Hearing problems in patients with hereditary gelsolin amyloidosis.

BACKGROUND: Gelsolin amyloidosis (AGel amyloidosis) is a hereditary form of systemic amyloidosis featuring ophthalmological, neurological and cutaneous symptoms. Previous studies based mainly on patients' self-reporting have indicated that hearing impairment might also be related to the disease, considering the progressive cranial neuropathy characteristic for AGel amyloidosis. In order to deepen the knowledge of possible AGel amyloidosis-related hearing problems, a clinical study consisting of the Speech, Spatial and Qualities of Hearing Scale (SSQ) questionnaire, clinical examination, automated pure-tone audiometry and a speech-in-noise test was designed. RESULTS: Of the total 46 patients included in the study, eighteen (39%) had self-reported hearing loss. The mean scores in the SSQ were 8.2, 8.3 and 8.6 for the Speech, Spatial and Qualities subscales, respectively. In audiometry, the mean pure tone average (PTA) was 17.1 (SD 12.2) and 17.1 (SD 12.3) dB HL for the right and left ears, respectively, with no difference to gender- and age-matched, otologically normal reference values. The average speech reception threshold in noise (SRT) was - 8.2 (SD 1.5) and - 8.0 (SD 1.7) dB SNR for the right and left ears, respectively, which did not differ from a control group with a comparable range in PTA thresholds. CONCLUSION: Although a significant proportion of AGel amyloidosis patients experience subjective difficulties in hearing there seems to be no peripheral or central hearing impairment at least in patients up to the age of 60 years.

Cardiac manifestations in Finnish gelsolin amyloidosis patients.

INTRODUCTION: Finnish gelsolin amyloidosis (AGel amyloidosis) is an inherited systemic amyloidosis with well-known ophthalmological, neurological and cutaneous symptoms. Additionally, cardiomyopathies, conduction disorders and need of cardiac pacemakers occur in some patients. This study focuses on electrocardiographic (ECG) findings in AGel amyloidosis and their relation to cardiac magnetic resonance (CMR) changes. We also assessed whether ECG abnormalities were associated with pacemaker implantation and mortality. MATERIALS AND METHODS: In this cohort study, 51 genetically verified AGel amyloidosis patients (mean age 66 years) without cardiac pacemakers underwent 12-lead ECG and CMR imaging with contrast agent in 2017. Patients were followed-up for 3 years. RESULTS: Conduction disturbances were found in 22 patients (43%). Nine (18%) presented with first-degree atrioventricular block, six (12%) with left anterior hemiblock, seven (14%) with left or right bundle branch block and two (4%) with non-specific intraventricular conduction delay. Low QRS voltage was present in two (4%) patients. Late gadolinium enhancement (LGE) concentrating on the interventricular septum and inferior parts of the heart was present in 19 (86%) patients with conduction abnormalities. During the follow-up, only one patient received a pacemaker, and one patient died. DISCUSSION: Conduction disorders and septal LGE are common in AGel amyloidosis, whereas other ECG and CMR findings typically observed in most common cardiac amyloidosis types were rare. Septal pathology seen in CMR may interfere with the cardiac conduction system in AGel amyloidosis, explaining conduction disorders, although pacemaker therapy is rarely required.

Finnish gelsolin amyloidosis causes significant disease burden but does not affect survival: FIN-GAR phase II study.

BACKGROUND: Hereditary gelsolin (AGel) amyloidosis is an autosomal dominantly inherited systemic amyloidosis that manifests with the characteristic triad of progressive ophthalmological, neurological and dermatological signs and symptoms. The National Finnish Gelsolin Amyloidosis Registry (FIN-GAR) was founded in 2013 to collect clinical data on patients with AGel amyloidosis, including altogether approximately one third of the Finnish patients. We aim to deepen knowledge on the disease burden and life span of the patients using data from the updated FIN-GAR registry. We sent an updated questionnaire concerning the symptoms and signs, symptomatic treatments and subjective perception on disease progression to 240 members of the Finnish Amyloidosis Association (SAMY). We analyzed the lifespan of 478 patients using the relative survival (RS) framework. RESULTS: The updated FIN-GAR registry includes 261 patients. Symptoms and signs corresponding to the classical triad of ophthalmological (dry eyes in 93%; corneal lattice amyloidosis in 89%), neurological (numbness, tingling and other paresthesias in 75%; facial paresis in 67%), and dermatological (drooping eyelids in 86%; cutis laxa in 84%) manifestations were highly prevalent. Cardiac arrhythmias were reported by 15% of the patients and 5% had a cardiac pacemaker installed. Proteinuria was reported by 13% and renal failure by 5% of the patients. A total of 65% of the patients had undergone a skin or soft tissue surgery, 26% carpal tunnel surgery and 24% at least unilateral cataract surgery. As regards life span, relative survival estimates exceeded 1 for males and females until the age group of 70-74 years, for which it was 0.96. CONCLUSIONS: AGel amyloidosis causes a wide variety of ophthalmological, neurological, cutaneous, and oral symptoms that together with repeated surgeries cause a clinically significant disease burden. Severe renal and cardiac manifestations are rare as compared to other systemic amyloidoses, explaining in part the finding that AGel amyloidosis does not shorten the life span of the patients at least for the first 75 years.

Severe elastolysis in hereditary gelsolin (AGel) amyloidosis.

AGel amyloidosis is a dominantly inherited systemic amyloidosis caused by mutations p.D214N or p.D214Y resulting in gelsolin amyloid (AGel) formation. AGel accumulates extracellularly in many tissues and alongside elastic fibres. AGel deposition associates with elastic fibre degradation leading to severe clinical manifestations, such as cutis laxa and angiopathic complications. We analysed elastic fibre pathology in dermal and vascular tissue and plasma samples from 35 patients with AGel amyloidosis and 40 control subjects by transmission electron microscopy, immunohistochemistry and ELISA methods. To clarify the pathomechanism(s) of AGel-related elastolysis, we studied the roles of MMP-2, -7, -9, -12 and -14, TIMP-1 and TGFß. We found massive accumulation of amyloid fibrils along elastic fibres as well as fragmentation and loss of elastic fibres in all dermal and vascular samples of AGel patients. Fibrils of distinct types formed fibrous matrix. The degradation pattern of elastic fibres in AGel patients was different from the age-related degradation in controls. The elastin of elastic fibres in AGel patients was strongly decreased compared to controls. MMP-9 was expressed at lower and TGFß at higher levels in AGel patients than in controls. The accumulation of amyloid fibrils with severe elastolysis characterises both dermal and vascular derangement in AGel amyloidosis.

Amyloid in parenchymal organs in gelsolin (AGel) amyloidosis.

Objectives: Previous clinical studies have shown frequent cardiac symptoms in patients with hereditary gelsolin (AGel) amyloidosis, possibly related to amyloid deposition in the heart and other internal organs. Previous studies on internal organ amyloid deposition in AGel amyloidosis have been based on small patient series. Methods: Paraffin-embedded tissue sections from 25 autopsied individuals (age at death 44.4-88.6 years) with AGel amyloidosis were stained with HE, Congo red and Herovici stains and immunohistochemistry against the low molecular weight gelsolin fraction was performed. The amount of amyloid was estimated semi-quantitatively. Results: AGel-based amyloid deposits were found in the myocardium and cardiac blood vessels in every patient. The deposits were mainly small and co-localized with regions with excess fibrosis in the myocardium. The lungs were positive for amyloid in 79%, renal parenchyma in 54% and renal blood vessels in 71% of the cases. The amount of myocardial, renal and hepatic amyloid correlated with age at death of the patients. Conclusions: We show the constant presence of AGel amyloid in the hearts of patients with AGel amyloidosis. Although the deposits were mainly small, the co-localization of amyloid with fibrosis may amplify the effect of pure amyloid deposition, possibly leading to clinical signs and symptoms.

Common origin of the gelsolin gene variant in 62 Finnish AGel amyloidosis families.

Finnish gelsolin amyloidosis (AGel amyloidosis) is an autosomal dominantly inherited systemic disorder with ophthalmologic, neurologic and dermatologic symptoms. Only the gelsolin (GSN) c.640G>A variant has been found in the Finnish patients thus far. The purpose of this study was to examine whether the Finnish patients have a common ancestor or whether multiple mutation events have occurred at c.640G, which is a known mutational hot spot. A total of 79 Finnish AGel amyloidosis families including 707 patients were first discovered by means of patient interviews, genealogic studies and civil and parish registers. From each family 1-2 index patients were chosen. Blood samples were available from 71 index patients representing 64 families. After quality control, SNP array genotype data were available from 68 patients from 62 nuclear families. All the index patients had the same c.640G>A variant (rs121909715). Genotyping was performed using the Illumina CoreExome SNP array. The homozygosity haplotype method was used to analyse shared haplotypes. Haplotype analysis identified a shared haplotype, common to all studied patients. This shared haplotype included 17 markers and was 361 kb in length (GRCh37 coordinates 9:124003326-124364349) and this level of haplotype sharing was found to occur highly unlikely by chance. This GSN haplotype ranked as the largest shared haplotype in the 68 patients in a genome-wide analysis of haplotype block lengths. These results provide strong evidence that although there is a known mutational hot spot at GSN c.640G, all of the studied 62 Finnish AGel amyloidosis families are genetically linked to a common ancestor.

Decreased Aerobic Capacity in ANO5-Muscular Dystrophy.

BACKGROUND: Anoctaminopathies are muscle diseases caused by recessive mutations in the ANO5 gene. The effects of anoctaminopathy on oxidative capacity have not previously been studied in a controlled setting. OBJECTIVE: To characterize oxidative capacity in a clinically and genetically well-defined series of patients with anoctaminopathy. METHODS: We sequenced the ANO5 gene in 111 Finnish patients with suspected LGMD2. Patients with positive findings underwent close clinical examination, including electromyography, muscle MRI, and, in selected cases, muscle biopsy. Oxidative capacity was analyzed using spiroergometry and compared to age-matched healthy controls. RESULTS: We characterized 12 newly identified and 2 previously identified patients with ANO5 mutations from 11 families. Our material was genetically homogeneous with most patients homozygous for the Finnish founder variant c.2272C>T (p.Arg758Cys). In one family, we found a novel p.Met470Arg variant compound heterozygous with p.Arg758Cys. Lower limb muscle MRI revealed progressive fatty degeneration of specific posterior compartment muscles. Patients' spiroergometric profiles showed that anoctaminopathy significantly impaired oxidative capacity with increasing ventilation. CONCLUSIONS: Our findings support earlier reports that anoctaminopathy progresses slowly and demonstrate that the disease impairs the capacity for aerobic exercise.

Increasing amount of amyloid are associated with the severity of clinical features in hereditary gelsolin (AGel) amyloidosis.

BACKGROUND: Patients with hereditary gelsolin (AGel) amyloidosis (HGA) present with hanging skin (cutis laxa) and bilateral cranial neuropathy, and require symptomatic plastic surgery. Our clinical observation of tissue fragility prompted us to design a prospective study. METHODS: Twenty-nine patients with HGA undergoing surgery were interviewed and clinically examined. The height and thickness of skin folds in standard anatomical localizations were measured. The presence and distribution of amyloid in skin samples were analyzed using Congo red staining and immunohistochemistry using antibodies against gelsolin amyloid (AGel) subunit. RESULTS: The measured skin folds stretched more in patients with HGA (e.g. skin over olecranon, p < 0.001). The skin folds were thinner in patients with HGA (e.g. forehead skin, p < 0.001). The skin and subcutaneous fat were abnormally fragile during surgery. The total amount of AGel amyloid, and its presence in the deep layers of the skin and subcutaneous fat correlated with the measurements of skin folds, age and extent of cranial neuropathy. CONCLUSIONS: The AGel amyloid in the skin and subcutis, together with morphologic changes in the dermal stroma and skin adnexa contribute to the atrophied and fragile structure of HGA skin. This is the first study to demonstrate the correlation between AGel amyloid accumulation and clinical disease severity.

Causes of death and life span in Finnish gelsolin amyloidosis.

BACKGROUND: Finnish type of hereditary gelsolin amyloidosis (AGel amyloidosis) is an autosomal dominant disorder. Until recently, there has only been little knowledge of fatal complications of the disease and its possible impact on the patients' life span. METHODS: We identified 272 deceased patients based on patient interviews and genealogical data. After collecting their death certificates, we recorded the patients' underlying and immediate causes of death (CoD) and life span and compared them to the general Finnish population. We then calculated proportional mortality ratios (PMR), standardised for age and sex, for the CoDs. RESULTS: The underlying CoD in 20% of the patients was AGel amyloidosis (PMR = 114.2; 95% CI: 85.6-149.4). The frequency of fatal cancers (10%) was significantly diminished (PMR = 0.47; 95% CI: 0.31-0.69). Renal complications were overrepresented as the immediate CoD in female patients (PMR = 2.82 95% CI: 1.13-5.81). The mean life span for male patients was 73.9 years (95% CI: 72.0-75.6) and 78.0 years for female patients (95% CI: 76.4-79.5) compared to 72.1 and 80.1 years for the general population. CONCLUSIONS: Our results suggest that the disease increases the risk of fatal renal complications but does not substantially shorten the life span, possibly due to the significantly lower frequency of fatal cancers. Key Messages AGel amyloidosis may increase the risk of renal complications, especially among female patients. The frequency of fatal cancers is significantly lower. The patients' life span is comparable to that of the general population.

Gelsolin amyloid angiopathy causes severe disruption of the arterial wall.

Hereditary gelsolin amyloidosis (HGA) is a dominantly inherited systemic disease reported worldwide. HGA is characterized by ophthalmological, neurological, and dermatological manifestations. AGel amyloid accumulates at basal lamina of epithelial and muscle cells, thus amyloid angiopathy is encountered in nearly every organ. HGA patients have cardiovascular, hemorrhagic, and potentially vascularly induced neurological problems. To clarify pathomechanisms of AGel angiopathy, we performed histological, immunohistochemical, and electron microscopic analyses on facial temporal artery branches from 8 HGA patients and 13 control subjects. We demonstrate major pathological changes in arteries: disruption of the tunica media, disorganization of vascular smooth muscle cells, and accumulation of AGel fibrils in arterial walls, where they associate with the lamina elastica interna, which becomes fragmented and diminished. We also provide evidence of abnormal accumulation and localization of collagen types I and III and an increase of collagen type I degradation product in the tunica media. Vascular smooth muscle cells appear to be morphologically and semi-quantitatively normal, only their basal lamina is often thickened. In conclusion, angiopathy in HGA results in severe disruption of arterial walls, characterized by prominent AGel deposition, collagen derangement and severe elastolysis, and it may be responsible for several, particularly hemorrhagic, disease manifestations in HGA.

Mutations in DNMT3B Modify Epigenetic Repression of the D4Z4 Repeat and the Penetrance of Facioscapulohumeral Dystrophy.

Facioscapulohumeral dystrophy (FSHD) is associated with somatic chromatin relaxation of the D4Z4 repeat array and derepression of the D4Z4-encoded DUX4 retrogene coding for a germline transcription factor. Somatic DUX4 derepression is caused either by a 1-10 unit repeat-array contraction (FSHD1) or by mutations in SMCHD1, which encodes a chromatin repressor that binds to D4Z4 (FSHD2). Here, we show that heterozygous mutations in DNA methyltransferase 3B (DNMT3B) are a likely cause of D4Z4 derepression associated with low levels of DUX4 expression from the D4Z4 repeat and increased penetrance of FSHD. Recessive mutations in DNMT3B were previously shown to cause immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome. This study suggests that transcription of DUX4 in somatic cells is modified by variations in its epigenetic state and provides a basis for understanding the reduced penetrance of FSHD within families.

A novel transthyretin Lys70Glu (p.Lys90Glu) mutation presenting with vitreous amyloidosis and carpal tunnel syndrome.

OBJECTIVE: We describe a novel TTR mutation with vitreous opacities and carpal tunnel syndrome. MATERIALS AND METHODS: A 78 year-old woman with vitreous opacities, her daughter with dry eye syndrome, and brother with carpal tunnel syndrome were tested for a mutation in the TTR gene. The vitreous opacities were removed and stained with Congo red and immunohistochemistry against wild type TTR. Skin and gut biopsies and specimens of soft tissue were examined histopathologically. Leukocyte DNA from the proband was analysed by direct sequencing of exons 1 to 4 of the TTR gene and DNA from her daughter and brother using segregation analysis. RESULTS: A point mutation c.268 A>C, in the TTR gene, leading to a missense mutation p.Lys90Glu was found in all subjects. The vitreous opacities were pearl string-like. Histopathology showed red to green birefringence in Congo red, typical to amyloid, and the specimens were immunoreactive with antibodies against TTR. CONCLUSION: We present a novel autosomally inherited Lys90Glu mutation in the TTR gene. This is the first reported FAP family with this mutation in Finland.

Gender differences in the clinical course of Finnish gelsolin amyloidosis.

PURPOSE: To investigate gender differences in Finnish gelsolin amyloidosis (AGel amyloidosis). PATIENTS AND METHODS: AGel amyloidosis patients, who were members of Finnish Amyloidosis Association (SAMY), filled in a questionnaire compiling known and suspected aspects of their disease. Telephone interviews and hospital medical records, when available, complemented the questionnaire. The data were entered to the database in order to create a national AGel amyloidosis patient registry (FIN-GAR). RESULTS: A total of 227 patients, 156 women and 71 men, participated in the study. The women in our registry noticed their first symptoms at the median age of 39 years versus 43 years for men (p = 0.01). At the age in which the diagnosis was made there was a trend to be observed between men and women (women: 39 years versus men: 43 years, p = 0.053). Corneal lattice dystrophy was diagnosed in significantly younger women than men (median ages 41 versus 49 years, respectively, p = 0.01). Of other ophthalmological manifestations, corneal ulcer, impaired vision and glaucoma were all diagnosed at least 5 years earlier in women, although differences were not statistically significant. Ophthalmological manifestations, such as dry eyes and corneal ulcer; dermatological signs, such as blepharochalasis, and also neurological symptoms, such as myokymia and carpal tunnel syndrome, were more prevalent among women. CONCLUSIONS: In the largest so far available study on AGel amyloidosis we show that women developed symptoms and signs of AGel amyloidosis at younger age. Especially eye-related problems occurred earlier and together with nerve and skin manifestations, the characteristic clinical triad in AGel amyloidosis, were more common in women. However, a clear limitation of our study was a selection bias caused by a significant underrepresentation of men in the study population.

Progressive cranial nerve involvement and grading of facial paralysis in gelsolin amyloidosis.

INTRODUCTION: Hereditary gelsolin amyloidosis (GA) is a rare condition caused by the gelsolin gene mutation. The diagnostic triad includes corneal lattice dystrophy (type 2), progressive bilateral facial paralysis, and cutis laxa. Detailed information on facial paralysis in GA and the extent of cranial nerve injury is lacking. METHODS: 29 GA patients undergoing facial corrective surgery were interviewed, examined, and studied electroneurophysiologically. RESULTS: All showed dysfunction of facial (VII) and trigeminal (V) nerves, two-thirds of oculomotor (III) and hypoglossal (XII) nerves, and half of vestibulocochlear (acoustic) (VIII) nerve. Clinical involvement of frontal, zygomatic, and buccal facial nerve branches was seen in 97%, 83%, and 52% of patients, respectively. Electromyography showed marked motor unit potential loss in facial musculature. CONCLUSIONS: Cranial nerve involvement in GA is more widespread than previously described, and correlates with age, severity of facial paralysis, and electromyographic findings. We describe a grading method for bilateral facial paralysis in GA, which is essential for evaluation of disease progression and the need for treatment.

Natural course of Finnish gelsolin amyloidosis.

BACKGROUND: Finnish type of hereditary gelsolin amyloidosis (FGA) is one of the most common diseases of Finnish disease heritage. Existing FGA knowledge is based only on smaller patient series, so our aim was to elucidate the natural course of the disease in a comprehensive sample of patients and to build up a national FGA patient registry. METHODS: An inquiry about the known and suspected signs of FGA, sent to the members of Finnish Amyloidosis Association, telephone contacts, and hospital records were utilized to create the registry. RESULTS: A total of 227 patients were entered to the database. The first symptom was ophthalmological for 167 patients (73.6%) at the mean age of 39 years. Corneal lattice dystrophy (CLD) was reported at the mean age of 43 years. Impaired vision, polyneuropathy, facial nerve paresis, and cutis laxa appeared on average between 52 and 57 years. Carpal tunnel syndrome (CTS) was reported by 86 patients (37.9%). Nine patients (4.0%) had a pacemaker, and 12 (6.1%) had cardiomyopathy. CONCLUSIONS: The first symptom was ophthalmological in most cases. Except for CLD no prominent difference in the age of appearance was found between the major symptoms. CTS, cardiac pacemakers, and cardiomyopathy were remarkably more common compared to the general population.

Novel mutations in DNAJB6 gene cause a very severe early-onset limb-girdle muscular dystrophy 1D disease.

DNAJB6 is the causative gene for limb-girdle muscular dystrophy 1D (LGMD1D). Four different coding missense mutations, p.F89I, p.F93I, p.F93L, and p.P96R, have been reported in families from Europe, North America and Asia. The previously known mutations cause mainly adult-onset proximal muscle weakness with moderate progression and without respiratory involvement. A Finnish family and a British patient have been studied extensively due to a severe muscular dystrophy. The patients had childhood-onset LGMD, loss of ambulation in early adulthood and respiratory involvement; one patient died of respiratory failure aged 32. Two novel mutations, c.271T > A (p.F91I) and c.271T > C (p.F91L), in DNAJB6 were identified by whole exome sequencing as a cause of this severe form of LGMD1D. The results were confirmed by Sanger sequencing. The anti-aggregation effect of the mutant DNAJB6 was investigated in a filter-trap based system using transient transfection of mammalian cell lines and polyQ-huntingtin as a model for an aggregation-prone protein. Both novel mutant proteins show a significant loss of ability to prevent aggregation.

CHCHD10 variant p.(Gly66Val) causes axonal Charcot-Marie-Tooth disease.

OBJECTIVE: We describe the phenotype consistent with axonal Charcot-Marie-Tooth disease type 2 (CMT2) in 4 families with a c.197G>T (p.(Gly66Val)) variant in CHCHD10. METHODS: We sequenced the CHCHD10 gene in a cohort of 107 families with CMT2 of unknown etiology. The patients were characterized by clinical examination and electroneuromyography. Muscle MRI and biopsy of the muscle or nerve were performed in selected cases. Neuropathologic autopsy was performed in 1 case. RESULTS: The c.197G>T variant in CHCHD10 was found in 6 families, 4 of which included multiple individuals available for detailed clinical study. Variants in this gene have recently been associated with amyotrophic lateral sclerosis-frontotemporal dementia, mitochondrial myopathy, or spinal muscular atrophy Jokela type (SMAJ), but not with CMT2. Our patients had a late-onset distal axonal neuropathy with motor predominance, progressing to involve sensory nerves. Neurophysiologic and neuropathologic studies confirmed the diagnosis of sensorimotor axonal neuropathy with no loss of anterior horn neurons. Muscle biopsies showed occasional cytochrome c oxidase-negative fibers, combined with small amounts of mitochondrial DNA deletions. CONCLUSIONS: CHCHD10 c.197G>T (p.(Gly66Val)) is a cause of sensorimotor axonal neuropathy. This gene should be considered in patients presenting with a pure CMT2 phenotype, particularly when motor symptoms predominate.

Relation of gelsolin amyloidosis and periodontal health.

OBJECTIVE: Hereditary gelsolin amyloidosis (AGel amyloidosis) is a rare, dominantly inherited systemic disease with worldwide distribution, caused by a gelsolin gene mutation. We studied the periodontal conditions and microbiological plaque composition of AGel amyloidosis patients. MATERIAL AND METHODS: A voluntary study group of 36 AGel amyloidosis patients (mean age 61) filled in a questionnaire. A thorough periodontal examination included periodontal pocket depth and attachment level measurements, registrations of visible plaque, bleeding on probing and panoramic radiographs. The presence of oral Candida was studied by fungal culture method. Bacterial samples from deepened pockets (≥4 mm) were analyzed with checkerboard DNA-DNA hybridization method. RESULTS: VPI (15.3 %) and BOP (11.2 %) of the patients were modest reflecting relatively adequate oral self-care. Still 89 % of the patients had at least one PPD of ≥4 mm; 78.5 % of the PPDs ≥6 mm were found in molars. Patients had lost one third of the molars due to periodontitis and/or tooth decay. Half of the patients (53 %) were Candida carriers. Bacterial analysis of subgingival plaque samples revealed bacterial species common to chronic periodontitis. CONCLUSION: AGel amyloidosis may increase the risk for periodontitis even when the oral self-care is adequate. Molar teeth appear to be mostly affected, leading to tooth loss. CLINICAL RELEVANCE: AGel amyloidosis as a systemic disease is related with a vast variety of symptoms with variable severity. Even though a causal relationship of the systemic disease and periodontitis has not yet been proven, increased risk for periodontal problems should be considered when examining AGel amyloidosis patients.

Subtle neuropsychiatric and neurocognitive changes in hereditary gelsolin amyloidosis (AGel amyloidosis).

Hereditary gelsolin amyloidosis (AGel amyloidosis) is an autosomal dominant form of systemic amyloidosis caused by a c.640G>A or c.640G>T mutation in the gene coding for gelsolin. Principal clinical manifestations include corneal lattice dystrophy, cranial neuropathy and cutis laxa with vascular fragility. Signs of minor CNS involvement have also been observed, possibly related to cerebral amyloid angiopathy (CAA). To investigate further if AGel amyloidosis carries a risk for a specific neuropsychological or psychiatric symptomatology we studied 35 AGel patients and 29 control subjects. Neuropsychological tests showed abnormalities in visuocontructional and -spatial performance in AGel patients, also some indication of problems in processing efficacy was found. At psychiatric evaluation the patient group showed more psychiatric symptomatology, mainly depression. In brain MRI, available in 16 patients and 14 controls, we found microhemorrhages or microcalcifications only in the patient group, although the number of findings was small. Our study shows that AGel amyloidosis can be associated with visuoconstructional problems and depression, but severe neuropsychiatric involvement is not characteristic. The gelsolin mutation may even induce cerebrovascular fragility, but further epidemiological and histopathological as well as longitudinal follow-up studies are needed to clarify gelsolin-related vascular pathology and its clinical consequences.

Screening for late-onset Pompe disease in Finland.

Pompe disease (glycogen storage disease type II) is caused by autosomal recessive mutations in GAA gene. The estimated frequency of late-onset Pompe disease is around 1:60,000. However, only two infantile and one late-onset Pompe patients have been reported in Finland with a population of 5 million. We screened for late-onset Pompe disease in a cohort of undetermined myopathy patients with proximal muscle weakness and/or elevated serum creatine kinase values. Acid α-glucosidase (GAA) activity in dried blood spots was measured and clinical data collected in 108 patients. Four patients had low normal GAA activity; all the others had activities well within the normal range. Re-analyses of these patients did not reveal new Pompe patients. Our findings suggest that Pompe disease is extremely rare in Finland. Finland is an example of an isolated population with enrichment of certain mutations for genetic disorders and low occurrence of some autosomal recessive diseases.