Response to Gasparini et al Echaniz‐Laguna, Andoni
European journal of neurology,
November 2021, 2021-11-00, 20211101, Letnik:
28, Številka:
11
Journal Article
Background and purpose
This study was undertaken to assess skin biopsy as a marker of disease onset and severity in hereditary transthyretin amyloidosis with polyneuropathy (ATTRv‐PN), a treatable ...disease.
Methods
In this single center retrospective study, skin Congo red staining and intraepidermal nerve fiber density (IENFD) were evaluated in symptomatic ATTRv‐PN patients and asymptomatic TTR gene mutation carriers between 2012 and 2019. Non‐ATTRv subjects with suspected small fiber neuropathy who underwent skin biopsy during the same timespan were used as controls.
Results
One hundred eighty‐three symptomatic ATTRv‐PN patients, 36 asymptomatic carriers, and 537 non‐ATTRv patients were included. Skin biopsy demonstrated amyloid depositions in 80% of the 183 symptomatic cases. Skin amyloid deposits were found in 75% of early stage ATTRv‐PN patients, and in 14% of asymptomatic carriers. All 183 symptomatic and 34 of 36 asymptomatic patients displayed decreased ankle IENFD with a proximal–distal gradient distribution, and reduced IEFND correlated with disease severity and duration.
Conclusions
Our study demonstrates skin amyloid deposits are a marker of ATTRv‐PN disease onset, and decreased IENFD a marker of disease progression. These results are of major importance for the early identification of ATTRv‐PN patients in need of disease‐modifying treatments.
Skin biopsy provides useful information in hereditary transthyretin amyloidosis with polyneuropathy. Amyloid deposition in skin is a biomarker of disease onset in paucisymptomatic subjects, especially in early onset Val30Met. Small nerve fiber reduction, which often precedes disease onset, correlates with disease severity.
Amyotrophic lateral sclerosis (ALS) is the most common fatal motor neuron disease in adults. Numerous studies indicate that ALS is a systemic disease that affects whole body physiology and metabolic ...homeostasis. Using a mouse model of the disease (SOD1G86R), we investigated muscle physiology and motor behavior with respect to muscle metabolic capacity. We found that at 65 days of age, an age described as asymptomatic, SOD1G86R mice presented with improved endurance capacity associated with an early inhibition in the capacity for glycolytic muscle to use glucose as a source of energy and a switch in fuel preference toward lipids. Indeed, in glycolytic muscles we showed progressive induction of pyruvate dehydrogenase kinase 4 expression. Phosphofructokinase 1 was inhibited, and the expression of lipid handling molecules was increased. This mechanism represents a chronic pathologic alteration in muscle metabolism that is exacerbated with disease progression. Further, inhibition of pyruvate dehydrogenase kinase 4 activity with dichloroacetate delayed symptom onset while improving mitochondrial dysfunction and ameliorating muscle denervation. In this study, we provide the first molecular basis for the particular sensitivity of glycolytic muscles to ALS pathology.
Synopsis
Altered metabolic homeostasis is an early event in amyotrophic lateral sclerosis (ALS) manifestation. This study reveals that skeletal muscles stop using glucose as a source of energy but use lipids instead and this chronic pathologic alteration in muscles is exacerbated with disease progression.
The early alteration of muscle metabolic equilibrium between glucose and lipid use impacts on the capacity for muscle to efficiently adapt to increased energetic demands in the SOD1G86R ALS mouse model.
PDK4 is central to these metabolic changes, being upregulated at early asymptomatic stages and increasing throughout disease progression in the SOD1G86R model, as well as in ALS patients.
The metabolic alterations described are specific to glycolytic muscle (TA) in the SOD1G86R model.
Regulation of the glycolytic pathway presents as a potential therapeutic strategy as a drug targeting of PDK4 improves muscle function and overall metabolic status in the SOD1G86R model.
Altered metabolic homeostasis is an early event in amyotrophic lateral sclerosis (ALS) manifestation. This study reveals that skeletal muscles stop using glucose as a source of energy but use lipids instead and this chronic pathologic alteration in muscles is exacerbated with disease progression.
Heterozygous mutations in the inverted formin‐2 (INF2) gene provoke focal segmental glomerulosclerosis (FSGS) and intermediate Charcot‐Marie‐Tooth (CMT) disease with FSGS. Here, we report four ...patients from a three‐generation family with a new cryptic splicing INF2 mutation causing autosomal dominant intermediate CMT with minimal glomerular dysfunction. Three males and one female with a mean age of 51 years (26‐87) presented with a slowly progressive sensorimotor polyneuropathy, pes cavus, and kyphoscoliosis. Mean age at CMT disease onset was 11.5 years (3‐17), and electrophysiological studies showed demyelinating and axonal features consistent with intermediate CMT. Plasma albumin and creatinine were normal in all four cases, and urine protein was normal in one case and mildly raised in three patients (mean: 0.32 g/L 0.18‐0.44, N < 0.14). Genetic analysis found a c.271C > G (p. Arg91Gly) variation in INF2 exon 2, and in vitro splicing assays showed the deletion of the last 120 nucleotides of INF2 exon 2 leading to a 40 amino acids in‐frame deletion (p. Arg91_p. Gln130del). This report expands the genetic spectrum of INF2‐associated disorders and demonstrates that INF2 mutations may provoke isolated CMT with no clinically relevant kidney involvement. Consequently, INF2 mutation analysis should not be restricted to individuals with coincident neuropathy and renal disease.
Calcium (Ca2+) acts as a ubiquitous second messenger, and normal cell and tissue physiology strictly depends on the precise regulation of Ca2+ entry, storage, and release. Store‐operated Ca2+ entry ...(SOCE) is a major mechanism controlling extracellular Ca2+ entry, and mainly relies on the accurate interplay between the Ca2+ sensor STIM1 and the Ca2+ channel ORAI1. Mutations in STIM1 or ORAI1 result in abnormal Ca2+ homeostasis and are associated with severe human disorders. Recessive loss‐of‐function mutations impair SOCE and cause combined immunodeficiency, while dominant gain‐of‐function mutations induce excessive extracellular Ca2+ entry and cause tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK). TAM and STRMK are spectra of the same multisystemic disease characterized by muscle weakness, miosis, thrombocytopenia, hyposplenism, ichthyosis, dyslexia, and short stature. To date, 42 TAM/STRMK families have been described, and here we report five additional families for which we provide clinical, histological, ultrastructural, and genetic data. In this study, we list and review all new and previously reported STIM1 and ORAI1 cases, discuss the pathomechanisms of the mutations based on the known functions and the protein structure of STIM1 and ORAI1, draw a genotype/phenotype correlation, and delineate an efficient screening strategy for the molecular diagnosis of TAM/STRMK.
Electron microscopy showing tubular aggregates in muscle fibers from a TAM/STRMK patient.
Background and purpose
Charcot–Marie–Tooth (CMT) disease, an untreatable hereditary polyneuropathy, may mimic chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), a treatable neuropathy.
...Methods
In this retrospective study, we analyzed the characteristics of CMT patients misdiagnosed as CIDP at 16 university hospitals in three countries, compared these patients with a reference group of CIDP patients, and estimated the cost of misdiagnosis.
Results
Among 1104 CIDP cases, we identified 35 CMT patients misdiagnosed as CIDP (3.2%). All were initially diagnosed with definite or probable CIDP (European Federation of Neurological Societies/Peripheral Nerve Society criteria), and mutations in PMP22, MPZ, and 10 other CMT genes were found in 34%, 31%, and 35% of cases, respectively. In comparison with a reference group of 35 CIDP patients, CMT patients were younger (median age at disease onset = 39 vs. 56 years) and more frequently had motor weakness at disease onset (80% vs. 29%), hearing loss (14% vs. 0%), normal brachial plexus imaging (70% vs. 40%), lower cerebrospinal fluid protein content (median = 0.5 vs. 0.8 g/L), and lower treatment response (20% vs. 69%). Treatment cost in these 35 misdiagnosed patients was estimated at 4.6 million euros (M€), whereas the cost of CMT genetic analysis in 1104 patients was estimated at 2.7 M€.
Conclusions
In this study, 35 of 1104 (3.2%) patients initially diagnosed with CIDP had CMT. Importantly, the cost of treating these 35 misdiagnosed patients was significantly higher than the cost of performing CMT genetic analysis in 1104 patients (4.6 M€ vs. 2.7 M€), suggesting that CMT genetic investigations should be more widely used before diagnosing CIDP.
Amongst 1,104 CIDP cases, we identified 35 CMT patients misdiagnosed as CIDP (3.2%). In comparison with a reference group of 35 CIDP patients, CMT patients were younger, had more frequently motor weakness at disease onset, hearing loss, lower cerebrospinal fluid protein content, and lower treatment response. The cost of treating these 35 misdiagnosed patients was significantly higher than the cost of performing CMT genetic analysis in 1,104 patients (4.6 M€ vs 2.7 M€).
Phosphoglycerate kinase (PGK) deficiency is a rare X‐linked metabolic disorder caused by mutations in the PGK1 gene. Patients usually develop various combinations of nonspherocytic hemolytic anemia ...(NSHA), myopathy, and central nervous system disorders. In this national multicenter observational retrospective study, we recorded all known French patients with PGK deficiency, and 3 unrelated patients were identified. Case 1 was a 32‐year‐old patient with severe chronic axonal sensorimotor polyneuropathy resembling Charcot–Marie–Tooth (CMT) disease, mental retardation, microcephaly, ophthalmoplegia, pes cavus, and the new c.323G > A PGK1 hemizygous mutation. Case 2 was a 71‐year‐old patient with recurrent exertional rhabdomyolysis, and a c.943G > A PGK1 hemizygous mutation. Case 3 was a 48‐year‐old patient with NSHA, retinitis pigmentosa, mental retardation, seizures, stroke, parkinsonism, and a c.491A > T PGK1 hemizygous mutation. This study confirms that PGK deficiency is an extremely rare disorder with a wide phenotypic spectrum, and demonstrates for the first time that PGK deficiency may affect the peripheral nervous system and present as a CMT‐like disorder.
ABSTRACT
Introduction
McArdle disease is a glycogen storage disease caused by mutations in the PYGM gene encoding myophosphorylase. It manifests classically with childhood‐onset exercise‐induced ...pain.
Methods
We report the characteristics of 2 unrelated patients with a new homozygous mutation of the PYGM gene.
Results
Two patients, aged 76 and 79 years, presented with severe upper and lower limb atrophy and weakness. Additionally, 1 patient presented with bilateral ptosis, and the other with camptocormia. In both patients, symptoms had developed progressively in the 2 preceding years, and there was no history of exercise intolerance. Both patients demonstrated myogenic abnormalities on electromyography, multiple glycogen‐containing vacuoles and undetectable muscle myophosphorylase activity on muscle biopsy, and a novel homozygous frameshift p.Lys42Profs*48 PYGM mutation.
Conclusions
This report expands the phenotype and genotype of McArdle disease and suggests that PYGM mutations should be looked for in patients with very late‐onset myopathy with no previous history of exercise intolerance. Muscle Nerve 57: 157–160, 2018
Background and purpose
In this retrospective study involving 14 university hospitals from France and Switzerland, the aim was to define the clinicopathological features of chronic neuropathies with ...anti‐disialosyl ganglioside immunoglobulin M (IgM) antibodies (CNDA).
Results
Fifty‐five patients with a polyneuropathy evolving for more than 2 months and with at least one anti‐disialosyl ganglioside IgM antibody, that is, anti‐GD1b, ‐GT1b, ‐GQ1b, ‐GT1a, ‐GD2 and ‐GD3, were identified. Seventy‐eight percent of patients were male, mean age at disease onset was 55 years (30–76) and disease onset was progressive (82%) or acute (18%). Patients presented with limb sensory symptoms (94% of cases), sensory ataxia (85%), oculomotor weakness (36%), limb motor symptoms (31%) and bulbar muscle weakness (18%). Sixty‐five percent of patients had a demyelinating polyradiculoneuropathy electrodiagnostic profile and 24% a sensory neuronopathy profile. Anti‐GD1b antibodies were found in 78% of cases, whilst other anti‐disialosyl antibodies were each observed in less than 51% of patients. Other features included nerve biopsy demyelination (100% of cases), increased cerebrospinal fluid protein content (75%), IgM paraprotein (50%) and malignant hemopathy (8%). Eighty‐six percent of CNDA patients were intravenous immunoglobulins‐responsive, and rituximab was successfully used as second‐line treatment in 50% of cases. Fifteen percent of patients had mild symptoms and were not treated. CNDA course was progressive (55%) or relapsing (45%), and 93% of patients still walked after a mean disease duration of 11 years.
Conclusion
Chronic neuropathies with anti‐disialosyl ganglioside IgM antibodies have a recognizable phenotype, are mostly intravenous immunoglobulins‐responsive and present with a good outcome in a majority of cases.
Objective
Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a recessively inherited multisystem ataxia compromising cerebellar, vestibular, and sensory nerves, which has ...been associated to a pathogenic AAGGG(n) biallelic expansion repeat in the
RFC1
gene. Our objective was to assess its prevalence in a French cohort of patients with idiopathic sporadic late-onset ataxia (ILOA), idiopathic early-onset ataxia (IEOA), or Multiple System Atrophy of Cerebellar type (MSA-C).
Methods
163 patients were recruited in 3 French tertiary centers: 100 ILOA, 21 IEOA, and 42 patients with possible or probable MSA-C.
Results
A pathogenic biallelic
RFC1
AAGGG(n) repeat expansion was found in 15 patients: 15/100 in the ILOA group, but none in the IEOA and MSA-C subgroups. 14/15 patients had a CANVAS phenotype. Only 1/15 had isolated cerebellar ataxia, but also shorter biallelic expansions. Two
RFC1
AAGGG(n) alleles were found in 78% of patients with a CANVAS phenotype. In one post-mortem case, the pathophysiological involvement of cerebellum and medullar posterior columns was found.
Conclusion
Our study confirms the genetic heterogeneity of the CANVAS and that
RFC1
repeat expansions should be searched for preferentially in case of unexplained ILOA associated with a sensory neuronopathy, but not particularly in patients classified as MSA-C.
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