ADGRG6-related disorder: a novel mutation resulting in distal arthrogryposis and a patchy neuropathy.

Arthrogryposis multiplex congenita (AMC) is associated with >150 genes, including ADGRG6, which codes for an adhesion G protein-coupled receptor. Biallelic loss of function variants in ADGRG6 have been linked to lethal congenital contracture syndrome. Here we present an atypical, milder phenotype associated with a novel ADGRG6 variant.

A Case Series of Unilateral Peripheral Neuropathy.

Background And Aims: Peripheral neuropathy may present with a variety of phenotypes depending on the pattern of weakness and sensory loss, the neurophysiological characteristics (axonal or demyelinating) and additional features such as involvement of the autonomic nervous system or the cranial nerves. The most common phenotype is a symmetrical length-dependent sensory and motor neuropathy. Other phenotypes include non-length-dependent forms such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) or a sensory neuronopathy or ganglionopathy.

Disease Progression in Charcot-Marie-Tooth Disease Type 4B (CMT4B) Associated With Mutations in Myotubularin-Related Proteins 2 and 13.

Background And Aims: In 2019, we conducted a cross-sectional study, collecting information on 50 patients with CMT4B, an ultrarare CMT subtype, to better define the clinical phenotype. We now aimed at investigating disease progression in 26 patients with CMT4B1/CMT4B2, recruited from the previous study and among the Inherited Neuropathy Consortium.

Materials And Methods: We retrospectively analysed disease progression in patients with CMT4B1/CMT4B2, collecting MRC scores from nine muscle pairs, Charcot-Marie-Tooth Examination Score (CMTES), and a minimal dataset of clinical information (walking difficulties, aids dependency, upper limb impairment, cranial nerves involvement) at baseline and follow-up visits.

Heterozygous PNPT1 Variants Cause a Sensory Ataxic Neuropathy.

Background: Biallelic variants in polyribonucleotide-nucleotidyltransferase-1 (PNPT1) have been associated with a range of phenotypes from syndromic hearing loss to Leigh's syndrome. More recently, heterozygous variants in PNPT1, have been reported in three families with cerebellar ataxia and prominent sensory neuropathy.

Methods: Whole genome sequencing was performed in two families with autosomal dominant sensory ataxic neuropathy (SAN).

Recessive Variants in PIGG Cause a Motor Neuropathy with Variable Conduction Block, Childhood Tremor, and Febrile Seizures: Expanding the Phenotype.

Biallelic variants in phosphatidylinositol glycan anchor biosynthesis, class G (PIGG) cause hypotonia, intellectual disability, seizures, and cerebellar features. We present 8 patients from 6 families with a childhood-onset motor neuropathy and neurophysiology demonstrating variable motor conduction block and temporal dispersion. All individuals had a childhood onset tremor, 5 of 8 had cerebellar involvement, and 6 of 8 had childhood febrile seizures.

A recurrent missense variant in ITPR3 causes demyelinating Charcot-Marie-Tooth with variable severity.

Charcot-Marie-Tooth (CMT) disease is a neuromuscular disorder affecting the peripheral nervous system. The diagnostic yield in demyelinating CMT (CMT1) is typically ∼80%-95%, of which at least 60% is due to the PMP22 gene duplication. The remainder of CMT1 is more genetically heterogeneous.

Intermediate conduction velocity in two cases of Charcot-Marie-Tooth disease type 1A.

Background And Purpose: Charcot-Marie-Tooth disease type 1A (CMT1A) is the most prevalent hereditary neuropathy worldwide and classically has slow nerve conduction velocity (NCV), in most cases below 38 m/s. Two unrelated patients with motor NCVs in the upper limbs above 38 m/s are reported.

Method: Case report.

Digenic FLNA and UCHL1 variants resulting in a complex phenotype.

Aim: X-linked variants in Filamin A (FLNA) are associated with the Ehlers-Danlos-syndrome-variant form of periventricular heterotopia, and autosomal dominant variants in ubiquitin C-terminal hydrolase L1 (UCHL1) are associated with a late-onset spastic ataxia, peripheral neuropathy and optic atrophy. Here we present a rare case involving both a novel heterozygous whole-gene deletion of UCHL1 and a heterozygous frameshift variant in the FLNA gene resulting in a complex phenotype.

Methods: A 67-year-old female with a confirmed pathogenic variant in the FLNA gene, resulting in an enlarged aorta and joint pains, presented with a 4-year history of severe sensory ataxia, upper motor neuron signs, eye movement abnormalities and severe sensory loss.

Mutations in alpha-B-crystallin cause autosomal dominant axonal Charcot-Marie-Tooth disease with congenital cataracts.

Background And Purpose: Mutations in the alpha-B-crystallin (CRYAB) gene have initially been associated with myofibrillar myopathy, dilated cardiomyopathy and cataracts. For the first time, peripheral neuropathy is reported here as a novel phenotype associated with CRYAB.

Methods: Whole-exome sequencing was performed in two unrelated families with genetically unsolved axonal Charcot-Marie-Tooth disease (CMT2), assessing clinical, neurophysiological and radiological features.

Post-transcriptional microRNA repression of PMP22 dose in severe Charcot-Marie-Tooth disease type 1.

Copy number variation (CNV) may lead to pathological traits, and Charcot-Marie-Tooth disease type 1A (CMT1A), the commonest inherited peripheral neuropathy, is due to a genomic duplication encompassing the dosage-sensitive PMP22 gene. MicroRNAs act as repressors on post-transcriptional regulation of gene expression and in rodent models of CMT1A, overexpression of one such microRNA (miR-29a) has been shown to reduce the PMP22 transcript and protein level. Here we present genomic and functional evidence, for the first time in a human CNV-associated phenotype, of the 3' untranslated region (3'-UTR)-mediated role of microRNA repression on gene expression.

Neurology and the histiocytoses: a case of Rosai-Dorfman-Destombes disease.

The histiocytoses are a group of rare disorders characterised by the accumulation of neoplastic or non-neoplastic activated histiocytes in various tissues. Phenotypes vary widely from cutaneous lesions or lymphadenopathy that regress spontaneously to disseminated disease with poor prognosis. Neurological symptoms can be a presenting feature or appear during the course of disease.

Charcot-Marie-Tooth disease type 2CC due to variants causes a progressive, non-length-dependent, motor-predominant phenotype.

Objective: Neurofilaments are the major scaffolding proteins for the neuronal cytoskeleton, and variants in have recently been described to cause axonal Charcot-Marie-Tooth disease type 2CC (CMT2CC).

Methods: In this large observational study, we present phenotype-genotype correlations on 30 affected and 3 asymptomatic mutation carriers from eight families.

Results: The majority of patients presented in adulthood with motor-predominant and lower limb-predominant symptoms and the average age of onset was 31.

Genetic and phenotypic characterisation of inherited myopathies in a tertiary neuromuscular centre.

Diagnosis of inherited myopathies can be a challenging and lengthy process due to broad genetic and phenotypic heterogeneity. In this study we applied focused exome sequencing to investigate a cohort of 100 complex adult myopathy cases who remained undiagnosed despite extensive investigation. We evaluated the frequency of genetic diagnoses, clinical and pathological factors most likely to be associated with a positive diagnosis, clinical pitfalls and new phenotypic insights that could help to guide future clinical practice.

A multicenter retrospective study of charcot-marie-tooth disease type 4B (CMT4B) associated with mutations in myotubularin-related proteins (MTMRs).

Objective: Charcot-Marie-Tooth (CMT) disease 4B1 and 4B2 (CMT4B1/B2) are characterized by recessive inheritance, early onset, severe course, slowed nerve conduction, and myelin outfoldings. CMT4B3 shows a more heterogeneous phenotype. All are associated with myotubularin-related protein (MTMR) mutations.

Development of MRC Centre MRI calf muscle fat fraction protocol as a sensitive outcome measure in Hereditary Sensory Neuropathy Type 1.

Objectives: Hereditary sensory neuropathy type 1 (HSN1) is a rare, slowly progressive neuropathy causing profound sensory deficits and often severe motor loss. L-serine supplementation is a possible candidate therapy but the lack of responsive outcome measures is a barrier for undertaking clinical trials in HSN1. We performed a 12-month natural history study to characterise the phenotype of HSN1 and to identify responsive outcome measures.

Prognostic factors for response to treatment by corticosteroid injection or surgery in carpal tunnel syndrome (palms study): A prospective multicenter cohort study.

Introduction: Studies of prognosis for surgery and corticosteroid injection for carpal tunnel syndrome (CTS) have considered only a limited range of explanatory variables for outcome.

Methods: Data were prospectively collected on patient-reported symptoms, physical and psychological functioning, comorbidity, and quality of life at baseline and every 6 months for up to 2 years. Outcomes were patient-rated change over a 6-month period and symptom-severity score at 18 months.

Sensory neuronopathy associated with cholangiocarcinoma diagnosed 6 years after symptom onset.

A pure sensory neuronopathy (also referred to as a sensory ganglionopathy) is one of a handful of classical neurological paraneoplastic syndromes. Current guidelines recommend that in cases of sensory neuronopathy, a search for an underlying malignancy be pursued for up to 4 years. We report the case of a 52-year-old woman with a sensory neuronopathy who was eventually diagnosed with a cholangiocarcinoma 6 years after the onset of her disease.

Association of psychological distress, quality of life and costs with carpal tunnel syndrome severity: a cross-sectional analysis of the PALMS cohort.

Objectives: The Prediciting factors for response to treatment in carpal tunnel syndrome (PALMS) study is designed to identify prognostic factors for outcome from corticosteroid injection and surgical decompression for carpal tunnel syndrome (CTS) and predictors of cost over 2 years. The aim of this paper is to explore the cross-sectional association of baseline patient-reported and clinical severity with anxiety, depression, health-related quality of life and costs of CTS in patients referred to secondary care.

Methods: Prospective, multicentre cohort study initiated in 2013.