Gastrointestinal and urinary complaints in adults with hereditary spastic paraparesis.

BACKGROUND: Hereditary spastic paraparesis (HSP) is a group of rare genetic disorders affecting the central nervous system. Pure HSP is limited to lower limb spasticity and urinary voiding dysfunction. Complex HSP involves additional neurological features. Beyond the described core symptoms, knowledge about the burden of disease for adults with HSP is limited, particularly regarding gastrointestinal functions, fecal incontinence, and urinary symptoms. METHODS: We conducted a cross-sectional self-report survey with 108 adult HSP patients (Mage = 57.7 years, SD = 11.5, range 30 to 81; 54.2% females) recruited from a national HSP user group association and a national (non-clinical) advisory unit for rare disorders. HSP data was compared to data from a Norwegian population study, HUNT-3 (N = 46,293). RESULTS: The HSP group reported more gastrointestinal and urinary complaints compared to controls. Gastrointestinal complaints included at least "much" complaints with constipation (14.6%) and alternating constipation/diarrhea (8.0%), and at least daily uncontrollable flatulence (47.6%), fecal incontinence (11.6%), and inability to hold back stools (38.5%). Urinary complaints included frequent urination (27.4% > 8 times daily), sudden urge (51.9%) and urinary incontinence (30.5% at least daily/nightly). CONCLUSION: This survey of adults with HSP recruited from non-clinical settings showed constipation, alternate constipation and diarrhea, fecal incontinence, and voiding dysfunction represent considerable problems for many persons with HSP. Health care providers should screen and manage often unrecognized gastrointestinal and fecal incontinence complaints among HSP patients.

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.

Health survey of adults with hereditary spastic paraparesis compared to population study controls.

BACKGROUND: Hereditary spastic paraparesis (HSP) is a rare neurodegenerative condition characterized by slowly progressive spastic weakness of the lower limbs and urinary sphincter dysfunction. Complex HSP involves additional neurologic symptoms and signs like ataxia, extra pyramidal signs, polyneuropathy, and cognitive decline. Little is known about the disease burden for adults with HSP beyond the described core symptoms. METHODS: A cross-sectional survey of 108 adults aged 30 years and older (Mage = 57.7 years, SD = 11.5, range 30 to 81; 54.2 % females) recruited from a national center of expertise for rare disorders and a patient advocacy organization in Norway. Self-report data from the HSP sample was compared to self-report data from a large Norwegian population study, HUNT3 (N = 46,293), covering health-related variables such as overall life satisfaction, mental wellbeing, memory function, perceived pain, and co-morbid diseases. In addition, the HSP sample reported specific items developed for this study in co-operation with the patient advocacy organization. RESULTS: The HSP sample more frequently lived alone. Overall, the HSP sample reported lower life satisfaction, lower mental wellbeing and lower social support, as well as poorer memory and sleep, compared to controls. Furthermore, the HSP sample more frequently reported musculoskeletal pain, constipation, and urinary incontinence compared to controls. There was no difference between samples in frequency of physical activity and alcohol and tobacco use. Men with HSP reported higher impact of HSP, lower life satisfaction, and less ability to perform activities of daily living compared to women with HSP. CONCLUSIONS: Adults with HSP experience disease burden on a larger number of areas than previously documented, and men with HSP may represent a particularly vulnerable group.

A 1 Mb de novo deletion within 11q13.1q13.2 in a boy with mild intellectual disability and minor dysmorphic features.

We report a 11 year old male patient ascertained for mild intellectual disability and minor dysmorphic features, carrying a 1 Mb de novo deletion on chromosome 11q13.1q13.2 detected by aCGH. This is the first report of a deletion in this region in a patient presenting with intellectual impairment and mild dysmorphic traits. The 1 Mb deleted area encompasses 47 RefSeq genes, including Cornichon homologue 2 (CNIH2), Cofilin-1 (CFL1) and neuronal PAS domain-containing protein 4 (NPAS4), which are highly expressed in the central nervous system. Knockout of the CNIH2 and CFL1 orthologues in animals results in migration disturbances, while low or no expression of Npas4 in mice results in impairment of memory and learning. These three genes have previously been suggested as candidate genes for neurological disorders.

2-methylbutyryl-CoA dehydrogenase deficiency associated with autism and mental retardation: a case report.

BACKGROUND: 2-methylbutyryl-CoA dehydrogenase deficiency or short/branched chain acyl-CoA dehydrogenase deficiency (SBCADD) is caused by a defect in the degradation pathway of the amino acid L-isoleucine. METHODS: We report a four-year-old mentally retarded Somali boy with autism and a history of seizures, who was found to excrete increased amounts of 2-methylbutyryl glycine in the urine. The SBCAD gene was examined with sequence analysis. His development was assessed with psychometric testing before and after a trial with low protein diet. RESULTS: We found homozygosity for A > G changing the +3 position of intron 3 (c.303+3A > G) in the SBCAD gene. Psychometric testing showed moderate mental retardation and behavioral scores within the autistic spectrum. No beneficial effect was detected after 5 months with a low protein diet. CONCLUSION: This mutation was also found in two previously reported cases with SBCADD, both originating from Somalia and Eritrea, indicating that it is relatively prevalent in this population. Autism has not previously been described with mutations in this gene, thus expanding the clinical spectrum of SBCADD.

Microphthalmia and brain atrophy: a novel neurodegenerative disease.

OBJECTIVE: To delineate the features of a novel neurodegenerative disease. METHODS: We report three children of three related families with congenital microphthalmia and blindness, and progressive spasticity, microcephaly, seizures, and profound mental retardation. RESULTS: A magnetic resonance imaging scan was normal at birth. However, follow-up studies showed progressive atrophy involving the cerebral white matter and cortex, cerebellum, brainstem, and corpus callosum. The white matter changes extended into the subcortical region leaving only small islands of remaining cortical tissue. Known metabolic conditions involving white matter degeneration were excluded. INTERPRETATION: We propose this to be a novel autosomal recessive neurodegenerative disorder to be coined MOBA (microphthalmia brain atrophy) disease.