Natural history of alpha-thalassemia X-linked intellectual disability syndrome: A case report of a 45-year-old man.

We have followed the clinical course of a 45-year-old man with a severe form of alpha-thalassemia X-linked intellectual disability syndrome for 40 years. The most challenging health issue is the combination of rumination, drooling, and vomiting. The patient achieved present adaptive and motor skills in his teenage years. He is able to move on the floor in a sitting position. He seems happy and has not shown any behavioral or psychiatric symptoms. New signs not described in the literature before are accelerated growth after puberty and atypical sleeping position with upper body resting on legs.

Adult phenotype of the homozygous missense mutation c.655G>A, p.Gly219Arg in SLC13A5: A case report.

Homozygous recessive or compound heterozygous mutations in SLC13A5-gene as a cause of Early Infantile Epileptic Encephalopathy subtype 25 (OMIM 615905) were published in 2014. Previous clinical reports describe young patients, aged <34 years. We describe 54- and 56-year-old siblings and show that the disorder linked to SLC13A5 is not just a pediatric problem but may affect the patient for decades resulting in profound intellectual disability, severe motor handicap, and abnormal electroencephalography without active epilepsy. Other diagnostic hints in adults are small size, spasticity and severe abrasion due to amelogenesis imperfecta of the hypoplastic type.

Two middle-aged women with the Finnish variant of muscle-eye-brain disease (MEB).

Muscle-eye-brain disease (MEB) is a recessively inherited rare disease. Sixteen different gene mutations are known, with the most common mutations in the POMGNT1 gene. The disease is now called congenital muscular dystrophy-dystroglycanopathy type A3 (MDDGA3). It manifests itself as muscular dystrophy with eye and brain anomalies and intellectual disability. Previous clinical reports describe young patients. We have been able to follow two patients for almost 40 years. Their clinical picture has remained quite stable since adolescence, appearing as severe intellectual and motor disability, extremely limited communication skills, visual impairment, epilepsy, joint contractures, repeated bowel obstructions, teeth abrasion due to bruxism, an irregular sleep pattern and as a previously unreported feature hypothermic periods manifesting as excessive sleepiness.

Variants p.Q1236H and p.E1143G in mitochondrial DNA polymerase gamma POLG1 are not associated with increased risk for valproate-induced hepatotoxicity or pancreatic toxicity: A retrospective cohort study of patients with epilepsy.

OBJECTIVE: Previous studies have suggested that heterozygous variants p.Q1236H and p.E1143G in mitochondrial DNA polymerase gamma (POLG1) increase the risk for liver injury for patients on valproate (VPA) therapy. We assessed the prevalence of these common variants and seven other pathogenic mutations in POLG1 and determined the occurrence of VPA-induced hepatotoxicity (VHT) or pancreatic toxicity in a cohort of patients with epilepsy. METHODS: Patients with epilepsy (N = 367) were retrospectively identified from medical record files and screened for mutations in POLG1. Patients who had received VPA monotherapy and carried either of the two variants, p.Q1236H or p.E1143G, without other pathogenic mutations in POLG1 (n = 33, variant group) and patients without these variants (n = 28, nonvariant group) were included in the study. Clinical data on epilepsy, characteristics of VPA treatment, risk factors for VHT, laboratory data on liver and pancreas functions, and adverse effects were collected. RESULTS: A total of 122 patients had either the POLG1 p.Q1236H (n = 99) or p.E1143G (n = 24) variant in the heterozygous or homozygous state. Transient liver dysfunction was identified in three (n = 33, 9.1%) variant group patients and in one (n = 28, 3.6%) nonvariant group patient (P = 0.62). Mild to moderate elevations in liver enzymes were encountered in both groups. Furthermore, two patients on VPA polytherapy developed acute pancreatitis, and two pediatric patients with heterozygous p.Q1236H variants and mutations in IQSEC2 and GLDC, respectively, had elevated levels of VPA metabolites in urine, elevated plasma glycine, and/or increased acylglycine excretion. SIGNIFICANCE: POLG1 p.Q1236H and p.E1143G variants could not be identified as statistically significant risk factors for VHT or pancreatic toxicity. We suggest that VPA treatment could be suitable for patients who harbor these common variants in the absence of other pathogenic mutations in POLG1.

The TREAT-NMD DMD Global Database: analysis of more than 7,000 Duchenne muscular dystrophy mutations.

Analyzing the type and frequency of patient-specific mutations that give rise to Duchenne muscular dystrophy (DMD) is an invaluable tool for diagnostics, basic scientific research, trial planning, and improved clinical care. Locus-specific databases allow for the collection, organization, storage, and analysis of genetic variants of disease. Here, we describe the development and analysis of the TREAT-NMD DMD Global database (http://umd.be/TREAT_DMD/). We analyzed genetic data for 7,149 DMD mutations held within the database. A total of 5,682 large mutations were observed (80% of total mutations), of which 4,894 (86%) were deletions (1 exon or larger) and 784 (14%) were duplications (1 exon or larger). There were 1,445 small mutations (smaller than 1 exon, 20% of all mutations), of which 358 (25%) were small deletions and 132 (9%) small insertions and 199 (14%) affected the splice sites. Point mutations totalled 756 (52% of small mutations) with 726 (50%) nonsense mutations and 30 (2%) missense mutations. Finally, 22 (0.3%) mid-intronic mutations were observed. In addition, mutations were identified within the database that would potentially benefit from novel genetic therapies for DMD including stop codon read-through therapies (10% of total mutations) and exon skipping therapy (80% of deletions and 55% of total mutations).

Does the absence or presence of sleep spindles on EEG have prognostic value for cognitive outcome in children with infantile epileptic spasms syndrome? A systematic literature review.

Infantile Epileptic Spasms Syndrome (IESS) is an epileptic encephalopathy in childhood that affects infants under the age of two years. When spasm series occur, prognosis for cognitive outcome is poor in the majority of cases. The encephalopathy in IESS includes delayed maturation of normal sleep phenomena in the EEG, such as sleep spindles. Children with intellectual disabilities often have abnormal sleep, and children with sleep problems have difficulties learning at school. We examined whether there is evidence of prognostic value of detection of sleep spindles in the EEG of children with IESS on their future cognitive development. A systematic literature search yielded five studies touching this question. They were evaluated by two scorers independently. The lack of normal sleep patterns including lack of sleep spindles was used as a biomarker of poor cognitive outcome. Positive (PPV) and Negative (NPV) prognostic values were calculated. A summary of all five studies indicates a PPV of 82% and an NPV of 45%. Given the small amount of data, the retrospective quality of most studies, and the differences in the outcome parameters reported, it is prudent to say that currently available data do not allow us to conclude whether spindles have a specific and independent role in the cognitive prognosis of affected children. Since sleep spindles are needed for memory consolidation and demonstrate the active role of sleep for learning and memory, the hypothesis remains that their absence in the EEG may indicate an increased risk of cognitive delay, but more supporting data are needed to reach such a firm conclusion.

The TREAT-NMD Duchenne muscular dystrophy registries: conception, design, and utilization by industry and academia.

Duchenne muscular dystrophy (DMD) is an X-linked genetic disease, caused by the absence of the dystrophin protein. Although many novel therapies are under development for DMD, there is currently no cure and affected individuals are often confined to a wheelchair by their teens and die in their twenties/thirties. DMD is a rare disease (prevalence <5/10,000). Even the largest countries do not have enough affected patients to rigorously assess novel therapies, unravel genetic complexities, and determine patient outcomes. TREAT-NMD is a worldwide network for neuromuscular diseases that provides an infrastructure to support the delivery of promising new therapies for patients. The harmonized implementation of national and ultimately global patient registries has been central to the success of TREAT-NMD. For the DMD registries within TREAT-NMD, individual countries have chosen to collect patient information in the form of standardized patient registries to increase the overall patient population on which clinical outcomes and new technologies can be assessed. The registries comprise more than 13,500 patients from 31 different countries. Here, we describe how the TREAT-NMD national patient registries for DMD were established. We look at their continued growth and assess how successful they have been at fostering collaboration between academia, patient organizations, and industry.

Manifestations of Intellectual Disability, Dystonia, and Parkinson's Disease in an Adult Patient with ARX Gene Mutation c.558_560dup p.(Pro187dup).

We describe a 38-year-old male patient with intellectual disability and progressive motor symptoms who lacked an etiological diagnosis for many years. Finally, clinical exome sequencing showed a likely pathogenic variant of the ARX gene suggesting Partington syndrome. His main symptoms were mild intellectual disability, severe kinetic apraxia, resting and action tremor, dysarthria, tonic pupils, constant dystonia of one upper limb, and focal dystonia in different parts of the body, axial rigidity, spasticity, epilepsy, and poor sleep. Another likely pathogenic gene variant was observed in the PKP2 gene and is in accordance with the observed early cardiomyopathy. Single-photon emission computed tomography imaging of dopamine transporters showed a reduced signal in the basal ganglia consistent with Parkinson's disease. Therapies with a variable number of drugs, including antiparkinsonian medications, have yielded poor responses. Our case report extends the picture of the adult phenotype of Partington syndrome.

Report of a novel missense mutation in the MECP2 gene in a middle-aged man with intellectual disability syndrome.

Exome sequencing revealed the cause of our 35-year-old male patient's progressive and severe intellectual and motor disability, namely a previously undescribed missense mutation of MECP2.

ACTH Treatment of Infantile Spasms: Low-Moderate- Versus High-Dose, Natural Versus Synthetic ACTH-A Retrospective Cohort Study.

BACKGROUND: High dosages of natural adrenocorticotropic hormone are used in many centers in the United States for the treatment of infantile spasms. However, lower dosages of synthetic adrenocorticotropic hormone (tetracosactide) might be equally efficient as high dosages. We analyzed the treatment options for infantile spasms, especially regarding the adrenocorticotropic hormone dosage and the formulation (natural versus synthetic) and evaluated which options were more effective in a retrospective cohort from 1960 to 1976. METHODS: We compared the short-term response rates of patients treated with high dosages of natural adrenocorticotropic hormone (120 IU/day) (N = 31) (Group1) with those of patients treated with low-moderate dosages of natural adrenocorticotropic hormone (40 IU/day) (N = 52) (Group2). We also compared the short-term response rates of patients treated with natural adrenocorticotropic hormone (N = 83) with those of patients treated with synthetic adrenocorticotropic hormone, (N = 23) (Group3). The responses were evaluated clinically and by electroencephalography at two to three weeks after the onset of therapy. RESULTS: A response was seen in 24 of 31 children treated with high dosages and in 43 of 52 children treated with low-moderate dosages of natural adrenocorticotropic hormone (P = 0.56). All children with an unknown etiology responded to both high and low-moderate dosages of natural adrenocorticotropic hormone. The proportion of children with a good early response to synthetic adrenocorticotropic hormone (16 of 23) did not differ from the proportion of children with a good early response treated with natural adrenocorticotropic hormone (67 of 83) (P = 0.25). CONCLUSIONS: High dosages of adrenocorticotropic hormone are not more effective than low-moderate dosages in the short term for treating infantile spasms. Synthetic adrenocorticotropic hormone is equally effective as natural adrenocorticotropic hormone.

Non-invasive therapeutic brain stimulation for treatment of resistant focal epilepsy in a teenager.

AIMS: A 13-year-old boy with symptomatic focal epilepsy due to a right parietal dysembryoplastic neuroepithelial tumor (DNET) presented pre- and post-operatively fluctuating tinnitus and sensory symptoms which became persistent after incomplete tumor resection. He received low-frequency rTMS treatment and cathodal tDCS treatment. METHODS: Case report with clinical details and pictures from rTMS and tDCS stimulation targets. RESULTS: The patient became symptom free with an initial low-frequency rTMS treatment series targeted to the EEG-verified epileptic zone followed by maintenance therapy at the same region with cathodal tDCS at home. CONCLUSIONS: Both rTMS and tDCS could be more often used in adolescents when drug treatment and surgery do not cease focal epilepsy, here with fluctuating tinnitus.

Clinical Outcomes in Duchenne Muscular Dystrophy: A Study of 5345 Patients from the TREAT-NMD DMD Global Database.

BACKGROUND: Recent short-term clinical trials in patients with Duchenne Muscular Dystrophy (DMD) have indicated greater disease variability in terms of progression than expected. In addition, as average life-expectancy increases, reliable data is required on clinical progression in the older DMD population. OBJECTIVE: To determine the effects of corticosteroids on major clinical outcomes of DMD in a large multinational cohort of genetically confirmed DMD patients. METHODS: In this cross-sectional study we analysed clinical data from 5345 genetically confirmed DMD patients from 31 countries held within the TREAT-NMD global DMD database. For analysis patients were categorised by corticosteroid background and further stratified by age. RESULTS: Loss of ambulation in non-steroid treated patients was 10 years and in corticosteroid treated patients 13 years old (p = 0.0001). Corticosteroid treated patients were less likely to need scoliosis surgery (p < 0.001) or ventilatory support (p < 0.001) and there was a mild cardioprotective effect of corticosteroids in the patient population aged 20 years and older (p = 0.0035). Patients with a single deletion of exon 45 showed an increased survival in contrast to other single exon deletions. CONCLUSIONS: This study provides data on clinical outcomes of DMD across many healthcare settings and including a sizeable cohort of older patients. Our data confirm the benefits of corticosteroid treatment on ambulation, need for scoliosis surgery, ventilation and, to a lesser extent, cardiomyopathy. This study underlines the importance of data collection via patient registries and the critical role of multi-centre collaboration in the rare disease field.

A novel sequence variation in the transactivation regulating domain of the androgen receptor in two infertile Finnish men.

OBJECTIVE: To study a new sequence variant at the beginning of the CAG repeat in the exon 1 of the androgen receptor gene. DESIGN: Controlled clinical study. SETTINGS: Healthy volunteers in an academic research environment. PATIENT(S): Sixty-two Finnish men with spermatogenic failure and 60 controls. INTERVENTION(S): ABI PRISM 377 (Applied Biosystems, Foster City, CA) automated sequencing. MAIN OUTCOME MEASURE(S): Determining the sequence around the CAG repeat of the AR gene. RESULT(S): A new 173A-->T (Q58L) substitution at the beginning of the CAG repeat in the transactivation-regulating domain of the androgen receptor was found in 2 infertile Finnish men but not in 60 other infertile men or 60 controls. CONCLUSION(S): As the polyglutamine tract coded by the CAG repeat is crucial to spermatogenesis, the 173A-->T (Q58L) substitution might be the cause of infertility in these two Finnish men.

Mapping the differences in care for 5,000 spinal muscular atrophy patients, a survey of 24 national registries in North America, Australasia and Europe.

Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder characterised by the degeneration of motor neurons and progressive muscle weakness. It is caused by homozygous deletions in the survival motor neuron gene on chromosome 5. SMA shows a wide range of clinical severity, with SMA type I patients often dying before 2 years of age, whereas type III patients experience less severe clinical manifestations and can have a normal life span. Here, we describe the design, setup and utilisation of the TREAT-NMD national SMA patient registries characterised by a small, but fully standardised set of registry items and by genetic confirmation in all patients. We analyse a selection of clinical items from the SMA registries in order to provide a snapshot of the clinical data stratified by SMA subtype, and compare these results with published recommendations on standards of care. Our study included 5,068 SMA patients in 25 countries. A total of 615 patients were ventilated, either invasively (178) or non-invasively (437), 439 received tube feeding and 455 had had scoliosis surgery. Some of these interventions were not available to patients in all countries, but differences were also noted among high-income countries with comparable wealth and health care systems. This study provides the basis for further research, such as quality of life in ventilated SMA patients, and will inform clinical trial planning.

Epilepsy caused by CDKL5 mutations.

Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) have been identified in female patients with early onset epileptic encephalopathy and severe mental retardation with a Rett-like phenotype. Subsequently CDKL5 mutations were shown to be associated with more diverse phenotypes including mild epilepsy and autism without epilepsy. Furthermore, CDKL5 mutations were found in patients with Angelman-like phenotype. The severity of epilepsy associated with CDKL5 mutations was recently shown to correlate with the type of CDKL5 mutations and epilepsy was identified to involve three distinct sequential stages. Here, we describe the phenotype of a severe form of neurodevelopmental disease in a female patient with a de novo nonsense mutation of the CDKL5 gene c.175C > T (p.R59X) affecting the catalytic domain of CDKL5 protein. Mutations in the CDKL5 gene are less common in males and can be associated with a genomic deletion as found in our male patient with a deletion of 0.3 Mb at Xp22.13 including the CDKL5 gene. We review phenotypes associated with CDKL5 mutations and examine putative relationships between the clinical epilepsy phenotype and the type of the mutation in the CDKL5 gene.

Elements of working memory as predictors of goal-setting skills in children with attention-deficit/ hyperactivity disorder.

The aim of the study was to examine how goal-setting skills of children with attention-deficit/hyperactivity disorder (ADHD) can be predicted with elements of working memory. The study involved 30 children with an ADHD diagnosis and 30 healthy volunteers. The IQ of the participants was assessed, and ADHD symptoms were evaluated by parents. Each of the elements of working memory was assessed with two measures as well as goal-setting skills. In the tests of the central executive and in one of the tests of the visuospatial sketch pad, children with ADHD performed more poorly than did controls but not in the tests of the phonological loop. Children with ADHD performed more poorly than controls did on the mastery scores of the goal-setting measures but not on the Strategy scores. According to regression analysis, central executive functions are critical for the variance in goal-setting skills in children with ADHD.

Quantitative HMRS and MRI volumetry indicate neuronal damage in the hippocampus of children with focal epilepsy and infrequent seizures.

PURPOSE: Seizures induce progressive morphologic and functional changes in particular in the hippocampus, but whether and at what stage the hippocampus is affected in children with focal, temporal, nonintractable epilepsy is poorly known. We have now studied eventual metabolic and volume changes in the hippocampus of children with nonsymptomatic focal epilepsy taking antiepileptic medication (AEDs) but still having infrequent seizures. METHODS: Quantitative proton magnetic resonance spectroscopy ((1)HMRS) and volumetric MRI were used to study the hippocampal region of 11 pediatric outpatients (age 10 to 17 years) with cryptogenic localization-related epilepsy, and eight healthy volunteers (age 9 to 16 years) served as controls. The spectra were obtained bilaterally from the hippocampi by using the 1.5-T MR imager. The spectral resonance lines of N-acetyl group (NA), creatine and phosphocreatine group (Cr), choline-containing compounds (Cho), and myoinositol (mI) were analyzed quantitatively. The volume of the hippocampus was semiautomatically calculated. RESULTS: The mean concentration of NA was significantly decreased both in the focus side (9.02 +/- 2.00 mM) and in the nonfocus side (8.88 +/- 2.09 mM) of the patients compared with the controls (10.76 +/- 1.86 mM), in particular if the children had a history of generalized tonic-clonic seizures. The mean concentrations of Cho, Cr, and mI did not differ significantly between the patients and controls. Moreover, the mean hippocampal volume of the focus side of patients was significantly reduced compared with that of the controls. CONCLUSIONS: Metabolic changes in hippocampi were detected in children with nonsymptomatic localization-related epilepsy and infrequent seizures. Reduced NA could reflect neuronal metabolic dysfunction and/or neuronal damage, as indicated by our volumetric findings.

MECP2 mutation analysis in patients with mental retardation.

Mutations in the methyl-CpG-binding protein 2 (MECP2) gene are known to underlie Rett' syndrome, the most common cause of mental retardation (MR) in girls. Since the original report, phenotypes resulting from MECP2 mutations have been shown to extend, for example, to several Rett variants, autism, atypical Angelman syndrome, and nonspecific MR. It was earlier proposed that MECP2 mutations might account for approximately 2% of the male cases with nonspecific MR. Thereby, the frequency of MECP2 mutations in the mentally retarded population would be comparable to that of Fragile-X syndrome. The aim of this study was to analyze well-characterized cases with MR and to clarify the role of the MECP2 gene in the etiology of MR and atypical Angelman syndrome. The coding sequence of the MECP2 gene was analyzed in a sample of 118 patients (103 males, 15 females) by direct sequencing. Two coding sequence variants, 602C > T (A201V) and 1189G > A (E397K), were identified. In addition, we identified four variants in the intronic or 3'UTR regions. None of these variants is likely to be causal. We conclude that the evidence across all the mutation screening studies implies that MECP2 mutations do not represent a major cause of nonspecific MR.

Long CAG repeats in the AR gene are not associated with infertility in Finnish males.

BACKGROUND: The modulatory domain of the human androgen receptor gene contains a polymorphic CAG repeat coding for a polyglutamine tract. The length of the polyglutamine tract is inversely correlated with transcriptional activity of the androgen receptor. As androgens are crucial to spermatogenesis, decreased transcriptional activity of the androgen receptor associated with a long polyglutamine tract could lead to failure in spermatogenesis. Accordingly, long CAG repeats within the normal range have been suggested to be more common in infertile males than in the control population. METHODS: To test this hypothesis, we examined the CAG repeat number of 192 Finnish males with moderate or severe spermatogenic failure and 149 control males. RESULTS: Our results did not support the hypothesis, the controls harbored slightly longer CAG repeats than the infertile males. CONCLUSION: At least in the present study population from Finland, long CAG repeats in the androgen receptor gene do not play a significant role in spermatogenic failure.

Identification of two AGTR2 mutations in male patients with non-syndromic mental retardation.

Mutations in the coding region of the angiotensin II type 2 receptor gene (AGTR2) were recently identified to cause X-linked recessive mental retardation. We report a mutation screening of the AGTR2 gene in 57 Finnish male patients with non-syndromic mental retardation. We identified two mutations, a 62G-->T transversion, which leads to a substitution of glycine for valine (G21V) and a 157A-->T transversion, which causes a substitution of isoleucine for phenylalanine (I53F). The patients with AGTR2 sequence variants had severe/profound mental retardation, epileptic seizures, restlessness, hyperactivity, and disturbed development of speech.