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.

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.

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.

Dominant GDAP1 founder mutation is a common cause of axonal Charcot-Marie-Tooth disease in Finland.

We describe a founder mutation in the gene encoding ganglioside-induced differentiation associated-protein 1 (GDAP1), leading to amino acid change p.H123R, as a common cause of autosomal dominant axonal Charcot-Marie-Tooth (CMT2) neuropathy in Finland. The mutation explains up to 14 % of CMT2 in Finland, where most patients with axonal neuropathy have remained without molecular diagnosis. Only three families out of 28 were found to carry putative disease mutations in the MFN2 gene encoding mitofusin 2. In addition, the MFN2 variant p.V705I was commonly found in our patients, but we provide evidence that this previously described mutation is a common polymorphism and not pathogenic. GDAP1-associated polyneuropathy caused predominantly a mild and slowly progressive phenotype. Besides distal leg muscle weakness, most patients showed mild proximal weakness, often with asymmetry and pes cavus. Our findings broaden the understanding of GDAP1 mutations in CMT2 phenotypes and provide support for the use of whole-exome sequencing in CMT gene diagnostics.

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.

[Hereditary gelsolin amyloidosis--40 years of Meretoja disease]. / Hereditary gelsolin amyloidosis--40 years of Meretoja disease.

Hereditary gelsolin amyloidosis is an autosomally dominantly inherited systemic disease, first described in 1969 by the Finnish ophthalmologist Jouko Meretoja. The estimated number of disease carriers in Finland is almost 1 000, and the disease has subsequently been found in many other countries as well. It's typical initial manifestation is lattice corneal dystrophy, detected at biomicroscopic examination of the eye by the age of 25 to 30 years, followed by slowly progressing cranial neuropathy with bilateral facial palsy, polyneuropathy and generalized cutis laxa. Meretoja's disease is caused by mutations of the gelsolin gene, leading to the production and aberrant processing of variant gelsolin and deposition of its fragments in various tissues in the form of amyloid fibrils.

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.

Outcome of renal transplant in hereditary gelsolin amyloidosis.

Amyloid nephropathy is an unusual manifestation of hereditary gelsolin amyloidosis and may present with proteinuria and progressive renal failure. We report the first case of renal transplantation in a patient with hereditary gelsolin amyloidosis complicated by end-stage renal disease. The patient was a 44-year-old man from the Northwest of Iran who had undergone hemodialysis for 1 year. He finally received a living, unrelated renal transplant. During a 6-year posttransplant period, the patient maintained stable allograft function without proteinuria. No significant infectious or cardiac complications were noted. Although a definite conclusion cannot be reached with a single case, this report may indicate that renal transplantation can be successfully attempted in patients with hereditary gelsolin amyloidosis and amyloid nephropathy. Renal transplantation has been performed in various hereditary, primary, and secondary amyloidoses. A brief review of this topic is presented.

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.

Severe ataxia with neuropathy in hereditary gelsolin amyloidosis: a case report.

Hereditary gelsolin amyloidosis (AGel amyloidosis) is a systemic disorder caused by a G654A or G654T gelsolin mutation, reported from Europe, North America, and Japan. Principal clinical signs are corneal lattice dystrophy, cutis laxa and cranial neuropathy, often deleterious at advanced age. Peripheral neuropathy, if present, is usually mild. We report a 78-year-old male Finnish patient who presented with ataxia and mainly sensory peripheral polyneuropathy (PNP) signs, causing severe disability and ambulation loss. Electrophysiological studies showed severe generalized chronic mainly axonal sensorimotor PNP with facial paralysis. In magnetic resonance imaging proximal lower limb and axial muscle atrophy with fatty degeneration as well as moderate spinal cord atrophy were seen. A G654A gelsolin mutation was demonstrated but no other possible causes of his disability were found. At age 79 years he became bedridden and died of pulmonary embolism. Neuropathological examination revealed marked gelsolin amyloid deposition at vascular and connective tissue sites along the entire length of the peripheral nerves extending to the spinal nerve roots, associated with severe degeneration of nerve fibers and posterior columns. Our report shows that advanced AGel amyloidosis due to degeneration of central and distal sensory nerve projections results in deleterious ataxia with fatal outcome. Severe posterior column atrophy may reflect radicular AGel deposition, although even altered gelsolin-actin interactions in neural cells possibly contribute to neurodegeneration with successive ataxia in carriers of a G654A gelsolin mutation.

Senile systemic amyloidosis, cerebral amyloid angiopathy, and dementia in a very old Finnish population.

Senile systemic amyloidosis (SSA) and cerebral amyloid angiopathy (CAA) are amyloid disorders, which typically manifest with old age. The aim of our study was to examine the possible association of these disorders in very old Finns. We performed a prospective, population-based post mortem study and used histological and immunohistochemical staining methods to verify the presence of these types of amyloid. All 63 subjects (59% of the 107 individuals 95 years of age or more, who died during the 10-year follow-up study), 53 women and 10 men), had been neurologically examined. The prevalence of SSA and its association with CAA, dementia, and neuropathologically verified AD was analyzed. Overall SSA occurred in 23 (37%) and CAA in 28 (44%) of the 63 subjects. At clinical examination 41 individuals (65%) were demented; 24 (38%) had Alzheimer's disease. SSA showed no association with the presence of CAA (P = 0.45), clinical dementia (P = 0.09), or Alzheimer's disease (P = 0.21), or sex (P = 0.53). Our prospective population based study shows that SSA and CAA are frequent in very old Finns, but they do not associate.

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.

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.

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.

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.

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.