Myotonic dystrophy type 1 - a multiorgan disorder. / Dystrofia myotonika type 1 ­ en multiorgansykdom.

Myotonic dystrophy type 1 is an autosomal dominant, inherited multiorgan disorder that can affect people of all ages. It is the most prevalent inherited muscular disease in adults. Late diagnosis points to limited knowledge among the medical community that symptoms other than typical muscular symptoms can dominate. The condition often worsens with each generation and some families are severely affected. Significantly delayed diagnosis means a risk of more serious development of the disorder and inadequate symptomatic treatment. We hope that this clinical review article may lead to more rapid diagnosis and better follow-up of this patient group.

Health Survey of Adults with Neurofibromatosis 1 Compared to Population Study Controls.

Neurofibromatosis type 1 (NF1) is a genetic, autosomal dominant multi-organ disease characterized by susceptibility to tumor formation, changes in skin pigmentation, skeletal abnormalities, and neuropsychological deficits. Clinical studies have shown impaired health-related quality of life (HQoL) in adults with NF1. However, little is known about HQoL in non-clinical NF1 samples. We conducted a cross-sectional self-report survey of 142 persons with NF1 (M age = 50.3 years, SD = 12.0, range 32 to 80; 62.0% females) recruited from non-clinical settings. Several HQoL domains, including life satisfaction, mental health, sleep, pain, gastrointestinal problems, oral health, and social support, were compared between the NF1 sample and 46,293 controls from the HUNT3 population study. We also examined gender differences within the NF1 sample and predictors of HQoL. Compared to controls, the NF1 sample reported significantly poorer life satisfaction, mental health, sleep, and oral health, and more pain, gastrointestinal problems, comorbid diseases, and memory problems. Several HQoL domains were significantly correlated. Mental health was the only unique significant predictor of overall life satisfaction. Women with NF1 reported significantly more mental health, sleep, and pain problems than men with NF1. Mental health assessment and management should be integrated into clinical care of persons with NF1 to potentially improve their HQoL.

Effect of epilepsy on autism symptoms in Angelman syndrome.

Background: Autism spectrum disorder and epilepsy often co-occur; however, the extent to which the association between autism symptoms and epilepsy is due to shared aetiology or to the direct effects of seizures is a topic of ongoing debate. Angelman syndrome (AS) is presented as a suitable disease model to explore this association. Methods: Data from medical records and questionnaires were used to examine the association between age of epilepsy onset, autism symptoms, genetic aberration and communication level. Forty-eight participants had genetically verified AS (median age 14.5 years; range 1-57 years). A measure of autism symptoms (the Social Communication Questionnaire; SCQ) was completed for 38 individuals aged ≥ 4 years. Genetic cause was subgrouped into deletion and other genetic aberrations of the 15q11-q13 area. The number of signs used to communicate (< 20 sign and ≥ 20 signs) was used as a measure of nonverbal communication. Results: Mean age of epilepsy onset was 3.0 years (range 3 months-7.8 years). Mean SCQ score for individuals without epilepsy was 13.6 (SD = 6.7) and with epilepsy 17.0 (SD = 5.6; p = 0.17); 58% used fewer than 20 signs to communicate. There were no age differences between groups according to presence of epilepsy, level of nonverbal communication or type of genetic aberration. SCQ scores were higher in individuals with the deletion than in those with other genetic aberrations (18.7 vs 10.8 p = 0.008) and higher in the group who used < 20 signs to communicate (19.4 vs 14.1 p = 0.007). Age of epilepsy onset was correlated with SCQ (r = - 0.61, p < 0.001). Multiple regression showed that age of seizure onset was significantly related to SCQ score (ß = - 0.90; p = 0.006), even when the type of genetic abnormality was controlled (R2 = 0.53; F = 10.7; p = 0.001). Conclusions: The study provides support for the notion that seizures themselves contribute more to autism symptoms than expected from the underlying genetic pathology alone. The study demonstrates how a rare genetic syndrome such as Angelman syndrome may be used to study the relation between epilepsy and autism symptomatology.

Biallelic variants in KIF14 cause intellectual disability with microcephaly.

Kinesin proteins are critical for various cellular functions such as intracellular transport and cell division, and many members of the family have been linked to monogenic disorders and cancer. We report eight individuals with intellectual disability and microcephaly from four unrelated families with parental consanguinity. In the affected individuals of each family, homozygosity for likely pathogenic variants in KIF14 were detected; two loss-of-function (p.Asn83Ilefs*3 and p.Ser1478fs), and two missense substitutions (p.Ser841Phe and p.Gly459Arg). KIF14 is a mitotic motor protein that is required for spindle localization of the mitotic citron rho-interacting kinase, CIT, also mutated in microcephaly. Our results demonstrate the involvement of KIF14 in development and reveal a wide phenotypic variability ranging from fetal lethality to moderate developmental delay and microcephaly.

Parents' Attitudes toward Clinical Genetic Testing for Autism Spectrum Disorder-Data from a Norwegian Sample.

Clinical genetic testing (CGT) of children with autism spectrum disorder (ASD) may have positive and negative effects. Knowledge about parents' attitudes is needed to ensure good involvement of caregivers, which is crucial for accurate diagnosis and effective clinical management. This study aimed to assess parents' attitudes toward CGT for ASD. Parent members of the Norwegian Autism Society were given a previously untested questionnaire and 1455 answered. Linear regression analyses were conducted to evaluate contribution of parent and child characteristics to attitude statements. Provided it could contribute to a casual explanation of their child's ASD, 76% would undergo CGT. If it would improve the possibilities for early interventions, 74% were positive to CGT. Between 49-67% agreed that CGT could have a negative impact on health insurance, increase their concern for the child's future and cause family conflicts. Parents against CGT (9%) were less optimistic regarding positive effects, but not more concerned with negative impacts. The severity of the children's ASD diagnosis had a weak positive association with parent's positive attitudes to CGT (p-values range from <0.001 to 0.975). Parents prefer that CGT is offered to those having a child with ASD (65%), when the child's development deviates from normal (48%), or before pregnancy (36%). A majority of the parents of children with ASD are positive to CGT due to possibilities for an etiological explanation.

[«A most strange instance of illness in several siblings¼--first description of a rare neurological disease in 1830?]. / «Et høist mærkeligt Sygdomstilfælde hos flere Sødskende¼--en norsk førstegangsbeskrivelse fra 1830?

Was district medical officer Jensen the first doctor to describe patients with Pantothenate Kinase-Associated Neurodegeneration (PKAN) in Volda in 1830? A case series of four siblings with the same disease written by district medical officer Peter Jensen (1799-1832) in Aalesund in 1830, was published in the Norwegian medical journal Eyr in 1832. The children, who were healthy almost up to school age, developed dystonic involuntary movements and deformities in all extremities, lost their ability to speak and were emaciated before they died at around the age of nine years. Further information about the family and a fifth affected child has been found in the parish records. The clinical picture is consistent with Pantothenate Kinase-Associated Neurodegeneration (PKAN), a rare condition with basal ganglia iron deposition, described in 1922 by the German neuropathologists Julius Hallervorden (1882-1965) and Hugo Spatz (1888-1969). The disease was formerly called Hallervorden-Spatz syndrome, but because of the medical activities undertaken by these two researchers before and during the Second World War, this eponym is no longer recommended.

Parents' attitudes toward genetic research in autism spectrum disorder.

OBJECTIVE: Genetic research in autism spectrum disorder (ASD) is mainly performed in minors who are legally unable to provide consent. Thus, knowledge of the attitudes, fears, and expectations toward genetic research of the parents is important. Knowledge of the attitudes toward genetic research will improve cooperation between researchers and participants, and help establish confidence in ASD genetic research. The present study aimed to assess these attitudes. MATERIALS AND METHODS: Questionnaire-based assessments of attitudes toward genetic research and toward procedures in genetic research of n=1455 parents of individuals with ASD were performed. RESULTS: The main motivation for participation in genetic research is to gain more knowledge of the causes and disease mechanisms of ASD (83.6%), and to contribute toward development of improved treatment in the future (63.7%). The parents also had a positive attitude towards storing genetic information (54.3%) and they requested confidentiality of data (82.9%) and expressed a need to be informed about the purpose (89%) and progress of the research (83.7%). We found a slightly more positive attitude to participation in genetic research among older parents (P=0.015), among fathers compared with mothers (P=0.01), among parents of girls compared with boys (P=0.03), and infantile autism compared with Asperger syndrome (P=0.002). However, linear regression analysis showed that parent and child characteristics seem to have too small an influence on attitudes toward genetic research to be of any relevance (R(2)=0.002-0.02). CONCLUSION: Parents of children with ASD have, in general, a very positive attitude toward genetic research. Data confidentiality is important, and they express a need for information on the purpose and progress of the research.

Understanding the experience of myotonic dystrophy. Mixed method study.

Myotonic dystrophy (DM) is a progressive multi-systemic disorder characterized by myotonia and muscle weakness where currently no effective treatment or cure to prevent or delay the disorder exists. This study used mixed methods to examine the experience of living with DM, in patients and their close relatives. Thirteen patients and eight next of kin responded completing Quality of Life and Psychological distress questionnaires in this cross-sectional study, and participating in a semi-structured interview. The findings indicate a higher level of anxiety and hopelessness in next of kin compared to patients, while patients were more depressed. Next of kin reported higher physical, but lower emotional quality of life than patients. Qualitative interviews confirmed the questionnaire findings. The findings from this study may be helpful in genetic counseling. Genetic counselors and geneticists should not only be aware of the burden of being a next of kin, but include discussions about opportunities to minimize the burden in families affected with DM. The findings may be of relevance in counseling for other types of neuromuscular disorders.

Familial globotriaosylceramide-associated cardiomyopathy mimicking Fabry disease.

OBJECTIVE: To characterise a globotriaosylceramide (Gb3) storage cardiomyopathy mimicking Fabry. METHODS: We investigated five patients from two unrelated families with early adult onset unexplained left ventricular hypertrophy. Endomyocardial biopsy was performed in all patients and diagnostic kidney biopsies in two of them. We measured α-galactosidase A activity in all patients. Three patients were checked for LAMP1 or LAMP2 deficiency and screened for congenital disorders of glycosylation. Gb3 concentration was quantified in plasma, urinary sediment and cardiac muscle. We sequenced the Fabry and Danon genes and looked for other genetic causes by single-nucleotide polymorphism array haplotyping and whole exome sequencing. RESULTS: Three patients had a striking fat distribution around the buttocks and upper thighs. All patients developed bradyarrhythmias and needed pacemakers. Cardiac transplantation was performed in three patients due to end-stage heart failure, one patient died before transplantation. The cardiomyocytes contained lysosomal vacuoles with lamellar myelin-like deposits. Interstitial cells had vacuoles containing granular material. Deposits were found in the kidneys without renal dysfunction. The histological pattern was atypical for Fabry disease. Biochemical studies revealed normal activity of α-galactosidase A and other relevant enzymes. There was a selective accumulation of Gb3 in cardiomyocytes, at levels found in patients with Fabry disease, but no mutations in the Fabry gene, and Fabry disease was excluded. Other known lysosomal storage diseases were also excluded. Single-nucleotide polymorphism array haplotyping and whole exome sequencing could not identify the genetic cause. CONCLUSIONS: We describe a novel familial Gb3-associated cardiomyopathy. Autosomal recessive inheritance is likely, but the genetic and metabolic cause remains to be identified.

Occipital horn syndrome and classical Menkes Syndrome caused by deep intronic mutations, leading to the activation of ATP7A pseudo-exon.

Menkes disease is an X-linked disorder of copper metabolism caused by mutations in the ATP7A gene. Whereas most of the patients exhibit a severe classical form, about 9% of the patients exhibit a milder form of Menkes disease. The mildest form is called occipital horn syndrome (OHS). Mutations in the ATP7A gene can be identified in 95-98% of the Menkes disease patients by standard screening techniques. Investigation of RNA isolated from the fibroblasts of eleven patients with no identified mutations was performed, and revealed inclusion of new pseudo-exons into the ATP7A mRNA from three unrelated patients: two patients with OHS and one patient with classical Menkes disease. The pseudo-exons were inserted between exons 10 and 11, between exons 16 and 17 and between exons 14 and 15 in the three patients, as a result of deep intronic mutations. This is the first time the activation of pseudo-exons is demonstrated in the ATP7A gene, and it demonstrates the usefulness of RNA analysis, in terms of revealing disease-causing mutations in noncoding regions. The fact that three different mutations cause disease by the activation of pseudo-exon inclusion also indicates that in Menkes disease this is an important mechanism, which has hitherto been overlooked.

Children with autism spectrum disorders - the importance of medical investigations.

BACKGROUND: Considerable knowledge about medical comorbidity in cases of Autism Spectrum Disorders (ASD) is available, still it is not well established how extensive the medical investigations should be in individual cases. The aim is to explore proportions of possible specific medical conditions in ASD. METHODS: 79 subjects went through extensive medical evaluations according to pre-defined procedures, including medical and developmental history, physical and biomedical investigations. RESULTS: Clinical neurological findings were quite common, and we found a high number of pathological findings in the additional medical investigations. Our study revealed that these pathological deviations occurred more frequently in patients with childhood autism than in the other diagnostic sub-groups, the exception were chromosomal findings which occurred more often in patients not-diagnosed with childhood autism. CONCLUSION: Medical and laboratory investigations should still be performed as a consequence of the patient's history, clinical presentations or family history. We should basically continue the use of non-routine and invasive procedures which do not put the patient at some unnecessary risk, in the absence of relevant clinical indications.

Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature.

Adenosine deaminases acting on RNA (ADARs) catalyze the hydrolytic deamination of adenosine to inosine in double-stranded RNA (dsRNA) and thereby potentially alter the information content and structure of cellular RNAs. Notably, although the overwhelming majority of such editing events occur in transcripts derived from Alu repeat elements, the biological function of non-coding RNA editing remains uncertain. Here, we show that mutations in ADAR1 (also known as ADAR) cause the autoimmune disorder Aicardi-Goutières syndrome (AGS). As in Adar1-null mice, the human disease state is associated with upregulation of interferon-stimulated genes, indicating a possible role for ADAR1 as a suppressor of type I interferon signaling. Considering recent insights derived from the study of other AGS-related proteins, we speculate that ADAR1 may limit the cytoplasmic accumulation of the dsRNA generated from genomic repetitive elements.

Hereditary motor neuron disease in a large Norwegian family with a "H46R" substitution in the superoxide dismutase 1 gene.

Mutant genes associated with Charcot Marie Tooth type 2, distal hereditary motor neuropathy and familial amyotrophic lateral sclerosis may cause overlapping clinical phenotypes. We performed whole genome linkage analysis, haplotype analysis, sequencing and detailed clinical and neurophysiological investigations in a large Norwegian kindred with a condition that clinically had been classified as Charcot Marie Tooth type 2. The mutation c.140A>G, p.His47Arg (alias p.His46Arg or H46R) in the superoxide dismutase 1 gene (SOD1) segregated with the disease. The patients present a hereditary motor neuropathy-like clinical picture and long survival (mean 29years). To our knowledge, this is the first extensive report describing a large non-Japanese kindred. The prognostic implications of the condition seen in this family have little in common with what is normally associated with sporadic amyotrophic lateral sclerosis and illustrates the complexity of the genetic etiology of lower motor neuron disease.

Vestibular schwannomas occur in schwannomatosis and should not be considered an exclusion criterion for clinical diagnosis.

Schwannomatosis is a recently delineated inherited condition that has clinical overlap with neurofibromatosis type 2 (NF2). Diagnostic criteria have been developed to distinguish schwannomatosis from NF2, but the existence of mosaic NF2, which may closely mimic schwannomatosis, makes even these criteria problematic. In particular, it is not clear why there is a relative sparing of the cranial nerves from schwannomas in schwannomatosis. We have identified two individuals with schwannomatosis and a unilateral vestibular schwannoma (VS), where a diagnosis of NF2 has been excluded. A third case with an identified SMARCB1 mutation was reported by two radiologists to have a VS, but this was later confirmed as a jugular schwannoma. These cases question whether the current exclusion of a VS from the clinical diagnosis of schwannomatosis is justified.