Stojan Peric

Update of the pompe disease mutation database with 60 novel GAA sequence variants and additional studies on the functional effect of 34 previously reported variants

Pompe disease is an autosomal recessive lysosomal glycogen storage disorder, characterized by progressive muscle weakness. Deficiency of acid α‐glucosidase (EC; 3.2.1.20/3) can be caused by numerous pathogenic variants in the GAA gene. The Pompe Disease Mutation Database at http://www.pompecenter.nl aims to list all variants and their effect. This update reports on 94 variants. We examined 35 novel and 34 known mutations by site‐directed mutagenesis and transient expression in COS‐7 cells or HEK293T cells. Each of these mutations was given a severity rating using a previously published system, based on the level of acid α‐glucosidase activity in medium and transfected cells and on the quantity and quality of the different molecular mass species in the posttranslational modification and transport of acid α‐glucosidase. This approach enabled to classify 55 missense mutations as pathogenic and 13 as likely nonpathogenic. Based on their nature and the use of in silico analysis (Alamut® software), 12 of the additional 25 novel mutations were predicted to be pathogenic including 4 splicing mutations, 6 mutations leading to frameshift, and 2 point mutations causing stop codons. Seven of the additional mutations were considered nonpathogenic (4 silent and 3 occurring in intron regions), and 6 are still under investigation. Hum Mutat 33:1161–1165, 2012.

Cognitive Impairment in Myotonic Dystrophy Type 1 Is Associated with White Matter Damage

Objective To investigate grey (GM) and white matter (WM) abnormalities and their effects on cognitive and behavioral deficits in a large, phenotypically and genotypically well-characterized cohort of classic adult (aDM1, age at onset ≥20 years) or juvenile (jDM1, age at onset <20 years) patients with myotonic dystrophy type 1 (DM1). Methods A case-control study including 51 DM1 patients (17 jDM1 and 34 aDM1) and 34 controls was conducted at an academic medical center. Clinical, cognitive and structural MRI evaluations were obtained. Quantitative assessments of regional GM volumes, WM hyperintensities (WMHs), and microstructural WM tract damage were performed. The association between structural brain damage and clinical and cognitive findings was assessed. Results DM1 patients showed a high prevalence of WMHs, severe regional GM atrophy including the key nodes of the sensorimotor and main cognitive brain networks, and WM microstructural damage of the interhemispheric, corticospinal, limbic and associative pathways. WM tract damage extends well beyond the focal WMHs. While aDM1 patients had severe patterns of GM atrophy and WM tract damage, in jDM1 patients WM abnormalities exceeded GM involvement. In DM1, WMHs and microstructural damage, but not GM atrophy, correlated with cognitive deficits. Conclusions WM damage, through a disconnection between GM structures, is likely to be the major contributor to cognitive impairment in DM1. Our MRI findings in aDM1 and jDM1 patients support the hypothesis of a degenerative (premature aging) origin of the GM abnormalities and of developmental changes as the principal substrates of microstructural WM alterations in DM1.

Influence of multisystemic affection on health-related quality of life in patients with myotonic dystrophy type 1.

AIM To assess health-related quality of life (HRQoL) in patients with DM1, to identify muscular, multisystemic, central and social factors that may affect QoL and to define a DM1 patient in risk of poor QoL. PATIENTS AND METHOD This cross-sectional study comprised 120 DM1 consecutive patients. The following scales were used: Multidimensional Scale of Perceived Social Support (MSPSS), Muscular Impairment Rating Scale (MIRS), battery of neuropsychological tests, acceptance of illness scale (AIS), Hamilton rating scale for depression (Ham-D), Krupps Fatigue Severity Scale (FSS), Daytime Sleepiness Scale (DSS) and SF-36 questionnaire. RESULTS HRQoL was impaired in DM1 patients in both physical and mental domains (PCS was 41.8±23.5, MCS 47.0±24.3 and total SF-36 score 45.6±24.0). The most significant factors correlating with better SF-36 total score were younger age (β=-0.45, p<0.001), shorter duration of disease (β=-0.27, p=0.001), higher education (β=0.20, p=0.009), less severe muscular weakness (β=-0.52, p<0.001), normal swallowing (β=0.22, p=0.005), absence of fainting (β=0.31, p=0.002), absence of snoring (β=0.21, p=0.036), better acceptance of disease (β=-0.17, p=0.036), lower depressiveness (β=-0.46, p=0.001), lower fatigue (β=-0.32, p=0.001), absence of cataract (β=-0.21, p=0.034), absence of kyphosis (β=0.31, p=0.004) and absence of constipation (β=0.24, p=0.016). Second linear regression analysis revealed that depressed (β=-0.38, p<0.001) and elder patients (β=-0.27, p=0.007) and as well as those with poor acceptance of illness (β=-0.21, p=0.006) were in especially higher risk of having poor HRQoL (R(2)=0.68). CONCLUSION We identified different central, social, muscular, cardiorespiratory and other factors correlating with HRQoL. It is of great importance that most of these factors are amenable to treatment.

Significant impact of behavioral and cognitive impairment on quality of life in patients with myotonic dystrophy type 1.

OBJECTIVE To assess an impact of cognitive and behavioral impairment on QoL in a larger cohort of patients with DM1. METHODS Sixty six genetically confirmed DM1 patients (22 with juvenile (jDM1) and 44 with adult form (aDM1) of the disease) were recruited. Following behavioral tests were used: Hamilton scales for depression and anxiety (HamD and HamA), Daytime Sleepiness Scale (DSS), and Krupps Fatigue Severity Scale (FSS). Patients also underwent detailed classic neuropsychological investigation and Cambridge Neuropsychological Test Automated Battery (CANTAB). Individualized Neuromuscular Quality of Life questionnaire (INQoL) was used as a measure of QoL. RESULTS Patients with jDM1 scored lower than aDM1 patients regarding total INQoL score and all INQoL subdomains, except for myotonia. Significant predictors of total INQoL score in patients with jDM1 were severity of fatigue (β=+0.60, p<0.01) and percentage of correct responses on Spatial Recognition Memory test from CANTAB that measures visuospatial abilities (β=-0.38, p<0.05). The most important predictors of total INQoL score in patients with aDM1 were severity of fatigue (β=+0.36, p<0.05) and level of education (β=-0.29, p<0.05). CONCLUSION Our results showed clear influence of different central manifestations on QoL in patients with both aDM1 and jDM1.

Peripheral neuropathy in patients with myotonic dystrophy type 1

Abstract Objectives: To assess the frequency and type of peripheral neuropathy (PNP) in patients with myotonic dystrophy type 1 (DM1), as well as to identify factors that may be associated with this abnormality. Methods: This study comprised 111 adult patients with DM1. Nerve conduction study was performed on sural, peroneal and median nerves of both limbs. Results: PNP was somewhat more frequent in DM1 patients with glucose intolerance and diabetes mellitus (66·7 vs 33·7%, P = 0·05). In DM1 patients with no glucose intolerance, diabetes mellitus and thyroid dysfunction, the most frequent type of PNP was demyelinating (70·0%) and motor (83·3%). PNP was more frequent in males (45·7 vs 20·9%, P<0·05). Patients with PNP were older (43·7±7·3 vs 39·6±9·6 years, P<0·05) and had a longer duration of DM1 compared to those without PNP (18·6±9·9 vs 12·7±8·3 years, P<0·01). DM1 patients with PNP had a higher body mass index) (24·9±5·5 vs 22·4±4·2 kg/cm2, P<0·05), higher triglycerides (3·1±3·3 vs 1·8±0·8 mmol/l, P<0·01), total cholesterol (6·2±1·4 vs 5·4±1·1 mmol/l) and LDL cholesterol (4·3±1·2 vs 3·4±1·0, P<0·05). Achilles reflexes were absent in 76·9% patients with PNP and in 51·9% patients without PNP (P<0·05). Patellar reflexes and muscle strength were similar in both groups (P>0·05). Conclusions: PNP was present in one-third of DM1 patients. The most common type was motor and demyelinating PNP. Our results suggest the association between the presence of peripheral nerve impairment in DM1 and male gender, age, duration of disease and certain metabolic parameters.

Cardiologic predictors of sudden death in patients with myotonic dystrophy type 1

The aim of this study was to analyze survival, causes of death and cardiologic predictors of sudden death in a large cohort of patients with myotonic dystrophy type 1 (DM1). The study was comprised of 171 adult DM1 patients hospitalized at the Neurology Clinic in a 20-year period. Severe electrocardiographic (ECG) abnormality included at least one of the following: rhythm other than sinus, PR interval of ≥240 ms, QRS complex duration of 120 ms or more, and second-degree or third-degree atrioventricular (AV) block. Survival data were analyzed by the Kaplan-Meier test, log-rank test and Cox regression analysis. During the mean follow-up period of 9.4±5.4 years, a pacemaker was implanted in 5.8% of DM1 patients and 14% of patients died. The mean age at death was 55.6±12.5 years. The most common causes of death in our cohort were sudden death (41.7%) and respiratory failure (29.2%). The presence of palpitations (hazard ratio [HR]=4.7, p<0.05) and increased systolic blood pressure (HR=9.8, p<0.05) were significant predictors of sudden death. Among ECG parameters, severe ECG abnormality (HR=4.7, p<0.05), right bundle branch block (RBBB; HR=3.9, p<0.05) and bifascicular block (HR=5.8, p<0.05) were significant predictors of sudden death.

Transcranial sonography in patients with myotonic dystrophy type 1

Introduction: In this study we analyzed transcranial sonography (TCS) in patients with myotonic dystrophy type 1 (DM1). Methods: This cross‐sectional study included 66 DM1 patients and 55 matched healthy controls (HCs). Echogenicity of the brainstem raphe (BR) and substantia nigra (SN) and third ventricle width (DTV) were assessed by TCS. Results: BR hypoechogenicity was more common in DM1 patients than in HCs (37.7% vs. 7.8%, P < 0.01). Patients with depression or fatigue were more likely to have BR hypoechogenicity (80.0% vs. 29.4%, P < 0.01 and 51.9% vs. 24.2%, P < 0.05, respectively). Both hypoechogenicity and hyperechogenicity of SN were more frequent in DM1 patients than in controls (26.2% vs. 10.9% and 13.1% vs. 1.8%, respectively, P < 0.01). DTV was increased in DM1 patients compared with HCs (6.0 ± 1.4 vs. 4.9 ± 0.9 mm, P < 0.01). Conclusion: TCS can offer new insight into structural changes of several cerebral areas in patients with DM1. Muscle Nerve 50:278–282, 2014

Transcranial sonography in patients with Parkinson's disease with glucocerebrosidase mutations.

OBJECTIVES The aim of this study was to search for possible differences in the findings of transcranial sonography (TCS) between groups of patients with glucocerebrosidase (GBA)-associated Parkinsons disease (PD) (4 patients with Gaucher disease type 1 and parkinsonism [GD+PD+] and 18 PD patients with heterozygous GBA mutations; [GBA+PD+]) and groups of 12 patients with Gaucher disease type 1 and no signs of parkinsonism (GD+PD-), 9 asymptomatic carriers of heterozygous GBA mutations (GBA+PD-), 32 sporadic PD patients (sPD), and 43 healthy controls. RESULTS In all groups of patients, except asymptomatic carriers of heterozygous GBA mutations (mean ± SD: 0.16 ± 0.03 cm(2)), the maximal areas of substantia nigra hyperechogenicity (aSN-max) was higher (GD+PD+: 0.28 ± 0.15 cm(2); GD+PD-: 0.18 ± 0.06 cm(2); GBA+PD+: 0.27 ± 0.06 cm(2); sPD: 0.28 ± 0.10 cm(2)) when compared to controls (0.12 ± 0.08 cm(2)) (p = 0.001). In GBA-associated PD (GD+PD+ and GBA+PD+) and sPD, aSNmax values were very similar. Moderate or marked SN hyperechogenicity was present in 87.5% of sPD patients and in 83% of PD patients with heterozygous GBA mutations, but in only 11.6% of controls, and in 22.2% and 33.3% of patients from GBA+PD- and GD+PD- groups, respectively (p < 0.001). The prevalence of interrupted or missing echogenicity of the brainstem raphe differed between the groups (p = 0.046), while no difference was observed in the diameter of the third ventricle. CONCLUSIONS TCS findings in GBA-associated PD were consistent to those of patients with sporadic PD.

Cardiac autonomic control in patients with myasthenia gravis and thymoma.

OBJECTIVE To evaluate cardiac autonomic control in patients with myasthenia gravis (MG) and thymoma. MATERIALS AND METHODS The study was performed on 21 patients with MG and thymoma and the same number of matched healthy volunteers. Standard cardiovascular reflex tests according to Ewing and baroreflex sensitivity (BRS) at rest was applied. Spectral analysis of heart rate variability (HRV) at rest was assessed using a 20-minute ECG recording (normalized low- and high-frequency bands-LFnu-RRI, HFnu-RRI and LF/HF-RRI) Time-domain analysis of HRV was derived from 24-hour ECG monitoring. RESULTS Overall autonomic score according to Ewing was significantly increased in patients with MG and thymoma (p<0.05), mostly due to parasympathetic dysfunction. Time-domain parameters representing the overall and long-term sympathetic activity of HRV did not differ significantly between the two groups (p>0.05), but there was a significant decrease in measures of the short-term vagal variations in HRV (p<0.01). HFnu-RRI was lower, while LFnu-RRI and LF/HF-RRI were higher in patients with MG and thymoma in comparison to healthy controls but these differences were not of statistical significance (p>0.05). BRS at rest was highly significantly reduced in patients group (p<0.01). CONCLUSIONS Our results showed mainly parasympathetic cardiac impairment in patients with myasthenia gravis and thymoma. Since autonomic dysfunction may lead to cardiac conduction abnormalities and sudden death, the investigation of autonomic nervous system function in these patients may be significant in everyday clinical practice.

Leptin and the metabolic syndrome in patients with myotonic dystrophy type 1

Rakocevic Stojanovic V, Peric S, Lavrnic D, Popovic S, Ille T, Stevic Z, Basta I, Apostolski S. Leptin and the metabolic syndrome in patients with myotonic dystrophy type 1.
Acta Neurol Scand: 2010: 121: 94–98.
© 2009 The Authors Journal compilation