Giant axonal neuropathy: cross-sectional analysis of a large natural history cohort.

Giant axonal neuropathy (GAN) is an ultra-rare autosomal recessive, progressive neurodegenerative disease with early childhood onset that presents as a prominent sensorimotor neuropathy and commonly progresses to affect both the PNS and CNS. The disease is caused by biallelic mutations in the GAN gene located on 16q23.2, leading to loss of functional gigaxonin, a substrate specific ubiquitin ligase adapter protein necessary for the regulation of intermediate filament turnover. Here, we report on cross-sectional data from the first study visit of a prospectively collected natural history study of 45 individuals, age range 3-21 years with genetically confirmed GAN to describe and cross-correlate baseline clinical and functional cohort characteristics. We review causative variants distributed throughout the GAN gene in this cohort and identify a recurrent founder mutation in individuals with GAN of Mexican descent as well as cases of recurrent uniparental isodisomy. Through cross-correlational analysis of measures of strength, motor function and electrophysiological markers of disease severity, we identified the Motor Function Measure 32 to have the strongest correlation across measures and age in individuals with GAN. We analysed the Motor Function Measure 32 scores as they correspond to age and ambulatory status. Importantly, we identified and characterized a subcohort of individuals with a milder form of GAN and with a presentation similar to Charcot-Marie-Tooth disease. Such a clinical presentation is distinct from the classic presentation of GAN, and we demonstrate how the two groups diverge in performance on the Motor Function Measure 32 and other functional motor scales. We further present data on the first systematic clinical analysis of autonomic impairment in GAN as performed on a subset of the natural history cohort. Our cohort of individuals with genetically confirmed GAN is the largest reported to date and highlights the clinical heterogeneity and the unique phenotypic and functional characteristics of GAN in relation to disease state. The present work is designed to serve as a foundation for a prospective natural history study and functions in concert with the ongoing gene therapy trial for children with GAN.

Giant axonal neuropathy with novel GAN pathogenic variant in a patient of consanguineous origin from Poonch Jammu and Kashmir-India.

Giant axonal neuropathy (GAN) is a severe and rare autosomal recessive neurodegenerative disorder of childhood affecting both the peripheral and central nervous systems (CNS). It is caused by mutations in the GAN (gigaxonin) gene linked to chromosome 16q24. Here, we present a 15-year-old male patient with GAN from a consanguineous family of Poonch, Jammu and Kashmir (J&K)-India. Whole-exome sequencing (WES) was employed to unravel the genetic cause of GAN in the proband. Pathogenic variant identified with WES was confirmed in other affected sibling using Sanger sequencing. Magnetic resonance imaging (MRI) and detailed clinical investigation was also carried out on proband. WES revealed a novel homozygous stopgain GAN mutation (NM_022041, c.C1028G, p.S343X) in the patient. MRI of brain displayed bilateral symmetrical confluent areas of deep white matter signal changes affecting periventricular regions (with sparing of subcortical U-fibers), posterior limbs of internal capsules, thalami, external capsules, and semioval centers. The patient was initially suspected to be a case of metachromatic leukodystrophy. However, WES analysis revealed a pathogenic variant in GAN gene as causative. No other pathogenic variant relevant to any other type of dystrophy was reported in WES. Our findings extend the geographical distribution of GAN to even a very remote region in India, extend the mutational and imaging spectrum of GAN and substantiate the need for introducing genetic testing and counselling in primary referral centers/district hospitals in India.

Giant axonal neuropathy: a multicenter retrospective study with genotypic spectrum expansion.

Giant axonal neuropathy (GAN) is an autosomal recessive disease caused by mutations in the GAN gene encoding gigaxonin. Patients develop a progressive sensorimotor neuropathy affecting peripheral nervous system (PNS) and central nervous system (CNS). Methods: In this multicenter observational retrospective study, we recorded French patients with GAN mutations, and 10 patients were identified. Mean age of patients was 9.7 years (2-18), eight patients were female (80%), and all patients met infant developmental milestones and had a family history of consanguinity. Mean age at disease onset was 3.3 years (1-5), and progressive cerebellar ataxia and distal motor weakness were the initial symptoms in all cases. Proximal motor weakness and bulbar symptoms appeared at a mean age of 12 years (8-14), and patients used a wheelchair at a mean age of 16 years (14-18). One patient died at age 18 years from aspiration pneumonia. In all cases, nerve conduction studies showed a mixed demyelinating and axonal sensorimotor neuropathy and MRI showed brain and cerebellum white matter abnormalities. Polyneuropathy and encephalopathy both aggravated during the course of the disease. Patients also showed a variety of associated findings, including curly hair (100% of cases), pes cavus (80%), ophthalmic abnormalities (30%), and scoliosis (30%). Five new GAN mutations were found, including the first synonymous mutation and a large intragenic deletion. Our findings expand the genotypic spectrum of GAN mutations, with relevant implications for molecular analysis of this gene, and confirm that GAN is an age-related progressive neurodegenerative disease involving PNS and CNS.

Autonomic nervous system involvement in the giant axonal neuropathy (GAN) KO mouse: implications for human disease.

PURPOSE: Giant axonal neuropathy (GAN) is an inherited severe sensorimotor neuropathy. The aim of this research was to investigate the neuropathologic features and clinical autonomic nervous system (ANS) phenotype in two GAN knockout (KO) mouse models. Little is known about ANS involvement in GAN in humans, but autonomic signs and symptoms are commonly reported in early childhood. METHODS: Routine histology and immunohistochemistry was performed on GAN KO mouse specimens taken at various ages. Enteric dysfunction was assessed by quantifying the frequency, weight, and water content of defecation in GAN KO mice. RESULTS: Histological examination of the enteric, parasympathetic and sympathetic ANS of GAN KO mice revealed pronounced and widespread neuronal perikaryal intermediate filament inclusions. These neuronal inclusions served as an easily identifiable, early marker of GAN in young GAN KO mice. Functional studies identified an age-dependent alteration in fecal weight and defecation frequency in GAN KO mice. CONCLUSIONS: For the first time in the GAN KO mouse model, we described the early, pronounced and widespread neuropathologic features involving the ANS. In addition, we provided evidence for a clinical autonomic phenotype in GAN KO mice, reflected in abnormal gastrointestinal function. These findings in GAN KO mice suggest that consideration should be given to ANS involvement in human GAN, especially when considering treatments and patient care.

Abnormal intermediate filament organization alters mitochondrial motility in giant axonal neuropathy fibroblasts.

Giant axonal neuropathy (GAN) is a rare disease caused by mutations in the GAN gene, which encodes gigaxonin, an E3 ligase adapter that targets intermediate filament (IF) proteins for degradation in numerous cell types, including neurons and fibroblasts. The cellular hallmark of GAN pathology is the formation of large aggregates and bundles of IFs. In this study, we show that both the distribution and motility of mitochondria are altered in GAN fibroblasts and this is attributable to their association with vimentin IF aggregates and bundles. Transient expression of wild-type gigaxonin in GAN fibroblasts reduces the number of IF aggregates and bundles, restoring mitochondrial motility. Conversely, silencing the expression of gigaxonin in control fibroblasts leads to changes in IF organization similar to that of GAN patient fibroblasts and a coincident loss of mitochondrial motility. The inhibition of mitochondrial motility in GAN fibroblasts is not due to a global inhibition of organelle translocation, as lysosome motility is normal. Our findings demonstrate that it is the pathological changes in IF organization that cause the loss of mitochondrial motility.

Giant axonal neuropathy.

Giant axonal neuropathy is an autosomal recessive disorder of childhood with distinct morphological features. An 8-year-old boy presented with progressive walking difficulty and recurrent falls. Evaluation showed frizzy hair, characteristic facies, sensory motor neuropathy, and ataxia. Magnetic resonance imaging (MRI) showed bilateral symmetric white matter signal changes in the cerebellum and periventricular regions along with involvement of the posterior limb of the internal capsule. Sural nerve biopsy demonstrated giant axons with neurofilament accumulation. The clinicopathologic manifestations of giant axonal neuropathy are discussed along with the clinical and histologic differential diagnoses.

Measuring disease progression in giant axonal neuropathy: implications for clinical trial design.

As part of a natural history study of giant axonal neuropathy, we hypothesized that the Friedreich Ataxia Rating Scale and the Gross Motor Function Measure would show a significant change over 6 months, reflecting subjects' decline in motor function. The Friedreich Ataxia Rating Scale was performed on 11 subjects and the Gross Motor Function Measure was performed on 10 subjects twice with a six-month interval. A paired two-tailed t-test was used to assess the difference in each subject's score. Significant changes were found over six months of 11.7 ± 11.0 (P = 0.006) for the Friedreich Ataxia Rating Scale and -10.0 ± 13.5 (P = 0.043) for the Gross Motor Function Measure, reflecting subjects' decline in motor function on examination and by report. These standardized assessments of clinical function are the first to be validated in giant axonal neuropathy and will be used in an upcoming gene therapy clinical trial.

Giant axonal neuropathy: An updated perspective on its pathology and pathogenesis.

Giant axonal neuropathy (GAN) is a rare pediatric neurodegenerative disease. It is best known for the "giant" axons caused by accumulations of intermediate filaments. The disease is progressive, with onset around age 3 years and death by the third decade of life. GAN results from recessive mutations in the GAN gene encoding gigaxonin, and our analysis of all reported mutations shows that they are distributed throughout the protein structure. Precisely how these mutations cause the disease remains to be determined. In addition to changes in peripheral nerves that are similar to those seen in neuropathies such as Charcot-Marie-Tooth type 2, GAN patients exhibit a wide range of central nervous system signs. These features, corroborated by degeneration of central tracts apparent from postmortem pathology, indicate that GAN is also a progressive neurodegenerative disease. To reflect this phenotype more precisely, we therefore propose that the disease should be more appropriately referred to as "giant axonal neurodegeneration."

Ultrasound differentiation of axonal and demyelinating neuropathies.

INTRODUCTION: Ultrasound can be used to visualize peripheral nerve abnormality. Our objective in this study was to prove whether nerve ultrasound can differentiate between axonal and demyelinating polyneuropathies (PNPs). METHODS: Systematic ultrasound measurements of peripheral nerves were performed in 53 patients (25 with demyelinating, 20 with axonal, 8 with mixed neuropathy) and 8 healthy controls. Nerve conduction studies of corresponding nerves were undertaken. RESULTS: Analysis of variance revealed significant differences between the groups with regard to motor conduction velocity, compound muscle action potential amplitude, and cross-sectional area (CSA) of different nerves at different locations. Receiver operating characteristic curve analysis revealed CSA measurements to be well suited for detection of demyelinating neuropathies, and boundary values of peripheral nerve CSA could be defined. CONCLUSIONS: Systematic ultrasound CSA measurement in different nerves helped detect demyelination, which is an additional cue in the etiological diagnosis of PNP, along with nerve conduction studies and nerve biopsy.

Giant axonal neuropathy.

Giant axonal neuropathy (GAN) is a rare hereditary autosomal recessive neurodegenerative disease affecting both the peripheral and the central nervous system. Clinically it is characterized by an age of onset during the first decade, progressive and severe motor sensory neuropathy followed, in some patients, by the occurrence of various central nervous system signs such as cerebellar syndrome, upper motor neuron signs, or epilepsy. Although kinky hairs are reported in the majority of patients, it is not a constant finding. The prognosis is usually severe with death occurring during the second or third decade; nevertheless a less severe course is reported in some patients. The presence of a variable number of giant axons filled with neurofilaments in the nerve biopsy represents the pathological feature of the disease and it is usually associated to a variable degree with axonal loss and demyelization. Giant axons are also found in the central nervous system associated with Rosenthal fibers and a variable degree of involvement of white matter and neuronal loss. The disease is caused by mutation in the GAN gene encoding for gigaxonin, a member of BTB-Kelch. Up to now 37 mutations in the GAN gene have been reported. These mutations are scattered over the 11 exons of the gene without a clear genotype-phenotype correlation. These mutations resulting in gigaxonin deficiency lead to a slow down in ubiquitin-mediated protein degradation and possibly of other unidentified proteins. GAN represents a good model of a neurodegenerative disorder in which there is a primary defect of the ubiquitin proteasome system and its network with neurofilaments. The clarification of molecular mechanisms involved in GAN can help in understanding other frequent neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Parkinson disease.

Involvement of the globus pallidus in giant axonal neuropathy.

Giant axonal neuropathy is a rare autosomal recessive disorder commonly characterized by chronic, progressive dysfunction in the peripheral nervous system. Lesions also can occur in the central nervous system, especially in the brainstem and cerebellum. We present cranial magnetic resonance imaging and magnetic resonance spectroscopy findings in a 5-year-old Turkish girl with giant axonal neuropathy. This study is the second to describe involvement of the globus pallidus on T(2)-weighted imaging in giant axonal neuropathy. Magnetic resonance spectroscopy of cerebellar white matter lesions and globus pallidus revealed metabolic changes, including increased choline/creatine ratios, increased lactate, and reduced N-acetyl aspartate/creatine ratios. Thus, magnetic resonance spectroscopy did not produce findings specific to giant axonal neuropathy, but indicated progressive neuronal loss, demyelination, and gliosis in the cerebellar white matter.

Clinical and genetic studies in a Chinese family with giant axonal neuropathy.

The objective of the study was to investigate a girl with giant axonal neuropathy and detect the mutation of GAN gene in her family. The encoding exons of GAN gene were amplified from genomic DNA of the proband and her parents by polymerase chain reaction and directly sequenced after purification. The proband manifested typical neurological symptoms and pathological abnormalities. The case had 2 heterozygous missense mutations in GAN gene: 1. c. 224 T>A in exon 2, her mother was a heterozygote of this mutation and had normal phenotype; 2. c.1634G>A in exon 10, and her father was a heterozygote of this mutation and had normal phenotype. Both of the mutations caused amino acid changes in the gigaxonin protein. In this family, missense mutation of c.224 T>A and missense mutation of c.1634G>A in GAN gene caused the phenotype of giant axonal neuropathy in the proband. Her parents are heterozygotes of the disease without symptoms.