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. RESULTS: The pathogenic CRYAB variant c.358A>G;p.Arg120Gly was segregated in all affected patients from two unrelated families. The disease presented as late onset CMT2 (onset over 40 years) with distal sensory and motor impairment and congenital cataracts. Muscle involvement was probably associated in cases showing mild axial and diaphragmatic weakness. In all cases, nerve conduction studies demonstrated the presence of an axonal sensorimotor neuropathy along with chronic neurogenic changes on needle examination. DISCUSSION: In cases with late onset autosomal dominant CMT2 and congenital cataracts, it is recommended that CRYAB is considered for genetic testing. The identification of CRYAB mutations causing CMT2 further supports a continuous spectrum of expressivity, from myopathic to neuropathic and mixed forms, of a growing number of genes involved in protein degradation and chaperone-assisted autophagy.

An approach to assessing immunoglobulin dependence in chronic inflammatory demyelinating inflammatory polyneuropathy.

Regular immunoglobulin treatment maintains strength and prevents disability in chronic inflammatory demyelinating polyneuropathy (CIDP). Discrimination between active disease, with optimum symptom control on treatment, and disease in remission not requiring treatment is essential for therapeutic decision-making and clinical trial design. To compare treatment cessation versus gradual dose reduction in assessment of disease activity (immunoglobulin dependence) in a cohort of stable CIDP patients on maintenance immunoglobulin treatment. An approach to restabilization of immunoglobulin-dependent individuals is also described. Retrospective review of IVIg cessation or gradual reduction in 33 patients with stable CIDP on maintenance IVIg. Demographic, clinical and treatment data were collected; clinical monitoring data were recorded prospectively as part of routine clinical practice. A total of 21/33 patients (62.6%) were immunoglobulin dependent, (gradual dose reduction:11, cessation:10). Mean change in Inflammatory Rasch-built Overall Disability Scale (I-RODS) (-15, standard deviation [SD] 16) and Medical Research Council Sum Score (MRC-SS) (-4, SD: 4) was clinically and statistically meaningful (>75% exceeded minimum clinically important differences). Mean time to deterioration was 5.0 (SD: 4.6) months, shorter in cessation group (3.5 months) than gradual reduction group (8.8 months). All patients were restabilized to previous baseline (M: 2.3, SD: 4.3 months), half within 1 week of retreatment. A total of 12 patients (37.4%) remained stable without treatment for ≥2 years (remission). A total of 50% were identified rapidly by cessation and 50% by gradual dose reduction requiring mean 4.8 (SD: 2.8) years follow-up and costing £113 623 per person Ig spend. No predictors of disease activity were identified. A treatment cessation trial with close clinical monitoring is an efficient, cost-effective and safe approach to assessing disease activity in CIDP.

Human biallelic MFN2 mutations induce mitochondrial dysfunction, upper body adipose hyperplasia, and suppression of leptin expression.

MFN2 encodes mitofusin 2, a membrane-bound mediator of mitochondrial membrane fusion and inter-organelle communication. MFN2 mutations cause axonal neuropathy, with associated lipodystrophy only occasionally noted, however homozygosity for the p.Arg707Trp mutation was recently associated with upper body adipose overgrowth. We describe similar massive adipose overgrowth with suppressed leptin expression in four further patients with biallelic MFN2 mutations and at least one p.Arg707Trp allele. Overgrown tissue was composed of normal-sized, UCP1-negative unilocular adipocytes, with mitochondrial network fragmentation, disorganised cristae, and increased autophagosomes. There was strong transcriptional evidence of mitochondrial stress signalling, increased protein synthesis, and suppression of signatures of cell death in affected tissue, whereas mitochondrial morphology and gene expression were normal in skin fibroblasts. These findings suggest that specific MFN2 mutations cause tissue-selective mitochondrial dysfunction with increased adipocyte proliferation and survival, confirm a novel form of excess adiposity with paradoxical suppression of leptin expression, and suggest potential targeted therapies.