scholarly journals HINT1 neuropathy in Norway: clinical, genetic and functional profiling

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Silvia Amor-Barris ◽  
Helle Høyer ◽  
Lin V. Brauteset ◽  
Els De Vriendt ◽  
Linda Strand ◽  
...  
Keyword(s):  
Axonal Neuropathy ◽  
Functional Characterization ◽  
Treatment Strategies ◽  
Central Nervous System Involvement ◽  
Sensory Neuropathy ◽  
Muscle Stiffness ◽  
Compound Heterozygous ◽  
Clinical Genetic ◽  
Cellular Models ◽  
New Variant

Abstract Background Autosomal recessive axonal neuropathy with neuromyotonia has been linked to loss of functional HINT1. The disease is particularly prevalent in Central and South-East Europe, Turkey and Russia due to the high carrier frequency of the c.110G > C (p.Arg37Pro) founder variant. Results In a cohort of 748 Norwegian patients with suspected peripheral neuropathy, we identified two seemingly unrelated individuals, compound heterozygous for a new variant (c.284G > A, p.Arg95Gln) and the most common pathogenic founder variant (c.110G > C, p.Arg37Pro) in the HINT1 gene. Probands presented with motor greater than sensory neuropathy of various onset, accompanied by muscle stiffness and cramps in the limbs. Furthermore, they displayed non-classical symptoms, including pain in the extremities and signs of central nervous system involvement. Haplotype analysis in both patients revealed a common chromosomal background for p.Arg95Gln; moreover, the variant was identified in Swedish carriers. Functional characterization in HINT1-knockout and patient-derived cellular models, and in HNT1-knockout yeast, suggested that the new variant is deleterious for the function of HINT1 and provided mechanistic insights allowing patient stratification for future treatment strategies. Conclusion Our findings broaden the genetic epidemiology of HINT1-neuropathy and have implications for molecular diagnostics of inherited peripheral neuropathies in Scandinavia.

scholarly journals Novel ARG1 variants identified in a patient with arginase 1 deficiency

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Katsuyuki Yokoi ◽  
Yoko Nakajima ◽  
Toshihiro Yasui ◽  
Makoto Yoshino ◽  
Tetsushi Yoshikawa ◽  
...  
Keyword(s):  
Sanger Sequencing ◽  
Arginase Activity ◽  
Compound Heterozygous ◽  
Measurement Sensitivity ◽  
Protein Core ◽  
Arginase 1 ◽  
Conserved Domain ◽  
New Variant ◽  
Compound Heterozygous Variants

AbstractWe report a case of a 13-year-old boy with arginase 1 deficiency carrying a new variant in ARG1. Sanger sequencing identified the compound heterozygous variants: NM_000045.4: c.365G>A (p.Trp122*)/c.820G>A (p.Asp274Asn). Although not previously reported, the p.Asp274Asn variant is predicted to have strong pathogenicity because it is located in a highly conserved domain in the protein core and arginase activity in the patient was below measurement sensitivity.

SLC25A19 deficiency and bilateral striatal necrosis with polyneuropathy: a new case and review of the literature

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Francesco Porta ◽  
Barbara Siri ◽  
Nicoletta Chiesa ◽  
Federica Ricci ◽  
Lulash Nika ◽  
...  
Keyword(s):  
Axonal Neuropathy ◽  
Clinical Signs ◽  
Leigh Syndrome ◽  
High Dose ◽  
New Variant ◽  
Long Term Follow Up ◽  
Basal Ganglia Involvement ◽  
Biallelic Mutations ◽  
Thiamine Treatment ◽  
Striatal Necrosis

AbstractObjectivesBiallelic mutations in the SLC25A19 gene impair the function of the thiamine mitochondrial carrier, leading to two distinct clinical phenotypes. Homozygosity for the c.530G > C mutation is invariably associated to Amish lethal microcephaly. The second phenotype, reported only in 8 patients homozygous for different non-Amish mutations (c.373G > A, c.580T > C, c.910G > A, c.869T > A, c.576G > C), is characterized by bilateral striatal necrosis and peripheral polyneuropathy. We report a new patient with the non-Amish SLC25A19 phenotype showing compound heterozygosity for the new variant c.673G > A and the known mutation c.373G > A.Case presentationThe natural history of non-Amish SLC25A19 deficiency is characterized by acute episodes of fever-induced encephalopathy accompanied by isolated lactic acidosis and Leigh-like features at magnetic resonance imaging (MRI). Acute episodes are prevented by high-dose thiamine treatment (600 mg/day). As shown in the new case, both mild clinical signs and basal ganglia involvement can precede the acute encephalopathic onset of the disease, potentially allowing treatment anticipation and prevention of acute brain damage. Peripheral axonal neuropathy, observed in 7 out of 9 patients, is not improved by thiamine therapy. In two early treated patients, however, peripheral neuropathy did not occur even on long-term follow-up, suggesting a potential preventive role of treatment anticipation also at the peripheral level.ConclusionsNon-Amish SLC25A19 deficiency is an extra-rare cause of Leigh syndrome responsive to thiamine treatment. Ex adiuvantibus thiamine treatment is mandatory in any patient with Leigh-like features.

scholarly journals RFC1 AAGGG repeat expansion masquerading as Chronic Idiopathic Axonal Polyneuropathy

2021 ◽  
Author(s):  
Matteo Tagliapietra ◽  
Davide Cardellini ◽  
Moreno Ferrarini ◽  
Silvia Testi ◽  
Sergio Ferrari ◽  
...  
Keyword(s):  
Care Center ◽  
Axonal Neuropathy ◽  
Tertiary Care ◽  
Sensory Neuropathy ◽  
Nerve Fibers ◽  
Repeat Expansion ◽  
Sural Nerve Biopsy ◽  
Prevalence Odds Ratio ◽  
Axonal Polyneuropathy ◽  
Factor C

Abstract Background A biallelic intronic AAGGG repeat expansion in the Replication Factor C subunit 1 (RFC1) gene has been recently associated with Cerebellar Ataxia, Neuropathy, Vestibular Areflexia Syndrome, a disorder often presenting as a slowly evolving sensory neuropathy at the onset. “Chronic Idiopathic Axonal Polyneuropathy” (CIAP) is a common indolent axonal neuropathy of adulthood which remains without an identifiable cause despite thorough investigations. Methods We screened 234 probands diagnosed with CIAP for a pathogenic biallelic RFC1 AAGGG repeat expansion. Patients were selected from 594 consecutive patients with neuropathy referred to our tertiary-care center for a sural nerve biopsy over 10 years. Results The RFC1 AAGGG repeat expansion was common in patients with pure sensory neuropathy (21/40, 53%) and less frequent in cases with predominantly sensory (10/56, 18%, P < 0.001) or sensorimotor (3/138, 2%, P < 0.001) neuropathy. The mutation was associated with sensory ataxia (τb = 0.254, P < 0.001), autonomic disturbances (35% vs 8%, Prevalence Odds Ratio—POR 6.73 CI 95% 2.79–16.2, P < 0.001), retained deep tendon reflexes (score 18.0/24 vs 11.5/24, R = 0.275, P < 0.001). On pathology, we observed absent/scant regenerative changes (τb = − 0.362, P < 0.001), concomitant involvement of large (100% and 99%, n.s.), small myelinated (97% vs 81%, POR 7.74 CI 95% 1.03–58.4, P = 0.02) and unmyelinated nerve fibers (85% vs 41%, POR 8.52 CI 95% 3.17–22.9, P < 0.001). Cerebellar or vestibular involvement was similarly rare in the two groups. Conclusions This study highlights the frequent occurrence of the RFC1 AAGGG repeat expansion in patients diagnosed with CIAP and characterizes the clinical and pathological features of the related neuro(no)pathy.

Expanding the phenotype of SLC12A6-associated sensorimotor neuropathy

2021 ◽  
Vol 14 (10) ◽  
pp. e244641
Author(s):  
Petya Bogdanova-Mihaylova ◽  
Patricia McNamara ◽  
Sarah Burton-Jones ◽  
Sinéad M Murphy
Keyword(s):  
Corpus Callosum ◽  
Autosomal Recessive ◽  
Sensory Neuropathy ◽  
Rare Condition ◽  
Compound Heterozygous ◽  
Sensorimotor Neuropathy ◽  
Autosomal Recessive Condition ◽  
Solute Carrier ◽  
Compound Heterozygous Mutations ◽  
Clinical Phenotyping

Hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC) is a rare autosomal recessive condition characterised by early-onset severe progressive neuropathy, variable degrees of ACC and cognitive impairment. Mutations in SLC12A6 (solute carrier family 12, member 6) encoding the K+–Cl- transporter KCC3 have been identified as the genetic cause of HMSN/ACC. We describe fraternal twins with compound heterozygous mutations in SLC12A6 and much milder phenotype than usually described. Neither of our patients requires assistance to walk. The female twin is still running and has a normal intellect. Charcot-Marie-Tooth Examination Score 2 was 8/28 in the brother and 5/28 in the sister. Neurophysiology demonstrated a length-dependent sensorimotor neuropathy. MRI brain showed normal corpus callosum. Genetic analysis revealed compound heterozygous mutations in SLC12A6, including a whole gene deletion. These cases expand the clinical and genetic phenotype of this rare condition and highlight the importance of careful clinical phenotyping.

Monogenic Epilepsies: Disease Mechanisms, Clinical Phenotypes, and Targeted Therapies

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000012744
Author(s):  
Renzo Guerrini ◽  
Simona Balestrini ◽  
Elaine C. Wirrell ◽  
Matthew C. Walker
Keyword(s):  
Observational Studies ◽  
Current Knowledge ◽  
Functional Characterization ◽  
Treatment Strategies ◽  
Controlled Trials ◽  
Epileptogenic Zone ◽  
Missense Mutations ◽  
Number Of Patients ◽  
Functional Consequences ◽  
Genetic Epilepsies

A monogenic aetiology can be identified in up to 40% of people with severe epilepsy. To address earlier and more appropriate treatment strategies, clinicians are required to know the implications that specific genetic causes might have on pathophysiology, natural history, comorbidities and treatment choices. In this narrative review, we summarise concepts on the genetic epilepsies based on the underlying pathophysiological mechanisms and present the current knowledge on treatment options based on evidence provided by controlled trials or studies with lower classification of evidence. Overall, evidence robust enough to guide antiseizure medication (ASM) choices in genetic epilepsies remains limited to the more frequent conditions for which controlled trials and observational studies have been possible. Most monogenic disorders are very rare and ASM choices for them are still based on inferences drawn from observational studies and early, often anecdotal, experiences with precision therapies. Precision medicine remains applicable to only a narrow number of patients with monogenic epilepsies and may target only part of the actual functional defects. Phenotypic heterogeneity is remarkable, and some genetic mutations activate epileptogenesis through their developmental effects, which may not be reversed postnatally. Other genes seem to have pure functional consequences on excitability, acting through either loss- or gain-of-function effects, and these may have opposite treatment implications. In addition, the functional consequences of missense mutations may be difficult to predict, making precision treatment approaches considerably more complex than estimated by deterministic interpretations. Knowledge of genetic aetiologies can influence the approach to surgical treatment of focal epilepsies. Identification of germline mutations in specific genes contraindicates surgery while mutations in other genes do not. Identification, quantification and functional characterization of specific somatic mutations before surgery using cerebrospinal fluid liquid biopsy or after surgery in brain specimens, will likely be integrated in planning surgical strategies and re-intervention after a first unsuccessful surgery as initial evidence suggests that mutational load may correlate with the epileptogenic zone. Promising future directions include gene manipulation by DNA or mRNA targeting; although most are still far from clinical use, some are in early phase clinical development.

scholarly journals Biallelic variants in the small optic lobe calpain CAPN15 are associated with congenital eye anomalies, deafness and other neurodevelopmental deficits

2020 ◽  
Vol 29 (18) ◽  
pp. 3054-3063
Author(s):  
Congyao Zha ◽  
Carole A Farah ◽  
Richard J Holt ◽  
Fabiola Ceroni ◽  
Lama Al-Abdi ◽  
...  
Keyword(s):  
Optic Lobe ◽  
Critical Role ◽  
Genetic Diagnosis ◽  
Compound Heterozygous ◽  
Clinical Genetic ◽  
Eye Disorders ◽  
Neurodevelopmental Deficits ◽  
Independent Families ◽  
The Brain

Abstract Microphthalmia, coloboma and cataract are part of a spectrum of developmental eye disorders in humans affecting ~12 per 100 000 live births. Currently, variants in over 100 genes are known to underlie these conditions. However, at least 40% of affected individuals remain without a clinical genetic diagnosis, suggesting variants in additional genes may be responsible. Calpain 15 (CAPN15) is an intracellular cysteine protease belonging to the non-classical small optic lobe (SOL) family of calpains, an important class of developmental proteins, as yet uncharacterized in vertebrates. We identified five individuals with microphthalmia and/or coloboma from four independent families carrying homozygous or compound heterozygous predicted damaging variants in CAPN15. Several individuals had additional phenotypes including growth deficits, developmental delay and hearing loss. We generated Capn15 knockout mice that exhibited similar severe developmental eye defects, including anophthalmia, microphthalmia and cataract, and diminished growth. We demonstrate widespread Capn15 expression throughout the brain and central nervous system, strongest during early development, and decreasing postnatally. Together, these findings demonstrate a critical role of CAPN15 in vertebrate developmental eye disorders, and may signify a new developmental pathway.

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

2020 ◽  
Vol 11 ◽  
Author(s):  
Xujun Chu ◽  
Lingchao Meng ◽  
Wei Zhang ◽  
Jinjun Luo ◽  
Zhaoxia Wang ◽  
...  
Keyword(s):  
Nervous System ◽  
Peripheral Nervous System ◽  
Methylenetetrahydrofolate Reductase ◽  
Late Onset ◽  
Hot Spot ◽  
Axonal Neuropathy ◽  
Methylmalonic Aciduria ◽  
Lower Limbs ◽  
Compound Heterozygous ◽  
Limb Weakness

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&gt;A mutation. One patient concomitant with homozygote c.665C&gt;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&gt;A mutation is a hot spot mutation in late-onset cblC disease.

scholarly journals Update on Cerebellar Ataxia with Neuropathy and Bilateral Vestibular Areflexia Syndrome (CANVAS)

2020 ◽  
Author(s):  
Mathieu Dupré ◽  
Ruben Hermann ◽  
Caroline Froment Tilikete
Keyword(s):  
Cerebellar Ataxia ◽  
Late Onset ◽  
Genetic Disorder ◽  
Axonal Neuropathy ◽  
Sensory Neuropathy ◽  
Bilateral Vestibulopathy ◽  
Familial Form ◽  
Vestibulo Ocular Reflex ◽  
Classical Triad ◽  
Factor C

Abstract The syndrome of cerebellar ataxia with neuropathy and bilateral vestibular areflexia (CANVAS) has emerged progressively during the last 30 years. It was first outlined by the neurootology/neurophysiology community in the vestibular areflexic patients, through the description of patients slowly developing late-onset cerebellar ataxia and bilateral vestibulopathy. The characteristic deficit of visuo-vestibulo-ocular reflex (VVOR) due to the impaired slow stabilizing eye movements was put forward and a specific disease subtending this syndrome was suggested. The association to a peripheral sensory axonal neuropathy was described later on, with neuropathological studies demonstrating that both sensory neuropathy and vestibular areflexia were diffuse ganglionopathy. Clinical and electrophysiological criteria of CANVAS were then proposed in 2016. Besides the classical triad, frequent chronic cough, signs of dysautonomia and neurogenic pains were frequently observed. From the beginning of published cohorts, sporadic as well as familial cases were reported, the last suggestive of an autosomal recessive mode of transmission. The genetic disorder was discovered in 2019, under the form of abnormal biallelic expansion in the replication factor C subunit 1 (RFC1) in a population of late-onset ataxia. This pathological expansion was found in 100% of the familial form and 92% of sporadic ones when the triad was complete. But using the genetic criteria, the phenotype of CANVAS seems to expand, for exemple including patients with isolated neuronopathy. We propose here to review the clinical, electrophysiological, anatomical, genetic aspect of CANVAS in light of the recent discovery of the genetic aetiology, and discuss differential diagnosis, neuropathology and physiopathology.

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