxin A therapy and Functional Electrical Stimulation in children with cerebral palsy--a pilot study.

BACKGROUND: Among the ambulant population of children with spastic cerebral palsy (CP), dynamic equinus is one of the most common form of gait deviation that is encountered. OBJECTIVE: To investigate the combined effects of Functional Electrical Stimulation (FES) and Botulinum Toxin A (BTXA) therapy in children with spastic CP, and to demonstrate the feasibility of this combination therapy. METHODS: A single-subject design with repeated measures was adopted. Eight children (six males, two females; mean age 7 y 9 mo, SD 1 y 5 mo; range 7 y to 11 y) diagnosed with hemiplegic (n=6) or diplegic (n=2) spastic CP completed the study. Each subject participated in the study for twenty weeks. This period consisted of baseline (one week), BTXA phase (three weeks), first FES phase (four weeks), first control phase (four weeks), second FES phase (four weeks) and second control phase (four weeks). Subjects were assessed at the end of each phase. The ankle angle at the end of swing phase was selected as the primary outcome measure. The secondary outcome measure recorded was the foot contact pattern. RESULTS: There was an increase in ankle dorsiflexion at the end of the combined intervention in most subjects (n=6), accompanied by an improvement in foot contact pattern. CONCLUSIONS: This pilot study demonstrated that it is feasible to combine BTXA therapy with FES in ambulant children with spastic CP.

Pyruvate dehydrogenase E2 deficiency: a potentially treatable cause of episodic dystonia.

The association of progressive episodic dystonia and learning disability with distinctive neuroimaging findings may lead to consideration of atypical Pantothenate Kinase Associated Neurodegeneration (PKAN) and investigations directed towards that diagnosis. Recent reports indicate that deficiency of dihydrolipoamide acetyltransferase, the E2 component of the pyruvate dehydrogenase complex, may present similarly, and that this disorder should also be considered in the differential diagnosis. We describe two sisters with early onset episodic dystonia and pyruvate dehydrogenase deficiency caused by defects in the E2 subunit. Both have neuroimaging features similar to previously described patients and have mutations in the DLAT gene. As this condition is potentially treatable with a ketogenic diet, the possibility of this diagnosis should be considered in similar cases.