Clinical and biochemical characterization of asymptomatic carriers and symptomatic patients with hereditary transthyretin amyloidosis caused by TTR V30L mutation.

BACKGROUND: Hereditary transthyretin amyloidosis (ATTR) is an autosomal dominant disease characterized by amyloid fibril deposition. The TTR c.148G > T mutation (V30L) in ATTR is rarely reported, and its biochemical properties are unknown. METHODS: Seven patients and two asymptomatic carriers from two unrelated families diagnosed with V30L variant of ATTR were included. Data on clinical manifestations, laboratory examination, electrophysiology, ophthalmological corneal confocal microscopy (CCM), pathology and molecular biological experiments was collected and analyzed. RESULTS: Most patients initially experienced paresthesia, with varying degrees of peripheral neuropathy, autonomic dysfunction, and cardiac involvement. Nerve conduction studies showed extensive motor and sensory nerve involvement in upper and lower limbs. CCM revealed reduced corneal nerve density and fiber length. Sural nerve biopsies indicated loss of myelinated nerve fibers, with neurogenic patterns in gastrocnemius muscle biopsies. Asymptomatic carriers had nearly normal electrophysiology but mild reductions in corneal nerve fiber density and length. Sural nerve biopsies in carriers showed mild reductions in small myelinated nerve fibers. V30L mutation impaired thermodynamic and kinetic stability of the mutant protein. Plasma TTR tetramer concentration was lower in ATTR V30L patients compared to healthy donors. Small molecule stabilizers failed to exhibit satisfactory inhibition on fibril formation of V30L mutation in vitro. CONCLUSION: This study highlights the multisystem involvement in ATTR V30L patients, including neuropathy and cardiac issues. Both patients and carriers showed abnormalities in nerve conduction, corneal microscopy, and pathology. The V30L mutation impaired protein stability and reduced plasma TTR tetramer levels. Small molecule stabilizers were ineffective, indicating a need for alternative treatments.

Novel mutations in FLVCR1 cause tremors, sensory neuropathy with retinitis pigmentosa.

The mutations of the feline leukemia virus subgroup C receptor-related protein 1 (FLVCR1) cause ataxia with retinitis pigmentosa. Recent studies indicated a large variation in the phenotype of FLVCR1-associated diseases. In this report, we describe an adult male who manifested first with tremors in his third decade, followed by retinitis pigmentosa, sensory ataxia, and sensory neuropathy in his fourth decade. While retinitis pigmentosa and sensory ataxia are well-recognized features of FLVCR1-associated disease, tremor is rarely described. Whole-exome sequencing revealed novel compound heterozygous pathogenic FLVCR1 variants: c.498 G > A; p.(Trp166*) and c.369 T > G; p.(Phe123Leu). In addition, we have highlighted the ultrastructural abnormalities of the sural biopsy in this patient.

Spinal and bulbar muscular atrophy combined with hypertrophic cardiomyopathy and Brugada-pattern electrocardiographic changes: A case report.

Spinal and bulbar muscular atrophy (SBMA) is a rare X-linked recessive neurodegenerative disorder caused by the excessive expansion of cytosine-adenine-guanine repeat sequences in the androgen receptor gene encoded on the Xq11-12 chromosome. SBMA primarily affects adult males and is characterized by weakness and atrophy of the proximal limb muscles, often involving the bulbar muscles. In addition to neuromuscular deficits, nonneuronal symptoms such as hypertension, hyperlipidemia, and liver dysfunction are often observed in patients with SBMA. Previous studies have suggested that SBMA patients have been diagnosed with hypertrophic cardiomyopathy (HCM), while gene detection is lacked. Moreover, according to current reports, SBMA patients can carry Brugada syndrome or HCM respectively, while three kinds of diseases have not been reported to exist in the same patient. Here, we report the first case of a male diagnosed with SBMA combined with HCM and two types of Brugada-pattern electrocardiographic changes, with a heterozygous missense mutation in the TTN gene.

[Effects of cerium oxide nanoparticles on cognitive function in 48 h sleep deprived male mice].

OBJECTIVE: To study the effects of cerium oxide nanoparticles( CeO_2 NPs)on cognitive function in 48 hours of sleep deprived male mice and explore its mechanism. METHODS: Thirty-six healthy clean ICR male mice( four weeks old) were randomly divided into 6 groups: blank control group, solvent control group, sleep deprivation control group, low, medium and high dose groups of CeO_2 NPs. 1 m L of distilled water were given to mice of blank group, 1 m L of solvent were given to mice of solvent control and sleep deprivation control group, 1 mL of CeO_2 NPs solvent( 4, 8, 16 mg/kg) were administered to mice of low, medium and high dose groups of CeO_2 NPs. Each group of mice received intragastric administration for 30 days. On the 31 st day, a single platform water environment method was used for 48 hours of sleep deprivation on mice. Then, the cognitive ability of the mice was tested by Y-maze. Further, the antioxidant( CAT, MDA, T-AOC) and neurotransmitters( NO, Glu) in mice brain tissue were measured also. RESULTS: Compare with the solvent control group, 48 hours of sleep deprivation reduced the cognitive ability of mice [( 36 ± 2) times vs. ( 20 ± 2) times, P = 0. 0006; 10. 753%± 0. 031% vs. 24. 927% ± 0. 972%, P = 0. 00000045 ], CAT activity [( 78. 151 ±17. 683) nmol/mg prot vs. ( 198. 155 ± 14. 437) nmol/mg prot, P = 0. 0008]and the level of T-AOC [( 103. 630 ± 24. 209) U/mg prot vs. ( 264. 599 ± 50. 223) U/mg prot, P =0. 007], but improved the content of MDA [( 9. 499 ± 1. 249) nmol/mg prot vs. ( 6. 157± 0. 373) nmol/mg prot, P = 0. 0113 ], NO [( 11. 608 ± 1. 281) µmol/mg prot vs. ( 3. 628 ± 1. 064) µmol/mg prot, P = 0. 001]and Glu[( 4. 731 ± 0. 131) µg/mg prot vs. ( 4. 476 ± 0. 126) µg/mg prot, P = 0. 03] in the brain. Low, medium and high dose Ce O2 NPs enhanced cognitive performance of the sleep deprived mice. Among three dose groups, the medium dose groups most significantly improved the cognitive ability of mice[( 27 ± 2) times vs. ( 36 ± 2) times, P = 0. 005; 18. 743% ± 0. 245% vs. 10. 753% ±0. 031%, P = 0. 0000006 ], increased CAT activities [( 238. 065 ± 19. 393) nmol/mg prot vs. ( 78. 151 ± 17. 683) nmol/mg prot, P = 0. 00045] and T-AOC levels [( 210. 516± 11. 339) U/mg prot vs. ( 103. 630 ± 24. 209) U/mg prot, P = 0. 002], decreased MDA[( 6. 528 ± 1. 162) nmol/mg prot vs. ( 9. 499 ± 1. 249) nmol/mg prot, P = 0. 039], NO[( 5. 651 ± 0. 239) µmol/mg prot vs. ( 11. 608 ± 1. 281) µmol/mg prot, P = 0. 001]and Glu levels [( 4. 358 ± 0. 016) µg/mg prot vs. ( 4. 731 ± 0. 131) µg/mg prot, P = 0. 008]. CONCLUSION: Ce O2 NPs can improve the cognitive ability of sleep deprived male mice, improve the antioxidant capacity of brain, reduce free radical damage to the nerves of brain, and regulate the neurotransmitters of brain.

A novel variant of biallelic MME gene associated with autosomal recessive late-onset distal hereditary motor neuropathy in Chinese families.

Distal hereditary motor neuropathies (dHMN) are a group of heterogeneous diseases and previous studies have reported that the compound heterozygous recessive MME variants cause dHMN. Our study found a novel homozygous MME variant and a reported compound heterozygous MME variant in two Chinese families, respectively. Next-generation sequencing and nerve conduction studies were performed for two probands. The probands in two families presented with the muscle weakness and wasting of both lower limbs and carried a c.2122 A > T (p.K708*) and c.1342 C > T&c.2071_2072delinsTT (p.R448*&p.A691L) variant, respectively. Prominently axonal impairment of motor nerves and slight involvement of sensory nerves were observed in nerve conduction study. Our study reported a "novel" nonsense mutation and a missense variant of autosomal recessive late-onset dHMN and reviewed reported MME variants associated with dHMN phenotype.

Vagus nerve ultrasound in transthyretin familial amyloid polyneuropathy: A pilot study.

BACKGROUND AND PURPOSE: Autonomic dysfunction is common in transthyretin familial amyloid polyneuropathy (TTR-FAP). Because ultrasonography is a powerful tool to study peripheral neuropathy, vagus nerve (VN) ultrasonography was used in our study to investigate the possible changes of the dimension of VN in TTR-FAP. METHODS: Eighteen patients with TTR-FAP and 17 age- and gender-matched individuals without any neuropathies were enrolled in a pilot study. The cross-sectional areas (CSAs) were measured bilaterally on transverse scans of vagus, median, and ulnar nerves. Clinical data were collected to explore the correlations with CSAs of VN. RESULTS: The median CSAs of VN in TTR-FAP were 3.5 (2.0-6.0) mm2 on the right side and 2.5 (1.0-6.0) mm2 on the left side, compared with 2.0 (1.0-3.0) mm2 and 1.0 (1.0-2.0) mm2 for healthy controls (HCs). There was a significant difference between the two groups on both sides (p < .001). The mean VN CSAs were correlated positively with the course of disease (r = .7203, p = .0016)（not including the patient with the longest disease course), the Composite Autonomic Symptom Score 31 (r = .5252, p = .0252), the left ventricular posterior wall thickness (r = .5426, p = .0200), and the interventricular septum thickness (r = .5103, p = .0305). The cutoff values of right and left VN CSAs to identify TTR-FAP from HCs were 2.5 and 1.5 mm2 and the areas under the curve were .9395 and .8856, with a high sensitivity (.889 and .889) and specificity (.941 and .765), respectively. CONCLUSION: VN enlargement is prevalent among TTR-FAP patients. VN ultrasonography may be an important clinical tool for assessing the severity of autonomic dysfunction in TTR-FAP.

First Identification of Rare Exonic and Deep Intronic Splice-Altering Variants in Patients With Beta-Sarcoglycanopathy.

Background: The precise genetic diagnosis of a sarcoglycanopathy or dystrophinopathy is sometimes extremely challenging, as pathogenic non-coding variants and/or complex structural variants do exist in DMD or sarcoglycan genes. This study aimed to determine the genetic diagnosis of three patients from two unrelated families with a suspected sarcoglycanopathy or dystrophinopathy based on their clinical, radiological, and pathological features, for whom routine genomic detection approaches failed to yield a definite genetic diagnosis. Methods: Muscle-derived reverse transcription-polymerase chain reaction analysis and/or TA cloning of DMD, SGCA, SGCB, SGCD, and SGCG mRNA were performed to identify aberrant transcripts. Genomic Sanger sequencing around the aberrant transcripts was performed to detect possible splice-altering variants. Bioinformatic and segregation studies of the detected genomic variants were performed in both families. Results: In patients F1-II1 and F1-II2, we identified two novel pathogenic compound heterozygous variants in SGCB. One is a deep intronic splice-altering variant (DISV), c.243 + 1558C > T in intron 2 causing the activation of an 87-base pair (bp) pseudoexon, and the other one is a non-canonical splicing site variant, c.243 + 6T > A leading to the partial intron inclusion of 10-bp sequence. A novel DISV, c.243 + 1576C > G causing a 106-bp pseudoexon activation, and a nonsense variant in SGCB were identified in compound heterozygous state in patient F2-II1. Unexpectedly, the predicted nonsense variant, c.334C > T in exon 3, created a new donor splice site in exon 3 that was stronger than the natural one, resulting in a 97-bp deletion of exon 3 (r.333_429del). Conclusion: This is the first identification of rare exonic and DISVs in the SGCB gene.

Patterns of myelinated nerve fibers loss in transthyretin amyloid polyneuropathy and mimics.

OBJECTIVE: The present study was intended to analyze the characteristics of myelinated nerve fibers density (MFD) of transthyretin amyloid polyneuropathy (ATTR-PN) and other similar neuropathies. METHODS: A total of 41 patients with ATTR-PN, 58 patients of other common peripheral neuropathies, and 17 age-and gender-matched controls who visited the First Hospital of Peking University and performed sural nerve biopsy between June 2007 and August 2021 were included for analysis of MFD. RESULTS: Except the vasculitic neuropathy group, the total and small MFD of patients in the ATTR-PN group were significantly lower than those of other disease groups. There was an obvious negative correlation between the total MFD and the disease course in the ATTR-PN group. The disease course of early-onset and late-onset symptoms was similar, but the loss of large myelinated nerve fibers (MF) was more severe for the latter. In addition, all late-onset and most early-onset patients had severely reduced MFD after a 2 years' disease course. The MFD in ATTR-PN patients was negatively correlated with Neuropathy Impairment Score (NIS) and Norfolk Quality of life-diabetic neuropathy (Norfolk QOL-DN) score. CONCLUSION: MF is lost differently in ATTR-PN and in other common peripheral neuropathies. The late-onset and early-onset ATTR-PN patients have different patterns of loss of large and small MF.

Skeletal Muscle Involvement Pattern of Hereditary Transthyretin Amyloidosis: A Study Based on Muscle MRI.

Objects: This study was intended to explore the characteristics of muscle magnetic resonance imaging (MRI) of patients with hereditary transthyretin amyloidosis (ATTRv amyloidosis) prospectively. Methods: The clinical data of 20 patients with ATTRv amyloidosis at our hospital between July 2020 and August 2021 were analyzed. MRI of lower limbs including calf muscles was performed in all these 20 patients and MRI of thigh muscles was performed in 16 of them. Results: The mean age of the 20 patients with ATTRv amyloidosis was 44.2 years (ranging from 26 to 60) whose mean duration of weakness was 23.3 ± 23.0 (ranging from 0 to 84) months. All the patients presented with polyneuropathy, and 18 of them with weakness in their lower limbs. Muscle involvement was selective in these patients with ATTRv amyloidosis. The posterior group of muscles was heavily fatty, and the soleus muscle was the most heavily involved. The proportion of fatty infiltration scores at the calf level was higher than at the thigh level with paired comparison for most patients. Three of these patients had more severely fatty infiltration of muscles at the thigh level. The fatty infiltration of posterior compartments at the calf level was highly consistent with neuropathy impairment scores of lower limbs (weakness), the strength of ankle plantar flexion muscles, and the amplitude of the compound muscle action potential of the tibial nerve. Conclusions: It was found that the pattern of muscle fatty infiltration was consistent with a distal-to-proximal gradient on the whole and that proximal involvements in MRI of lower limbs in some patients could also be observed. Selective fatty infiltration of muscles of posterior compartments and fatty infiltration of the soleus muscle might be typical of ATTRv amyloidosis.

Clinical and biochemical characterization of hereditary transthyretin amyloidosis caused by E61K mutation.

Objects: This study was intended to find out more about the clinical characterizations of patients carrying transthyretin (TTR) E61K (p.Glu81Lys) gene mutation and the biochemical characterization of this mutant protein. Materials and methods: Five patients who had been diagnosed with hereditary transthyretin amyloidosis and two asymptomatic carriers carrying TTR E61K gene mutation were reported. Biochemical and biophysical tests were conducted to observe the thermodynamic and kinetic stability. Fibril formation tests measured by turbidity assay were performed to explore the pathogenicity of this mutation. Kinetic stabilizer responsiveness was measured to determine the inhibitory effect on protein aggregation. Results: The average age of onset for the five patients was 62 years, and the course of the disease ranged from 2 to 10 years. Cardiac disease was prominent in this group of patients. Nerve pathology revealed a mildly to moderately reduced myelinated fiber density and muscle pathology showed predominant neurogenic impairment accompanied by possible myogenic impairment. E61K-TTR was characterized as a kinetically destabilized protein compared to WT-TTR but its thermodynamic stability was not compromised. In addition, the subunit exchange of E61K with WT-TTR further destabilized the heterozygous tetramer. Meanwhile, the E61K:WT heterozygous tetramer exhibited a poor response to kinetic stabilizers in the fibril formation assay. Finally, the serum TTR tetramer concentration was low in E61K-TTR symptomatic patients and in one asymptomatic gene carrier. Vyndamax (Tafamidis) could increase the TTR tetramer concentration. Conclusions: Patients with E61K mutation tended to be late-onset. The concentration of TTR tetramer in the serum might serve as a biomarker to monitor disease progress, therapeutic window time, and therapeutic response to TTR kinetic stabilizer drugs.

TTR Gly83Arg Mutation: Beyond Familial Vitreous Amyloidosis.

BACKGROUND: Gly83Arg variation is a type of TTR mutation specific to the Chinese population. Patients of hereditary transthyretin amyloidosis (ATTR) with Gly83Arg variation predominantly present with blurred vision and most of these cases are reported by ophthalmologists. There is currently no systematic assessment of extraocular features of ATTR with Gly83Arg variation. METHODS: Six patients and two asymptomatic carriers with molecularly confirmed Gly83Arg variation of ATTR from three unrelated families were identified by sequencing the TTR gene. The clinical, electrophysiological, ultrasonic, and pathological data were collected and analyzed. RESULTS: This study included six patients and two carriers with TTR Gly83Arg mutation, all of whom came from the Han nationality of China. The average age of onset for the six patients was 39 years, and the course of disease ranged from 5 to 19 years. All the patients started with blurred vision, which was diagnosed as vitreous opacity (VO). Most of the patients developed sensory-motor polyneuropathies over years or even more than a decade (4-15 years) after VO. However, the heterogeneity of peripheral neuropathies among these patients remained large between families. Autonomic impairment also occurred after VO, with varying degrees of abnormalities seen in the associated autonomic assessments. None of the patients had any symptoms of cardiac impairment, but abnormal results were found in examinations. A combined biopsy of the sural nerve and muscle was also performed. Nerve pathology revealed the moderately reduced myelinated nerve fiber density and muscle pathology showed predominant neurogenic impairment accompanied by possible myogenic impairment. CONCLUSIONS: This is a detailed account of Gly83Arg mutation-related ATTR, focusing on the extraocular presentations of this special variant in Chinese. Clinical features of this variant are early-onset, ocular involvement predominance, neurological, and cardiac involvement along with the disease, and relatively long survival.

Peripheral Nervous System Involvement in Late-Onset Cobalamin C Disease?

Background: Cobalamin C (cblC) has a fundamental role in both central and peripheral nervous system function at any age. Neurologic manifestations may be the earliest and often the only manifestation of hereditary or acquired cblC defect. Peripheral neuropathy remains a classical but underdiagnosed complication of cblC defect, especially in late-onset cblC disease caused by mutations in the methylmalonic aciduria type C and homocysteinemia (MMACHC) gene. So the clinical, electrophysiological, and pathological characteristics of late-onset cblC disease are not well-known. Methods: A retrospective study of patients with late-onset cblC disease was conducted at our hospital on a 3-year period. The neuropathy was confirmed by the nerve conduction study. Sural biopsies were performed in 2 patients. Results: Eight patients were identified, with a mean onset age of 16.25 ± 6.07 years. All patients had methylmalonic aciduria, homocysteinemia, compound heterozygous MMACHC gene mutations were detected in all patients, and 7/8 patients with c.482G>A mutation. One patient concomitant with homozygote c.665C>T mutation in 5,10-methylenetetrahydrofolate reductase (MTHFR) gene. All patients showed limb weakness and cognitive impairment. Five patients had possible sensorimotor axonal polyneuropathy predominantly in the distal lower limbs. Sural biopsies showed loss of myelinated and unmyelinated fibers. Electro microscopy revealed crystalline-like inclusions bodies in Schwann cells and axonal degeneration. Conclusion: Late-onset cblC disease had possible heterogeneous group of distal axonal neuropathy. c.482G>A mutation is a hot spot mutation in late-onset cblC disease.

Reversible Cortical and Basal Ganglia Lesions in Late-Onset Methylmalonic Aciduria.

This case report describes reversible cortical and basal ganglia lesions in late-onset methylmalonic aciduria in a man in his mid-40s.